JPH0432830B2 - - Google Patents

Description

[Detailed description of the invention] The present invention is based on the formula: -S-A-R¹⁴ However, A is cyclopentylene, cyclohexylene
or C₁−C_FourAlkylene (one or more
C₁−C_Four(optionally substituted with an alkyl group)
Representation, R¹⁴is bonded to A by a quaternary nitrogen atom
Quaternized nitrogen-containing aromatic or non-aromatic
Carbape with a 2-position substituent;
The purpose of this study is to develop a new method for producing NEM derivatives. Carbapenem inducer produced by the method of the present invention
Conductors dated April 9, 1982 and March 8, 1983, respectively.
and U.S. Patent Application No. 366910, filed June 18, 1982.
Colleague Choung in No. 471379 and No. 389652
Disclosed by U. Kim and Peter F. Misco, Jr.,
claims; disclosures in each of those applications;
Incorporated herein by reference in its entirety. U.S. Patent Application No. 366910 and its continuations in part U.S.
No. 471379 filed on March 8, 1983.
This is the one corresponding to West German Published Patent Application No. 3312533.
It is a divisional continuation application, is a formula However, R⁸is hydrogen, and R¹is hydrogen;
Having a substituent or having no substituent:
Alkyl, alkenyl and alkynyl, 1-10 pieces
carbon atoms; cycloalkyl and cycloa
Rukylalkyl, cycloalkyl ring with 3-6
having a carbon atom and 1-6 carbon atoms in the alkyl moiety
Has an elementary atom; phenyl; aryl moiety is phenyl
and the aliphatic portion contains 1-6 carbon atoms.
aralkyl, aralkenyl and aralquini with
Heteroaryl, heteroaralkyl, hetero
cyclyl and heterocyclylalkyl,
Heteroatoms in the ring moiety are 1-4 oxygen, nitrogen
or a sulfur atom;
The alkyl moiety bonded to the tero ring moiety is 1-6
having carbon atoms; selected from the group consisting of
one or more related to the above groups;
Two or more substituents are With amino, halo, hydroxy or carboxyl
C that may be substituted₁−C₆alkyl Halo −OR³ −NR³R^Four -SO₂NR³R^Four −CO₂R³ =O −SR³ −CN −N₃ −OSO₃R³ −OSO₂R³ −NR³S.O.₂R^Four −NR³C.O.₂R^Four −NO₂ selected from the group consisting of; In relation to the above-mentioned substituents, the group R³and R^Four
are independently hydrogen; alkyl, alkenyl and alkyl
quinyl, having 1-10 carbon atoms; cycloal
Kyl, cycloalkylalkyl and alkylcyclo
loalkyl, 3-6 carbons in the cycloalkyl ring
atoms and 1-6 carbon atoms in the alkyl moiety
has a child; phenyl; the aryl part is phenyl
Yes, the aliphatic moiety has 1-6 carbon atoms
aralkyl, aralkenyl and aralkynyl;
and heteroaryl, heteroaralkyl, heterosyl
Chryl and heterocyclylalkyl, the above hetero
Heteroatoms in the ring moieties include 1-4 oxygen, nitrogen or
is selected from the group consisting of sulfur atoms, and the hetero
1-6 alkyl moieties are bonded to the ring moiety
carbon atoms selected from the group consisting of;
or R³and R^Fouris at least one of them
5-membered or 6-membered nitrogen together with the bound nitrogen
is capable of forming an element-containing heterocycle; R⁹Haso
R, except that it cannot be hydrogen.³definition regarding
It is the same as what was done; or R¹and R⁸together with C₂−C_Tenalkylidene or
C substituted with hydroxy₂−C_TenAlkylidene
Representation: A is cyclopentylene, cyclohexylene
or C₂−C₆Alkylene (one or more
C₁−C_Fouroptionally substituted with alkyl)
ri；R²is R²When is hydrogen or a protecting group, pair a
Hydrogen, anion, provided that anion also exists.
Charge or normal easily removable carboxyl retention
is a protecting group; [Formula] has at least one group in the ring. contains nitrogens and is bonded to A by the ring nitrogen
In this case, a quaternary ammonium group is formed.
One, two or more with or without substituents
represents a ring aromatic heterocyclic group; carbapenem antibiotic
In the method of manufacturing the substance and its pharmaceutically acceptable salts.
The following reaction scheme: Carbapenem antibiotics and their pharmaceutical acceptance by
Discloses a method for producing salts that can be used. U.S. Patent Application No. 389,652 and dated June 7, 1983
A continuation in part thereof, U.S. Patent Application No. 499,690, is However, R⁸is hydrogen and R¹is hydrogen; substituent
with or without substituents: alkyl,
alkenyl and alkynyl, 1-10 carbon atoms
has; cycloalkyl and cycloalkyl alkyl;
Kyl, 3-6 carbon atoms in the cycloalkyl ring
and having 1-6 carbon atoms in the alkyl part
phenyl; the aryl moiety is phenyl;
Aliphatic moieties are aral having 1-6 carbon atoms
Kir, aralkenyl and aralkynyl; heteroa
Ryl, heteroaralkyl, heterocyclyl and
heterocyclylalkyl, in the above heterocyclic moiety
Are heteroatoms 1-4 oxygen, nitrogen, or sulfur atoms?
selected from the group consisting of
The bonding alkyl moiety has 1-6 carbon atoms.
selected from the group consisting of; one or more related to the above groups.
The substituents are independently With amino, halo, hydroxy or carboxyl
C that may be substituted₁−C₆alkyl Halo −OR³ −NR³R^Four -SO₂NR³R^Four −CO₂R³ =O −SR³ −CN −N₃ −OSO₃R³ −OSO₂R³ −NR³S.O.₂R^Four −NR³C.O.₂R^Four −NO₂ selected from the group consisting of; In relation to the above-mentioned substituents, base R³and R^Fourare independently hydrogen; alkyl, alkyl
Kenyl and alkynyl, having 1-10 carbon atoms
Cycloalkyl, cycloalkylalkyl and
and alkylcycloalkyl, cycloalkyl ring
having 3-6 carbon atoms and 1 in the alkyl moiety
-having 6 carbon atoms; phenyl; aryl
The part is phenyl and the aliphatic part has 1-6 carbons.
Aralkyl, aralkenyl and aralkyl having elementary atoms
Ralkynyl; and heteroaryl, heteroaral
Kyl, heterocyclyl and heterocyclylalkyl
1-4 heteroatoms in the above heterocyclic moiety
selected from the group consisting of oxygen, nitrogen or sulfur atoms
and an alkyl bonded to the heterocyclic moiety
moiety has 1-6 carbon atoms; group consisting of
is selected from, or R³and R^Fouris the nitrogen to which at least one of them is bonded.
a 5- or 6-membered nitrogen-containing heterocycle
R⁹it becomes hydrogen
R except not get it³Same as defined for
can be; or R¹and R⁸together with C₂−C_Tenalkylidene or
C substituted with hydroxy₂−C_TenAlkylidene
Representation; R^Fivehas a substituent and has no substituent.
i: alkyl, alkenyl and alkynyl, 1-
Has 10 carbon atoms; cycloalkyl and cycloalkyl
Loalkylalkyl, 3-6 on the cycloalkyl ring
carbon atoms and 1-6 in the alkyl moiety
carbon atoms; phenyl; aryl moiety is phenyl;
enyl and the aliphatic portion contains 1-6 carbon atoms.
aralkyl, aralkenyl and aralquini with
Heteroaryl, heteroaralkyl, hetero
cyclyl and heterocyclylalkyl,
Heteroatoms in the ring moiety are 1-4 oxygen, nitrogen
or a sulfur atom;
1-6 alkyl moieties are bonded to the ring moiety
carbon atoms selected from the group consisting of;
Therefore, the above R^FiveIn some cases, the base is Amino, fluoro, chloro, carboxyl, hydrogen
May be substituted with droxy or carbamoyl
C₁−C₆Alkyl; fluoro, chloro or bromo; −OR³; −OCO₂R³; −OCOR³; −OCONR³R^Four; −OSO₂R³; -Oxo; −NR³R^Four; R³CONR^Four−; −NR³C.O.₂R^Four; −NR³CONR³R^Four; −NR³S.O.₂R^Four; −SR³; -SO₃R³; −CO₂R³; −CONR³R^Four; -CN; or 1-3 fluoro, chloro, bromo, C₁−
C₆Alkyl, −OR³, −NR³R^Four, −SO₃R³, −CO₂R³
or −CONR³R^Four(However, R³,R^Fourand R⁹is defined above
R being^Fiveis a substituent)
phenyl; independently selected from the group consisting of
may be substituted with 1-3 substituents.
Ku, or R^Fiveis [formula] linked to a ring and bridged Divalent phenylene or C forming a polycyclic group₁−
C_Fourwhich can represent an alkylene group; A is cyclopentylene, cyclohexylene or
C₂−C₆Alkylene (one or more C₁−C_Four
optionally substituted with alkyl); R²is R²is hydrogen or a protecting group.
Hydrogen, anion, provided that ions also exist.
Charge or normal easily removable carboxyl retention
It is a protection group; [Formula] contains at least one nitrogen in the ring bonded to A via the ring nitrogen, with the quaternary
having a substituent or forming a monium group
mono-, di- or polycyclic non-aromatic hetero
represents a ring group; carbapenem antibiotics and their
In the method for producing pharmaceutically acceptable salts, the following reaction
scheme: Carbapenem antibiotics and their pharmaceutical acceptance by
Discloses a method for producing salts that can be used. Elaborating with respect to the prior art scheme, starting from
The substance is dissolved in diphthalate in an inert organic solvent in the presence of a base.
Reacts with enyl chlorophosphate to give an intermediate
I can do it. The intermediate is then washed with a base in an inert organic solvent.
In the presence of a mercaptan reagent of formula HS-A-OH
reacts with to give an intermediate. The intermediate is then inactivated
methanesulfonyl in the presence of a base in a neutral organic solvent
Acylated with chloride to form an intermediate, which is
Reacts with an iodide ion source in an active organic solvent to form an intermediate
Give your body. The intermediate is in the presence of silver ions in an inert organic solvent.
Below, the product is quaternized by reacting with the desired amine.
’A or ’B is produced, which then creates a block.
Formula A or B with the corresponding protecting group removed
It can be a carbapenem. The process described above has several disadvantages. example
The tobacco process has multiple steps, so
We can advantageously reduce the ratio. Overall reaction yield is also low
After the quaternization process has been completed, the carbapenem compound
This is being implemented. (1) With fewer reaction steps,
(2) give higher yields and (3) first quaternize the amino acid.
form and bind to the carbapenem nucleus in the later stages of synthesis.
(4) For example, sterically hindered amines and low
P.K._bUsing various amines such as amines with values
Forming quaternary amine products more easily
Novel processes for producing compounds of formula A or B
It was desired to have a process. The present invention is based on the formula (In the formula, R⁸is hydrogen, and R¹is [formula] Yes; A is cyclopentylene, cyclohexylene
or C₂−C₆Alkylene (one or more C₁
−C_Four(optionally substituted with an alkyl group)
the law of nature; R²is hydrogen, anionic charge or normal easily removed
It is a carbonyl protecting group that can be removed (R²is hydrogen or
is a protecting group, a counter anion is also present); R¹⁴is bonded to A through the nitrogen of its ring, and its
When the quaternary ammonium group is formed, the quaternary
is a nitrogen-containing aromatic or non-aromatic heterocycle,
However, the aromatic heterocycle has the formula [formula] or is [formula] (In the formula, R^Five,R⁶and R⁷are independently hydrogen, C₁−
C_FourAlkyl, C₁−C_Fouralkoxy, hydroxy group
C replaced with₁−C_FourAlkyl, C₁−C_Fouralkyl
selected from the group consisting of thio and amino
So, R is C₁−C_Fouralkyl) and the non-aromatic heterocycle is a group of the formula (In the formula, [formula] is at least one in the ring is an alicyclic heterocyclic group containing a nitrogen atom,
R₁₆is C₁−C_Fouralkyl) carbapenem derivatives or pharmaceuticals thereof
In the method for producing acceptable salt, formula (However, R¹and R⁸is as defined above,
R^{twenty one}is the usual easily removable carboxyl protection
group and L is a conventional leaving group)
, the expression HS-A-R¹⁴ X (However, A and R¹⁴is as defined above,
X is the counter-anion), and
Reacted in the presence of a base in an inert solvent, the formula (However, R¹,R⁸,R^{twenty one},A,R¹⁴and X is above
carbapenem products (as defined above)
prepared and optionally carboxyl protecting group R^{twenty one}
compound with the corresponding protecting group removed from the formula
thing, or manufacturing a pharmaceutically acceptable salt thereof.
Provides a method for making features. According to the invention, intermediates of formula and such intermediates
A manufacturing method is also provided. The carbapenem compound of the formula is a powerful antibacterial agent or
It is a useful intermediate in the production of such antimicrobial substances. The compound with the above general formula has a carbapenem nucleus and therefore 1-carba-2-penem-
It can be called a 3-carboxylic acid derivative. a
Alternatively, a compound has a basic structure It can also be considered as having 7-oxo-
1-azabicyclo(3.2.0)hept-2-ene-
It can be called a 2-carboxylic acid derivative. Main departure
In light, the relative stereochemistry of the 5,6-proton is cis-aligned.
It includes compounds that are trans in the
New compounds are 5R, as in the case of thienamycin,
It has 6S (trans) stereochemistry. The following describes carbapenes, including those other than those of the present invention.
Each substituent on the mu nucleus will be explained. The compound of formula has a substituent at the 6-position.
May be absent or other carbapenem-induced
Substituted with previously disclosed substituents for
may have been done. For more details, please refer to R.⁸is hydrogen
It's good to be there, and R¹is hydrogen or e.g.
- Non-disclosed in Rotupa Patent Application No. 38869
Hydrogen substituent (R₆(see definition).
Or again, R⁸and R¹are together C₂−C_TenAl
substituted with kylidene or e.g. hydroxy
C₂−C_TenCan be alkylidene. R¹and R⁸Elaborating the definition of: (a) Aliphatic “alkyl”, “alkenyl” and “alkyl”
ruquinyl” group is a straight or branched chain containing 1-10
carbon atoms, preferably 1-6, most preferably
or a group having 1-4 carbons (atoms).
other substituents (e.g. cycloalkylalkyl);
or heteroaralkyl or aralkyl.
), alkyl, alkeni
and alkynyl groups preferably have 1-6,
Most preferably it has 1-4 carbon atoms. (b) “Heteroaryl” means 1-4 O, N or
Mono, bi, polycyclic aromatics containing S atoms
Includes heterocyclic groups; preferably 5- or 6-membered heterocyclic groups;
Bare rings such as thienyl, furyl, thiadiazoli
oxadiazolyl, triazolyl, isothiol
Azolyl, thiazolyl, imidazolyl, isoki
sazolyl, tetrazolyl, oxazolyl, piri
Zyl, pyrazinyl, pyrimidinyl, pyridazinyl
pyrrolyl, pyrrolyl, pyrazolyl, etc. (c) “Heterocyclyl” means 1-4 O, N or
Mono, Bi and polycyclic saturations containing S atoms
or unsaturated non-aromatic heterocyclic groups; preferred
or a 5- or 6-membered heterocycle, such as morpholini
Ru, piperazinyl, piperidyl, pyrazolini
pyrazolidinyl, imidazolinyl, imida
Zolidinyl, pyrrolinyl, pyrrolidinyl, etc.
Ru. (d) “Halo” refers to chloro, bromo, fluoro and iodine.
preferably chloro or bromo
be. The term “normal, easily removable carboxyl
"Protecting group" is a carboxyl group in the process of the following chemical reaction.
Known esters used to protect groups
group, which optionally refers to the rest of the molecule.
by a method that does not cause any decomposition, e.g. chemical
or enzymatic hydrolysis, chemical reduction under mild conditions.
Depends on treatment with base material, ultraviolet irradiation or catalytic hydrogenation.
It can be removed. of such ester protecting groups.
Examples include benzhydryl, p-nitrobenzyl,
2-naphthylmethyl, allyl, benzyl, tric
loloethyl, silyl e.g. trimethylsilyl, silyl
Enaacyl, p-methoxybenzyl, acetoni
, o-nitrobenzyl, 4-pyridylmethyl and
BiC₁−C₆Alkyl such as methyl, ethyl or t
-Butyl is included. Such protecting groups have physiological
Groups that are hydrolyzed under chemical conditions such as pivaloyl
Oxymethyl, acetoxymethyl, phthalidyl,
Included are indanyl and methoxymethyl. Special
Carboxyl protecting groups, which are advantageous for
easily removable p-nitrobenzyl and Pd
(pφ₃)_FourIt is an allele that can be removed by contact reaction. The pharmaceutically acceptable salts mentioned in the preamble are non-toxic.
Acid addition salts such as mineral acids such as hydrochloric acid, hydrobromic acid, iodine
Salts with hydrohydric acid, phosphoric acid, sulfuric acid, etc. and organic acids, e.g.
Maleic acid, acetic acid, citric acid, succinic acid, benzoic acid
Acid, tartaric acid, fumaric acid, mandelic acid, ascorbyl
Salts of phosphoric acid, lactic acid, gluconic acid and malic acid are included.
Included. A compound of the formula in the form of an acid addition salt is R²=H or protecting group (However, X indicates an acid anion).
Both are possible. Anti-anion is for therapeutic administration.
selected to provide a pharmaceutically acceptable salt for
However, in the case of intermediates of compounds of formula is poison
It may be a sexual anion. In this case, the ion is
then remove or remove with a pharmaceutically acceptable anion.
can be substituted into therapeutically active end products.
come. Acidic or basic group is R¹Radical or quaternized
R¹⁴If present on the radical, the main
The light is a suitable base or acid salt of these functional groups, e.g.
For example, acid addition salts for basic groups and acid addition salts for acidic groups.
Metal salts (e.g. sodium, potassium, calcium
ammonium salts and aluminum), ammonium salts and no
Toxic amines (e.g. trialkylamines, pro-
Caine, dibenzylamine, 1-ephenamine,
N-benzyl-β-phenethylamine, N,
N′-dibenzylethylenediamine, etc.)
Included. R²is hydrogen, anionically charged or physiologically hydrated
Compounds of the formula that are degradable ester groups are
Useful as an antibacterial substance with pharmaceutically acceptable salts of
It is. The remaining compounds in the formula are useful intermediates.
can be converted into the biologically active compounds listed above.
Ru. Preferred embodiments of the invention include R⁸is hydrogen,
and R¹is hydrogen, CH₃CH₂-, [formula] Converting an expression that is [expression] or [expression] compounds are included. Within this subclass, the preferred
The new compound is R¹A compound where is [formula], The most preferred compounds have the absolute configurations 5R, 6S, 8R.
are doing. Other preferred embodiments include R¹and R⁸are together
Forms an alkylidene group of formula [formula] Compounds of the formula are included. alkylene or cycloal in a compound of formula
Kiren Radical A is Cyclopentylene [Formula] Sik lohexylene [formula] or C₂−C₆Alkylene (one or more
C₁−C_Four(Optionally substituted with an alkyl substituent)
It can be. A preferred A substituent is cyclopentylene
cyclohexylene or formula (R^Ten,R¹¹,R¹²and R¹³are each independently hydrogen
or C₁−C_Fouralkyl) is an alkylene. In a preferred embodiment, substituent A is -CH₂CH₂-,
[Formula] [Formula] or [Formula] Ru. Cycloalkylene or branched alkylene A substitution
In the case of compounds with formulas having groups, 1 or 2
Another asymmetric carbon atom appears, diastereotically
O-isomers may be formed. The present invention includes
Mixtures of such diastereoisomers as well as individual
Purified diastereoisomers are included. Quaternized R¹⁴At least 1 substituent in the ring
containing nitrogen atoms, and to A via the ring nitrogen
Combined to form a quaternary ammonium group
(optionally having substituents) mono-, bis- or
can be a polycyclic aromatic or non-aromatic heterocyclic group
Ru. preferred class R¹⁴One of the substituents has the general formula This general formula can be expressed as
Contains at least one nitrogen atom and has no ring nitrogen
It is bonded to A via quaternary ammonium.
substituted or unsubstituted mono-, bis-forming group
or shall define a polycyclic heteroaryl group.
Ru. The heteroaryl group is C₁−C_Fouralkyl, hydroxy, amino, cal
Boxy or halo substituted C₁−C_FourAlkyl, C₃−
C₆cycloalkyl, C₁−C_FourAlkoxy, C₁−C_Four
alkylthio, amino, C₁−C_Fouralkylamino,
Ji (C₁−C_Fouralkyl) amino, halo, C₁−C_Foura
Lucanoylamino, C₁−C_Fouralkanoyloxy,
Carboxy, [Formula] alkyl, hydro xy, amidino, guanidino, trifluoromethyl
phenyl, 1, 2 or 3 amino, halo,
Hydroxyl, trifluoromethyl, C₁−C_Foura
Lukil or C₁−C_FourPhyl substituted with alkoxy group
enyl, heteroaryl and heteroaralkyl
(1-4 heteroatoms in the above heterocyclic moiety
selected from the group consisting of O, N or S atoms of
an alkyl moiety bonded to the heteroalkyl moiety;
substituents such as (having 1-6 carbon atoms)
may be replaced with . The heteroaryl group bonded to substituent A is
Quaternized nitrogen atom (alkylene or cycloalkyl)
directly bonded to the carbon atom of the ren group)
and optionally selected from O, N or S.
containing one or more additional heteroatoms
is preferably a 5- or 6-membered aromatic heterocyclic group.
stomach. Generally, it is bonded to A via a quaternized nitrogen.
All heteroaryl groups are biologically active.
Found to produce carbapenem derivatives
However, in a preferred embodiment, [formula] is represents a group selected from the group consisting of (a) to (g) below.
Compounds of the formula are included. The groups (a) to (g) are However, R^Five,R⁶and R⁷is independently hydrogen; C₁−C_Four
Alkyl; hydroxy, amino, carboxy or
C replaced by halo₁−C_FourAlkyl; C₃−C₆
Cycloalkyl; C₁−C_FourAlkoxy; C₁−C_Foura
Lukylthio; Amino; C₁−C_Fouralkylamino;
Ji (C₁−C_Fouralkyl)amino;halo;C₁−C_Foura
Lucanoylamino; C₁−C_FourAlkanoyloki
C; Carboxy; [Formula] Alkyl; H droxy; amidino; guanidino; trifluoro
Methyl; phenyl; 1, 2 or 3 amino, ha
B, hydroxyl, trifluoromethyl, C₁−
C_FourAlkyl or C₁−C_Foursubstituted with alkoxy
phenyl; and heteroaryl and heteroaral
Kill, 1-4 heteroatoms in the above heterocyclic moiety
selected from the group consisting of oxygen, nitrogen or sulfur atoms
and is combined with the heteroaralkyl moiety.
The lukyl moiety has 1-6 carbon atoms; selected from or R^Five,R⁶or R⁷2 in
fused together saturated carbocycles, fused aromatic carbons
A bare ring, a fused saturated heterocycle or a fused heteroaromatic ring
may be formed; [formula] [Formula] or [Formula] One or more substituents on a carbon atom in the formula
may be substituted with, and the substituents are independently
C₁−C_FourAlkyl; hydroxy, amino, carbo
C substituted with xy or halogen₁−C_FourArchi
Le；C₃−C₆Cycloalkyl; C₁−C_FourAlcoki
C;C₁−C_FourAlkylthio; amino; C₁−C_FourAl
Kylamino;C₁−C_FourAlkanoyloxy; cal
Boxy; [Formula] Alkyl; Hydroxy Amidino; Guanidino; Trifluoromethyl
phenyl; 1, 2 or 3 amino, halo,
Hydroxyl, trifluoromethyl, C₁−C_Foura
Lukil or C₁−C_FourPhyl substituted with alkoxy group
enyl; and heteroaryl or heteroaralky
1-4 heteroatoms in the above-mentioned heterocyclic moiety
selected from the group consisting of oxygen, nitrogen or sulfur atoms.
and is combined with the heteroaralkyl moiety
The alkyl moiety has 1-6 carbon atoms; or
selected from or optionally substituted with a fused carbocyclic ring
or form a heterocycle; [Formula] [Formula] [Formula] [Formula] [Formula] or [Formula] In the formula, one or more substitutions on the carbon atom
It may be substituted with a group, and the substituent is independently
C₁−C_FourAlkyl; hydroxy, amino, carbo
C substituted with xy or halogen₁−C_FourArchi
Le；C₃−C₆Cycloalkyl; C₁−C_FourAlcoki
C;C₁−C_FourAlkylthio; amino; C₁−C_FourAl
Kylamino;di(C₁−C_Fouralkyl) amino;
B；C₁−C_FourAlkanoylamino; C₁−C_FourArca
Noyloxy; Carboxy; [Formula] A hydroxy; amidino; guanidino;
Lifluoromethyl; phenyl; 1, 2 or 3
Amino, halo, hydroxyl, trifluoromethyl
le, C₁−C_FourAlkyl or C₁−C_Fourwith alkoxy group
substituted phenyl; and heteroaryl or
teroaralkyl, a heteroatom in the above heterocyclic moiety
is a group consisting of 1-4 oxygen, nitrogen or sulfur atoms
selected from and combined with the heteroaralkyl moiety
The standing alkyl moiety contains 1-6 carbon atoms.
selected from or optionally substituted with;
to form a fused carbocycle or heterocycle;
[Formula] [Formula] [Formula] [Formula] [Formula] or 【formula】 In the formula, one or more substitutions on the carbon atom
It may be substituted with a group, and the substituent is independently
C₁−C_FourAlkyl; hydroxy, amino, carbo
C substituted with xy or halogen₁−C_FourArchi
Le；C₃−C₆Cycloalkyl; C₁−C_FourAlcoki
C;C₁−C_FourAlkylthio; amino, C₁−C_FourAl
Kylamino;di(C₁−C_Fouralkyl) amino;
B；C₁−C_FourAlkanoylamino; C₁−C_FourArca
Noyloxy; Carboxy; [Formula] A rukyl; hydroxy; amidino; guazinino;
Lifluoromethyl; 1, 2 or 3 amino, ha
B, hydroxyl, trifluoromethyl, C₁−
C_FourAlkyl or C₁−C_Foursubstituted with alkoxy group
phenyl; and heteroaryl or heteroaryl;
rukyl, the heteroatoms in the above heterocyclic moiety are 1-4
selected from the group consisting of oxygen, nitrogen or sulfur atoms
and combined with the heteroaralkyl moiety
the alkyl moiety has 1-6 carbon atoms;
a fused carbon selected from or optionally substituted with
Forming a ring or heterocycle; [Formula] or 【formula】 In the formula, X is O, S or NR (R is C₁−C_FourArchi
or phenyl), and the above group is a carbon atom.
Substituted with one or more substituents on the child
and the substituent may be independently C₁−C_FourArchi
hydroxy, amino, carboxy or halogen
C replaced with₁−C_FourAlkyl; C₃−C₆cyclo
Alkyl; C₁−C_FourAlkoxy; C₁−C_Fouralkyl
Thio; Amino; C₁−C_FourAlkylamino; di(C₁
−C_Fouralkyl)amino;halo;C₁−C_Fourarcano
Ylamino;C₁−C_FourAlkanoyloxy; cal
Boxy; [Formula] Alkyl; Hydroxy Amidino; Guanidino; Trifluoromethyl
phenyl; 1, 2 or 3 amino, halo,
Hydroxyl, trifluoromethyl, C₁−C_Foura
Lukil or C₁−C_FourPhyl substituted with alkoxy group
enyl; and heteroaryl or heteroaralky
1-4 heteroatoms in the above heterocyclic moiety
selected from the group consisting of oxygen, nitrogen or sulfur atoms
and the alkyl group associated with the heteroaryl moiety
The kill moiety has 1-6 carbon atoms; or
fused carbocyclic ring or optionally substituted
forms a heterocycle; [formula] [Formula] [Formula] or [Formula] In the formula, X is O, S or NR (R is C₁−C_FourArchi
or phenyl), and the above group is a carbon atom.
Substituted with one or more substituents on the child
and the substituent may be independently C₁−C_FourArchi
hydroxy, amino, carboxy or halogen
C replaced with₁−C_FourAlkyl; C₃−C₆cyclo
Alkyl; C₁−C_FourAlkoxy; C₁−C_Fouralkyl
Thio; Amino; C₁−C_FourAlkylamino; di(C₁
−C_Fouralkyl)amino;halo;C₁−C_Fourarcano
Ylamino;C₁−C_FourAlkanoyloxy; cal
Boxy; [Formula] Alkyl; Hydroxy Amidino; Guanidino; Trifluoromethyl
phenyl; 1, 2 or 3 amino, halo,
Hydroxyl, trifluoromethyl, C₁−C_Foura
Lukil or C₁−C_FourPhyl substituted with alkoxy group
enyl; and heteroaryl or heteroaralky
1-4 heteroatoms in the above heterocyclic moiety
selected from the group consisting of oxygen, nitrogen or sulfur atoms
and the alkyl group associated with the heteroaryl moiety
The kill moiety has 1-6 carbon atoms; or
selected from; and [expression] [Formula] [Formula] [Formula] [Formula] or 【formula】 In the formula, R is C₁−C_Fouris alkyl or phenyl, The above groups may have one or more positions on the carbon atom.
It may be substituted with a substituent, and the substituent is independently
C₁−C_FourAlkyl; hydroxy, amino, cal
C substituted with boxy or halogen₁−C_FourArchi
Le；C₃−C₆Cycloalkyl; C₁−C_FourAlcoki
C;C₁−C_FourAlkylthio; amino; C₁−C_FourAl
Kylamino;di(C₁−C_Fouralkyl) amino;
B；C₁−C_FourAlkanoylamino; C₁−C_FourArca
Noyloxy; Carboxy; [Formula] A rukyl; hydroxy; amidino; guanidino;
Lifluoromethyl; phenyl; 1, 2 or 3
Amino, halo, hydroxyl, trifluoromethyl
le, C₁−C_FourAlkyl or C₁−C_Fourwith alkoxy group
Substituted phenyl; and heteroaryl and hetero
teroaralkyl, a heteroatom in the above heterocyclic moiety
is a group consisting of 1-4 oxygen, nitrogen or sulfur atoms
selected from and combined with the heteroaryl moiety
The alkyl moiety attached has 1-6 carbon atoms.
is; selected from: is. Among the above subclasses, preferred compounds are
Substituent A is -CH₂CH₂−, [formula] [Formula] or [Formula], and (a)R¹and R⁸together show [formula] or (b)R⁸is hydrogen and R¹is hydrogen, CH₃
CH₂−, [expression] [expression] or A compound that represents or is Ru. Particularly preferred is R⁸is hydrogen and R¹but
A compound having the formula [Formula], preferably It is a compound with absolute configurations 5R, 6S, and 8R. In a particularly preferred embodiment of the present invention, [Formula] is formula (R in the formula^Five,R⁶and R⁷are independently hydrogen, C₁−C_Four
Alkyl, C₁−C_Fouralkoxy, hydroxy group
replaced C₁−C_FourAlkyl, C₁−C_Fouralkirchi
Composed of carboxy, amino, carboxy and carbamoyl
(selected from the group)
A process for producing a compound of formula. Within this subclass, preferred compounds include substituents
A is -CH₂CH₂−, [formula] [Formula] or [Formula], and (a)R¹and R⁸together show [formula] or (b)R⁸is hydrogen and R¹is hydrogen, −CH₃
CH₂−, [expression] [expression] or A compound that represents or is Ru. Particularly preferred is R⁸is hydrogen and R¹but
A compound having the formula [Formula], preferably It is a compound with absolute configurations 5R, 6S, and 8R. The most preferred embodiment of the present invention is [Formula] is the formula (R in the formula^Five,R⁶and R⁷are independently hydrogen, C₁−C_Four
Alkyl, C₁−C_Fouralkoxy, hydroxy group
replaced C₁−C_FourAlkyl, C₁−C_Fouralkirchi
selected from the group consisting of
From the method for producing a compound of the formula represented by the group
Become. Within this subclass, preferred compounds are Substituent A is -CH₂CH₂−, [formula] [Formula] or [Formula], and (a)R¹and R⁸together show [formula] watermelon or (b)R⁸is hydrogen and R¹is hydrogen, −CH₃CH₂-,
[Formula] [Formula] or A compound that represents or is Ru. Particularly preferred is R⁸is hydrogen and R¹but
A compound having the formula [Formula], preferably is a compound with absolute configurations 5R, 6S, 8R.
Ru. A second preferred embodiment of the present invention is
[Formula] is expressed as a group of the formula [Formula] The method consists of a method for producing a compound having the formula: Within this subclass, preferred compounds are substituted A
is [formula] −CH₂CH₂-, [Formula] or [Formula], and (a)R¹and R⁸together, [formula] or (b)R⁸is hydrogen and R¹is hydrogen, −CH₃CH₂-,
[Formula] [Formula] or A compound that represents or is Ru. Particularly preferred is R⁸is hydrogen and R¹but
A compound having the formula [Formula], preferably is a compound with absolute configurations 5R, 6S, 8R.
Ru. A third preferred embodiment of the present invention is [Formula] Preparation of a compound of the formula represented by a pyridinium group
It consists of the manufacturing method. Within this subclass, the preferred
In the compound, substituent A is [formula] -CH₂CH₂ -, [expression] or [expression], and, (a)R¹and R⁸together show [formula] watermelon or (b)R⁸is hydrogen and R¹is hydrogen, −CH₃CH₂-,
[Formula] [Formula] or A compound that represents or is Ru. Particularly preferred compounds are R⁸is hydrogen,
R¹is a compound whose formula is [Formula], and is preferably or compounds with absolute configurations 5R, 6S, 8R.
be. The most preferred embodiment of the present invention has the formula However, [formula] is [Formula] R or S diastereo difference sexual body [Formula] or [Formula] R, R or
Diasterene isomer of S,S and R²is hydrogen, anionic charge or
It is a common and easily removable carboxyl protecting group.
(R²When is hydrogen or a protecting group, the counter anion is also
) and its pharmaceutically acceptable compounds.
This method consists of a method for producing an acid addition salt. Quaternized R^FourOther preferred classes of substituents are
General formula: However, R¹⁶has or does not have a substituent
i: alkyl, alkenyl and alkynyl, 1-
Has 10 carbon atoms; cycloalkyl and cycloalkyl
Loalkylalkyl, 3-6 on the cycloalkyl ring
carbon atoms and 1-6 carbons in the alkyl moiety
Has an atom; phenyl; alkyl moiety is phenyl
and the aliphatic portion has 1-6 carbon atoms.
Aralkyl, aralkenyl and aralquini
Heteroaryl, heteroaralkyl, hetero
Cyclyl and heterocyclylalkyl, the above complexes
Heteroatoms in the ring moieties include 1-4 oxygen, nitrogen or
is selected from the group consisting of sulfur atoms, and the complex
The alkyl moiety bonded to the ring part has 1-6
selected from the group consisting of; having a carbon atom;
and the above R¹⁶The base is Amino, fluoro, chloro, carboxyl, hydrogen
May be substituted with droxy or carbamoyl
C₁−C₆Alkyl; fluoro, chloro or bro
Mo; −OR³; −OCO₂R³; −OCOR³; −OCONR³R^Four; −OSO₂R³; -Oxo; −NR³R^Four; R³CONR^Four−; −NR³C.O.₂R^Four; −NR³CONR³R^Four; −NR³S.O.₂R^Four; −SR³; -SO₃R³; −CO₂R³; −CONR³R^Four; -CN; or 1-3 fluoro, chloro, bromo, C₁−
C₆Alkyl, −OR³, −NR³R^Four, −SO₃R³, −CO₂R³
or −CONR³R^Four(Karu R^FiveR in substituents³,R^FourReach
BiR⁹is the group consisting of (as defined above)
with 1-3 substituents independently selected from
or [However, [formula] must be at least one in the ring contains nitrogen (atom) and is connected to A via the ring nitrogen.
and form a quaternary ammonium group.
, with or without substituents,
No-, bi- or polycyclic non-aromatic (other aromatic or
represents a heterocyclic group (which may be fused to a non-aromatic ring)
vinegar〕 A divalent funile that combines with to form a crosslinked polycyclic group.
or C₁−C_FourCan also represent an alkylene group
It is. Heterocyclic groups are saturated or unsaturated (1-2
may have a double bond), and may have a quaternary
Contain up to two other heteroatoms other than nitrogen
is possible, and such another heteroatom is O, S(O)
_n,N,NR¹⁵or NR¹⁷R¹⁸Selected from [However, m
is 0, 1 or 2, and R¹⁵is hydrogen, has a substituent
C₁−C₆with alkyl or substituents
R is a phenyl which may be¹⁷and R¹⁸What is
C which may independently have a substituent₁−C₆Al
phenyl which may have a kill group or a substituent;
]. In a preferred embodiment is a non-aromatic 4- to 7-membered, preferably 5-, 6-membered
, 0-2 double bonds and O,S(O)_n,N,
NR¹⁵or NR¹⁷R¹⁸(In the formula, m is 0, 1 or 2.
R, R¹⁵is hydrogen, independently −OR³, −NR³R^Four,−
C.O.₂R³, oxo, phenyl, fluoro, chloro,
Bromo, −SO₃R³and CONR³R^Four1 selected from
-C optionally substituted with two substituents₁−C₆
alkyl, or independently C₁−C₆Alkyl, -
OR³, −NR³R^Four, fluoro, chloro, bromo, −
S.O.₃R³, −CO₂R²and −CONR³R^Fourselected from
Phenyl optionally substituted with 1-3 substituents
and R¹⁷and R¹⁸are each independently −
OR³, −NR³R^Four, −CO₂R³, -oxo, phenyl,
Fluoro, chloro, bromo, -SO₃R³and-
CONR³R^FourSubstituted with 1-2 substituents selected from
C that may be replaced₁−C₆alkyl or independent
Te-OR³, −NR³R^Four, fluoro, chloro, bro
Mo, −SO₃R³, −CO₂R²and −CONR³R^FourSelect from
may be substituted with 1-3 substituents
C₁−C₆alkyl; such a heterocycle NR¹⁵or
NR¹⁷R¹⁸R in the base³and R^Fouris R¹⁶In relation to substituents
0− selected from
N-containing heterocycle containing two separate heteroatoms
shows. In such a preferred embodiment, [Formula] The ring may be the following (a) ~ 1-3 substituents independently selected from (cc)
can be replaced with (a)～(cc) are (a)C₁−C₆Alkyl, (sometimes fluoro)
ro, chloro, bromo, −OR³, −OCOR³,−
OCONR³R^Four, -oxo, -NR³R^Four, −NR³
C.O.R.^Four, −NR³CONR³R^Four, −NR³S.O.₂R^Four, −SR³,
-SO₃R³, −CO₂R³and −CONR³R^Fourindependent from
substituted with 1-2 substituents selected by
); (b)C₂−C₆alkenyl (sometimes fluoro)
ro, chloro, bromo, −OR³, −OCOR³,−
OCONR³R^Four, -oxo, -NR³R^Four, −NR³
C.O.R.^Four, −NR³CONR³R^Four, −NR³S.O.₂R^Four, −SR³,
-SO₃R³, −CO₂R³and −CONR³R^Fourindependent from
substituted with 1-2 substituents selected by
); (c)C₂−C₆Alkynyl (in some cases, full
oro, chloro, bromo, -OR³, −OCOR³,−
OCONR³R^Four, -oxo, -NR³R^Four, −NR³
C.O.R.^Four, −NR³CONR³R^Four, −NR³S.O.₂R^Four, −SR³,
-SO₃R³, −CO₂R³and −CONR³R^Fourindependent from
substituted with 1-2 substituents selected by
); (d)C₃−C₆cycloalkyl (sometimes fluorine)
luoro, chloro, bromo, -OR³, −OCOR³,−
OCONR³R^Four, -oxo, -NR³R^Four, −NR³R^Four,−
NR³C.O.R.^Four, −NR³CONR³R^Four, −NR³S.O.₂R^Four,−
S.R.³, −SO₃R³, −CO₂R³and −CONR³R^Fourfrom
substituted with 1-2 independently selected substituents
); (e) Cycloalkylalkyl, cycloalkyl ring
3-6 carbon atoms in and 1- in the alkyl moiety
having 6 carbon atoms (in some cases)
Fluoro, chloro, bromo, -OR³, −OCOR³,
−OCONR³R^Four, -oxo, -NR³R^Four, −NR³
C.O.R.^Four, −NR³CONR³R^Four, −NR³S.O.₂R^Four, −SR³,
-SO₃R³, −CO₂R³and −CONR³R^Fourindependent from
substituted with 1-2 substituents selected by
); (f) heteroaryl, the heteroatoms are 1-4 acids
selected from the group consisting of nitrogen, nitrogen or sulfur atoms.
(in some cases, fluoro, chloro, butyl)
Lomo, −OR³, −OCOR³, −OCONR³R^Four, -Oki
So, -NR³R^Four, −NR³C.O.R.^Four, −NR³CONR³R^Four,
−NR³S.O.₂R^Four, −SR³, −SO₃R³, −CO₂R³as well as
−CONR³R^Four1-2 items independently selected from
); preferred hetero
The aryl group is a 5- or 6-membered aromatic heterocycle.
Ru; (g) heteroaralkyl, having 1-4 heteroatoms
selected from the group consisting of oxygen, nitrogen or sulfur atoms
and the alkyl moiety has 1-6 carbon atoms.
(in some cases fluoro, chloro, bromine)
Mo, −OR³, −OCOR³, −OCONR³R^Four, -Oki
So, -NR³R^Four, −NR³C.O.R.^Four, −NR³CONR³R^Four,
−NR³S.O.₂R^Four, −SR³, −SO₃R³, −CO₂R³as well as
−CONR³R^Four1-2 items independently selected from
); preferred hetero
The aryl group is a 5- or 6-heteroaryl group.
It is a membered aromatic heterocycle and the alkyl moiety is 1-
having 2 carbon atoms; (h) heterocyclyl, heteroatoms are 1-4 acids
selected from the group consisting of
(in some cases fluoro, chloro, bromine)
Mo, −OR³, −OCOR³, −OCONR³R^Four, -Oki
So, -NR³R^Four, −NR³C.O.R.^Four, −NR³CONR³R^Four,
−NR³S.O.₂R^Four, −SR³, −SO₃R³, −CO₂R³as well as
−CONR³R^Four1-2 items independently selected from
); preferred hetero
Cyclyl is a 5- or 6-membered saturated or unsaturated ring.
be; (i) heterocyclyl, heteroatoms are 1-4 acids
selected from the group consisting of nitrogen, nitrogen or sulfur atoms.
and the alkyl moiety has 1-6 carbon atoms.
(in some cases fluoro, chloro, bromine)
Mo, −OR³, −OCOR³, −OCONR³R^Four, -Oki
So, -NR³R^Four, −NR³C.O.R.^Four, −NR³CONR³R^Four,
−NR³S.O.₂R^Four, −SR³, −SO₃R³, −CO₂R³as well as
−CONR³R^Four1-2 items independently selected from
); preferred hetero
Cyclylalkyl has a heterocyclyl moiety of 5-
or a 6-membered saturated or unsaturated ring
is lylalkyl; (j) fluoro, chloro or bromo; (k) −OR³; (l) −OC₂R³; (m) −OCOR³; (n) −OCONR³R^Four; (o) −OSO₂R³; (p)OXO; (q) −NR³R^Four; (r)R³CONR^Four−; (s) −NR³C.O.₂R^Four; (t) −NR³CONR³R^Four; (u) −NR³S.O.₂R^Four; (v) −SR³; (y) −SO₃R³; (z) −CO₂R³; (aa) −CONR³R^Four; (bb) −CN; as well as (cc) phenyl (in some cases 1-3
Fluoro, chloro, bromo, C₁−C₆alkyl,
−OR³, −NR³R^Four, −SO₃R³, −CO₂R³Or-
CONR³R^Four). R mentioned above³,R^Fourand R⁹Substituent is substituent R¹related to
It is the same as defined as As defined above The ring is a non-aromatic heterocyclic group. This ring, however,
Can also be a saturated or unsaturated carbocyclic ring, preferably
O, N, S (O)_n,NR¹⁵or NR¹⁷R¹⁸Select from
4-7 containing 1-3 selected heteroatoms
Member heterocyclic (saturated or unsaturated) ring or O, S
(O)_n,N,NR¹⁵or NR¹⁷R¹⁸1 selected from
- 5-6 membered hetero containing 3 heteroatoms
Aromatic ring (in the above formula, m, R¹⁵,R¹⁷and R¹⁸ahead
fused to another ring, which is as defined in
It is also possible to Non-aromatic R¹⁴base R¹⁶A substituent has (1) a substituent.
C₁−C₆Alkyl, C₂−C_TenArche
Nil, C.₂−C_TenAlkynyl, C₃−C₆cycloalky
le, C₃−C₆cycloalkyl-C₁−C₆alkyl,
Phenyl, phenyl-C₁−C₆alkyl, feni
Lou-C₂−C₆alkenyl, phenyl-C₂−C₆Al
Quinyl, heteroaryl, alkyl moiety is 1-6
heteroaralkyl, alkyl having 4 carbon atoms
Heterosyclyl moieties having 1-6 carbon atoms
lyle or heterocyclylalkyl, or (2) divalent
Phenylene or C₁−C_Fourwith alkylene group A bridged ring polycyclic group such as quinuclidine
It is either one of the following. hetero
Aryl (or heteroaryl of heteroaralkyl)
The substituents (in the R part) contain 1-4 O, N, or S atoms.
mono-, bi- or polyaromatic heterocycle containing
group; preferred is a 5- or 6-membered heterocycle
Formula rings such as thienyl, furyl, thiadiazolyl,
Oxadiazolyl, triazolyl, isothiazolyl
ru, thiazolyl, imidazolyl, isoxazolyl
ole, tetrazolyl, oxazolyl, pyridyl, pyridyl
Radinyl, pyrimidinyl, pyridazinyl, pylori
and pyrazolyl. heterocyclyl (or
of the heterocyclyl part of heterocyclylalkyl)
Substituents contain 1-4 O, N or S atoms
Mono-, bi- or polycyclic saturated or unsaturated non-aromatic
a heterocyclic group; preferred is a 5- or 6-membered heterocyclic group;
Bare rings such as morpholinyl, piperazinyl, piperi
Dinyl, pyrazolinyl, pyrazolidinyl, imida
Zolinyl, imidazolidinyl, pyrrolinyl and pyrrolinyl
It is lolidinyl. R¹⁶Substituent is alkyl, alkenyl, alkynyl
cycloalkyl, cycloalkylalkyl,
phenyl, phenylalkyl, phenylalkeni
phenylalkynyl, heteroaryl, heteroaryl, phenylalkynyl,
loaralkyl, heterocyclyl or heterocyclyl
In the case of ralkyl groups, such groups are represented by (a) to (u) below.
substituted with 1-3 substituents independently selected from
may have been done. (a) to (u) are (a)C₁−C₆Alkyl, optionally substituent,
Preferably 1-3 amino, fluoro, chloro
b, carboxyl, hydroxy or carbamoy
having a group; (b) fluoro, chloro or bromo; (c) −OR³; (d) −OCO₂R³; (e) −OCOR³; (f) −OCONR³R^Four; (g) −OSO₂R³; (h) −oxo (i) −NR³R^Four; (j)R³CONR^Four−; (k) −NR³C.O.₂R^Four; (l) −NR³CONR³R^Four; (m) −NR³S.O.₂R^Four; (n) −SR³; (o) −SOR⁹; (p) −SO₂R⁹; (q) −SO₃R³; (r) −CO₂R³; (s) −CONR³R^Four; (t) −CN; and (u) Phenyl, sometimes fluoro, chloro
Ro, Bromo, C₁−C₆Alkyl, −OR³, −NR³
R^Four, −SO₃R³, −CO₂R³or −CONR³R^Fourfrom Germany
substituted with 1-3 substituents selected
, but the above R¹⁶related to substituents
and R³and R^Fourare independently hydrogen; alkyl, a
Lukenyl and alkynyl, 1-10 carbon atoms
has; cycloalkyl, cycloalkylalk
Kyl and alkylcycloalkyl, cycloalkyl
3-6 carbon atoms in the kill ring and an alkyl moiety
having 1-6 carbon atoms; phenyl; ali
The molecular moiety is phenyl and the aliphatic moiety is
Aralkyl having 1-6 carbon atoms, ara
lukenyl and aralkynyl; and heteroaryl
heteroaryl, heteroaralkyl, heterocyclyl and
Terocyclylalkyl, heteroaryl and
and heterocyclyl group or moiety is R¹⁶against
is the same as defined in
The alkyl moiety combined with the lyl moiety is 1-
having 6 carbon atoms; or
or R³and R^Fourare together at least one of them
5- or 6 with the nitrogen (atom) to which it is bonded
- member (R on top)^Fivedefined for
may form a nitrogen-containing heterocyclic ring (same as ).
ku; and R⁹R on top³also defined for
(However, it cannot be hydrogen).
Most preferred R¹⁶The substituent is C₁−C₆Alkyl, special
is methyl. R¹⁶is divalent phenylene or C₁−C₆alkylene
In the case of a group, such group is Atoms bonded and bridged polycyclic rings, e.g.
A quaternized quinuclidine ring of the formula is formed. A particularly preferred embodiment of the present invention is [Formula] but [Formula] [Formula] [Formula] [Formula] [Formula] [Formula] 【formula】 【formula】 [Formula] [Formula] or [formula] [In the formula, Y is hydrogen, C₁−C₆alkyl, hydro
Kishi, −SC₁−C₆alkyl, carboxyl, cal
Bamoyl, chloro, bromo, iodo, fluorocarbon
is phenyl]
It consists of the manufacturing method. Within this subclass, the preferred
For compounds where A is [formula] [Formula] [Formula] or -(CH₂)_o− (wherein m is 2, 3 or 4),
A more preferred compound is -CH₂CH₂−,−CH₂
CH₂CH₂−, [expression] [expression] or is a compound of [formula], most preferably In the compound, A is -CH₂CH₂−, and (a)R¹and R⁸together represent [formula] Wasuka or (b)R⁸is hydrogen and R¹is hydrogen, CH₃CH₂-,
[Formula] [Formula] or [Formula] or any compound be. Particularly preferred is R⁸is hydrogen and R¹but
It is a compound that has the formula It is a compound with pair (steric) configuration 5R, 6S, 8R.
Ru: An even more preferred embodiment of the present invention is
[expression] is [expression] [Formula] [Formula] 【formula】 【formula】 [Formula] [Formula] Indicated by [formula] or [formula] This method consists of a method for producing a compound of the formula: This preference
Within this subclass, preferred compounds are those in which A is
[Formula] [Formula] [Formula] or -(CH₂)_o-(in the formula, n is 2,3 or 4), which is a more preferred compound
In the compound, A is -CH₂CH₂−,−CH₂CH₂CH₂-,
[Formula] [Formula] or A compound of [formula], the most preferred formula In the compound, A is -CH₂CH₂−, and (a)R¹and
R⁸together represent [formula], or teeth (b)R⁸is hydrogen and R¹is hydrogen CH₃CH₂-,
[Formula] [Formula] or [Formula] or any compound be. Particularly preferred is R⁸is hydrogen and R¹but
A compound with the formula It is a compound with pair (steric) configuration 5R, 6S, 8R.
Ru. An even more preferred embodiment of the present invention is
[Formula] is [In the formula, Y is hydrogen, C₁−C₆alkyl, hydro
Kishi, −SC₁−C₆alkyl, carboxyl, cal
Bamoyl, chloro, bromo, iodine, fluorocarbon
is phenyl]
It consists of the manufacturing method. Within this preferred subclass, preferred compounds
A is -CH₂CH₂− and (a)R¹and R⁸together represent [formula] Wasuka or (b)R⁸is hydrogen and R¹is hydrogen, CH₃CH₂-,
[Formula] [Formula] or [Formula] or any compound be. Particularly preferred is R⁸is hydrogen and R¹but
It is a compound with the formula Compounds with pair (steric) configurations 5R, 6S, 8R
be: The most preferred embodiment of the present invention is [Formula] Production of a compound of the formula represented by [formula] It consists of a method. Within this preferred subclass, preferred compounds
The thing is that A is -(CH₂)_o- (where n is 2, 3 or 4)
The most preferred compound is a compound in which A is
−CH₂CH₂- and (a)R¹and R⁸together represent [formula] Wasuka or (b)R⁸is hydrogen and R¹is hydrogen, CH₃CH₂-,
[Formula] [Formula] or [Formula] or any compound be. Particularly preferred is R⁸is hydrogen and R¹but
It is a compound with the formula Compounds with pair (steric) configurations 5R, 6S, 8R
be. The most preferred embodiment of the invention is the formula [However, [formula] is [formula] [Formula] [Formula] [Formula] (α- and β-diastere (Both isomers) [Formula] or [Formula] and R²is hydrogen, Anionic charge or normal easily removable carboxylic acid
nyl protecting group, with the proviso that R²is hydrogen or a protecting group
counter ion is also present], and its
A method for producing a pharmaceutically acceptable acid addition salt. Certain products within the formula may contain optical isomers.
may be formed as a mixture of its epimers in
It will be recognized that there is. This invention is based on the patent
All such optical isomers and epimers are within the scope of our rights.
It shall include all mixtures. For example 6-
When the substituent at the position is hydroxyethyl, such
Substituents can be produced in either R or S configuration.
and the obtained isomer and its epimer.
Mixtures are included within the invention. The process of the invention is based on the formula For example, this intermediate is
- Disclosed in Rotupa Patent Application No. 38869,
Can be manufactured by the general method described therein
It is. L is (in European Patent Application No. 38869)
(expressed as “X”), e.g.
For example, chloro, bromo, iodine, benzenesulfony
p-toluenesulfonyloxy, p-
Nitrobenzenesulfonyloxy, methanesulfonyloxy
Nyloxy, trifluoromethanesulfonyloxy
cy, diphenoxyphosphonyloxy or di(tritrioxy)
chloroethoxy)phosphinyloxy. Like
A new leaving group is diphenoxyphosphonyloxy.
Ru. The intermediate of the formula is the formula [However, R¹,R⁸and R^{twenty one}is as defined above.
] intermediate with a suitable acylating agent: R°-L.
and generally formed within the device. L is Jihoo
The preferred intermediate is enoxyphosphonyloxy
The ketoester can be dissolved in an inert organic solvent such as methane.
Ren chloride, acetonitrile or dimethyl fluoride
Approximately equimolar amounts of diphenyl chloroform in lumamide
Sulphate and a base such as diisopropylethyl acetate
amine, triethylamine, 4-dimethylaminopylene
In the presence of lysine, etc., a temperature of approximately -20℃ to +40℃
and most preferably at about 0°C.
come. Intermediates can be liberated if desired
However, in the method of the present invention, it is not possible to release or purify
It is usually used as a starting material. In the method of the present invention, carbapenem intermediates of the formula HS-A-R¹⁴X [In the formula, A is cyclopentylene, cyclohexy
Ren or C₂−C₆Alkylene (1 or more
C₁−C_Fouroptionally substituted with an alkyl group),
Most preferably cyclopentylene, cyclohexy
Ren or (R^Ten,R¹¹,R¹²and R¹³each independently
Basic or C₁−C_Fouralkyl) and X teeth
Counteranions in combination with strong acids e.g. Cl^-，
Br^-,CH₃S.O._3-,CF₃S.O._3-or
[Formula], and R¹⁴contains quaternized nitrogen as defined above
Aromatic or non-aromatic heterocycle
react with antithiol compounds. This reaction is inactive
acetonitrile, acetonitrile-
dimethylformamide, tetrahydrofuran, tetra
Trahydrofuran-H₂O, acetonitrile-H₂
Carry out in the presence of a base in O or acetone.
The nature of the base is not critical. However, the best result
is a non-nucleophilic tertiary amine base, e.g.
Lopylethylamine, 1,8-diazabicyclo
[5.4.0] Undec-7-ene, 1,5-diazabi
cyclo[4.3.0] non-5-ene or tri(C₁−
C_Four) Alkylamines such as triethylamine,
Using tributylamine or tripropylamine
I got it when I was there. Intermediates and thiols
The reaction occurs over a wide temperature range, e.g. from -15°C to room temperature.
It can be carried out for up to, but preferably for about -
Temperatures in the range 15°C to +15°C, most preferably 0
It is carried out at around ℃. For the reaction between quaternary amine thiols and intermediates
Carbapenem products manufactured by
are combined [e.g. (C₆H_FiveO)₂P.O.₂,Cl
or an anion associated with a quaternary thiol
] counteranion, which can be determined by conventional methods.
with other counteranions, e.g. more pharmaceutically acceptable
It can be replaced with this step by counter-anion. another way
As such, the counter anion is removed during the next deblocking step.
You can leave. Quaternized carbapenem compounds and
If the ion forms an insoluble product,
The product can be crystallized and collected in pure form.
It's okay. Following the formation of the desired carbapenem product, in situ
In some cases, the carboxyl protecting group of the compound
R^{twenty one}the usual methods, e.g. solvolysis, chemical
It can be removed by reduction or hydrogenation.
Ru. p-nitrobenzyl, benzyl, benzhyde
Using protecting groups like lyl or 2-naphthylmethyl
If so, it can be removed by catalytic hydrogenation.
A suitable solvent such as dioxane-water-ethanol
tetrahydrophthene diethyl ether
buffer, tetrahydrofuran-hydrogen phosphate 2 liters
Intermediates in aqueous solution - isopropanol, etc.
' under hydrogen pressure of 1 to 4 atmospheres, hydrogenation catalyst, e.g.
For example, palladium on charcoal, palladium hydroxide, acid
In the presence of platinum chloride, etc., at a temperature of 0° to 50°C, approximately 0.24
It can be processed in 4 hours. R^{twenty one}is o-nitrobene
When using a protecting group such as zyl, photolysis can also be used for deblocking.
Can be used. such as 2,2,2-trichloroethyl
Protecting groups can be removed by mild zinc reduction. Ali
The protective groups are platinum compounds and triphenylphosphine.
A catalyst consisting of a mixture of
Tetrahydrofuran, methylene chloride or
It can be removed using diethyl ether. similar
Other common carboxyl protecting groups are known to those skilled in the art.
It can be removed by known methods. Finally, R^{twenty one}
esters that can be physiologically hydrolyzed, e.g.
Toxymethyl, phthalidyl, indanyl, hibaro
Formulas that are yloxymethyl, methoxymethyl, etc.
' Compounds (as described above) are such esters
is hydrolyzed in vivo under physiological conditions, so
It can be administered to a subject without removing the protecting group. R¹and/or R⁸bonded to a substituent or substituent A
Quaternized nucleophilic substituent R¹⁴interferes with the intended reaction pathway.
If it contains a functional group that may cause
After protecting such a group with a conventional blocking group,
The desired functional group can be released by removing the block.
I would like you to understand that. suitable blocking groups and
Introduction and removal of groups are well known to those skilled in the art.
It is that you are. As with other β-lactam antibiotics,
For the purposes of the present invention, compounds of the general formula
pharmaceutically acceptable salts that are substantially equivalent to the compound
can be converted using a known method. For example, R²
is an anionic charge.
an equivalent amount of a pharmaceutically acceptable solvent.
It is possible to add acid. The desired acid addition salt is
Conventional methods such as solvent precipitation, freeze drying, etc.
It is possible to recover depending on the situation. Other salts in the compound of formula
If basic or acidic functional groups are present, pharmaceutical
Acceptable base addition salts and acid addition salts can be prepared by known methods.
It can be manufactured in the same way. R²is a hydrogen or anionic charge
or its pharmaceutically acceptable salts in a conventional manner.
Depends, R²is an ester group that can be physiologically hydrolyzed.
can be converted into some corresponding compound, or R²
A compound of formula where is the usual carboxyl protecting group
R²is hydrogen, anionically charged or physiologically hydrated
The corresponding compound is a degradable ester group or
It can be converted into its pharmaceutically acceptable salt. Some thiol intermediates of the formula are e.g.
【formula】 [Formula] or [In the formula, R^Ten,R¹¹,R¹²and R¹³are each unique
hydrogen or C₁−C_FourAlkyl
formula a heteroaromatic amine (as defined above) or
is the expression a non-aromatic heterocyclic amine (as defined above) of
It can be produced by reacting with chlorine and strong acid. reaction
is an inert organic solvent, preferably methylene chloride.
Non-polar substances such as hydrogen, benzene, xylene, toluene, etc.
Can be carried out in the presence or absence of a neutral solvent.
It is. When amine and sulfide reagents are liquids
or solid amines are soluble in liquid sulfide reagents.
In this case, it is best to carry out the reaction without using an additional solvent.
preferable. The particular strong acid used in the reaction is not critical
For example, hydrochloric acid, hydrobromic acid, methanesulfone
acid, p-toluenesulfonic acid, trifluorometa
strong inorganic or organic acids such as sulfonic acid, etc.
can be obtained. The formation of the quaternary amine thiol intermediate is approximately −20
It can be carried out at temperatures ranging from 0.degree. C. to about 100.degree.
Preferred temperatures are generally in the range of about 50-70°C
It is. Sulfide reagents, aromatic amines and acids are preferred
For example, use approximately equimolar amounts of sulfide and acid.
and in excess for the amine used, e.g.
2 to 3 moles per mole of sulfide or acid
amine is used. The quaternary amine thiol intermediate is combined with it.
Let's have a vs. anion and it's used
It probably depends on the particular acid used. Of course, this
used in the next reaction with the carbapenem intermediate.
The anti-anio
can be replaced by R²is hydrogen, anionically charged or physiologically hydrated
Novel carbapenem derivatives of degradable formula or
is a pharmaceutically acceptable salt of various Gram-positive and
A potent compound with activity against both gram-negative and gram-negative bacteria.
antibiotics, and these promote growth, e.g.
Animal feed additive, food preservative, industrial application
For example, in water-based paints and paper mill white water
disinfectants to inhibit the growth of harmful bacteria, and
May destroy the growth of harmful bacteria in medical and dental equipment.
can be used as a disinfectant to inhibit
Ru. However, these are gram positive or gram positive.
Infections of humans and other animals caused by rum-negative bacteria
Particularly useful in treating sexually transmitted diseases. The pharmaceutically active compounds of the invention are used alone
or, alternatively, active carbapenem compounds.
minutes plus a pharmaceutically acceptable carrier, or diluent.
It may also be formulated as a pharmaceutical composition containing an agent.
Wear. Compounds can be administered in a variety of ways.
Ru. The means of primary interest are oral, topical or
includes parenteral (intravenous or intramuscular injection)
Ru. The pharmaceutical composition can be in solid form, e.g. capsules,
Tablets, powders, etc. or liquid forms e.g. solutions, suspensions
It can be a formulation or an emulsion. Injectable composition (preferably
route of administration) in ampoules or multi-dose containers.
Prepared in unit dosage form and used for prescription e.g.
may contain agents, stabilizers and dispersants.
Ru. The composition may be in ready-to-use form or in a suitable vehicle.
Powder form for reconstitution upon administration e.g. with sterile water
That's fine. The dosage for administration depends on the particular compound used,
the particular composition formulated, route of administration, and host characteristics;
and based on the specific site and microorganism being treated.
Depends on the width. Therefore, specific preferred dosage and application route
The choice is left to the discretion of the doctor. However, generally the compound is about 5-200mg/Kg/
For parenteral or oral administration to mammalian hosts at daily doses.
can be done. Administration is generally in divided doses
The dosage is, for example, 3 to 4 times/day. The following examples are for illustrative purposes only and do not fall within the scope of the invention.
It does not limit the scope. Example 1 3-(2-(1-pyridinium)ethylthio)-
6α−(1−(R)-hydroxyethyl)-7-o
xo-1-azabicyclo(3.2.0)hept-2
-Production of ene-2-carboxylate A 1-(2-mercaptoethyl)pyridium
Tansulfonate Add pyridine (8.0ml, 0.099mol) while cooling.
Tansulfonic acid (1.95ml, 0.03mol) was added dropwise;
Pyridinium methanesulfonate produced
Add ethylene sulfide (1.96 ml,
0.033mol) was added. The resulting mixture was heated at 55°C.
Stir for 16 hours and concentrate under reduced pressure to form a thick syrup.
Mixed with a few mL of water. This solution is μ−
Pour onto the top of a bondapak C-18 column (40 x 16 cm),
Freeze-drying of appropriate fractions eluted with water
6.5 g (91%) of colored syrup was obtained. ir (film) ν_nax:2300−2600 (br, SH),
1635 (pyridinium), 1490, 1200 (sulfone)
), 1068, 1060, 1045, 791, 780cm^-1,¹Hmr
(DMSO−d₆) δ: 2.32 (3H, s, CH₃S.O._3-),
2.61, 2.70, 2.73, 2.82 (1H, A₂B part of B system,
SH), 3.07 (2H, m [D₂So, 3.08 (2H, t,J=6.5Hz)〕,
CH₂S), 4.76 (2H, t,J=6.5Hz, CH₂N⁺),
8.19 (2H, m, Hm of pyridinium), 8.6 (1H,
m, pyridinium Ho), 9.08 (2H, dd,J=6.8
Hz,J= 1.4Hz, Pyridinium Ho)μV(H₂O)
λ_nax:206 (ε5230), 258 (ε3760) mμ. Method A B 1-(2-mercaptoethyl)pyridinium
Chloride Crude 1-(2-mercaptoethyl)pyridinium
Menthanesulfonate (9.4g, 0.04mol) was added to the par
Permutit S-1Cl^-column (2.5×
41 cm). Column at 0.5mL/min. speed of
Elute with water at 30°C, combine appropriate fractions and freeze.
7.0g of yellow syrup that is dried and used in the next process
(100%) obtained. ¹Hmr(D₂O) δ: 3.22 (2H, m, CH₂S),
4.88 (m, CH₂N⁺), 8.18 (2H, m; pyridinium
Hm), 8.7 (1H, m, Hp of pyridinium),
9.0ppm (2H, m, Ho of pyridinium). Method B Pyridine (5.6 mL, 70 mmol) pre-cooled in an ice bath
to pyridine hydrochloride (4.05 g, 35 mmol) and ethyl
Rensulfide (2.1 mL, 35 mmol) was added.
Heat the mixture to 65°C and stir for 75 minutes to form a two-phase system.
did. Remove the light phase and etherify the remaining oil.
(5 x 10 mL), reduce pressure to high vacuum, and write the title.
The compound (90-100%) was obtained and used in the next step. C paranitrobenzyl 3-[2-(1-pyridiny)
um)ethylthio)-6α-[1-(R)-hydro
xyethyl]-7-oxo-azabicyclo
(3.2.0) hept-2-ene-2-carboxylene
Tochloride p-Nitrobenzyl 6α-[1-(R) - Hydroxy
ethyl]-3,7-dioxo-1-azabicic
(3.2.0) Heptane-2-carboxylate
(6.09 g, 17.5 mmol) in acetonitrile (20 mL)
The solution was cooled to +5°C under a nitrogen atmosphere and the diiso
Propylethylamine (3.65mL, 21.0mmol)
Diphenyl chlorophosphate (4.34mL,
21.0 mmol). the product mixture
Stir at 5°C for 30 minutes, cool to -5°C and dissolve the crude 1-(2
-Mercaptoethyl)pyridinium chloride
(4.3g, 24mmol) of N,N-dimethylforma
Mido (10 mL) solution and one drop of diisopropyl
Treated sequentially with ethylamine (3.65mL, 21.0mmol).
I understood. The reaction mixture was stirred at 0 °C for 1 h and −30
It was cooled to 0.degree. C. and stirred for an additional 15 minutes. separate solids
and washed with cold (-30°C) acetonitrile. 5.77
g (65%), ir (nujol) ν_nax:3300(OH), 1775(β
-lactam C=O), 1690 (PNB ester C=O), 1690 (PNB ester C=O)
=O), 1630 (pyridinium), 1605 (PNB aesthetic
phenyl), 1515 (NO₂), 1335cm^-1(NO₂),
1Hmr (DMSO−d₆) δ: 1.17 (3H, d,J=6.1
Hz,CH ₃CHOH), 3.2-3.75 (5H, H-4, H-
6.CH₂S), 3.75-4.5 (2H, H-5, CH₃CH
OH), 4.92 (2H, brt, J=6.5Hz, CH₂N⁺), 5.18
(1H, d,J=4.9Hz, OH), 5.37(AB_qcenter of
-,J _a,b=14.2Hz, CH of PNB₂), 7.69 (2H, d,
J=8.7Hz, PNB Ho), 8.24(d,J=8.7Hz,
Hm of PNB), 8.0−8.4 (4H, Hm of PNB, Pyri
Hm of Zinium, 8.66 (1H, m, Hm of Pyridinium
Hp), 9.17 (2H, brd,J=5.5Hz, pyridinium
Ho), combine the liquid and washing liquid and make ether
(150 mL). Decant the supernatant.
and soak the gum in water containing sufficient acetonitrile.
Dissolve μ-bondapak in (40 mL) as a solution.
Injected onto the top of a C-18 column (3 x 10 cm). column
10%-acetonitrile-90% water (150mL) and
and 50% acetonitrile - 50% water (100mL) mixture
It was eluted with Combine the appropriate fractions,
Freeze-dry after removing acetonitrile under vacuum
A yellowish powder was obtained. The NMR results are
The title compound contains some p-nitrobenzyl 3-[2
-(1-pyridinium)ethylthio]-6α-[1-
(R)-hydroxyethyl]-7-oxo-1-a
Zabicyclo (3.2.0) hept-2-ene-2-ka
Mixed with ruboxylate diphenyl phosphate
(2:1) was shown to exist. powder
Dissolved in water (minimum amount), palm chit S-1Cl^-
water was passed through a column (1.5 x 21 cm). appropriate
1.8g (20%) of lyophilized fraction
The following compound was obtained. D Paranitrobenzyl 3-[2-(1-pyridiny)
um)ethylthio]-6α-[1-(R)-hydro
xyethyl]-7-oxo-1-azabicyclo
(3.2.0) hept-2-ene-2-carboxylene
diphenyl phosphate p-Nitrobenzyl 6α-[1-(R) - Hydroxy
ethyl]-3,7-dioxo-1-azabicic
(3.2.0) Heptane-2-carboxylate
(0.174 g, 0.50 mmol) in acetonitrile (2 mL)
The solution was cooled to 0 °C under nitrogen atmosphere and diisopropylene was added.
Pyrethylamine (0.105mL, 0.60mmol) and
Diphenyl chlorophosphate (0.124mL,
0.60 mmol) one after another. The obtained solution
Stir 1-(2-mercaptoethyl) at 0 °C for 30 min.
Pyridinium methanesulfonate (0.170g,
0.72 mmol) in acetonitrile (0.6 mL) and
diisopropylethylamine (0.105mL,
0.60 mmol) one after another. Reaction mixture to 0
Stir for 15 min at °C and dilute with cold (0 °C) water (7 mL).
and μ-bondapak C-18 column (1.5 x 6.4
cm) injected apically. Wash the column with acetonitrile (25
-50%) and water (75-50%).
Ta. Combine appropriate fractions and acetate under vacuum.
After removing the tonitrile, it is cooled and dried to remove the yellowish color.
Obtained 0.33g (92%) of powder: ir(KBr)ν_nax:
3600−3000 (OH), 1765 (C= of β-lactam
O), 1690 (C=O of PNB ester), 1625 (Pyri
Zinium), 1585 (Phenyl), 1510 (NO₂), 1330
(NO₂), 885cm^-1(NO₂),¹Hmr(DMSO−d₆)
δ: 1.16 (3H, d,J=6.2Hz,CH ₃CHOH),
4.87 (2H, brt,J=6.6Hz,CH₂S), 5.37 (AB_qof
Center,J _a,b=14.3Hz, CH of PNB₂), 6.7−7.5
(phenyl), 7.68 (d,J=8.8Hz. PNB Ho),
8.23(d,J=8.8Hz. , Hm of PNB), 8.0−8.3
(m, Hm of pyridinium), 8.4−8.8 (1H, pyridinium
Zinium Hp), 9.09 (2H, dd,J=6.7Hz,J=
1.3Hz, pyridinium Ho). E 3-[2-(1-pyridinium)ethylthio]
−6α−[1−(R)-hydroxyethyl]-7-
Oxo-1-azabicyclo(3.2.0)hept-
2-ene-2-carboxylate Method A In moist tetrahydrofuran (10 mL)
p-Nitrobenzyl 3-[2-(1-pyridinium)
) Ethylthio]-6α-[1-(R)-hydroxy
ethyl]-7-oxo-1-azabicyclo
(3.2.0) Hept-2-ene-2-carboxylate
Diphenyl phosphate (0.16g, 0.22mmol)
in ether (10 mL), monobasic potassium phosphate
Um - Sodium hydroxide buffer PH7.4
(16mL, 0.05M) and 10% palladium on charcoal
(0.16g) was added. The resulting mixture was heated at 25℃ for 1
Hydrogenated at 40 psi for an hour. Separate the two phases and organic phase
was extracted with water (2 x 3 mL), the aqueous solutions were combined,
Wash with ether (2 x 10 mL) to remove traces of organic solvent.
After removing the trace under vacuum, μ-bondapak C-18
column (1.5 x 6.2 cm). column
After elution with water and lyophilization of the appropriate fractions,
A yellowish powder was obtained. 0.062g (84%), ir (KBr) ν_nax: 3700-3000 (OH), 1755 (β-lactam C
=O), 1630 (pyridinium), 1590cm^-1(Carbo
xylate),¹Hmr(D₂O): 1.22 (3H, d,J=
6.4Hz, CH₃CHOH), 2.92(d,J=9.1Hz, H-
4), 2.97(d,J=9.1Hz, H-4), 3.20(dd,J
=2.5Hz,J=6.1Hz, H-6), 3.44(t,J=6.0
Hz, CH₂S), 3.93 (dd,J=9.1Hz,J=2.5Hz,
H-5), 4.82 (t,J=6.0Hz,CH₂N⁺), 8.04
(m, Hm of pyridinium), 8.5 (m, Hm of pyridinium)
HP), 8.82 (dd,J=3.2Hz,J= 1.1Hz), UV
(H₂O)λ_nax:259 (ε5800), 296 (ε7030) mU,
t₁/₂= 13.5h (phosphate buffer at 36.8℃ Ah PH7.4 out of 10^-FourMeasured at the concentration of M [hereinafter referred to as "Condition A"]
abbreviated as〕) Method B p-Nitrobenzyl 3-[2-(1-pyridiu
) Ethylthio]-6α-[1-(R)-hydroxy
ethyl]-7-oxo-1-azabicyclo
(3.2.0) Hept-2-ene-2-carboxylate
Tochloride (5.77g, 11.4mmol) monobasic
Potassium phosphate-sodium hydroxide buffer
(170mL, 0.2M, PH7.22) solution with tetrahydrofu
on run (30 mL), ether (30 mL) and charcoal
10% palladium (5.7g) was added. The resulting mixture
The mixture was hydrogenated at 22 °C and 40 psi for 1 h and then
I spent some time in Topad. Wash the pads with water (2x
15 mL). Combine the liquid and washing liquid, and add ether.
(100 mL). Separate the aqueous phase and
Wash with organic solution under vacuum (3 x 100 mL).
After removing the medium, remove the μ-bondapak C-18 color.
(4.5 x 20 cm). Column with water and
Eluted with a mixture of acetonitrile (1%) and water.
By freeze-drying an appropriate fraction, yellowish color can be obtained.
Obtained 2.48 g (65%) of the title compound as ivy powder.
Ta. Analytical data are for compounds prepared by method A.
It was the same as Example 2 3-[2-(1-(3,5-dimethylpyridinium)
) Ethylthio]-6α-[1-(R) - Hydroxy
ethyl]-7-oxo-1-azabicyclo
(3.2.0) hept-2-ene-2-carboxylene
Manufacture of sheets A 1-(2-mercaptoethyl)-3,5-dime
Chylpyridinium methanesulfonate in cold 3,5-lutidine (2.51 mL, 0.022 mol)
Add methanesulfonic acid (0.65mL, 0.010mol)
3,5-lutidine in the prepared 3,5-lutidine
Ethylene in a suspension of zincium methanesulfonate
Sulfide (0.655mL, 0.011mol) was added. profit
The resulting mixture was stirred at 55°C for 24 hours under nitrogen atmosphere.
Cool to 23°C and add water (5 mL) and ether.
(5 mL). Remove the organic layer and add the aqueous solution to
Washed with ether (6 x 4 mL). Etched under vacuum
Remove any traces of ether and rinse the solution with μ-bondapak C.
-18 column (2.5 x 6.0 cm). Kara
Elute the sample with water and freeze-dry the appropriate fractions.
A colorless syrup was obtained. 2.4g (91%); ir (film) ν_nax:2520(SH),
1628 (pyridinium), 1600, 1495, 1325, 1305,
1283, 1200 (sulfonate), 1040, 938, 765,
680cm^-1;¹Hmr(DMSOd₆) δ; 2.31 (3H, s,
CH₃S.O._3-), 2.47 (6H,s, on pyridinium
CH₃), 2.57, 2.66, 2.69, 2.78 (1H, A₂B of B series
part, SH), 3.06 (2H, m [D₂With the addition of O (2H, t,
J = 6.5Hz)], CH₂S), 4.65 (2H, t,J=6.5
Hz, CH₂N⁺), 8.34 (1H, s, pyridinium
Hp), 8.79 (2H, s, Ho of pyridinium); UV
(H₂O)λ_nax:271 (ε4860) mμ. Elemental analysis: Calculated value (C_TenH₁₇NO.₃S₂・0.5H₂O and
) C44.09, H6.66, N5.14, S23.54; Actual measurement
Values: C44.26, H6.49, N5.17, S24.18. B Paranitrobenzyl 3-[2-(1-3,5-
dimethylpyridinium)ethylthio]-6α-
[1-(R)-hydroxyethyl]-7-oxo-
1-Azabicyclo(3.2.0)hept-2-ene
-2-carboxylate diphenyl phosphate
to p-Nitrobenzyl 6α kept under nitrogen atmosphere
-(1-(R)-hydroxyethyl)-3,7-dio
xo-1-azabicyclo(3.2.0)heptane-2
- carboxylate (0.523g, 1.50mmol)
diiso in a cold (0°C) solution of setonitrile (6.0 mL).
Propylethylamine (0.314mL, 1.8mmol),
Next, diphenyl chlorophosphate (0.373g,
1.8 mmol) was added. Stir the reaction mixture for 30 minutes
and 1-(2-mercaptoethyl)-3,5-dime
Chylpyridinium methanesulfonate (0.493g,
1.87 mmol) in acetonitrile (1.9 mL),
Then diisopropylethylamine (0.314mL,
1.8 mmol). The reaction mixture was kept at 0°C for 1 hour.
Stir for a while and dilute with cold (0°C) water (26 mL) to μ-
Pour onto the top of the bondapak C-18 column (7.0 x 3.5 cm).
I entered. Coat the column with 25-50% acetonitrile-75-
Elute with a mixture of 50% water and appropriate fractions.
After freeze-drying, 1.01 g (90%) of the title compound was
It was obtained as a tasteless powder. ir(KBr)ν_nax:
3700−3100 (OH), 1778 (C= of β-lactam
O), 1700 (C=O of PNB ester), 1635 (Pyri
Zinium), 1595 (Phenyl), 1521 (NO₂), 1335
(NO₂), 895cm^-1(NO₂),¹Hmr (DMSO d₆)
δ: 1.16 (3H, d,J=6.1Hz,CH ₃CHOH),
2.43(s, CH on pyridinium₃), 4.75 (2H, m,
CH₂N⁺), 5.38 (AB_qcenter ofJ _a,b=14.3Hz,
PNB CH₂), 6.6−7.5 (10H, m, phenyl),
7.70 (2H, d,J=8.7Hz, PNB Ho), 8.0−8.5
(3H, m, Hp of pyridinium, Hm of PNB),
8.82 (2H, s, Ho of pyridinium), UV (H₂O)
λ_nax: 270 (ε11570), 306 (ε7343) mμ. elemental content
Analysis: Calculated value (C₃₇H₃₈N₃O_TenSP・H₂as O):
C58.03, H5.26, N5.48, S4.18; Actual values: C57.98, H5.05, N5.22, S4.34. C 3-[2-(1-(3,5-dimethylpyridiny)
um)ethylthio]-6α-[1-(R)-hydro
xyethyl]-7-oxo-1-azabicyclo
(3.2.0) hept-2-ene-2-carboxylene
root In moist tetrahydrofuran (36 mL)
p-nitrobenzyl 3-[2-(1-(3,5-
dimethylpyridinium))ethylthio]-6α-[1
−(R)-hydroxyethyl]-7-oxo-1-
Azabicyclo (3.2.0) hept-2-ene-2-
Carboxylate diphenyl phosphate
(0.600g, 0.80mmol) in ether
(36mL), monobasic potassium phosphate-sodium hydroxide
Um Batshua (0.05M, PH7.4, 44mL) and
10% palladium on charcoal (0.60 g) was added. profit
Hydrogenate the mixture at 40 psi and 23°C for 1.25 hours.
did. Remove the organic layer and buffer (2 x 5 mL)
Extracted with. Combine the water layers and use Celite butt
filtered, washed with ether (40 mL), and washed with organic solvent.
To remove any traces of
Pour into the top of the Tsuku C-18 column (2.5 x 10.0 cm),
Elute the column with water and freeze the appropriate fractions.
The title compound appears as a yellowish powder due to drying.
0.186g (64%) was obtained. ir(KBr)ν_nax:3700−3100(OH), 1760(β−
lactam C=O), 1595cm^-1(carboxylene
to),¹Hmr(D₂O) δ: 1.21 (3H, d, J = 6.3Hz,
CH ₃CHOH), 2.45 (6H,s, on pyridinium
CH₃), 2.81(d,J=9.2Hz, H-4), 2.96(d,
J=9.2Hz, H-4), 3.22(dd,J=2.6Hz,J=
6.2Hz, H-6), 3.40(t,J=6.2Hz,CH₂S),
3.84(dd,J=9.2Hz,J=2.6Hz, H-5), 4.15
(m, CH₃CHOH), 4.71(t,J=6.2Hz, CH₂
N⁺), 8.21 (1H, s, Hp of pyridinium), 8.46
(2H, s, Ho of pyridinium), UV (H₂O)
λ_nax:279(ε8345), 296(ε7714)m, [α]^{twenty three} _D+
40.7
(c.0.53，H₂O), t_1/2= 16.9h (measured under condition A). Example 3 (5R,6S)-3-[(2-(3-hydroxymeth)
Chilpyridinio)ethyl]thio]-6-[1-
(R)-Hydroxyethyl]-7-oxo-1-
Azabicyclo[3.2.0]hept-2-ene-2
- Manufacture of carboxylates A 3-hydroxymethyl-1-(2-mercap
(toethyl)pyridinium trifluoromethane
Luphonate Trifluoromethanesulfonic acid (1.327mL,
0.015mol) per drop of 3-pyridine methanol
(2.91mL, 0.030mol) and then ethylene sulfate
Fluid (0.89mL, 0.015mol) was added. generation average
one mixture N₂Heat at 50-70℃ (oil bath) for 20 hours under
It was hot. Then dissolve the reaction mixture in water (15 mL)
CH₂Cl₂(5 x 5 mL). Concentrate the aqueous phase in vacuo
C₁₈Added to reverse phase column. H₂Elution with O,
Evaporation of the relevant fractions gave a pale yellow oil. this
Substance is chromatographed again to make it almost colorless
of oil was obtained. Vacuum (P₂O_Five) After drying, the product (4.50
g, 94%) was obtained as a viscous oil. ir (film) ν_nax:3450 (s, OH), 2560 (w,
SH）cm^-1;1Hmr(d₆−acetone) δ: 9.10−
8.05 (m, 4H, aromatic), 5.01 (t,J=5.5Hz,
2H, N-CH₂), 4.93(s, 2H, −CH₂OH), 4.43
(brS, 1H, -OH), 3.43-3.18 (m, 2H, S-
CH₂), 2.34−2.10 (m, 1H, SH). B p-nitrobenzyl (5R,6S)-3-[2
-(3-hydroxymethylpyridinio)ethyl
Thio]-6-[1-(R)-Hydroxyethyl]-
7-oxo-1-azabicyclo[3.2.0]hep
T-2-ene-2-carboxylate diphenylene
Phosphate p-nitrobenzyl (5R,6S)-6-[1-
(R)-hydroxyethyl]-3,7-dioxo-
1-azabicyclo[3.2.0]-heptane-2-cal
2 mL of boxylate (0.174 g, 0.50 mmol)
Solution in water acetonitrile at 0 °C, N₂I'm downstairs
Sopropylethylamine (0.096mL, 0.55mmol)
added. Then diphenyl chlorophosphate
(0.114mL, 0.55mmol) was added dropwise to
The mixture was stirred at 0°C for 30 minutes. Then 3-hydroxymethylene
Ru-1-(2-mercaptoethyl)pyridinium
Trifluoromethanesulfonate (0.223g,
0.70 mmol) in acetonitrile (0.50 mL)
and further diisopropylethylamine
(0.122mL, 0.70mmol) was added. reaction mixture
After keeping at 0℃ for 30 minutes, concentrate in vacuo to remove remaining yellow color.
H gum₂O (sufficient acetate to help dissolve the gum)
Tonitrile was added). this
C the solution₁₈Used on reversed-phase columns and at 15%
Setonitrile-H₂It was eluted with O. relationship frac
Product (0.305g, 81%) by freeze-drying
was obtained as a beige solid. ir(KBr)ν_nax:3420 (br, OH), 1775 (β-ra
Kutum CO), 1695 (−CO₂PNB) cm^-1;¹Hmr(d₆
-acetone), δ: 9.44-7.72 (m, 8H, aromatic),
7.22−6.91 (m, 10H, diphenyl phosphate),
5.53, 5.27 (AB_q，J=14Hz, 2H, benzyl),
5.04(t,J=7.4Hz, 2H, N-CH₂), 4.75(s,
2H, CH₂OH), 4.5−3.1 (m, 8H), 1.21 (d,J
= 6.3Hz, 3H, CHMe). C (5R,6S)-3[(2-(3-hydroxymeth)
Chilpyridinio)ethyl)thio]-6-[1-
(R)-hydroxyethyl]-7-oxo-1-
Azabicyclo[3.2.0]hept-2-ene-2
-carboxylate p-nitrobenzyl (5R,6S)-3-[2-
(3-hydroxymethylpyridinio)ethylthio]
-6-[1-(R)-hydroxyethyl]-7-ox
So-1-Azabicyclo[3.2.0]-Hept-2-E
-2-carboxylate diphenyl phosphate
5 drops of H (0.145 g, 0.194 mmol)₂Contains O
6.0 mL of phosphate x in 10 mL of THF solution
Fur (0.05M, PH7.4), 0.145g of 10% palladium
charcoal and 10 mL of ether were added. mixture
Hydrogenate (Parr) the material at 40psi for 1 hour and then
I spent some time in Ito Patsudo. a small amount of fiter cake
H₂Wash with O and ether, separate the aqueous phase and evaporate.
Extracted with ether (3x). Cool the aqueous solution to 0℃
Then, the pH was set to 7.0 with a PH7.4 buffer. residual volatilization
After removing the minutes in vacuo, C₁₈Used for reversed phase columns,
The column was eluted with water. Freezing of relational fractions
Product (36 mg, 51%) as pale yellow solid upon drying
was obtained and further purified as a solid by reverse phase hplc.
The product (31 mg, 41%) was obtained. ir(KBr)ν_nax: 3300 (br, OH), 1755 (β-ra
Kutam CO), 1590(−CO_2-)cm^-1;¹Hnmr(D₂
O) δ: 8.78-7.94 (m, 4H, aromatic), 4.83 (t,
J=6.0Hz, 2H, N-CH₂), 4.83(s, 2H, CH₂
OH), 4.16 (d of q,J=J′=6.2Hz, 1H, H-
1'), 3.98 (d, t,J=9.1Hz,J′=2.6Hz, 1H,
H-5), 3.75-3.20 (m, 3H), 3.20-2.65 (m,
2H), 1.22(d,J=6.4Hz, 3H, CHMe);UV
(H₂O)λ_nax:294 (ε7614), 266 (ε6936), nm:t_1/2(PH7.4, 36.8℃) 14.0h. Example 4 (5R,6S)-3-[2-(4-hydroxymeth)
tylpyridinio)ethylthio]-6-[1-(R)
-hydroxyethyl]-7-oxo-1-aza
Bicyclo[3.2.0]Hept-2-ene-2-ka
Production of ruboxylates A 4-hydroxymethyl-1-(2-mercap
(toethyl)pyridinium trifluoromethane
Luphonate 10ml CH₂Cl₂4-pyridinemethanol in
(1.635g, 0.015mol) at 0℃N₂One drop below
Fluoromethanesulfonic acid (1.327ml,
0.015mol) was added. Yellow-brown oil rapidly separates
I let go. Add 4-pyridinemethanol to this mixture.
Add another equivalent of (1.635 g, 0.015 mol) and reduce the pressure.
The solvent was removed at bottom to give an oil. Add this oil
Add tyrene sulfide (0.891ml, 0.015mol)
Then, form a homogeneous mixture and heat it to about 60℃ (oil bath) for 3 minutes.
heated for an hour. Pour the reaction mixture into 15 ml of H₂To O
However, the aqueous solution is CH₂Cl₂(5 x 5 ml)
Ta. After removing the remaining organic solvent in vacuum, remove the aqueous solution.
C₁₈Used for reverse phase column. H₂Elution with O,
Oil is obtained by evaporation of the relevant fraction, which is then evaporated in vacuo.
P₂O_FiveThe product (4.64
g, 97%) was obtained. ir (film) ν_nax:3455(s,OH),2565
(w, SH)cm^-1;¹Hnmr(d₆- acetone) δ:
9.07, 8.18 (ABq,J=6.8Hz, 4H, aromatic),
5.03(s, 2H, CH₂OH), 4.96(t,J=6.5Hz,
2H, N-CH₂), 4.09 (br s, 1H, -OH), 3.5
−3.1(m, 2H, S-CH₂), 2.25(brs, 1H, −
SH). B p-nitrobenzyl (5R,6S)-3-[2
-(4-hydroxymethylpyridinio)ethyl
Thio]-6-[1-(R)-Hydroxyethyl]-
7-oxo-1-azabicyclo[3.2.0]hep
T-2-ene-2-carboxylate diphenylene
Phosphate p-Nitrobene in 5 ml anhydrous acetonitrile
Jill (5R,6S)-6-[1-(R) - Hydroxy
ethyl]-3,7-dioxo-1-azabicyclo
[3.2.0] Pentane-2-carboxylate
(0.348g, 1.0mmol) at 0℃N₂Below,
Diisopropylethylamine (0.191ml,
1.1 mmol) in one drop, then add the same amount of diphenyl
Add lolophosphate (0.228ml, 1.1mmol).
I got it. Stir the resulting golden solution for 40 minutes at 0°C.
did. Add to this solution 4 in 1 ml of acetonitrile.
-Hydroxymethyl-1-(2-mercaptome)
pyridinium trifluoromethane sulfonate
A solution of nate (0.447 g, 1.4 mmol) was then added to
diisopropylethylamine (0.191ml,
1.1 mmol) was added. Red and black gum reacts and mixes
Precipitated from substances. After 20 min at 0°C, the reaction mixture was
filtered and concentrated in vacuo. Minimum amount of acetate residue
Nitrile-H₂Comb to O (1:1) C₁₈Reverse phase force
Used for rum. 25% acetonitrile-H₂O
By elution using lyophilization of the relevant fractions
Product as a cream solid (0.353g, 47%)
was gotten. ir(KBr)ν_nax:3240(br,OH), 1775(β-
lactam CO), 1695(−CO₂PNB)cm^-1;
1Hnmr(d₆- acetone) δ: 9.24-7.84 (m,
8H, aromatic), 7.4−6.9(m, 10H, diphenyl
sulfonyl phosphate), 5.52, 5.54 (ABq,
J = 14Hz, 2H, benzyl), 5.15−4.80 (m,
4H), 4.45-3.05 (m, 7H), 1.35 (d,J=6.6
Hz, 3H, CHMe). C (5R,6S)-3-[2-(4-hydroxy
Methylpyridinio)ethylthio]-6-[1-
(R)-hydroxyethyl]-7-oxo-1-
Azabicyclo[3.2.0]hept-2-ene-2
-carboxylate p-nitrobenzyl (5R,6S)-3-[2
-(4-hydroxymethylpyridinio)ethyl
Thio]-6-[1-(R)-Hydroxyethyl]-
7-oxo-1-azabicyclo[3.2.0]hep
T-2-ene-2-carboxylate diphenylene
Ruphosphate (0.348g, 0.465mmol) and wood
11 ml of 10% palladium (0.35 g) on charcoal
Faet Batsuhua (0.05M, PH7.4), 5ml
mixture in THF and 10ml ether at 40psi
Hydrogenation was carried out for 1.25 hours. Sera with mixture
The aqueous phase was evaporated with ether.
Washed (3x). Furthermore, add a buffer of PH7.4
The pH of the aqueous solution was adjusted to 7.0. Residue in vacuum
After removing the remaining volatile components, the aqueous solution is₁₈to reversed phase column
I put it on. 2% acetonitrile H₂Elution with O
A tan solid was obtained by lyophilization and freeze drying. this
Rechromatograph the material (C₁₈Reverse phase/H₂O)
Desired product (0.060 g, 36%) as pale yellow solid
I got it. ir(KBr)ν_nax: 3400 (br, OH), 1755 (β-
lactam CO), 1590(−CO₂ ^-)cm^-1;¹Hnmr
(D₂O) δ: 8.73, 7.96 (ABq,J=6.8Hz, 4H,
aromatic), 4.93 (s, 2H, CH₂OH), 4.77(t,
J=6.0Hz, 2H, N-CH₂), 4.15 (d of q,J
=J'=6.3Hz, 1H, H-1'), 3.96 (d of t,J
=9.2Hz,J'=2.6Hz, 1H, H-5), 3.65-
3.20 (m, 3H), 3.13-2.62 (m, 2H), 1.21 (d,
J=6.3Hz, 3H, CHMe); nv(H₂O)λ_nax:
295 (ε6880), 256 (ε5595), 224 (ε8111) nm;
t₁/₂(PH7.4, 36.8℃) 14.5h. Example 5 3-[2-(1-(2-methylpyridinium))et
Chilthio]-6α-[1-(R)-Hydroxyethyl
]-7-oxo-1-azabicyclo (3.2.0)
Preparation of hept-2-ene-2-carboxylate
Construction A 1-(mercaptoethyl)-2-methylpyridi
nium methanesulfonate Cold 2-methylpyridine (2.17ml, 0.022mol)
Add methanesulfonic acid (0.65ml, 0.010mol) to
2-methylpyridinium methane prepared by adding
A suspension of sulfonate in 2-methylpyridine is
Add tyrene sulfide (0.655ml, 0.011mol)
I got it. The reaction mixture was incubated at 55 °C for 21 h under nitrogen atmosphere.
Stir for a while, cool to 23℃, and dilute with water (5 ml).
and wash this aqueous solution with ether (6 x 4 ml).
and apply vacuum to remove traces of organic solvent.
from μ-bondapakC-18 column (2.5×
10.0 cm). Elute the column with water
The title compound was prepared by lyophilization of the appropriate fraction.
2.13g (85%) of product was obtained. ir (film) ν_nax: 2520 (SH), 1623 (Piri)
Zinium), 1574, 1512, 1485, 1412, 1195 (S
Ruphonate), 1038cm^-1,¹Hmr(DMSO−d₆+
D₂O) δ: 2.37 (3H, s, CH₃S.O.₃ ^-), 2.83
(3H, s, CH on pyridinium₃), 3.09 (2H,
J = 6.9Hz, CH₂S), 4.71 (2H, t,J=6.9
Hz, CH₂N⁺), 7.93 (2H, m, pyridinium
Hm), 8.44 (1H, m, Hp of pyridinium),
8.89 (1H, m, Ho of pyridinium), uv (H₂O)
λ_nax:266 (ε3550) mμ. B Paranitrobenzyl 3-[2-(1-(2-method)
thylpyridinium))ethylthio]-6α-[1-
(R)-hydroxyethyl]-7-oxo-1-
Azabicyclo (3.2.0) hept-2-enca
ruboxylate diphenyl phosphate p-Nitrobenzyl kept under nitrogen atmosphere
6α−[1−(R)-hydroxyethyl]-3,7
-dioxo-1-azabicyclo(3.2.0)hep
Tan-2-carboxylate (0.523g,
1.50 mmol) of cold (0°C) acetonitrile (6
ml) solution of diisopropylethylamine
(0.314ml, 1.80mmol) followed by diphenyl
Chlorophosphate (0.373ml, 1.80mmol)
added. The reaction mixture was stirred at 0 °C for 30 min.
1-(2-mercaptoethyl)-2-methylpyri
Zinium methanesulfonate (0.530g,
2.16 mmol) in acetonitrile (18 ml),
Then diisopropylethylamine (0.314ml,
1.8 mmol). The reaction mixture was heated to 1
Stir for an hour and dilute with cold (0°C) water (26 ml).
−bondapakC−18 column (3.5×7.0cm)
I poured it. 25% acetonitrile - 75% water and 50%
Elution of the column with -acetonitrile-50% water
After freeze-drying the relevant fraction, the yellowish color and
1.06 g (96%) of the title compound was obtained as a powder.
It was done. ir(KBr)ν_nax:3650−3100(OH), 1770(β
-lactam C=O), 1695 and 1690 (PNB
C=O), 1630 (pyridinium), 1595 (phenylene)
), 1518 (NO₂), 1335 (NO₂), 890cm^-1
(NO₂),¹Hmr(DMSO, d₆) δ: 1.15 (3H, d,
J = 6.1Hz, CH ₃CHOH), 2.87(s, pyridini
CH on Umu₃), 3.6-4.4 (2H, m, H-5,
CH₃CHOH), 4.75 (2H, m, CH₂N⁺), 5.37
(center of ABq,J=14Hz, CH of PNB₂),
6.5−7.4 (10H, m, phenyl), 7.70 (2H, d,
J = 8.8Hz, PNB Ho), 8.0 (2H, m, pyridine
Hp), 8.24 (2H, d,J=8.8Hz,
Hm of PNB), 8.50 (1H, m, Pyridinium
Hp), 8.95 (1H, brd,J=6.1Hz, Pyridiniu
(Ho), uv (H₂0)λ_nax:265 (ε11990), 314
(ε8020) mμ. C 3-[2-(1-(2-methylpyridinium))
Ethylthio]-6α-[HR]-Hydroxyethyl
]-7-oxo-1-azabicyclo (3.2.0)
hept-2-ene-2-carboxylate p- in wet tetrahydrofuran (34 ml)
Nitrobenzyl-3-[2-(1-(2-methyl
pyridinium))ethylthio]-6α-[1-(R)
-hydroxyethyl]-7-oxo-1-aza
Bicyclo (3.2.0) hept-2-ene-2-ka
Ruboxylate diphenyl phosphate (0.66
g, 0.90 mmol), ether (34 ml),
Potassium phosphate monobasic - sodium hydroxide
Tsuhua (0.15M, 16.5ml, PH7.22) and charcoal
The above 10% palladium (0.66 g) was added. Generate
The mixture was hydrogenated at 40 psi and 23° C. for 1 hour.
The organic layer was removed and extracted with ether. (2×
6 ml) Combine the aqueous layer and pass through Celite pad.
and washed with ether (40 ml) and vacuumed.
Without traces of organic solvent, μ-bondapakC
-18 column (2.5 x 10 cm). Kara
Elute with water and freeze-dry the appropriate fractions.
0.098 of the title compound as a yellowish powder when dried
g (31%) was obtained. ir(KBr)ν_nax:3650−3100(OH), 1775(β
-lactam C=O), 1630 (pyridinium),
1590cm^-1(carboxylate),¹Hmr(D₂O)
δ: 1.20 (3H, d,J=6.3Hz,CH ₃CHOH),
2.83(s, CH on pyridinium₃), 2.7−3.1
(5H, H-4, CH on pyridinium₃), 3.1−
3.7 (3H, m, CH₂S, H-6), 3.90 (dd,J=
9.1Hz,J=2.6Hz, H-5)3.1(m, CH₃CH
OH), 4.78(t,J=6.2Hz,CH₂N⁺), 7.8
(2H, m, Hm of pyridinium), 8.3 (1H, m,
Hp of pyridinium), 8.65 (1H, m, pyridinium
Um Ho), uv(H₂O)λ_nax:268 (ε9350),
296 (ε8840) mμ [α]^23/D+41° (C0.5, H₂0),
t₁/₂= 15.0h (measured under condition A). Example 6 3-[2-(1-(4-methylpyridinium))et
Chilthio]-6α-[1-(R)-Hydroxyethyl
]-7-oxo-1-azabicyclo (3.2.0)
Preparation of hept-2-ene-2-carboxylate
Construction A 1-(2-mercaptoethyl)-4-methylpi
Lysinium methanesulfonate Chilled 4-picoline (2.14ml, 0.022mol)
Add hemethanesulfonic acid (0.65ml, 0.010mol).
4-picolinium methanesulfonate prepared by adding
Ethylene chloride in suspension in 4-picoline
Rufid (0.655ml, 0.011mol) was added. anti
The reaction mixture was stirred at 55°C for 24 hours under nitrogen atmosphere,
Cool to 23℃ and add water (5 ml) and ether (10 ml).
It was diluted with Remove the organic layer and evaporate the aqueous layer into ether.
(5 x 5 ml) and diluted with ether under reduced pressure.
After removing the traces, remove the μ-ponder pack C-18.
Lamb (2.5 x 10 cm) was added on top. 15% acetoni
Elution of the column with a mixture of tolyl 85% water is suitable.
After freeze-drying the fraction, a colorless syrup is produced.
yielded 2.66 g (100%). ir (film) ν_nax: 2500 (SH), 1640 (Piri)
Zinium), 1572, 1520, 1478, 1200 (Sulfone
), 1040, 833 and 768cm^-1,¹Hmr (DMSO
−d₆) δ: 2.31 (3H, s, CH₃S.O.₃ ^-), 2.62
(s, CH on pyridinium₃), 2.2−2.9 (4H,
SH, CH on pyridinium₃), 3.04 (2H, m,
CH₂S), 4.68 (2H, t,J=6.4Hz,CH₂N⁺),
8.01 (2H, d,J= 6.6Hz, pyridinium
Hm), 8.89 (2H, d,J=6.6Hz, Pyridiniu
(Ho), uv (H₂O)λ_nax:256 (ε4100), 221
(ε7544) mμ. B 1-(2-mercaptoethyl)-4-methylpi
Lysinium p-toluenesulfonate p-Toluenesulfonic acid (1.72g, 0.01mol)
4-picoline in a suspension of benzene (6.5 ml) of
(1.17ml, 0.012ml) and the resulting mixture
Stir for 30 min at 23°C under nitrogen atmosphere and add ethylene.
treated with sulfide (0.65ml, 0.011mol), 75
Stirred at ℃ for 24 hours. Furthermore, ethylene sulfide
(0.65ml, 0.011mol) and further cooled at 75℃ for 24 hours.
Stirring was continued for an hour. Cool the reaction mixture to 23 °C
and diluted with water (5 ml) and ether (8 ml).
Ta. Remove the aqueous layer and wash with ether (3 x 8 ml).
Clean and combine under vacuum to remove traces of organic solvents.
The sample was transferred onto μ-bondapakC-18 using water as the eluent.
It was chromatographically separated and labeled as a colorless syrup.
2.94 g (90%) of compound was obtained. ir (film) ν_nax: 2510 (SH), 1640 (Piri)
Zinium), 1595, 1582, 1475, 1200 (Sulfone
), 1031, 1010, 818cm^-1,¹Hmr (DMSO,
d₆) δ: 2.29 (3H,s, on pyridinium
CH₃), 2.61(s,CH ₃Ph), 2.4−2.8 (4H,
SH,CH ₃Ph), 3.03 (2H, m [D₂With the addition of O
accomplished t,J=6.4Hz, 3.04〕, CH₂S), 4.68
(2H, t,J=6.4Hz,CH₂N⁺) 7.11, 7.49
(2H, 2d,J=7.9Hz, phenyl), 8.00(2H,
d,J= 6.5Hz, Hm of pyridinium), 8.89
(2H, d,J=6.5Hz, pyridinium Ho),
uv(H₂O)λ_nax:256 (ε4315), 222 (ε17045)
mμ. C Paranitrobenzyl 3-[2-(1-(4-method)
thylpyridinium))ethylthio]-6α-[1-
(R)-hydroxyethyl]-7-oxo-1-
Azabicyclo (3.2.0) hept-2-ene-2
-carboxylate p-nitrobenzyl 6α-[1-(R)-hydro
xyethyl)-3,7-dioxo-1-azabi
cyclo(3.2.0)heptane-2-carboxylene
(0.522 g, 1.5 mmol) under nitrogen atmosphere
Cold (0°C) acetonitrile (6 ml) solution
to diisopropylethylamine (0.314 ml,
1.8 mmol), then diphenylchlorophosphene
Salt (0.373ml, 1.9mmol) was added. reaction mixture
The mixture was stirred for 45 minutes and the 1-(2-mercapto
ethyl)-4-methylpyrinidinium methane
Ruphonate (0.539g, 2.16mmol) in acetonate
Tolyl (1.8 ml) solution was added dropwise and then diisopropylene was added.
Treated with lopylethylamine (0.34ml, 1.8mmol)
I understood. The reaction mixture was stirred at 0 °C for 1 h and cooled.
(0°C) diluted with water (24 ml), μ-bondapak
It was poured onto the top of a C-18 column (2.5 x 8.5 cm). mosquito
First mix the rum with 25% acetonitrile and 75% water.
(100ml), then 50% acetonitrile - 50% water
Elute with a mixture (100 ml) of
After freeze-drying, it becomes a yellowish powder.
0.91 g (83%) of the title compound was obtained. ir(KBr)ν_nax:3700−2800(OH), 1770(β
-lactam C=0), 1700 (PNB ester
C=0), 1640 (pyridinium), 1595 (phenol)
), 1520 (NO₂), 1340 (NO₂), 890cm^-1
(NO₂), 1Hmr (DMSO, d₆) δ: 1.16 (3H,
d,J=6.2Hz,CH ₃CHOH) 2.61 (s, piri
CH on Zinium₃), 3.1−37 (3H, m, H−
6.CH₂S), 3.7-4.4 (2H, m, H-5, CH₃
CHOH), 4,79 (2H, brt,J=6.3Hz,CH₂
N⁺), 5.17(d,J= 4.9Hz, OH), 5.37 (ABq
Center,J=14.1Hz, CH of PNB₂), 6.7−
7.4 (10H, m, phenyl) 7.69 (2H, d,J=
8.8Hz, PNB Ho), 8.00(2H, d,J=6.5Hz,
Hm of pyridinium) 8.23 (2H, d,J=8.8
Hz, Hm of PNB), 8.92 (2H, d,J=6.5Hz,
Pyridinium Ho), uv(H₂0)λ_nax:262
(ε10835), 311 (ε9670) mμ. Elemental analysis: calculated value
(C₃₆H₃₆N₃O_TenSP・1.5H₂0):C
56.84, H 5.17, N 5.52, S 4.21; Actual measurement
Value: C 56.89, H 5.13, N 5.19, S
4.41. D 3-[2-(1-(4-methylpyridinium))
Ethylthio]-6α-[1-(R)-hydroxye
Chil]-7-oxo-1-azabicyclo
(3.2.0) Hept-2-ene-2-carboxylic acid
root p-Nitrobenzyl 3-[2-(1-(4-method)
thylpyridinium))ethylthio]-6α-[1-
(R)-hydroxyethyl]-7-oxo-1-
Azabicyclo (3.2.0) hept-2-ene-2
-Carboxylate diphenyl phosphate
(0.587g, 0.80mmol) of water-containing tetra
Add ether (30ml) to a solution of hydrofuran (30ml).
ml), monobasic potassium phosphate-sodium hydroxide
Mu Batuhua (0.15M, 14.7ml, PH7.22) and
Add 10% palladium (0.59g) on charcoal and
Ta. The resulting mixture was heated at 40 psi and 23°C for 1.25 hours.
Hydrogenated. Remove organic layer and buffer
(2 x 6 ml). Combine the aqueous extracts,
Ether (3x20
ml) and pump to remove traces of organic solvent.
vacuum with μ-bondapak C-18.
Pour onto the top of a column (2.5 x 10 cm). column water
Elution in, freeze-drying of related fractions gives a yellowish tinge.
0.136 (49%) of the title compound as a bulky powder
I got: ir(KBr)ν_nax:3700−3000(OH), 1700(β
-lactam C=0), 1642 (pyridinium),
1592cm^-1(carboxylate)¹Hmr(D₂O)
δ: 1.19 (3H, t,J=6.3Hz,CH ₃CHOH),
2.59(3H,s, CH on pyridinium₃), 2.84
(d,J=9.1Hz, H-4), 2.90(d,J=9,
1Hz, H-4), 3.0-3.6 (3H, m, CH₂S,H
−6), 3.86(dd,J=9.1Hz,J=2.6Hz, H-
5), 4.12 (m, CH₃CHOH), 4.5−4.9(CH₂
N⁺- Masked by HOD), 7.80 (2H,
d,J= 6.6Hz, Hm of pyridinium), 8.58
(2H, d,J=6.6Hz, pyridinium Ho),
uv(H₂0)λ_nax:256 (ε5510), 262 (ε5360),
296 (ε7050) m, [α]^23/D+20.8° (C 0.48, H₂
0), t₁/₂= 12.8h (measured under condition A). Example 7 (5R)3-[2-(4-methylthiopyridiny
e) Ethylthio]-(6S)−[(1R) - Hydroxy
ethyl]-7oxo-1-azabicyclo
[3.2.0] Hept-2-ene-2-alboxylene
Manufacture of sheets A 4-methylthiopyridine^* 4-Mercaptopyridine (5.55g,
50.0mmol; Aldrich) in boiling abs.EtOH (50ml)
Dissolved. Remove insoluble substances by passing through gelite
Ta. Heat the liquid to redissolve it and cool it to approximately 50℃.
Methyl iodide (3.17ml, 51.0mmol; Aldrich)
was added all at once. Cool the mixture to crystallize
Ta. The title compound as the hydroiodide salt separately as a solid
6.77 g (26.7 mmol, yield 53.5%) of: ¹Hmr(D₂O) δ: 2.70 (3H, s, -SCH₃)as well as
7.65−7.77−8.35−8.48ppm (4H, A₂B₂type, aroma
Family Hs);ir (Nujol)ν_nax: 1615, 1585 (aromatic) and
780cm^-1;uv(H₂0)λ_nax:227(ε2.02×10^Four) and
and 298nm (ε1.64×10^Four). This hydroiodide salt (6.33g, 25.0mmol) was dissolved in water.
(40ml), remove insoluble materials, and water (10ml)
Washed. Add NaOH tablet (5g) to the liquid at 0-5℃.
In addition, Et₂Extract with O (3 x 25 ml) and remove the aqueous layer with NaCl.
saturated with. Brine the combined organic extracts (×
2) Wash and dry (MgSO_Four) and evaporate,
2.92 g (23.4 mmol) of the title compound as oil
Overall yield (50%) was obtained: 1Hmr (CDCl₃) δ: 2.48 (3H, s, −SCH₃) and
and 7.03−7.13−8.38−8.48ppm (4H, A₂B₂type, aroma
Incense family - Hs); ir (film) ν_nax:1580 and 800cm^-
1. *The manufacturing method for this compound is described by King and Ware,J．．
Chem.Soc．． , 873 (1939), and this
The method described in the literature was followed. B 4-Methylthio-N-(2-mercaptoethyl
) Pyridinium methanesulfonate 4-methylthiopyridine (2.75g,
22.0 mmol) of methanesulfate cooled in an ice bath.
fonic acid^*(0.65ml, 10.5mmol) slowly.
I got it. This solid contains ethylene sulfide.^*(0.66
ml, 11.0 mmol, Aldrich) and this mixture
was heated to 50-60°C for 21 hours. As the reaction progresses
The solid became a solution. After cooling, pour the reaction mixture into water.
Dissolve in (5 ml) Et₂Wash with O (5 x 4 ml)
Ta. Pass the cloudy water layer through Celite and invert the liquid.
Phase silica gel column chromatography (C₁₈
micro bondapak 10g)₂Elute with O
and purified. Collect 10ml of each fraction
did. Combine fractions 2 and 3 and apply reverse phase power.
Repurified with rum. Fraction 2 is a viscous o
1.258g (4.48mmol, yield 42.6%) as il
gave the title compound of: 1Hmr (DMSO−d₆, CFT−20) δ: 2.32
(3H, s.MeSO₃ ), 2.72(3H,s,-SMe),
2.68 (1H, m, SH), 2.9−3.2 (3H, m, −CH₂
S-), 4.59 (2H, t,J=6.4Hz, -CH₂N ),
7.97 (2H, “d”,J=7.2Hz, aromatic −Hs) and
and 8,72ppm (2H, “d”,J=7.2Hz, aromatic
−Hs);ir(neat)ν_nax:1630, 1200 (br, −SO₃
), 7.85 and 770cm^-1. * Distilled prior to use. C (5R) p-Nitrobenzyl 3-[2-(4-
Methylthiopyridino)ethylthio]-(6S)−
[(1R)-hydroxyethyl]-7-oxo-1
-Azabicyclo[3.2.0]hept-2-ene-
2-carboxylate chloride (5R) p-nitrobenzyl 3,7-dioxy
So (6S)−[(1R)-hydroxyethyl]-1
−Azabicyclo[3.2.0)heptane−(2R)−
Carboxylate (475 mg, 1.36 mmol) and di
Isopropylethylamine (0.24ml,
1.4mmol) CH₃CN (5 ml) solution at 0° to 5°C.
Diphenyl chlorophosphate under nitrogen atmosphere
(0.29ml, 1.41mmol) was added. Mixture 0°~
The mixture was stirred at 5°C for 30 minutes. CH to this mixture₃CN
(1.5 ml) of 4-methylthio-N-(2-mer
captoethyl)pyridinium methanesulfone
(678 mg, 1.45 mmol; 60% purity) in an oily suspension.
body, then diisopropylethylamine (0.24
ml, 1.4 mmol) was added. Mixture at 0°-5°C
Stirred for 1 hour. A yellow color appears immediately after adding the base.
A sedimentation occurred. Separate this precipitate and CH₃
Wash with CN (3 ml) to obtain 413 mg of yellowish solid.
I got a body. H₂10% MeOH in O (5 ml)
341 mg as white crystals after grinding from
(0.618 mmol, yield 45.4%) of the title compound was obtained.
Ta: mp 118°−120℃;¹Hmr(DMSO−d₆,CFT
−20) δ: 1.16 (3H, d, J=6.1Hz, 1′−
CH₃), 2.72(3H,s,−SCH₃), 3.1−3.7 (5H,
m), 3.7−4.3 (2H, m), 4.71 (2H, t,J=
6.3Hz, -CH₂N ), 5.15 (1H, d,J=4.9Hz,
OH), 5.20−5.35−5.40−5.55(2H, ABq,
C.O.₂CH₂−Ar), 7.70 (2H, “d”,J=8.8Hz,
Nitrophenyl-Hs), 7.97 (2H, “d”,J=
7.0Hz, pyridinio-Hs), 8.25 (2H, “d”.J
=8.8Hz, nitrophenyl-Hs), and 8.76ppm
(2H, “d”,J=7.1Hz, pyridinio-Hs);ir
(Nujol)ν_nax:3250 (OH), 1775 (β-lacta
), 1700(ester) and 1625cm^-1(Pirijini
e); uv(ads, EtOH)λ_nax:308nm(ε4.47×
Ten^Four); [α]^{twenty three}°^/D+24.8 (c 0.5, MeOH); element
Analysis: Calculated value (C_{twenty four}H₂₆N₃O₆S₂Cl・H₂O and
): C 50.56, H 4.95, N 7.37; Actual measurement
Values: C 50.63, H 4.72, N 6.89. D (5R)3-[2-(4-methylthiopyridiny
e) Ethylthio]-(6S)-[(1R)-Hydroxy
ethyl]-7-oxo-1-azabicyclo
[3.2.0] Hept-2-ene carboxylate (5R) p-Nitrobenzyl 3-[2-(4-
Methylthio)ethylthio]-(6S) [(1R)−
hydroxyethyl]-7-oxo-1-azabi
cyclo[3.2.0]hept-2-ene-carboxy
Sylate chloride (380mg, 0.688mmol)
THF (31.5ml) and PH7.40 phosphate x
Dissolved in Fisher (31.5ml; 0.05M Fisher) and₂
Diluted with O (31.5 ml). Add this solution to 10% Pd−
C (380 mg, Engelhard) in a Parr shaker.
Hydrogenated at 35 psi and room temperature for 1 hour. Separate the water layer
Pass through a light to remove the catalyst, then use a celite pad.
Et the Tsudo₂Washed with O (2 x 30ml). organic solvent
For removal, the aqueous layer was evacuated and transferred to a reversed phase column.
Romantograph (C₁₈ micro bondapak, 13g,
Waters Associates) and purified by elution with water.
Manufactured. Fraction with UV absorption at 307nm
(approximately 1), freeze-dried, and turned yellowish.
127mg (0.334mmol, yield 48.5%) as powder
The title compound was obtained: ¹Hmr(D₂O, CFT-20) δ: 1.20 (3H, d,
J=6.4Hz, 1'-CH₃), 2.64(3H,s,−
SCH₃), 2.81 (2H, m, −SCH₂−), 3.19 (IH,
dd,J _6-1,=6.1Hz,J _6-5=2.6Hz, 6-H),
3.32 (2H, dd,J=11Hz,J=5.5Hz, 4-
Hs), 3.92 (1H, dt,J=9.2Hz,J _5-6=2.6Hz,
5-H), 4.1 (1H, m, 1'-H), 4.61 (2H,
t, J=5.9Hz, -CH₂N ), 7.70 (2H, “d”,
J = 7.1Hz, aromatic-Hs), and 8.40ppm (2H,
“d”, J = 7.1 Hz, aromatic-Hs); ir (KBr, disc) ν _nax : 3400 (OH), 1750 (β-lactam), 1630 (pyridinium) and 1590 cm ^-1 (carboxylate); uv (H ₂ O)λ _nax : 231 (ε9800)
and 307nm (ε25000); [α] ²³ ° ^/D +3.14 (c 0.5
，
_H2O ). Example 8 3-[2-(3-methoxy-1-pyridinium)
Ethylthio]-6α-[1′-( R )-hydroxyethyl]-7-oxo-1-azabicyclo (3.2.0)
Production of hept-2-ene-2-carboxylate A 1-(2-mercaptoethyl)-3-methoxypyridinium methanesulfonate Methanesulfonic acid (0.216ml, 3.05mmol) and ethylene sulfide (0.19ml, 3.2mmol) were added dropwise to pre-cooled (5°C) 3-methoxypyridine (698mg, 6.4mmol). The mixture was then heated to 60°C for 18 hours, cooled to 20°C, diluted with water (10ml) and washed with ether (3 x 10ml). The aqueous phase was pumped to high vacuum for 15 minutes and loaded onto a C ₁₈ reverse phase column. The title compound was eluted with water. The relevant fractions were combined and evaporated under high vacuum to give the desired thiol (6.16 mg, yield
76.3%). ir (CH ₂ Cl ₂ ) ν _nax : 2550 (w, SH) and 1620,
1600, 1585cm ^-1 (m, aromatic); ¹ Hmr (DMSO
_d6 ) δ: 8.90-7.90 (4H, m, C-H) 4.72
(2H, t, J = 6.6Hz, CH ₂ N ⁺ ), 4.01 (3H,
s, OCH ₃ ), 3.5−3.0 (m, hidden CH ₂ S),
2.66 (1H, dd, J = 9.5Hz, J = 7.5Hz, SH) and _2,31ppm (3H, S, _CH3SO3- ). B p-Nitrobenzyl 3-[2-(3-methoxy-1-pyridinium chloride)ethylthio]
-6α-[1'-( R )-hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0)-hept-2
-ene-2-carboxylate p-Nitrobenzyl 6α-[1'-( R )-hydroxyethyl]-3,7-dioxo-1-azabicyclo-(3.2.0)-heptane-2-carboxylate (1.04 g, 3 mmol) in acetonitrile (12 ml) ) The cold (0°C) solution was treated with diisopropylethylamine (0.63ml, 3.6mmol) and diphenylchlorophosphate (0.75ml, 3.6mmol) dropwise and stirred at 0°C for 30 minutes. The generated enol phosphate was converted to 1-(2-mercaptoethyl)-3-methoxypyridinium methanesulfonate (1.14 g, 4.30 mmol) [CH ₃ CN
(7 ml)], treated with diisopropylethylamine (0.63 ml, 4.30 mmol),
Stir for minutes and cool to -10°C for 30 minutes. The precipitated solid was separated from the mixture, washed with cold acetonitrile (2 ml) and dried to give the title compound (1.32 g, 82% yield): ir(nujol)ν _nax :3320(m,OH), 1780, 1765
(s, β-lactam C=O), 1700, 1695 (m,
ester C=O) and 1520 cm ^-1 (s, NO ₂ );
1Hmr (DMSO d ₆ ) δ: 9.01 (1H, bs, H-3,
aromatic), 8.75 (1H, bd, J = 5.4Hz, H-6
aromatic), 8.35−7.95 (4H, m, H-aromatic),
7.70 (2H, d, J = 7.7Hz, H-aromatic), 5.37
(2H, center of ABq, J = 13Hz, CH ₂
PNB), 5.17 (1H, d, J = 4.9Hz, OH), 4.87
(2H, t, J = 6.3Hz, CH ₂ N), 4.35−3.75
(2H, m, H-5 and H-1′), 4.00 (3H, s,
OCH ₃ ), 3.56 (part of t, J = 6.3Hz, CH ₂ S),
3.5-3.20 (3H, m, H-6, H-3) and
1.16ppm (3H, d, J = 6.1Hz, _CH3CHO ). C3-[2-(3-methoxy-1-pyridinium)ethylthio]-6α-[1'-( R )-hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0)-hept-2-ene -carboxylate p-Nitrobenzyl 3-[2-(3-methoxy-1-pyridinium chloride)ethylthio]
-6α-[1'-( R )-hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0)-hept-2
-ene-2-carboxylide (600mg,
A solution of 1.12 mmol) in THF (25 ml), ether (25 ml) and PH7.4 phosphate buffer (0.1 M, 25 ml) at 10% pd/C (1.1
g) Above, hydrogenated at 40 psi for 1 hour. The mixture was diluted with ether and the aqueous phase was filtered through #52 hardened paper. Wash the aqueous layer with ether (2 x 20 ml),
Evacuated to vacuum and poured onto a silica gel reverse phase column. The title compound was eluted with water containing 2 and 5% acetonitrile. The relevant fractions were combined and lyophilized to give a yellow solid, which was repurified by hplc to give penem carboxylate (150 g, 38
%) obtained: ir(nujol)ν _nax 1750(s, β-lactam C=
O) and 1580 cm ^-1 (s, carboxylate);
1Hmr (D ₂ O) δ: 8.55−8.30 (2H, m, H−
2, H-6 aromatic) 8.17-7.75 (2H, m, H-
3, H-4 aromatic), 4.77 (2H, t, J = 5.9Hz,
CH ₂ N ), 4.10 (1H, part of 5, J = 6.3Hz,
H-1′), 3.97 (3H, s, OCH ₃ ), 3.85, 3.82
(2 wires, part of dt, J = 2.6Hz, part of H-5),
3.42 (2H, t, J = 5.9Hz, CH ₂ −S), 3.25
(1H, dd, J = 6.1Hz, J 2.6Hz, H-6), 2.99
-2.60 (2H, 6 pieces, part of H-4) and
1.20ppm (3H, d, J = 6.4Hz, CH ₃ ); uv (H ₂
O, c 0.05) λ _nax : 290 (ε10517), 223
(ε6643); t ₁ / ₂ (0.1M PH7.4 phosphate, buffer, 37℃) 20h. Example 9 ( 5R ,6S)-3-[2-(3-methylthiopyridinio)ethylthio]-6-[1-( R )-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0 ] Production of hept-2-ene-2-carboxylate A 3-methylthio-1-(2-mercaptoethyl)pyridinium chloride 3-methylthiopyridine (2.00g,
0.016 mol) of 1NHCI in ether (10 mL)
Add 15 mL and mix well. The aqueous phase was removed, washed with 10 mL of ether and then evaporated. Residual hydrochloride in vacuum (P ₂ O ₅ )
After drying, a white solid was obtained. This solid hydrochloride was added with 3-methylthiopyridine (1.88
g, 0.015 mol) and ethylene sulfide (0.89 mL, 0.015 mol) were added and the resulting mixture was heated to 55-65 C (oil bath) under _N2 for 15 h.
A slightly cloudy oil was obtained and 125 mL of H ₂ O
It was washed with CH ₂ Cl ₂ . The aqueous phase was concentrated to 25 mL and a few drops of acetonitrile were added to make the mixture homogeneous. The resulting aqueous solution was applied to a _C3 reverse phase column. Elution with H ₂ O and evaporation of the relevant cracks gave the product (2.66 g, 80%) as a pale yellow, viscous oil. ir (film) ν _nax : 2410 (br, −SH) cm ^-1 ;
1Hnmr( _d6 -DMSO+ _D2O )δ:8.88-7.88
(m, 4H, aromatic), 4.70 (t, J=6.5Hz, 2H,
N-CH ₂ ), 3.08 (skewed t, J = 6.5Hz, 2H,
s- _CH2 ), 2.64 (s, 3H, S-Me). 1. JAZoltewiez and C. Nisi, J. Og.
Prepared according to the method of Chem.34, 765 (1969). B p-nitrobenzyl (5R, 6S)-3-[2-
(3-methylthiopyridinio)ethylthio]-6
-[1-( R )hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate chloride p-Nitrobenzyl (5R, 6S)-6-[1-
( R ) Hydroxyethyl]-3,7-dioxo-
A solution of 1-azabicyclo[3.2.0]heptane-2-carboxylate (0.522 g, 1.50 mmol) in anhydrous acetonitrile (7 mL) was cooled to 0 °C.
Diisopropylethylamine (0.287mL,
1.65 mmol) was added dropwise. Diphenylchlorosulfonate (0.342 mL, 1.65 mmNl) was added dropwise to the resulting tan solution and the reaction mixture was kept at 0° C. for 30 minutes. Then add diisopropylethylamine (0.313mL, 1.80mmol),
Then 3-methylthio-1-(2-mercaptoethyl)pyridinium chloride (0.398g,
1.80 mmol) in anhydrous DMF (0.70 ml) was added. A precipitate precipitated out of the reaction mixture about 1 minute after the addition was completed, and the mixture was further cooled to -10°C for 10 minutes to obtain a solid orange mass. The solid was triturated with acetonitrile and the residue was collected by filtration. The residue was washed with acetonitrile, then acetone, and finally dried in vacuo to give the product (0.455 g, 55%) as a cream solid.
I got it. The combined liquid is evaporated to a yellow oil and dissolved in a minimum amount of acetonitrile.
Cooled at ℃ for 30 minutes. After adding this mixture to
0.139g of product was obtained as a pale yellow solid. Total yield 0.594g (72%). ir (KBr) ν _nax : 3345 (br, −OH), 1770 (β−
lactam CO), 1680 (−CO ₂ PNB) cm ⁻¹ ; ¹
Hnmr (d ₆ -DMSOδ: 8.98-7.96 (m, 4H, pyridinium aromatic), 8.20-7.65 (ABq, J = 7.0
Hz, 4H, PNB aromatic), 5.53−4.80 (m, 4H),
4.37-3.7 (m, 2H), 3.6-3.25 (m, 6H), 2.66
(s, 3H, S-Me), 1.16 (d, J = 6.0Hz,
3H, CHMe). C( 5R , 6S )-3-[2-(3-methylthiopyridinio)ethylthio]-6-[1-( R )-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0] hept-2-ene-2-carboxylate 25ml phosphate buffer (0.05M,
p-nitrobenzyl (5R, 6S) in pH7.4)
3-[2-(3-methylthiopyridinio)ethylthio]-6-[1-(R)-hydroxyethyl]-
A mixture of 7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate chloride (0.551 g, 1.0 mmol) and 10% palladium on charcoal (0.55 g) with THF (5 ml) Ether (25ml) was added. 40psi for 1 hour
This mixture was hydrogenated (Parr). Pass the reaction mixture through Celite to remove the Fitter cake.
Washed with H ₂ O and ether. The aqueous layer was removed and further washed with ether (3x). After removing the remaining organic solvent in vacuo, the aqueous solution was cooled to 0° C. and the pH was adjusted to 7.0 with saturated aqueous NaHCO ₃ solution. This solution was immediately applied to a C ₁₈ reverse phase column. Elution with H ₂ O and lyophilization of the relevant fractions gave 0.25 g of a bright yellow solid. This material was purified by reverse phase hplc to give the product (0.210 g, 55%) as a pale yellow solid. ir (KBr) ν _nax : 3400 (br, −OH), 1755 (β−
Lactam CO), 1590 (−CO ₂ ) cm ⁻¹ ; ¹ Hnmr
(D ₂ ) δ: 8.60−7.76 (m, 4H, aromatic), 4.76
(t, J = 5.8Hz, 2H, N-CH ₂ ), 4.13 (d of q, J = J ' = 6.3Hz, H-1'), 3.95 (d of t,
J=9.0Hz, J '=2.8Hz, 1H, H-5), 3.45-
2.75 (m, 5H), 2.59 (s, 3H, S-Me), 1.20
(d, J = 6.4Hz, 3H, CHMe); uv (H ₂ O)
λ _nax : 296 (ε8509), 273 (ε13005), 231 (ε11576
)
nm; t _1/2 ( _PH7.4 , 36.8℃) 20h. Example 10 3-[2-(1-(2,6-dimethylpyridinium)ethylthio]-6α-[1-( R )-hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0)hept-2 -Production of ene-2-carboxylate A 1-(2-mercaptoethyl)-2,6-dimethylpyridinium methanesulfonate 2,6-dimethylpyridine (19.2ml,
0.165mol) and methanesulfonic acid (3.27ml,
The mixture was stirred for 15 minutes, treated with ethylene sulfide (4.17ml, 0.070mol) and stirred at 100°C for 42 hours under nitrogen atmosphere.
After cooling to 25°C, the reaction mixture was dissolved in ether (45ml).
and diluted with water (30ml). Separate the two phases,
The organic layer was extracted with water (2x5ml). Add the aqueous phase, pass through a pad of Celite, and ether (2
The mixture was washed with 15 ml of μ-bondapak C-18 column (3.0×12 cm) under vacuum to remove traces of organic solvent. Elution with a 3% acetonitrile-97% water mixture and lyophilization of the appropriate fractions gave 2.5 g of impure title compound as a syrup. hplc (μ−bondapak
Purification by C-18) yielded 0.90 g (7%) of the title compound: ir (film) ν _nax : 2520 (SH), 1640 and
1625 (pyridinium), 1585, 1490, 1200cm ^-1
(Sulfonate), ¹ Hmr (DMSO-d ₆ + D ₂ O)
δ: 2.36 (3H, s, CH ₃ SO _3- ), 4.62 (2H, m,
CH ₂ N ⁺ ), 7.74 (2H, m, pyridinium
Hm), 8.24 (1H, m, Hp of pyridinium), uv
(H ₂ O) _nax : 272 (4080) mμ. B Paranitrobenzyl 3-[2-(1-(2,6
-dimethylpyridinium)ethylthio]-6α-
[1-(R)-hydroxyethyl]-7-oxo-
1-Azabicyclo(3.2.0)hept-2-ene-2-carboxylate diphenyl phosphate P-nitrobenzyl 6α-[1-(R)-hydroxyethyl]-3,7-dioxo-1-azabicyclo(3.2.0) heptane-2-carboxylate (0.658 g, 1.89 mmol) kept under nitrogen atmosphere diisopropylethylamine (0.394 ml,
2.26 mmol) and diphenylchlorophosphate (0.468 ml, 2.25 mmol) were added. The reaction mixture was stirred for 30 minutes and then treated with a solution of 1-(2-mercaptoethyl)-2,6-dimethylpyridinium methanesulfonate (0.720 g, 2.73 mmol) in acetonitrile (3 ml) followed by diisopropylethylamine (0.394 ml, 2.26 mmol). Processed with. The reaction mixture was stirred for 2 hours, diluted with cold (°C) water (27 ml) and injected onto a column of μ-bondapak C-18 (2.5 x 9.0 cm). Elution with an acetonitrile-water mixture and lyophilization of the appropriate fractions gave 0.92 g (65%) of the title compound. ir (KBr) ν _nax : 3700−3000 (OH), 1765 (β
- Lactam C=0), 1690 (PNB ester C=0), 1620 (pyridinium), 1590 (phenyl), 1517 (NO ₂ ), 1330 (NO ₂ ), 880 cm ^-1
(NO ₂ ), ¹ Hmr (DMSO−d ₆ ) δ: 1.15 (3H, d,
J=6.2Hz, _CH3CHOH ), 2.7−3.7(11H,
CH ₂ S, 2-CH ₃ on pyridinium, H-4,
H-6), 3.7-4.4 (2H, CH ₃ CHOH, H-
5), 4.7 (2H.m, CH ₂ N ⁺ ), 5.14 (1H, d, J
=4.5Hz, OH), 5.37 (center of ABq, J =
13.2Hz, PNB _CH2 ), 6.7-7.5 (10H, m, phenyl), 7.5-8.7 (7H, pyridinium, PNB
H′ (plural), uv (H ₂ O) λ _nax : 274 (ε14150),
319 (ε9445) mμ. C 3-[2-(1-(2,6-dimethylpyridinium)ethylthio]-6α-[1-(R)-hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0)hept-2-ene -2-carboxylate P-nitrobenzyl 3-[2-(1-(2,6
-dimethylpyridinium))ethylthio]-6α
-[1-(R)-Hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylate diphenyl phosphate (0.80 g, 1.07 mmol) To a solution in tetrahydrofuran (42 ml) was added ether (42 ml), monobasic potassium phosphate-sodium hydroxide buffer (0.15 M, PH 7.22, 21 ml) and 10% palladium on charcoal (0.80 g). The resulting mixture was hydrogenated at 40 pai for 1 hour at 23°C and filtered through a pad of Celite. Separate the two layers, extract the organic layer with buffer (3 x 8 ml), combine the aqueous layer with the extract, and add ether (50
ml), evacuated to remove traces of organic solvent, and injected onto the top of a μ-bondapak C-18 column (3.0 x 10.2 cm). Elution of the column with a 5% acetonitrile-95% water mixture and lyophilization of the relevant fractions gave 0.246 g (63%) of the title compound as a yellowish powder. ir (KBr) ν _nax : 3700−2800 (OH), 1750 (β
-lactam C=0), 1620 (pyridinium),
1585cm ^-1 (carboxylate), ¹ Hmr (D ₂ O)
δ: 1.23 (3H, d, J = 6.4Hz, CH ₃ CHOH),
2.5-3.5 (11H, H-4, H-6, CH2S, _2CH3 on _pyridinium ), 3.8-4.4 (2H, _CH3
CHOH, H−5), 4.5−4.9(CH ₂ N ⁺ , HOD),
7.64 and 7.74 (2H, A part of A ₂ B system, Hm of pyridinium), 8.07, 8.16, 8.18 and 8.27 (1H,
A ₂ B part of B system, Hp of pyridinium), uv (H ₂
O) λ _nax : 277 (ε9733), 300 (ε8271) mμ, [α]
^23/D +50.7 (C 0.48, H ₂ O). Elemental analysis: Calculated value (as C ₁₈ H ₂₂ N ₂ O ₄ S・1.5H ₂ O) C55.51,
H6.47, N7.19; Actual value: C55.14, H, 6.23,
N6.46. Example 11 ( 5R , 6S )-3-[2-(2-methylthio-
3-methylimidazolio)ethylthio]-6-
[1-( R )-hydroxyethyl]-7-oxo-
Azabicyclo[3.2.0]hept-2-ene-2
- Manufacture of carboxylates A 2-methylthio-3-methyl-1-(2-mercaptoethyl)imidazolium trifluoromethanesulfonate Trifluoromethanesulfonic acid (1.38ml,
0.015 mmol) at 0 °C under _N2 , 2-methylthio-1-methylimidazole (4.0 g),
0.03mol). Then ethylene sulfide (0.9ml, 0.015mol) was added and the mixture
Heated to 55 °C for 24 h under _N2 . The reaction mixture was triturated with ether (3x) and the residue was taken up in acetone, filtered and evaporated. This gave the product (4.2 g, 82%) as a semi-crystalline solid, which was used without further purification (in the next reaction). ir (film) ν _nax : 2550 (W, sh) cm ^-1 ; ¹
Hnmr ( _d6 -acetone) δ: 7.97 (s.2H), 4.66
(t, J=7Hz, 2H, methylene), 4.17(s,
3H, N-Me), 3.20 (d of t, J = 7Hz, J ′
=9Hz, 2H, methylene), 2.72(s, 3H, S-
Me), 2.20 (t, J = 9Hz, 1H, -SH). 1 Prepared according to A. Wohl and W.
Marcwald, Chem . Ber ． 22 , 1353 (1889). B p-nitrobenzyl (5 R ,6 S )-3-[2
-(2-methylthio-3-imidazolio)ethylthio]-6-[1-( R )-hydroxyethyl]
-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate diphenyl phosphate p-Nitrobenzyl (5 R ,6 S )-6-[1
-( R )-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]pentane-2
- To a solution of carboxylate (1.40 g, 4.0 mmol) in anhydrous acetonitrile (50 ml), add a drop of diisopropylethylamine (0.76 ml, 4.4 mmol), then diphenylchlorophosphate (0.91
ml, 4.1 mmol) was added. After stirring the reaction mixture at room temperature for 1 hour, diisopropylethylamine (0.76 ml, 4.4 mmol) was added followed by 2-methylthio-3-methyl-1-(2-mercabutoethyl)imidazolium trifluoromethanesulfonate (2.0 g, A solution of 5.9 mmol) in acetonitrile (5 ml) was added dropwise. The reaction mixture was kept at room temperature for 1.5 hours and then concentrated in vacuo to give a gum. This gum was dissolved in H ₂ O and applied to a C ₁₈ reverse phase column. Elution with H ₂ O, then 20% acetonitrile-water and finally 30% acetonitrile-water, followed by lyophilization of the relevant fractions gave the product as a pale yellow solid (0.90 g, 30%).
was gotten. ir (KBr) ν _nax : 3380 (br, OH), 1770 (β−
lactam CO) cm ^-1 ; ¹ Hnmr (d ₆ -acetone)
δ: 8.35 (br, s, 1H), 8.24, 7.78 (AB q,
J=8.8Hz, 4H, aromatic) 7.89 (br, s, 1H),
7.25-6.91 (m, 10H, diphenyl phosphate), 5.50, 5.25 (AB q, J = 12Hz, 2H, Benjirik), 4.75-4.27 (m, 3H), 4.03 (s,
3H, N-Me), 4.15-2.75 (m, 8H), 2.59
(s, 3H, S-Me), 1.22 (d, J=6.2Hz,
3H, −CHMe). C (5 R ,6 S )-3-[2-(2-methylthio-3-methylimidazolio)ethylthio]-6
-[1-( R )-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate p-Nitrobenzyl ( 5R , 6S )-3 in a mixture of THF (70ml), ether (70ml) and phosphate buffer (0.05M, PH7.4)
-[2-(2-methylthio-3-methylimidazolio)ethylthio]-6-[1-( R )-hydroxyethyl]-7-oxo-1azabicyclo[3.2.0]hept-2-ene-2- Carboxylate diphenyl phosphate (1.20g,
10% palladium on charcoal in a solution of 1.56 mmol)
Added 1.2g. This mixture was hydrogenated at 35pai for 55 minutes (Parr) and the reaction mixture was then filtered through a pad of Celite to remove the filter cake.
Washed with H ₂ O and ether. The aqueous phase was removed, cooled to 0 °C, and the pH was adjusted with saturated aqueous _NaHCO3 .
It was set to 7.0. After removing the residual organic solvent in vacuo,
The aqueous solution was applied to a _C18 reverse phase column. Elution with _H2O and then 8% acetonitrile- _H2O ,
Solid on freeze-drying with the relevant fraction of 0.25
g was obtained. This material was repurified by reverse phase hplc to yield the product (0.114 g, 19%) as an off-white solid.
I got it. ir (KBr) ν _nax : 3420 (OH), 1750 (β-lactam CO), 1590 (−CO ₂ ) cm ⁻¹ ; ¹ Hnmr (D ₂ )
δ: 7.58 (s, 2H), 4.52 (t, J = 6Hz, 2H),
4.28−3.82 (m, 2H), 3.90 (s, 3H, N−
Me), 3.40−2.87 (m, 5H), 2.40 (s, 3H, S
-Me), 1.20 (d, J = 6.4Hz, 3H, -CHMe);
uv (H ₂ O) λ _nax : 297 (ε7572), 262 (ε6259),
222 (ε7955) nm. Example 12 ( 5R , 6S )-3-[2-(3-aminopyridinio)ethylthio]-6-[1-( R )-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept Production of -2-ene-carboxylate A 3-amino-1-(2-mercaptoethyl)
Pyridinium chloride 3-aminopyridine (1.50g, 0.016mol)
It was dissolved in 15 ml of 1 N methanolic HCl and the resulting solution was evaporated to give the hydrochloride as an oil. To this oil was added 3-aminopyridine (1.32 g, 0.015 mol) and ethylene sulfide (0.89 ml, 0.015 mol) and the resulting mixture was heated to 60-65 °C (oil bath) under _N2 for 2 hours. Heated. Furthermore, an equal volume of ethylene sulfide (0.89 ml,
0.015 mol) was added and heating continued at 55-65°C for 65 hours. The reaction mixture was washed with CH ₂ Cl ₂ and then dissolved in H ₂ O (25 ml). The aqueous solution was applied to a C ₁₈ reverse phase column and eluted with H ₂ O. Evaporation of the relevant fractions gave the product (1.26 g, 44%) as a colorless, viscous oil. ir (film) ν _nax : 3180 (NH ₂ ) cm ^-1 ;
1Hnmr( _d6 -DMSO)δ:8.19-7.59(m,4H,
aromatic), 4.59 (t, J = 6.2Hz, 2H, N-
CH ₂ ), 3.5 (br s, 2H, -NH ₂ ), 3.20−2.77
(m, 3H). B p-nitrobenzyl (5 R ,6 S )-3-[2
-(3-aminopyrudinio)ethylthio]-6-
[1-( R )-hydroxyethyl]-7-oxo-
1-Azabicyclo[3.2.0]hept-2-ene-2-carboxylate diphenyl phosphate p- _nitrobenzyl (5 R ,
6S )-6-(1-( R )-hydroxyethyl)-
3.7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (0.696g,
2.0 mmol) in anhydrous acetonitrile (10 ml) was added dropwise diisopropylethylamine (0.382 ml, 2.2 mmol) followed by diphenylchlorophosphate (0.457 ml, 2.2 mmol). After stirring for 30 minutes at 0°C, 3-amino-1-
(2-mercaptoethyl)pyridinium chloride (0.475 g, 2.5 mmol) in anhydrous DMF (1 ml)
The solution was then added with diisopropylethylamine (0.435ml, 2.5mmol) and the reaction mixture was kept at 0°C for 1.5 hours before being concentrated in vacuo. The resulting gum was dissolved in acetonitrile-H ₂ O (1:1).
The mixture was dissolved and added to a reverse phase column. Elution with H ₂ O, then 20% acetonitrile-H ₂ O, followed by lyophilization of the relevant fractions gave the product (0.730 g, 50%) as a beige solid. ir (KBr) ν _nax : 3330 (br, OH), 3180 (br,
_NH2 ), 1770 (β-lactam CO), 1690 ( _-CO2
PNB) cm ^-1 ; ¹ Hnmr (d ₆ −DMSO) δ: 8.29−
763 (m, 8 aromatic), 7.2-6.7 (m, 10H, diphenyl phosphate), 5.47, 5.18 (AB q, J
= 14Hz, 2H, Benjirik), 4.73-4.45 (m,
3H), 4.2-3.8 (m, 1H), 3.6-2.6 (m, 8H),
1.15 (d, J = 6.2Hz, 3H, CHMe). C( 5R , 6S )-3-(2-(3-aminopyridinio)ethylthio)-6-(1-( R )-hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0)hept-2 -ene-2-carboxylate Phosphate buffer (0.05M, PH
7.4), p-nitrobenzyl (5 R , 6
S)-3-(2-(3-aminopyridinio)ethylthio]-6-(1-( R )-hydroxyethyl)
-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate diphenyl phosphate (0.730 g, 1.0 mmol) in a mixture of 10% palladium (0.7 g) on charcoal.
THF (8ml) and ether (20ml) were added. This mixture was hydrogenated at 40 psi for 1 hour (Parr). The resulting mixture was passed through a pad of Celite;
The filter cake was washed with H ₂ O and ether. The aqueous phase was removed and washed with ether (2x) and the remaining bright components were removed in vacuo. The aqueous solution was immediately applied to a _C18 reverse phase column and eluted with _H2O . Lyophilization of the relevant fraction yielded 0.45 g of an off-white solid, and this material was repurified by reverse phase hplc to yield the desired product (0.123 g, 35%) as an ivory solid. ir (KBr) ν _nax : 3340 (br), 1750 (br, β-lactam CO), 1580 (br, −CO ₂ ) cm ^-1 ; ¹ Hnmr
(D ₂ O) δ: 8.07−7.59 (m, 4H, aromatic),
4.61 (b, J = 5.8Hy, 2H, N-CH ₂ ), 4.14
(t of q, J = 6.3Hz, 1H, H-1') 3.97 ( J =
9.2Hz, J ′=2.6Hz, 1H, H-5), 3.38(t,
J = 5.8Hz, 2H, S-CH ₂ ), 3.24 (d of d, J
=6.0Hz, J '=2.6Hz, 1H, H-6), 3.17-
2.57 (m, 2H, H-4), 1.21 (d, J = 6.3Hz,
3H, CHMe); uv (H ₂ O) λ _nax : 299 (ε7949),
256 (ε8822) nm; _t1 / ₂ (PH7.4, 36.8℃) 18.5h. Example 13 ( 5R , 6S )-3-[1-( S )-methyl-2-
(1-pyridinium)ethylthio]-6-[1-
( R )-hydroxyethyl]-7-oxo-1-
Azabicyclo (3.2.0) hept-2-ene-2
-carboxylate and ( 5R , 6R )-3-[1-( R )-methyl-2
-(1-pyridinium)ethylthio]-6-[1
-( R )-hydroxyethyl]-7-oxo-1
-Azabicyclo(3.2.0)hept-2-ene-
Production of 2-carboxylate A d-1-(2-mercapto-2-methylethyl)pyridinium methanesulfonate d
-1-(2-mercapto-1-methylethyl)
Pyridinium methanesulfonate Methanesulfonic acid (1.95 ml, 0.030 mol) was slowly added to cold pyridine (7.83 ml, 0.097 mol) and the resulting mixture was stirred at 40 °C for 15 min.
d-propylene sulfide (2.59ml,
0.033mol) for 90 hours under nitrogen atmosphere.
Stir at 60°C. Pyridine is removed under vacuum,
The residue was mixed with water and subjected to chromatography (hplc,
Prep.Bondapak C-18). Appropriate fractions were combined and lyophilized to produce d-1-(2-mercapto-2) as a colorless syrup.
1.14 g (15%) of -methylethyl)pyridinium methanesulfonate were obtained. ; ir (film) ν _nax : 2520 (SH), 1640 (pyridinium), 1180 (s, CH ₃ SO _3- ), 1040 (CH ₃
SO _3- ) cm ^-1 , ¹ Hmr (DMSO d ₆ ) δ: 1.35 (d,
J=6.8Hz, 3H, CH ₃ CHS), 2.30(s, 3H,
_CH3SO3- ) _, 2.90 (d, J = 8.5Hz, 1H, SH),
3.2−3.7 ( mCH SH), 4.52 (dd, Jgen = _12.9Hz ,
J=8.4Hz, CHC H2N ⁺ ), 4.87( _dd , Jgen ₌
12.9Hz, J =6.0Hz, _CHC H2N ⁺ ), 8.0−8.4
(m, 2H, Hm of pyridinium), 8.5−8.8 (m,
1H, Hp of pyridinium), 9.04 (dd, J = 1.4
Hz, J = 6.7Hz, 2H, pyridinium Ho), uv
(H ₂ O) λ _nax : 208 (ε5267), 259 (ε3338), Elemental analysis: Calculated value (as C ₉ H ₁₅ NO ₃ S ₂・2H ₂ O):
C 37.88, H 6.71, N 4.91, S 22.47;
Actual measurements: C 37.49, H 6.85, N 4.86, S
22.09 and d-1-(2-mercapto-1-methylethyl)pyridinium methanesulfonate
0.82 g (11%) (also as colorless syrup); ir (film) νmax: 2500 (SH), 1628 (pyridinium), 1180 (sulfonate), 1035 (sulfonate) cm ^-1 , ¹ Hmr (DMSO d ₆ ) δ: 1.69 (d,
J=6.8Hz, 3H, CH ₃ CHN ⁺ ), 2.31(s, 3H,
_CH3SO3- ), 3.0-3.3 (m, 2H _{, CH2S} ), 4.2-
5.2 (m, 1H, CHN ⁺ ), 8.0−8.4 (m, 2H, Hm of pyridinium), 8.5−8.8 (m, 1H, Hp of pyridinium), 9.0−9.2 (m, 2H, Ho of pyridinium), uv (H ₂ O)λ _nax : 209 (ε4987), 258
(ε3838). Elemental analysis: Calculated value (C ₉ H ₁₅ NO ₃ S ₂・
_1.5H2O ): C 39.11, H 6.56, N 5.07; Actual values: C 39.3, H 5.92, N 5.20. B (5 R ,6 S ) paranitrobenzyl 3-[1
-( R , S )methyl-2-(1-pyridinium)
Ethylthio]-6-[1-( R )-hydroxyethyl]-7-oxo-1-azabicyclo (3.2.0)
Hept-2-ene-2-carboxylate diphenyl phosphate (5 R ,6 S ) paranitrobenzyl 6-[1
-( R )-hydroxyethyl]-3,7-dioxo-1-azabicyclo(3.2.0)heptane-2
-carboxylate (0.523 g, 1.5 mmol) in acetonitrile (6 ml) kept under nitrogen atmosphere
To a cold (0°C) solution was added diisopropylethylamine (0.314 ml, 1.8 mmol) followed by diphenylchlorophosphate (0.373 ml, 1.8 mmol).
added. The reaction mixture was stirred for 30 min and d-
1-(2-mercapto-2-methylethyl)pyridinium methanesulfonate (0.539g,
2.16 mmol) in acetonitrile (2 ml) and diisopropylethylamine (0.314 ml,
1.8 mmol). The reaction mixture was heated to 1
Stir for an hour, dilute with cold (0°C) water (24 ml),
Prep Bondapak C-18 column (2.5 x 8.5cm)
Above, chromatographic fractionation using water containing 25-50% acetonitrile as eluent, 1.07 g after freeze-drying.
(97%) of the title compound was obtained as a yellowish powder: ir(KBr)ν _nax : 3700−3100(OH), 1770(β
-lactam C=O), 1965 (PNB ester C=O), 1630 (pyridinium), 1590 (phenyl), 1518 (NO ₂ ), 1348 (NO ₂ ), 885 (NO ₂ ) cm
⁻¹ , ¹ Hmr (DMSO d ₆ ) δ: 1.14 (d, J = 6.1
Hz, 3H, CH ₃ CHO), 1.33 (d, J = 6.3Hz,
3H, CH ₃ CHS), 4.6−5.0 (m, CH ₂ N ⁺ ),
5.14 (d, J = 5.2Hz, 1H, OH), 5.37 (center of ABq, J = 12.4Hz, 2H, CH ₂ of PNB),
6.6−7.5 (m, 10H, phenyl phosphate),
7.69 (d, J = 8.7Hz, 2H, PNB Ho), 8.0−
8.4 (m, 4H, Hm of PNB, pyridinium
Hm), 8.4−8.8(m, 1H, pyridinium
Hp), 9.08 (d, J = 5.6Hz, 2H), uv (H ₂ O)
λ _nax : 263 (ε13325), 308 (ε8915). Elemental analysis:
Calculated value (C ₃₆ H ₃₆ N ₃ O ₁₀ SP・H ₂ O): C 57.52,
H 5.10, N 5.59, S 4.27; Actual value: C 57.69, H 4.96, N 5.36, S
4.35. C( 5R , 6S )3-[1-( R and S )-methyl-2-(1-pyridinium)ethylthio]-6
-[1-( R )-Hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylate (5 R ,6 S )paranitrobenzyl 3-[1
-( R , S )methyl-2-(1-pyridinium)
Ethylthio]-6-[1-( R )-hydroxyethyl]-7-oxo-1-azabicyclo (3.2.0)
A solution of hept-2-ene-2-carboxylate diphenyl phosphate (0.60 g, 0.82 mmol) in aqueous tetrahydrofuran (33 ml) in ether (33 ml), monobasic potassium phosphate
Sodium hydroxide powder (17ml,
0.15 N, PH 7.22) and 10% palladium on charcoal (0.60 g) and the resulting mixture was heated at 40 psi, 23
Hydrogenated at °C. The two layers were separated and the organic layer was extracted with water (3x7ml). The aqueous layer (extract and) was combined, filtered through ceride pad, washed with ether (3 x 20 ml), and prep.Bondapak C-
Chromatography was performed on a 18 column (2.5 x 9.5 cm) using water as eluent to obtain 0.18 g (63%) of a mixture of diasterene isomers. The two diastereoisomers were determined by hplc (Prep.Bondapak C-18).
Isomer with low retention time using water as eluent, 0.068 g (23%), compound “B”, ir(KBr) ν _nax : 1770 (C=
O), 1633 (pyridinium), 1593 (carboxylate) cm ^-1 , 1Hmr (D ₂ O) δ: 1.20 (d, J =
6.3Hz, 3H, CH ₃ CHO), 1.42 (d, J = 6.9Hz,
3H, C H ₃ CHS), 2.3-3.2 (m, 3H.H-4, H
-6), 3.5-3.9 (m, 1H, SCH), 3.9-4.2
(m, 2H, H-5, CH ₃ C H O), 4.3-5.1 (m,
CH ₂ N ⁺ ), 7.8−8.2 (m, 2H, pyridinium
Hm), 8.4−8.7(m, 1H, pyridinium
Hp), 8.7−9.0 (m, 2H, Ho of pyridinium),
uv (H ₂ O) λ _nax : 260 (ε6727), 300 (ε8245)
[α] ^23/D −39.3° (c, H ₂ O), t ₁ / ₂ = 12.6 h (measured under condition A); and isomer with higher retention time, 0.081 g (28%), compound “A”, ir (KBr) ν _nax : 1755 (C= of β-lactam
O), 1630 (pyridinium), 1590 (carboxylate) cm ^-1 , ¹ Hmr (D ₂ O) δ: 1.18 (d, J =
6.3Hz, 3H, CH ₃ CHO), 1.40 (d, J = 7.0Hz,
3H, CH ₃ CHS), 2.84 (d, J = 9.3Hz, 2H,
H-4), 3.26 (dd, J = 2.7Hz, J = 5.9Hz,
1H, H-6), 3.4-4.2 (m, 3H, SCH, CH ₃
C H O, H-5), 4.2-5.1 (m.CH ₂ N ⁺ ), 7.7-
8.1 (m, 2H, Hm of pyridinium), 8.3−8.65
(m, 1H, Hp of pyridinium), 8.65−8.9 (m,
2H, pyridinium Ho), uv (H ₂ O) λ _nax :
259 (ε5694), 296 (ε6936), [α] ^23/D +96.9° (
c.
0.56, H ₂ O) and t ₁ / ₂ = 15.6 h (measured under condition A). Example 14 ( 5R , 6S )-3-[2-[( S )-(1-pyridinium)]-1-( S )-cyclohexylthio]-
6-[1-( R )-Hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0)hept-2-
En-2-carboxylate and ( 5R , 6S )-3-[2-[( R )-(1-pyridinium)]-1-( R )-cyclohexylthio]
-6-[1-( R )-hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0)hept-2
Preparation of -ene-2-carboxylate A d -1-(2-mercapto-1-cyclohexyl)pyridinium methanesulfonate Methanesulfonic acid (0.65ml, 0.01mol) to a drop of pyridine (2.42ml, 0.03mol) while cooling
added to. The mixture was stirred for 10 min under nitrogen atmosphere and d -cyclohexene sulfide [1.377
g (85% purity), 0.0102mol] at 72.℃
The mixture was stirred for 25 hours. Excess pyridine was removed under vacuum and traces were azeotroped with water. Mix the residue,
Chromatography was carried out through a Prep. Bondapak C-18 column (5 x 13 cm) using water containing 0-2% acetonitrile as the eluent, and after freeze-drying, 1.57 g (53%) of a colorless syrup was obtained. ir (film) ν _nax : 2500 (SH), 1625 (pyridinium), 1190 (SO _3- ), ¹ Hmr (DMSO d ₆ )
δ: 1.2-2.5 (m, 8H, cyclohexyl H),
2.32 (S, 3H, CH ₃ SO ₃ ^- ), 2.82 (d, J = 9.8
Hz, SH), 3.0-3.5 (m, 1H, CH SH ), 4.2-
4.9 (m, 1H, CHN ⁺ ), 8.0−8.3 (m, 2H, Hm of pyridinium), 8.4−8.8 (m, 1H, Hp of pyridinium), 8.9−9.3 (m, 2H, Ho of pyridinium), uv (H ₂ O)λ _nax : 214 (ε5365), 258
(ε3500). Elemental analysis: Calculated value (C ₁₂ H ₁₉ NO ₃ S ₂・
(as H ₂ O): C 46.88, H 6.88, N
4.56; Actual value: C 46.61, H 6.46, N
4.65. B (5 R ,6 S ) paranitrobenzyl 3-[2
-[( R or S )-(1-pyridinium)]-1-
( R or S )-cyclohexylthio]-6-(1-
( R )-hydroxyethyl]-7-oxo-1-
Azabicyclo (3.2.0) hept-2-ene-2
-carboxylate ( 5R , 6S ) paranitrobenzyl 6-[1-( R )-hydroxyethyl] kept in a nitrogen atmosphere
A solution of -3,7-dioxo-1-azabicyclo(3.2.0) heptane-2-carboxylate (1.37 g, 3.93 mmol) in cold (0°C) acetonitrile (15 ml) was added with diisopropylethylamine (0.822 ml, 4.7 mmol) and Diphenyl chlorophosphate (0.979ml, 4.7mmol) was added. The resulting mixture was stirred for 30 minutes and d-
(2-Mercapto-1-cyclohexyl)pyridinium methanesulfonate (1.64g,
5.66 mmol) in acetonitrile (4.7 ml) followed by diisopropylethylamine (0.822 ml, 4.7 mmol). The reaction mixture was stirred at 0 °C for 1 h and then added with cold (0 °C) water (175 ml).
Dilute with Prep.Bondapak C-18, 25~
After chromatographic fractionation using water containing 50% acetonitrile as eluent and lyophilization of the appropriate fractions, 1.9 g (53%) of the title compound was obtained. ir (KBr) ν _nax : 3700−3000 (OH), 1770 (β
-lactam C=O), 1700 (PNB ester C=O), 1628 (pyridinium), 1590 (phenyl), 1515 (NO ₂ ), 1345 (NO ₂ ), 880 (NO ₂ ) cm
⁻¹ , ¹ Hmr (D ₂ O) δ: 1.13 (d, J = 6.1Hz, 3H,
CH ₃ CHO), 1.2-2.5 (m, 8H, cyclohexyl H), 2.7-3.5 (m, 4H, H-4, H6,
CHS), 3.5-4.4 (m, 2H, CH ₃ CHO, H-
5), 4.4−5.0 (m, 1H, CHN ⁺ ), 5.30 (center of ABq, J = 12.8Hz, CH ₂ of PNB), 6.7−
7.4 (m, 10H, phenyl), 7.65 (d, J = 8.6
Hz, 2H, PNB Ho), 7.9−8.4 (m, 4H,
Hm of PNB, Hm of pyridinium), 8.4−8.8
(m, 1H, Hp of pyridinium), 9.0−9.4 (m,
2H, pyridinium Ho), uv (H ₂ O) λ _nax :
263 (ε9038), 309 (ε6394). Elemental analysis: Calculated values (as C ₃₉ H ₄₀ N ₃ O ₁₀ SP·H ₂ O): C 59.16, H 5.35, N 5.31; actual values: C 58.95, H 5.15, N 5.57. C( 5R , 6S )-3-[2-[( R or S )-(1
-pyridinium)]-1-( R or S )-cyclohexylthio]-6-[1-( R )-hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0)
hept-2-ene-2-carboxylate ( 5R , 6S )paranitrobenzyl 3-[2
-[( R or S )-(1-pyridinium)]-1-
( R or S )-cyclohexylthio]-6-[1-
( R )-hydroxyethyl]-7-oxo-1-
Azabicyclo (3.2.0) hept-2-ene-2
- a solution of carboxylate diphenyl phosphate (1.85 g, 2.34 mmol) in wet tetrahydrofuran (96 ml), ether (96 ml),
Monobasic potassium phosphate-sodium hydroxide buffer (0.15M, PH 7,22, 50ml) and 10% palladium on charcoal (1.9g) were added. The resulting mixture was hydrogenated at 23° C. and 40 psi for 1.25 hours. The organic layer was removed and extracted with water (3x20ml). The aqueous solution was filtered through a ceride pad, washed with ether (2 x 60 ml) and evacuated to remove traces of organic solvent Prep.Bondapak C-18.
Chromatography was carried out on a column (4.5 x 9 cm) using water containing 0-5% acetonitrile as the eluent, and after freeze-drying, 0.705 g (76%) of the diastereoisomer mixture was obtained. Separation of diastereoisomers was carried out by HPC (Prep.Bondapak C-18) with 4% acetonitrile water as eluent, and the diastereoisomer with lower retention time, compound “A”, (0.29 g, 31% ), ir
(KBr) ν _nax : 1750 (C=O of β-lactam),
1620 (sh, pyridinium), 1685 (carboxylate) cm ^-1 , 1Hmr (D ₂ O) δ: 1.21 (d, J =
6.3Hz, 3H, CH3CHO ), 1.4-2.5(m, _8H ,
Synchhexyl H), 2.5-3.05 (m, 2H, H
-4), 3.05-3.25 (m, 1H, H-6), 3.3-3.7
(m, 1H, CHS), 3.9-4.3 (m, 2H, H-5,
CH ₃ C H O), 4.3−4,8 (m.CHN ⁺ ), 7.8−
8.2 (m, 2H, Hm of pyridinium), 8.3−8.7
(m, 1H, Hp of pyridinium), 8.8−9.1 (m,
2H, pyridinium Ho), uv (H ₂ O) λ _nax :
260 (ε7123), 300 (ε8685), [α] ²³ _D +6.2° ( c

0.63, H ₂ O), t ₁ / ₂ = 16.6 h (measured under condition A), elemental analysis: Calculated value (as C ₂₀ H ₂₄ N ₂ O ₄ S・2H ₂ O): C56.59, H6.65 , N6.60, S7.55; Actual values: C56.83, H6.47, N6.59, S7.43; High retention time diastereoisomer, compound "B" (0.35 g, 38%) ir (KBr) ν _nax : 1750 (β
-lactam C=O), 1622 (sh, pyridinium), 1588 (carboxylate) cm ^-1 , ¹ Hmr (D ₂
O) δ: 1.19 (d, J = 6.4Hz, 3H, CH ₃
CHO), 1.3-2.5 (m, 8H, synchrohexyl H), 2.5-3.1 (m, 2H, H-4), 3.1-3.3 (m,
1H, H-6), 3.3-3.8 (m, 2H, H-5,
CHS), 4.1 (center of m, 1H; CH ₃ C H O),
4.25−4,7 (m, 1H, CHN ⁺ ), 7.8−8.1 (m,
2H, Hm of pyridinium), 8.3−8.7(m, 1H,
Hp of pyridinium), 8.75-9.0 (m, 2H, Ho of pyridinium), uv (H ₂ O) λ _nax : 259
(ε5992), 296 (ε7646), [α]t _1/2 +65.3° ( c

0.43, H ₂ O) and t _1/2 = 20.2h (measured under condition A). Example 15 A ( 5R ) Allyl 3-[(2-pyridinioethyl)thio]-( 6S )-[( 1R )-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]
Hept-2-ene-2-carboxylate diphenyl phosphate (5 R ) allyl 3,7-dioxo-(6 S )-
[( 1R )-Hydroxyethyl]-1-azabicyclo[3.2.0]heptane-(2R)-carboxylate (472 mg, 1.87 mmol) was added to a solution of _CH3CN (6 ml) at about -10°C under a nitrogen atmosphere. diisopropylethylamine (0.42 ml. 2.4 mmol) and then diphenylchlorophosphate (0.50 ml.
2.4 mmol) was added. The mixture was stirred at 0°C for 30 minutes and cooled to -15°C. Add 5 drops of DMF to this
N-( ₂ -mercaptoethyl)pyridinium chloride (527 mg,
3.00 mmol) of the oily suspension was added followed by diisopropylethylamine (0.42 ml, 2.4 mmol). The mixture was stirred at −15 °C for 30 min and then heated with _H2
Diluted with O (20ml). This mixture was directly mixed with reversed phase silica gel (C ₁₈ PrepPAK, 12 g,
Waters Associates), H ₂ O (200 ml), 10%
_CH3CN / _H2O (100ml), 20% _CH3CN / _H2O
(100 ml), eluting with 30% CH ₃ CN/H ₂ O (100 ml) then 40% CH ₃ CN/H ₂ O (100 ml). The appropriate fractions were collected and the organic solvent was removed with a vacuum pump to give 786 mg (1.26 mmol, yield 67.3
%) of the title compound: ¹ Hmr(DMSO- _d6 ,
CFT-20) δ: 1.16 (3H, d, J = 6Hz, 1'-
CH ₃ ), 2.6−3.7 (m), 3.75−4.3 (2H, m, 5−
H and 1′−H), 4.65(2H, m, −CO ₂ CH ₂
−), 4.87 (2H, t, J = 6Hz, −CH ₂ −N ⁺ ),
5-6.2 (3H, m, olefinic proton), 6.6
−7.4 (m, aromatic proton), 8.15 (2H, “t”,
J7Hz, aromatic proton meta to nitrogen),
8.63 (1H, “t”, J 7Hz, aromatic proton para to nitrogen) and 9.07ppm (2H, “d”, J 7
Hz, aromatic proton of orca to nitrogen); ir (film) ν: 3400 (OH), 1770 (β-lactam),
1690 (ester), 1625 (pyridinio). B (5 R )-3-[(2-pyridinioethyl)thio]-(6 S )-[(1 R )-hydroxyethyl]-
7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (5 R )Allyl 3-[(2-pyridinioethyl)thio]-(6 S )-[(1 R )-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]
Hept-2-ene-2-carboxylate diphenyl phosphate (156 mg, 0.25 mmol)
Potassium ₂ -ethylhexanoate (0.5 M , 0.6 ml;
0.3 mmol) in EtOAc, triphenylphosphine (15 mg, 0.057 mmol) and tetrakis triphenylphosphine palladium (15 mg,
0.013 mmol) was added. The mixture was stirred at about 22° C. for 2 hours under nitrogen atmosphere. After addition of anhydrous Et ₂ O (7 ml), the precipitate was separated, washed with anhydrous Et ₂ O (7 ml) and dried in vacuo to give 101 mg of a brownish solid. This was subjected to reverse phase column chromatography (C ₁₈ PrepPAK, 12 g, Waters Associates).
Purification was carried out by elution with H ₂ O. Appropriate fractions (fractions 7-12, 20ml each)
was collected and lyophilized to give 53 mg (0.16 mmol, yield
64%) of the title compound was obtained as a yellowish powder. This material contained potassium 2-ethylhexanoate: ¹ Hmr(D ₂ O, CFT-
20) δ: 0.80 (t, J = 6.4 Hz, Me from ethylhexanoate), 1.21 (3H, d, J = 6.3 Hz,
1'-Me), 2.93 (2H, dd, J _1-5 = 9Hz, J _gen
=4Hz, 1-Hs) _{, 3.28(1H, dd, J6-1} = 6.2
Hz, J _6-5 = 2.5Hz, 6-H), 3.42 (2H, t, J
= 6Hz, -CH ₂ S), 3.98 (1H, td, J _5-1 = 9
Hz, J _5-6 = 2.5Hz, 5-H), 4.15 (1H, q, J
= 6.2Hz, 1'-H), 4.80 (2H, t, J = 6.0Hz, -
CH ₂ N ₊ ), 7-7.5 (m, phenyl proton from diphenyl phosphate), 8.03 (2H, m,
Hm of pyridinium), 8.56 (1H, m, Hp of pyridinium) and 8.81ppm (2H, "d", J 6.5
Hz, pyridinium Ho). Example 16 3-[2-(N-methyl-thiomorpholinium)
Production of ethylthio]-6α-[1'-( R )-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate A N-methyl-N-(1-mercaptoethyl)
Thiomorpholinium methanesulfonate To precooled (ice bath) N-methylthiomorpholine (5.00 g, 42.7 mmol) ^* was added methanesulfonic acid (1.47 ml, 20.5 mmol) and ethylene sulfide (1.30 ml, 21.4 mmol). The mixture was heated to 65°C for 24 hours and diluted with water (25ml). The aqueous solution was washed with diethyl ether (3 x 25ml) and after vacuum applied to a silica gel reverse phase column, the title compound was eluted with water. The relevant fractions were combined and evaporated to give the thiol as an oil (4.80 g, 86% yield); ir (film) ν _nax : 2550 cm ^-1 (w, SH);
1Hmr (DMSO d ₆ ) δ: 3.25−2.95 (6H, m,
CH ₂ N), 3.32 (3H, s, CH ₃ N), 3.20−
2.65 (7H, m, CH ₂ S, SH) and 2.32ppm
(3H, s, CH ₃ SO ₃ ). * J.M.Lehn and J.Wagner. Tetrahedron ,
26, 4227 (1970) B paranitrobenzyl 3-[2-(N-methyl-
thiomorphonylium diphenyl phosphate)
Ethylthio]-6α-[1'-( R )-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Paranitrobenzyl-6α-[1′-( R )-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate (557 mg, 1.60 mmol) in _CH3CN (8 ml) )
The cold (ice bath) solution was treated dropwise with diisopropylethylamine (0.336ml, 1.92mmol) and diphenylchlorophosphate (0.400ml, 1.92mmol). The reaction mixture was converted to N-methyl-N-
(2-Mercaptoethyl)thiomorpholinium methanesulfonate (893 mg, 2.29 mmol)
Treated with CH ₃ CN (4 ml) solution and diisopropylethylamine (0.336 ml, 1.92 mmol) and stirred for 30 minutes. The solution was diluted with water (20ml) and applied to a silica gel reverse phase column. 50% of desired product
Eluted with an acetonitrile-water mixture. The appropriate fractions were combined, pumped under vacuum for 2 hours and lyophilized to give the title compound (1.01 g, 85% yield). ir(nujol)ν _nax :1760(s, β-lactam C=
O) and 1510 cm ^-1 (s, NO ₂ ); ¹ Hmr (DMSO
_-d6 ) δ: 8.25 (2H, d, J = 8.8Hz, H-aromatic), 7.70 (2H, d, J = 8.8Hz, H-aromatic),
7.33−6.84 (10H, m, H-aromatic), 5.37 (2H,
Center of ABq, J = 14.2Hz, CH ₂ ), 5.14
(1H, d, J = 4.5Hz, OH), 4.35−3.80 (2H,
m, H-1' and H-5), 3.75-3.45 (6H, m,
CH ₂ N ⁺ ), 3.31 (3H, s, CH ₃ N ⁺ ), 3.45−2.75
(9H, m, CH ₂ S, H-6 and H-4) and
1.15ppm (3H, d, J = 6.2Hz, _CH3 ). C3-[2-(N-methyl-thiomorpholinium)ethylthio]-6α-[1'-( R )-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]-hept-2- En-2-carboxylate p-Nitrobenzyl 3-[2-(N-methyl-
thiomorpholinium diphenyl phosphate)
Ethylthio]-6α-[1'-( R )-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]
A 10% solution of hept-2-ene-2-carboxylate (1.31 g, 1.76 mmol) in 0.1 M PH7.4 phosphate buffer (48.8 ml), tetrahydrofuran (20 ml) and diethyl ether (20 ml) was added in a Parr shaker. pd/C (1.5g) top,
Hydrogenated at 40pai for 1 hour. The reaction mixture was diluted with diethyl ether (40ml) and the two phases were separated. The organic phase was extracted with water (2x5ml). The combined aqueous phases were filtered through #52 hardened paper, washed with diethyl ether (2 x 20 ml) and evacuated. Pour the aqueous solution onto a silica gel reverse phase column and
% acetonitrile-water to elute the desired carbapenem. The appropriate fractions were combined and lyophilized to yield the title compound (205 mg,
31%); ir (nujol) ν _nax : 1750 (s, β-lactam C=
O) and 1590 cm ^-1 (s, C=O); ¹ Hmr (D ₂ )
δ: 4.25-3.95 (2H, m, H-1', H-5),
3.70−3.40 (6H, m, CH ₂ N ⁺ ), 3.35 (1H, dd,
J = 6.1Hz, J = 2.6Hz, H-6), 3.08 (3H,
s, CH ₃ N ⁺ ), 3.25−2.75 (8H, m, CH ₂ S,
H-4), and 1.24ppm (3H, d, J = 6.4Hz,
CH ₃ ); uv (H ₂ O, c0.062) λ _nax : 299 (ε10,
962) t _1/2 17.7h (0.1M PH7 phosphate buffer, 37°C) Example 17 ( 5R , 6S )-3-[2-(1-methylmorpholino)ethylthio]-6-[( R ) -1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate production A 1-methyl-1-(2-mercaptoethyl)
Morpholinium trifluoromethanesulfonate N-methylmorpholine (3.29ml, 0.030mol)
Trifluoromethanesulfonic acid (1.327ml, 0.015mol) was added dropwise at 10°C, followed by ethylene sulfide (0.89ml, 0.015mol). The resulting tan solution was heated to 50-60<0>C (oil bath) under _N2 for 18 hours. The volatiles were then removed in vacuo and the residual oil was dissolved in 10 ml of water. The aqueous solution was washed with diethyl ether (3 x 5ml) and residual organic solvent was removed in vacuo. The resulting aqueous solution was applied to a _C18 reverse phase column and eluted with _H2O , then 5% acetonitrile-water and finally 10% acetonitrile-water. Evaporation of the relevant fractions gave a white solid which was dried in vacuo (P ₂ O ₅ ) to give the product (1.92 g, 41%). ir (KBr) ν _nax : 2560 (−SH) cm ^-1 ; ¹ Hnmr
( _d6 -acetone) δ: 4.25-3.6 (m, 8H), 3.49
(s, 3H, N-Me), 3.35-2.7 (m, 5H). B p-nitrobenzyl (5 R ,6 S )-3-[2
-(1-methylmorpholino)ethylthio]-6-
[( R )-1-hydroxyethyl]-7-oxo-
1-Azabicyclo[3.2.0]hept-2-ene-2-carboxylate diphenyl phosphate p-Nitrobenzyl ( 5R , 6S )-6-
[( R )-1-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-
2-carboxylate (0.348g, 1.0mmol)
One drop of diisopropylethylamine (0.191 ml,
1.1 mmol) was added followed by diphenylchlorophosphate (0.228 ml, 1.1 mmol) at 0<0>C under _N2 . After stirring for 1 hour at 0°C, the enol phosphate formed was treated with diisopropylethylamine (0.226 ml, 1.3 mmol) followed by 1-methyl-1-(2-mercaptoethyl)morpholinium trifluoromethanesulfonate (0.373 ml, 1.3 mmol).
g, 1.2 mmol) was added. Reaction mixture at room temperature
Stirred for 1.5 hours then concentrated in vacuo. The residual material was dissolved in H ₂ O and applied to a C ₁₈ reverse phase column. _H2
O, then 20% acetonitrile- _H2O , and finally
Elution with 30% acetonitrile- _H2O and lyophilization of the relevant fractions gave the product (0.360 g, 40%) as an amorphous solid. ir (film) 3300 (-OH), 1770 (β-lactam CO), 1700 (-CO ₂ PNB) cm ^-1 ; ¹ Hmr (d ₆
- acetone) δ: 8.25, 7.80 (ABq, J = 8.6Hz,
4H, aromatic), 7.4−6.8 (m, 10H, diphenyl phosphate), 5.56, 5.27 (ABq, J = 14.2Hz,
2H, Benjirik), 4.42 (d of t, J = 9.2Hz,
J' = 2.7Hz, 1H, H-5), 4.1-2.7 (m, 17H),
3.40 (s, 3H, N-Me), 1.22 (d, J = 6.2Hz,
3H, −CHMe). C ( 5R , 6S )-3-[2-(1-methylmorpholino)ethylthio]-6-[( R )-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept- 2-ene-2-carboxylate p-Nitolbenzyl (5 R ,6 S )-3-[2
-(1-methylmorpholino)ethylthio]-6-
[( R )-1-hydroxyethyl]-7-oxo-
1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate diphenyl phosphate (0.360 g, 0.49 mmol) in 13 ml of phosphate buffer (0.05 M PH 7.4) with 10% palladium on charcoal. (0.36g), tetrahydrofuran (20ml) and diethyl ether (20ml)
added. The mixture was hydrogenated (Parr) at 32 psi for 1 hour. The mixture was filtered through celide and the overpad was washed with H ₂ O and diethyl ether. The aqueous phase was removed and another PH7.4 phosphate buffer was added to bring the pH to 7.0.
After removing the residual organic solvent in vacuo, the aqueous solution was applied to a C ₁₈ reverse phase column. Elution with H ₂ O and lyophilization of the relevant fractions gave 0.130 g of an amorphous solid. This material was purified by reverse phase HPLC to give the pure product (0.058 g, 34%) as an amorphous solid.
I got it. ir (KBr) ν _nax : 3420 (br, OH), 1750 (β−
lactam CO), 1590 (−CO _2- ) cm ⁻¹ ; ¹ Hmr (D ₂
O) δ: 4.35−2.77 (m, 17H), 3.18 (s, 3H,
N-Me), 1.23 (d, J = 6.3Hz, 3H,
CHMe); uv (H ₂ O) λ _nax : 300 (ε6344) nm;
t _1/2 (PH7.4, 36.8℃) 18.5h. Example 18 ( 5R , 6S )-3-[2-(1,4-dimethyl-1-piperazinium)ethylthio]-6-[1
-( R )-hydroxyethyl]-7-oxo-1
-Azabicyclo[3.2.0]hept-2-ene-
Production of 2-carboxylate A 1-(2-acetylthioethyl)-1,4-dimethylpiperazinium bromide 2-bromoethylthiol acetate ^*
(2.20 g, 0.012 mol) and 1,4-dimethylpiperazine (1.95 ml, 0.014 mol) in acetone (4
ml) The solution was stirred at 50°C for 65 hours. After cooling to 25° C., the liquid phase was decanted and the gum was triturated twice in diethyl ether to yield 3.2 g (90%) of a yellowish hygroscopic powder; Nujol) ν _nax : 1685 (C= of thioester
O) cm ^-1 ; ¹ Hmr (D ₂ O) δ: 2.37, 2.39 (2s,
6H, [formula] [formula]), 3.18 (s, 3H, [formula]). *B.Hansen, Acta Chem . Scand ． 11 ,
537-40 (1957) B 1,4-dimethyl-1-(2-mercaptoethyl)piperazinium bromide hydrochloride 1-(2-acetylthioethyl)-1,4-dimethylpiperazinium bromide (1.1 g,
A solution of 3.7 mmol) of 6 N hydrochloric acid (4 ml) was heated to 80° C. for 1 hour under a nitrogen atmosphere. The solution was concentrated under reduced pressure to yield a white powder, 0.14 g (38%); ¹ Hmr
(DMSO, d ₆ ) δ: 2.90 (s,
[Formula]), 3.26(s, [Formula]). Elemental analysis: Calculated values (as C ₈ H ₂₀ N ₂ SBrCl・H ₂ O): C31.03, H7.16, N9.05, S10.35; Actual values: C31.62, H7.46, N9.19 , S10.19. C (5 R ,6 S ) paranitrobenzyl 3-[2
-(1.4-dimethyl-1-piperazinium)-ethylthio]-6-[1-( R )-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]
Hept-2-ene-2-carboxylate diphenyl phosphate ( 5R , 6S ) paranitrobenzyl 6-[1-( R )-hydroxyethyl]-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-( R ) kept under nitrogen atmosphere - Diisopropylethylamine (0.278 ml, 1.59 mmol) and diphenylchlorophosphate (0.33 ml, 1.59 mmol) in a cold (0°C) solution of carboxylate (0.465 g, 1.33 mmol) in acetonitrile (2 ml).
added. The reaction mixture was stirred for 30 minutes and 1,4-dimethyl-1-(2-mercaptoethyl)piperazinium bromide hydrochloride (0.40%
g, 1.37 mmol) and diisopropylethylamine (0.278 ml, 1.59 mmol). After stirring for 18 hours at 5°C, cold water (15ml) was added to the mixture. The obtained solution was transferred to PrepPak-500/
C ₁₈ (Waters Associates) column (2.5 x 7.5 cm)
chromatographic fractionation using water containing 25-35% acetonitrile as an eluent, and after freeze-drying,
0.50 g (50%) of yellowish powder was obtained; ir (KBr) ν _nax : 1765 (C=
_{1 Hmr} ^{_ _}
(DMSO, d ₆ ) δ: 1.16, 1.18 (2d, J = 6.1Hz,
3H, CH ₃ CHOH), 2.44 (s,
[Formula]), 3.14 (s, [Formula]), 5.31 (d, J = 6Hz, OH), 5.39 (center of ABq), J = 13Hz,
_CH2 of PNB), 6.6−7.4 (m, 10H, phenyl of phosphate), 7.71 (d, J = 8.8Hz, 2H,
PNB's Ho), 8.26 (d, J = 8.8Hz, PNB's
Hm). D( 5R , 6S )-3-[2-(1,4-dimethyl-1-piperazinium)ethylthio]-6-
[1-( R )-hydroxyethyl]-7-oxo-
1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate ( 5R , 6S )paranitrobenzyl 3-[2
-(1,4-dimethyl-1-piperazinium)
Ethylthio]-6-[1-( R )-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]
A solution of hept-2-ene-2-carboxylate diphenyl phosphate (0.47 g, 0.623 mmol) in wet tetrahydrofuran (25 ml) in diethyl ether (25 ml), monobasic potassium phosphate-sodium hydroxide buffer ( 13
ml, PH 7.22) and 10% palladium on charcoal (0.47 g) were added. The resulting mixture was heated to 23°C.
Hydrogenated at 40 psi for 1 hour. The two layers were separated and the organic layer was extracted with water (2x7ml). The combined aqueous phases were filtered through a pad of Celite, washed with diethyl ether (2 x 15 ml) and washed with PrepPak-500/C _18.
(Waters Associates) Column (2.5 x 9.5cm)
After chromatographic fractionation using water as the eluent and freeze-drying, 0.097 g (43%) of the product was obtained; ir (KBr) ν _nax : 3000−3700 (OH), 1750 (β
-lactam C=O), 1585 (carboxylate) cm ^-1 ; 1 Hmr (D ₂ ) δ: 1.24 (d, J = 6.4
Hz, 3H, CH ₃ CHOH), 2.33 (s, 3H,
[Formula]), 3.15 (s, [Formula]), 4.0-4.5 (m, H-5, CH ₃ C H OH), uv (H ₂ O) λ _nax : 296 (ε9476),
[α] ²³ _D 61.1° (C0.26, H ₂ O), t _1/2 = 12.4h (condition A
). Example 19 ( 5R , 6S )-3-[2-(N-methyl-thiomorpholinium oxide)ethylthio]-6-[1
-( R )-hydroxyethyl]-7-oxo-1-
Azabicyclo[3.2.0]-hept-2-ene-2-
Production of carboxylates ( 5R , 6S )-3-[2-(N-methyl-thiomorpholinium)ethylthio]-6-[1-( R )-
Hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate (608 mg, 1.65 mmol) in a 1:1 mixture of acetonitrile and water (9 ml) cold (-10°C) m in solution
-Chloroperbenzoic acid (334.8 mg, 1.65 mmol) was added in portions over 1 hour. Then mix the mixture with water (15
ml) and washed with diethyl ether (3 x 15 ml). The aqueous phase was pumped to vacuum and passed through a reverse phase silica gel column (H ₂ O) to obtain a solid consisting of a mixture of compounds. This mixture was separated by reverse phase hplc to give 52.4 mg (12% yield) of fraction A and 23.6 mg (6% yield) of fraction B as diastereomers of the title compound; fraction A: ir(nujol)v _nax :1750(s, β
-lactam C=O) and 1580cm ^-1 (s, C=
O); ¹ Hmr (D ₂ O) δ: 4.26−2.91 (20H, m, H
-4, H-5, H-6, H-1', CH ₂ S, CH ₂ S
−O, CH ₃ −N ⁺ and CH ₂ N ⁺ ) and 1.24ppm
(3H, d, J = 6.4Hz, CH ₃ ); uv (H ₂ O, c0.06)
λ _nax : 302 (ε10425); t _1/2 : 12h (0.065M, PH7.4 phosphate buffer, 37°C). Fraction B: ir (nujol) ν _nax : 1750 (s, β-lactam C=
O and 1585cm ^-1 (s, C=O); 1Hmr (D ₂ O)
δ: 3.86-2.90 (17H, m, H-4, H-5, H-
6, H−1′, CH ₂ S, CH ₂ S−O, CH ₂ −N ⁺ ),
3.25 (3H, s, CH ₃ N ⁺ ) and 1.24 ppm (3H, d,
J=6.4Hz, CH ₃ ); uv (H ₂ O, c0.05) λ _nax : 2.99
(ε65175); t _1/2 : 10.75h (0.065M, PH7.4 buffer solution, 37°C). Example 20 ( 5R , 6S )-3-[2-(1,<4,4-trimethyl-1-piperazinium)ethylthio]-
6-[1 R -hydroxyethyl]-7-oxo-
Production of 1-azabicyclo(3.2.0)hept-2-ene-2-carboxylate chloride A 1-(2-acetylthioethyl)-1,4,4
-Trimethylpiperazinium bromide iodide 1- in isopropyl alcohol (10ml)
(2-acetylthioethyl)-1,4-dimethylpiperazinium bromide (1.48g,
A suspension of 5.0 mmol) was treated with methyl iodide (0.373 ml, 6.0 mmol) and incubated at 55−60 °C for 30
heated for an hour. The solvent was evaporated under reduced pressure, the residue was triturated in hexane and the solids were separated. 1.85
This solid was dissolved in hot water (8 ml) and diluted with acetone until cloudy (70-80 ml). 1.5g after two consecutive recrystallizations, melting point 220-5℃ (dec.), 68%
The title compound was obtained; ir (KBr) ν _nax : 1692 cm ^-1 (C=O); ¹ Hmr
(D ₂ O) δ: 2.40 (s, 3H, CH ₃ COO), 3.37
(s, N-CH ₃ ), 3.39 (s, N-CH ₃ ), 3.99
(s); uv (H ₂ O) λ _nax : 226 (ε13144). Elemental analysis: Calculated value (C ₁₁ H ₂₄ N ₂ OSBrI): C30.08,
H5.51, N6.38; Actual value: C30.48, H5.53,
N6.86. B 1-(2-mercaptoethyl)-1,4,4-
Triethylpiperazinium bischloride 1-(2-acetylthioethyl)-1,4,4
-trimethylpiperazinium bromide iodide (1.84 g, 4.19 mmol) and 6 N hydrochloric acid (15
ml) was heated at 57° C. for 2.5 h under nitrogen atmosphere. This solution was concentrated to dryness under reduced pressure.
The solid was suspended in water (10 ml) and the well-stirred suspension was passed through palm chit S-1 until a solution was obtained.
Treated with ^C- . Pour the solution into palm chit S-1
It was poured into a column of C ^- (1.2 x 60 cm). The column was eluted with water (1.5ml/min). Combine appropriate fractions and freeze-dry to produce a white powder,
Obtained 0.93 g, melting point 190-191 °C, 85%; ir (nujol) ν _nax ; 2460 (SH); ¹ Hmr (D ₂ O)
δ: 3.4 (s, N-CH ₃ ), 3.45 (s, N-CH ₃ ),
4.07(s). Elemental analysis: Calculated value (C ₉ H ₂₂ N ₂ SCI ₂・
0.75H ₂ O): C39.34, H8.62, N10.20,
S11.67; Actual value: C39.48, H8.39, N10.55,
S11.15. C (5 R ,6 S ) paranitrobenzyl 3-[2
-(1,4,4-trimethyl-1-piperazinium)-ethylthio]-6-[1 R -hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylate Bischloride (5 R ,6 S ) paranitrobenzyl 6-[1 R -hydroxyethyl]- kept under nitrogen atmosphere
3,7-dioxo-1-azabicyclo (3.2.0)
Heptane- 2R -carboxylate (0.94g,
2.7 mmol) of acetonitrile (3 ml) cold (5
To the solution were added diisopropylethylamine (0.557ml, 3.2mmol) and diphenylchlorophosphate (0.663ml, 3.2mmol).
The reaction mixture was stirred at 5°C for 30 minutes and diisopropylethylamine (0.599 ml, 3.44 mmol) and 1-(2-mercaptoethyl)-1,4,4-trimethylpiperazinium bischloride (0.90
g, 3.44 mmol) in water (4 ml).
After 1.25 hours, diisopropylethylamine (0.1 ml, 0.57 mmol) was added and stirring continued for 2 hours. Part of the acetonitrile was removed under reduced pressure, and the resulting red mixture was transferred to PrepPak-500/C ₁₈
It was chromatographed on a (Water Associates) column using water containing 25-75% acetonitrile as the eluent and lyophilized to give a yellowish powder (1.4 g). Dissolve this powder in water and apply it to a palmchit S-1 Cl ^- column (1.2 x 58 cm).
was passed through water as the eluent. Freeze-drying of the appropriate fraction yielded 1.17 g of powder, which was repurified on a PrepPak-500/C ₁₈ column, and freeze-drying of the appropriate fraction yielded 0.80 g (53%) of a yellowish powder. : ir (KBr) ν _nax : 3400 (br, OH), 1770 (β−
lactam C=O), 1690 (PNB ester C
=O), 1605 (aromatic), 1515 (NO ₂ ), 1345
(NO ₂ ) cm ^-1 ; ¹ Hmr (D ₂ O) δ: 1.26 (d, J =
6.3Hz, 3H, CH ₃ CHOH), 3.39(s, N-
CH ₃ ), 4.00 (s), 5.37 (br, s, CH ₂ of PNB),
7.60 (d, J = 8.6Hz, 2H, PNB Ho), 8.20
(d, J = 8.7Hz, 2H, Hm of PNB); uv (H ₂
O) λ _nax : 276 (ε12094), 306 (ε10752). Elemental analysis: Calculated values (as C ₂₅ H ₃₆ N ₄ O ₆ SCl ₂・3H ₂ O): C46.51, H6.56, N8.68, S4.97,
Cl10.98; Actual value: C46.31, H6.18, N8.57,
S5.36, Cl11.37. D( 5R , 6S )-3-[2-(1,4,4-trimethyl-1-piperazinium)ethylthio]
-6-[1 R -hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylate chloride ( 5R , 6S )paranitrobenzyl 3-[2
-(1,4,4-trimethyl-1-piperazinium)ethylthio]-6-[1 R -hydroxyethyl]-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylate bis Chloride (0.40g, 0.68mmol), phosphate buffer (30ml, 0.05M, PH
7.0) Tetrahydrofuran (10ml), ether (30ml) and 10% palladium on charcoal (0.40g)
The mixture was hydrogenated at 23° C. and 35 psi for 1 hour. The two phases were separated and the organic phase was extracted with water (10ml). The aqueous phase was passed through a Celite pad and ether (10
ml), vacuum concentrated to 10 ml and PrepPak-
Chromatographed on a 500/C ₁₈ column (2.2 x 11 cm) using water as the eluent, and after freeze-drying, 70 mg
(25%); ir (KBr) ν _nax : 3400 (br, OH), 1755 (C=O of β-lactam), 1585 (carboxylate) cm ^-
1 ; ¹ Hmr (D ₂ O) δ: 1.24 (3H, d, J = 6.3Hz,
C H ₃ CHOH), 3.36 (s, NCH ₃ ), 3.98 (s); uv
(H ₂ O) λ _nax : 296 (ε7987); [α] ²³ _D 35.9° (c
，
0.30, H ₂ O), t _1/2 = 9.8 h (measured under condition A). The carbapenems obtained by the method of the invention have a potent broad-spectrum antibacterial activity, to illustrate which, with respect to the preferred carbapenem compounds according to the invention, the in vitro and in vivo bioactivity of the compounds The scientific data and low toxicity are shown below. In Vitro Activity Samples of carbapenem compounds obtained according to the invention have the following minimum inhibitory concentrations (MICs) determined by incubation overnight at 37° C. by dilution in tubes after dilution in aqueous solution and nutrient broth. (meg/
ml) versus the indicated microorganism). [Table] [Table] In Vivo Activity The in vivo therapeutic efficacy of the compound of Example 1 after intramuscular administration to mice experimentally infected with various microorganisms is shown in the following table. PD ₅₀ (dose required to confer protection in 50% of infected mice, mg/Kg) is shown. [Table] [Table] Treatment plan: Intramuscular treatment of mice with drugs at 0 and 2 hours after infection (A21559, A15167-2,
A9900, A9843a, A20481, A20599)
or 1 and 3.5 hours (all others); 5 mice were used for each test. Toxicity The toxicity of the compound of Example 1 after intracranial administration in mice was determined and compared to N-formimidoylthienamycin and is shown in the following table. [Table] *Average of 25 mice/compound

Claims (1)

[Claims] 1 formula ( _wherein R ⁸ is hydrogen _{and R} ¹ _is R ² is hydrogen, an anionic charge or a conventional easily removable carbonyl protecting group (if R ² is hydrogen or a protecting group, a counteranion is also present); ; R ¹⁴ is a quaternized nitrogen-containing aromatic or non-aromatic heterocycle bonded to A via its ring nitrogen, thereby forming a quaternary ammonium group;
However, the aromatic heterocycle has the formula [Formula] or [Formula] (wherein R ⁵ , R ⁶ and R ⁷ are independently hydrogen, C ₁ -
selected from the group consisting of C ₄ alkyl, _{C 1} -C ₄ alkoxy, C 1 -C ₄ alkyl substituted with hydroxy group, C ₁ -C ₄ alkylthio and amino, where R is C ₁ -C ₄ alkyl ), and the non-aromatic heterocycle is of the formula (In the formula, [formula] is an alicyclic heterocyclic group containing at least one nitrogen atom in the ring, and R ₁₆
is a C ₁ -C ₄ alkyl group) or a pharmaceutically acceptable salt thereof, the method for producing a carbapenem derivative of the formula (However, R ¹ and R ⁸ are as defined above,
R ² ' is a conventional easily removable carboxyl protecting group and L is a leaving group selected from the group consisting of halogen, organic sulfonyloxy and organic phosphinyloxy). -A-R ¹⁴ X (However, A and R ¹⁴ are as defined above,
X is a counter anion) and is reacted with a thiol compound of the formula (wherein R ¹ , R ⁸ , R ² ′, A, R ¹⁴ and A formula characterized by obtaining a deprotected compound or a pharmaceutically acceptable salt thereof A method for producing a carbapenem derivative or a pharmaceutically acceptable salt thereof. 2 The base is a non-nucleophilic tertiary amine or tri(C _1
-C4 ) The method according to claim 1, wherein the alkylamine is an alkylamine. 3. The method according to claim 2, wherein the base is a non-nucleophilic tertiary amine. 4. The method according to claim 1, 2 or 3, wherein the reaction is carried out at a temperature from -15°C to room temperature. 5. The method of claim 4, wherein the reaction is carried out at a temperature in the range of about -15°C to +15°C. 6 The inert solvent is acetonitrile, a mixture of acetonitrile, dimethylformamide, tetrahydrofuran, a mixture of tetrahydrofuran and water,
6. A method according to any one of claims 1, 2, 3, 4 or 5 selected from the group consisting of acetonitrile and a mixture of water and acetone.