AU745980B2

AU745980B2 - Titanium catalyzed preparation of carbapenem intermediates

Info

Publication number: AU745980B2
Application number: AU34908/99A
Authority: AU
Inventors: Philip J. Pye; Paul J. Reider; Kai Rossen; Ralph P. Volante
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1998-04-16
Filing date: 1999-04-12
Publication date: 2002-04-11
Anticipated expiration: 2019-04-12
Also published as: EP1071685A4; CA2328219A1; JP2002511470A; EP1071685A1; WO1999052908A1; AU3490899A

Description

WO 99/52908 PCT/US99/07956 TITLE OF THE INVENTION TITANIUM CATALYZED PREPARATION OF CARBAPENEM INTERMEDIATES BACKGROUND OF THE INVENTION The present invention relates to a process for synthesizing 1-p-methyl-2- hydroxymethyl carbapenem intermediates. Generally the carbapenems are substituted at the 2-position. The intermediate compounds are included as well.

European applications 0330108, 0102239, 0212404, 0695753 and 0476649 disclose methods for synthesizing various antibiotic derivatives.

Many of the carbapenems are useful against gram positive microorganisms, especially methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS). These antibacterials thus comprise an important contribution to therapy for treating infections caused by these difficult to control pathogens. There is an increasing need for agents effective against such pathogens (MRSA/MRCNS) which are at the same time relatively free from undesirable side effects.

SUMMARY OF THE INVENTION The invention describes a short and high yielding synthesis of protected 1-P-methyl-2-hydroxymethyl substituted carbapenems as key intermediates for the synthesis of anti-MRSA carbapenem antibiotics.

The synthesis involves a highly diastereoselective addition of a titanium, zirconium or hafnium enolate of a suitably protected 1-hydroxy-2butanone derivative with 4-acyl-2-azetidinone. Using this enolate, the resulting derivatized 2-azetidinone product is obtained largely as a single diastereomer rather than a mixture. Additionally, the two chiral centers which are produced are of the correct absolute stereochemical -1configuration for subsequent synthesis of 1-p-methyl-2-hydroxymethyl substituted carbapenems.

The first aspect of the invention provides a process of synthesizing a compound of formula 2:

OR

1

X

H

3 C HH YR 2 NH O 0 2 wherein R' represents H or a suitable protecting group for an alcohol; R 2 represents a benzyl, CI- 6 alkyl or aryl; Y represents C 1 -3 alkyl, 0, NH or S; and X represents O, NH, or

S

comprising reacting a compound of formula 1: OR1

H

3 C HH R4

NH

10 1 wherein R' is described above and R 4 represents C 1 1 5 alkyl, aryl or Ci-6 aralkyl; with a compound of formula 3: O

YR

2 X 3 wherein R 2 X and Y are as previously defined in the presence of WZ 4 and an amine to S I5 produce a compound of formula 2, wherein W is a titanium, zirconium or hafnium metal and Z represents halo, sulfonate, alkoxy, aryloxy or combination thereof.

The second aspect of the invention provides a process of synthesizing compound of formula x H3C H1- Y R 2 N 0 0 O-R wherein R' represents H or a suitable protecting group for an alcohol; R 2 represents a benzyl, C.-6 alkyl or aryl; Y represents CI-3 alkyl, 0, NH or S; X represents O, NH, or S and R 5 represents a carboxy protecting group, comprising reacting a compound of formula 2: [I:\DAYLIB\LIBXX]03085.do:aak wherein R 2 X and Y are as previously described, with an activated protected oxalic acid agent in the presence of a base to produce a compound of formula The third aspect of the present invention provides a process of synthesizing a compound of structural formula 6:

OR

1 H H

H

3 O YR 2

CO

2

R

5 6 wherein R' represents H or a suitable protecting group for an alcohol; R 2 represents a benzyl, Ci- 6 alkyl or aryl; Y represents C1- 3 alkyl, 0, NH or S; X represents O, NH, or S and R 5 represents a carboxy protecting group, comprising reacting a compound of formula

OR

1

H

3 C H H YR2

N

0 O-R wherein R 2

R

5 X and Y are as previously described with a phosphite or phosphonite reagent to produce a compound of formula 6.

The fourth aspect of the present invention, a process of synthesizing a carbapenem compound of formula 6: wherein R' represents H or a suitable protecting group for an alcohol; R 2 represents a benzyl, C 1 6 alkyl or aryl; Y represents Ci.3 alkyl, 0, NH or S; X represents O, NH, or S and R 5 represents a carboxy protecting group, comprising reacting a compound of formula 2: [I:\DAYLIB\LIBXX]3085.odocaak u 2 wherein R 1

R

2 X and Y are as previously described, with an activated protected oxalic acid agent in the presence of a base to produce a compound of formula

OR

1 x

H

3 C H H "I YR 2 O 0 S

O-R

and reacting a compound of formula 5, wherein R 2

R

The fifth aspect of the invention provides a process of synthesizing a carbapenem compound of formula 6:

OR

1

H

O s H O

CO

2 R5 6 *i 10 wherein R' represents H or a suitable protecting group for an alcohol; R 2 represents a benzyl, CI- 6 alkyl or aryl; Y represents Ci 1 3 alkyl, 0, NH or S; X represents O, NH, or S and R represents a carboxy protecting group, comprising reacting a compound of formula 1:

OR

1

H

3 C H O R4

NH

O 1 is wherein R' is described above and R 4 represents C 1 15 alkyl, aryl or C 1 6 aralkyl; with a compound of formula 3: O YR 2 x 3 2 wherein R 2 X and Y are as previously defined in the presence of WZ 4 and an amine to F i Sduce a compound of formula 2:

H

3 C H YR2 NH 0 0 2 wherein W is a titanium, zirconium or hafnium metal and Z represents halo, sulfonate, alkoxy, aryloxy or combination thereof, and R 2 X and Y are as previously described, reacting a compound of formula 2 with an activated protected oxalic acid agent in the presence of a base to produce a compound of formula

OR

1

X

H

3 C HH 0 O YR 2 N 0 O 0 O O-R 2 and reacting a compound of formula 5, wherein R R 2

R

The sixth aspect of the invention provides a process of synthesizing a carbapenem 10 compound of formula

OR

H3C HH 0AYR2

N

t O 0--R 5 0 O-R wherein R' represents H or a suitable protecting group for an alcohol; R 2 represents a benzyl, C 1 -6 alkyl or aryl; Y represents C 1 3 alkyl, 0, NH or S; X represents O, NH, or S S..and R 5 represents a carboxy protecting group, comprising reacting a compound of formula 1:

OR

1

H

3 C H o R 4

NH

O

wherein R' is described above and R 4 represents C1- 1 5 alkyl, aryl or CI- 6 aralkyl; with a compound of formula 3: I O YR 3 ZZx [I:\DAYLIB\LIBXX]03085.doc:aak S 1" 2d wherein R 2 X and Y are as previously defined in the presence of WZ 4 and an amine to produce a compound of formula 2:

OR

1

H

3 C H H YR 2 NH O 0 2 wherein W is a titanium, zirconium or hafnium metal and Z represents halo, sulfonate, alkoxy, aryloxy or combination thereof, and R 2 X and Y are as previously described, and reacting a compound of formula 2 with a pNB oxalimide forming agent in the presence of a base to produce a compound of formula The seventh aspect of the present invention provides a process of synthesizing a compound of formula 2:

OR

1

X

H

3 C HH 0 YR 1 2 wherein R represents a member selected from the group consisting of: H, TES, TMS, TBDMS, and pNB; R 2 represents ethyl or isobutyl; Y represents 0; and X represents O comprising reacting a compound of formula 1:

OR

1 0

H

3 C H H R

NH

15 wherein R 1 is described above and R 4 represents Ci- 15 alkyl, aryl or Ci-6 aralkyl; with a compound of formula 3: X 3 wherein R 2 X and Y are as previously defined in the presence of WZ 4 and an amine to produce a compound of formula 2, wherein W is a titanium and Z represents chloride.

The eighth aspect of the invention further provides a process of synthesizing a carbapenem compound of formula 6:

OR

1 SH3

SCO

2 R 6 C 0 2R 6 [I:\DAYLIB\LIBXX]03085.doc:aak 2e wherein R' represents a member selected from the group consisting of H, TES, TMS, TBDMS, and pNB; R 2 represents ethyl or isobutyl; Y represents 0; and X represents O; and R 5 represents p-nitrobenzyl (PNB) or benzyl comprising reacting a compound of formula 1:

OR

H3C H H 0

R

4

NH

O 1 wherein R' is described above and R 4 represents C1- 15 alkyl, aryl or C 1 6 aralkyl; with a compound of formula 3: O

R

2 x 3 wherein R 2 X and Y are as previously defined, in the presence of WZ 4 and amine to produce a compound of formula 2, wherein W is a titanium and Z represents chloride to produce a compound of formula 2:

OR

H

3 C YR o NH O 0 2 reacting a compound of formula 2 with a pNB oxalyl chloride in the presence of a base such as pyridine, lutidine or collidine to produce a compound of formula

OR'

1

X

H

3 C HH 0 2YR2

N

15 O O-R and reacting a compound of formula 5, wherein R 2

R

5 X and Y are as previously described with triethylphosphite to produce a compound of formula 6.

The ninth aspect of the invention further provides a compound of formula 2 produced in accordance to the process of aspect 1 or 7.

The tenth aspect of the invention provides a compound of formula 2a produced in accordance to the process of aspect 1 or 7.

The eleventh aspect of the invention provides a compound of formula 5 produced in 7accordance to the process of aspect 2 or 6.

[I:\DAYLIB\LIBXX]03085.doc:aak 2f The twelfth aspect of the invention provides a compound of formnula 6 produced in accordance to the process of any one of the aspects 3, 4, 5 and 8.

[I:\DAYLIB\LIBXX]03085.doc~aak Detailed Description of the Invention The present invention relates to a process for making protected 1-P-methyl-2-hydroxymethyl substituted carbapenems which are key intermediates in the synthesis of anti-MRSA carbapenem antibiotics (such as those disclosed in WO 99/52908 filed on April 08, 1997, the teachings of which are hereby incorporated by reference).

The intermediates can be readily coupled to a wide range of functional groups (see WO 99/52908).

The invention is described herein in detail using the terms defined below unless otherwise specified.

The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl and cyclohexyl. When substituted, alkyl groups may be substituted with up to four substituent groups, selected from Rd and as defined, at any available 15 point of attachment. When the alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group".

Cycloalkyl is a species of alkyl containing from 3 to 15 carbon atoms, without alternating or resonating double bonds between carbon atoms. It may contain from 1 to 4 S: rings which are fused.

The term "alkenyl" refers to a hydrocarbon radical straight, branched or cyclic i: containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond.

Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl.

The term "alkynyl" refers to a hydrocarbon radical straight or branched, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Preferred 25 alkynyl groups include ethynyl, propynyl and butynyl.

e Aryl refers to aromatic rings phenyl, substituted phenyl and the like as well as rings which are fused, naphthyl, phenanthrenyl and the like. An aryl group thus contains at least one [I:\DAYLIB\LIBXX]03085.doc:aak WO 99/52908 PCT/US99/07956 ring having at least 5 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. The preferred aryl groups are phenyl, naphthyl and phenanthrenyl. Aryl groups may likewise be substituted as defined. Preferred substituted aryls include phenyl and naphthyl.

Aryl also refer to heteroaryl, which is a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a polycyclic aromatic group having 8 to 16 atoms, containing at least one heteroatom, 0, S, S02 or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from 0 or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, said heteroaryl group being optionally substituted as described herein. Examples of this type are pyrrole, pyridine, oxazole, thiazole and oxazine. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole and the like.

As used herein, "aralkyl" is intended to mean an aryl or heteroaralkyl moiety, as defined above, attached through a C1.

6 alkyl linker, where alkyl is defined above. Examples of aralkyls include, but are not limited to, benzyl, naphtylmethyl, phenylpropyl, 2-pyridylmethyl, 2-imidazolylethyl, 2-quinolinylmethy, 2-imidazolylmethyl and the like.

Examples of polycyclic heteroaromatics include benzopyrans, benzofurans, benzopyrroles, benzimidazoles, benzothiazoles, quinolines, purines, isoquinolines, benzopyrimidines, dibenzofurans, dibenzothiophenes, 1,8-naphthosultams, The term "heterocycle" (heterocyclyl) refers to a 5-16 membered cycloalkyl group (nonaromatic) with 1-4 rings, in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S or N, and in which up to three additional carbon atoms may be replaced by heteroatoms.

The term "heteroatom" means O, S, S(O) 2 or N, selected on an independent basis.

-4- WO 99/52908 PCT/US99/07956 Halogen and "halo" refer to bromine, chlorine, fluorine and iodine.

When a group is termed "protected", such as R 1

R

5 and the like, this means that the group is in modified form to preclude undesired side reactions at the protected site. Suitable protecting groups for the compounds of the present invention will be recognized from the present application taking into account the level of skill in the art, and with reference to standard textbooks, such as Greene, T. W. et al. Protective Groups in Organic Synthesis Wiley, New York (1991). Examples of suitable protecting groups are contained throughout the specification.

In some of the compounds of the present invention, R 1 and

R

5 represent alcohol and carboxyl protecting groups, respectively.

Likewise, Y may represent a protecting group for X, which in turn represents 0 or N. These groups are generally removable, they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing agents under mild conditions, treatment with a transition metal catalyst and a nucleophile and catalytic hydrogenation.

Examples of carboxyl protecting groups R 5 include allyl, benzhydryl, 2-naphthylmethyl, benzyl, silyl groups such as t-butyldimethylsilyl (TBDMS), trimethylsilyl, (TMS), triethylsilyl (TES), phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl, pnitrobenzyl (pNB), 4-pyridylmethyl and t-butyl, preferably pNB and benzyl.

Examples of suitable alcohol protecting groups R 1 include hydrogen, trialkylsilyl, diarylalkylsilyl, aryldialkylsilyl or trityl such as TMS, TES, TBDMS, alkyl carbonates such as benzyl carbonate, allyl carbonate, benzyl ether, diarylalkylsilyl, aryldialkylsilyl trityl and the like. Preferred R 1 groups are trialkylsilyl or hydrogen.

Another aspect of the process that is of particular interest is the synthesis of a compound of formula WO 99/52908 PCT/US99/07956

H

3 C' O YR 2

OO

TN T 0 0 0 O-R wherein R' represents H or a suitable protecting group for an alcohol; R 2 represents a benzyl, C 1 alkyl or aryl; Y represents C l alkyl, 0, NH or S; X represents O, NH, or S and R 5 represents a carboxy protecting group, comprising reacting a compound of formula 2:

R

1

H

3 C H 0 YR2 NH 0 0 2 wherein R1, R 2 X and Y are as previously described, with an activated oxalic acid agent in the presence of a base to produce a compound of formula In another aspect of the invention a process for synthesizing a compound of structural formula 6

R'

Hx

H

3 C H IX yR2 S O YR 0 N 6 CO 2

R

is disclosed wherein R 1 represents H or a suitable protecting group for an alcohol; R 2 represents a benzyl, C, 6 alkyl or aryl; Y represents C.

3 alkyl, WO 99/52908 PCT/US99/07956 O, NH or S; X represents O, NH, or S and R 5 represents a carboxy protecting group, comprising reacting a compound of formula R x HHC H

H

3 0 O0 YR 2

N

0 0 O' 0 0-R wherein R 2

R

Another aspect of the process that is of interest is the synthesis of a carbapenem compound of formula 6

R'

H

3 C H H 0 YR2 N

O

CO2R 6 C 2

R

wherein R' represents H or a suitable protecting group for an alcohol; R 2 represents a benzyl, C.

6 alkyl or aryl; Y represents C1 3 alkyl, 0, NH or S; X represents O, NH, or S and R 5 represents a carboxy protecting group, comprising reacting a compound of formula 2:

R

1

H

3 C HO YR2

NH

0 O 2 -7- WO 99/52908 PCT/US99/07956 wherein R1, R 2 X and Y are as previously described, with an activated oxalic acid agent in the presence of a base to produce a compound of formula

H

3

C

YR

2 O 'O-R and reacting a compound of formula 5, wherein R 2

R

H

3

C

x YR 2 wherein R 1 represents H or a suitable protecting group for an alcohol; R 2 represents a benzyl, C.G alkyl or aryl; Y represents C 1 .3 alkyl, 0, NH or S; X represents O, NH, or S and R 5 represents a carboxy protecting group, comprising reacting a compound of formula 1: WO 99/52908 PCT/US99/07956

H

3

C/

NH

0 1 wherein R' is described above and R 4 represents C15, alkyl, aryl or C,.

aralkyl; with a compound of formula 3: ^Y O YR 2 x 3 wherein R 2 X and Y are as previously defined in the presence of WZ 4 and an amine to produce a compound of formula 2:

R

1 x

H

3C 0/ YR 2

O

NH

0 2 wherein W is a titanium, zirconium or hafnium metal and Z represents halo, sulfonate, alkoxy, aryloxy or combination thereof, and R1, R 2

X

and Y are as previously described, reacting a compound of formula 2 with an activated oxalic acid agent in the presence of a base to produce a compound of formula WO 99/52908 PCT/US99/07956

R'

1 x H3C O YR 2 0 o 0 O-R and reacting a compound of formula 5, wherein R 1

R

2

R

Another aspect of the process that is of particular interest is the synthesis of a compound of formula

R

1 x H

H

3 C 0 A

YR

2 O0 N 0 0 0 0 O-R wherein R 1 represents H or a suitable protecting group for an alcohol; R 2 represents a benzyl, C 1 alkyl or aryl; Y represents C 1 3 alkyl, 0, NH or S; X represents O, NH, or S and R 5 represents a carboxy protecting group, comprising reacting a compound of formula 1: OR 0

-NH

01 WO 99/52908 PCT/US99/07956 wherein R 1 is described above and R 4 represents C 1 1 alkyl, aryl or C 1 6 aralkyl; with a compound of formula 3: O

YR

2

X

3 wherein R 2 X and Y are as previously defined in the presence of WZ 4 and an amine to produce a compound of formula 2:

R'

H

3 c0 HH o YR2

O

NH

X

and Y are as previously described, and reacting a compound of formula 2 with an oxalimide forming agent in the presence of a base to produce a compound of formula Suitable amines includes trialkylamines such as triethylamine, tributylamine, trimethylamine, ethyldimethylamine, trin-propylamine, di-isopropylethylamine, aniline, N,N-di-C1.alkylanilines such as N,N-diethylaniline and the like.

Suitable bases include trialkylamines such as triethylamine, trimethylamine, ethyldimethylamine, tri-n-propylamine and the like, 1,8-diazabicyclo[5.4.0.]undec-7-ene (DBU), pyridine, imidazole, lutidine, collidine, 4-dimethylaminomethylpyridine, inorganic carbonates and bicarbonates such as sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, and the like and tartrates such as potassium sodium tartrate, potassium tartrate, potassium bitartrate, sodium tartrate, sodium bitartrate and the like, preferably pyridine, lutidine or collidine.

11 WO 99/52908 PCT/US99/07956 Suitable phosphites include P(ORa)(ORb)(ORC); P(ORa)(ORb)(NRcRd); P(Ra)(R b

)(R

C

catechol phosphites or catechol dimer phosphites, wherein R Rb, R and Rd may be the same or different and represent a straight or branched chain C 1 6 alkyl or a phenyl, both of which may be optionally substituted with, for example, a C 1 3 alkyl.

Preferable phosphites are trialkylphosphites such as triethyl phosphite, tributyl phosphite, triisopropyl phosphite, trimethyl phosphite and the like, most preferably triethylphosphite.

Suitable phosphonites include wherein R e and R' independently represent C 1 4 alkyl, allyl, benzyl or phenyl, optionally substituted with C 1 3 alkyl or C 1 3 alkoxy and R9 presents C1-4 alkyl, trifluoromethyl or phenyl, which is optionally substituted with C 1 3 alkyl or C 13 alkoxy.

Suitable activated oxylic acid agents include acid and carbodiimide moieties such as oxalyl chloride and benzyl oxalyl chloride.

In particular, processes of interest are those described above wherein R' represents an alcohol protecting group selected from the group consisting of: H, TES, TMS, TBDMS, pNB, pnitrobenzyloxycarbonyl, allyl and allyloxycarbonyl.

Other processes that are of particular interest are those described above wherein R 5 represents an carboxylic acid protecting group selected from the group consisting of: p-nitrobenzyl (pNB), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), allyl, p-methoxybenzyl, benzyl, trichloroethyl, 2trimethylsilylethyl, and the like.

Still other processes that are of particular interest are those described above wherein X represents O.

Still other processes that are of particular interest are those described above wherein Y represents O or CH 2 Still other processes that are of particular interest are those described above wherein Y represents O.

Still other processes that are of particular interest are those described above wherein W represents zirconium metal.

-12- WO 99/52908 PCT/US99/07956 Still other processes that are of particular interest are those described above wherein W represents titanium metal.

Still other processes that are of particular interest are those described above wherein W represents hafnium metal.

Still other processes that are of particular interest are those described above wherein Z represents a halogen, most preferably chloride.

The process of the present invention is illustrated by the following generic scheme: SCHEME A

TBDMS

H H OAc

H

3

C

NH

0

TES

1 .rO OR2 0

Y

Metaltetrahalide Trialkylamine 2. Acid p-nitrobenzyloxalyl chloride

O'-R

Trialkylphosphite reagent

H

3

C

1-Hydroxy-2-butanone is readily available and can be suitably protected by a number of synthetic methods. (3R,4R)-4-acetoxy- 3-[(R)-(tertbutylmethylsilyloxy)ethyl]-2-azetidinone and (3R,4R)-4acetoxy-3-[(R)-(hydroxyethyl]-2-azetidinone are both readily available and undergo the addition reaction with high diastereoselectivity and in high yield.

-13- WO 99/52908 PCT/US99/07956 Typical conditions for the reaction involve generation of the titanium, zirconium or hafnium enolate of a suitably protected derivative of 1-hydroxybutanone such as an alkyl or aryl carbonate, preferably ethyl carbonate or isobutylcarbonate. This can be achieved by the addition of the corresponding metal tetrahalide to the derivative of 1hydroxybutanone followed by addition of a trialkylamine. The stoichiometry of the enolate formation requires at about 0.5 to equivalents, preferably 1 to 2.0 equivalents of metal tetrahalide. About to about 5 equivalents, preferably about 1 to about 3 equivalents and most preferably about 1 to about 2.0 equivalents of trialkyl amine is used.

The enolate generation is generally carried out at a temperature of about to about 60°C, preferably about -40°C to about 30 0

C.

Generally, the azetidinone is added to the enolate and the reaction temperature warmed to about 0°C 30 0 C. The stoichiometry of the reaction requires about 1.0 to about 5 equivalents, preferably about 1 to about 2.0 equivalents of the enolate of the alkyl or aryl carbonate of 1hydroxybutanone or its synthetic equivalent.

Suitable solvents for the reaction include aromatic solvents such as benzene, toluene, xylene and the like, ethereal solvents such as tetrahydrofuran (THF), diethyl ether, dioxane and the like and haloalkyl solvents such as 1,2 dichloroethane, dichloromethane, chloroform,and the like, preferably the aromatic solvents.

In a typical reaction, the azetidinone is reacted with, for example, a titanium enolate of the ethyl or isobutyl carbonate of 1hydroxy-2-butanone, preferably the isobutyl carbonate moiety. The protecting group TBDMS) is then preferably removed by the addition of an acid such as hydrofluoric acid HC1, or fluorosilicic acid

(H

2 SiF, and subsequently reprotected with another alcohol protecting group TES derivative, typically using TESC1, benzyl ethers or allyl ethers), in the presence of a base such as imidazole or pyridine.

Reaction with p-nitrobenzyloxalyl chloride affords the oxalimide, the precursor to the cyclization step. The cyclization step typically involves reacting the oxalimide in the presence of a phosphite or phosphonite reagent, preferably a trialkylphosphite agent. The stoichiometry of the -14cyclization requires from about 2 to about 6 equivalents, preferably about 2.5 to about equivalents of the phosphite or phosphonite. The cyclization is generally carried out at a temperature of about 25 0 C to about 200 0 C, depending on the nature of the phosphorus reagent used. When using a trialkylphosphite reagent the temperature is generally about s 90 0 C to about 160°C.

The carbapenem produced in the cyclization is a key intermediate in the synthesis of anti-MRSA carbapenem antibiotics and can be readily coupled to a wide range of functional groups in via methods taught in WO 99/52908.

The final product may be characterized structurally by techniques such as NMR, IR, MS, and UV. For ease of handling, the final product, if not crystalline, may be lyophilized from water to afford an amorphous, easily handled solid.

The compounds of the present invention are valuable intermediates for antibacterial agents that are active against various Gram-positive and to a lesser extent Gram-negative bacteria, and accordingly find utility in human and veterinary medicine.

15 Many of the compounds that can be made in accordance with the present invention are biologically active against MRSA/MRCNS. In vitro antibacterial activity is :predictive of in vivo activity when the compounds are administered to a mammal infected with a susceptible bacterial organism.

~The invention is further described in connection with the following non-limiting examples.

EXAMPLE 1 O OiBu *O OTBDMS 0 0 0 H H A 4

H

3 C 0 OiBu TiCI 4 NH Bu 3 N

H

PhMe O 0 [I:\DAYLIB\LIBXX]03085.doc:aak WO 99/52908 PCT/US99/07956 (3R,4R)-4-acetoxy-3-[(R)-tertbutyldimethylsilyloxy)ethyl]-2-azetidinone isobutyl 1-(2-oxobutane)carbonate titanium tetrachloride (1M in toluene) tributylamine toluene 32.0g (0.11 mol) 29.4g (0.156 mol) 156 mL 44 mL 400 mL Titanium tetrachloride solution was added to a solution of the isobutyl carbonate in toluene at -40 0 C. Tributylamine was added. The acetoxy azetidinone was then added and the reaction stirred at room temperature. After 3 hours the reaction was quenched with dilute hydrochloric acid. The toluene layer was washed with dilute HC1. The toluene layer was used in the subsequent step.

Isolated prod, 13C NMR (CDC13) 8 11.7, 17.9, 18.8, 22.5, 25.8, 27.8, 44.6, 51.0, 61.7, 65.4, 69.8, 74.8, 154.8, 168.3, 205.65 EXAMPLE 2 SOiBu '0 kOiBu H C'

HF

MeCN PhMe .H O TBDMS azetidinone isobutyl carbonate in toluene solution from above Examplel HF (48% aqueous) Acetonitrile 40g in 450 mL 20 mL 400 mL To the toluene solution from Example 1 was added acetonitrile and the HF solution. After 6 hours the reaction was quenched with aq. Rochelles salt. The toluene layer was dried and the solvent was removed. The crystalline product was swished with hexanes and filtered to yield 4-[3- ((1-oxy-2-oxobutane)isobutyl carbonate)]-2-azetidinone (23.3g) as a white solid.

-16- WO 99/52908 WO 9952908PCTIUS99/07956 1H NMR 8 0.95 1.25 3H), 1.3 3H), 2.0 (in, 1H), 2.9 (in, 2H), 3.85 (in, 1H), 3.9 2H), 4.1 (mn, 1H), 4.75 (in, 2H), 6.3 1H) EXAMPLE 3 H 0jT ES0

H

3 C H0 IkOiBu TESCI H 3 C 0 OiBu NH MeON NH 0 0 4- 1-oxy-2-oxobutane)isobutyl carbonate)] 8 .04g (0.027 inol) 2-azetidinone triethylsilyl chloride 4.7 mL (0.028 mol) imidazole 2.Og (0.029 inol) acetonitrile To a slurry of the azetidinone in acetonitrile was added imidazole. The reaction became homogeneous and triethylsilyl chloride was added.

After 2 hours the reaction was given an aqueous work up and the organics were concentrated in vacuo to afford 11.Og of TES azetidinone isobutyl carbonate.

1H NMR 8 0.5 9H), 0.9 6H), 0.9 6H), 1.2 2 doublets, 6H), 2.0 (in, 1H), 2.9 (mn, 2H), 3.8 (mn, 1H), 3.9 2H), 4.1 (mn, 1H), 4.7 (mn, 2H), 6.4 (s, 1H) EXAMPLE 4 0 0 TES 0 .3L4 TES 0 H H HHC

T

3 O~Iu I 3 10 0 OiBu H C NH 0 0 i u o N r '1 N 0 0 Pyddine 0o MeCN 01 OpNB 17 WO 99/52908 PCT/US99/07956 TES azetidinone isobutyl carbonate p-NB oxalylchloride pyridine acetonitrile 11.0g (0.027 mol) 7 .15g (0.029 mol) 4 mL 150 mL Pyridine was added to a solution of pNB oxalylchloride in acetonitrile.

After 20 minutes the TES azetidinone isobutyl carbonate was added. The reaction was given an aqueous work up, the organics were concentrated in vacuo to afford TES oxalimide isobutyl carbonate (15.2 g) as a white solid.

13C NMR 5 4.8, 6.7, 14.0, 18.8, 22.5, 27.8, 40.9, 54.4, 61.3, 64.7, 66.7, 69.9, 74.8, 123.8, 129.0, 141.2, 148.0, 154.7, 156.0, 159.4, 164.9, 204.6.

EXAMPLE 0 0 kOiBu P(OEt) 3 p-xylene 'O-pNB CO2pNB TES oxalimide isobutyl carbonate triethyl phosphite xylene 15.2g (0.024 mol) 8.8 mL 200 mL Triethyl phosphite was added to a solution of TES oxalimide isobutyl carbonate in xylene. The reaction was heated to 135°C for 3 hours. The reaction was given several aqueous washes, dried and the solvent removed in vacuo to afford the desired compound (12.2g).

1 H NMR (399.87 MHz, CDC13) d 8.22 2 7.66 2 5.57 (d, J=14.5, 1 5.46 J=13.7, 1 5.27 J=13.7, 1 4.83 (dd, J=14.5, 1.2, 1 4.26 (overlapping m, 2 3.95 J=6.8, 2 3.33 1 3.28 18- WO 99/52908 WO 9952908PCTIUS99/07956 (dd, J=5.6, 3.2, 1 1.99 (in, 1 1.26 J=6.0, 3 1.20 J=7.2, 3 H), 0.95 J=8.0, 9 0.60 (in, 6 H) 1 3 C NMR (100.55 MHz, CDC13) d 174.8, 160.4, 155.0, 147.7, 145.5, 142.6, 128.4, 128.1, 123.7, 74.5, 65.7, 65.5, 61.6, 60.7, 55.9, 40.3, 27.8, 22.5, 18.8, 15.3, 6.7, 4.9 -19-

Claims

21. NOV. 2001 11:43 20222Y SPRUSON AND FERGUSON 61292615486 NO. 9584 P. 8 PCT/US 99/ 79 56 auS AUG 2000 WHAT IS CLAIMED IS: 1. A process of synthesizing a compound of formula 2: SR1 H3C 0 YR 2 NH O 0 2 is disclosed wherein R I represents H or a suitable protecting group for an alcohol; R 2 represents a benzyl, CI-6 alkyl or aryl; Y represents C1- 3 alkyl, 0, NH or S; and X represents 0, NH, or S comprsing reacting a compound of formula 1: 0 .0 R 4 H3C wherein R 1 is described above and R 4 represents CI-15 alkyl, aryl or CI-6 aralkyl; with a compound of formula 3: 0 YR 3 wherein R 2 X and Y are as previously defined in the presence of WZ 4 and an amine to produce a compound of formula 2, wherein W is a titanium, zirconium or hafnium and Z represents halo, sulfonate, alkoxy, aryloxy or combination thereof. 20 AMENDED SHEEt 2. A process compound of formula 'YR 2 U 'I"N wherein R' represents H or a suitable protecting group for an alcohol; R 2 represents a benzyl, Ci- 6 alkyl or aryl; Y represents C 1 -3 alkyl, 0, NH or S; X represents O, NH, or S and R 5 represents a carboxy protecting group, comprising reacting a compound of formula 2: OR 1 x H 3 C H 10O YR NH 0 0 2 wherein R 2 X and Y are as previously described, with an activated protected oxalic acid agent in the presence of a base to produce a compound of formula o 3. A process of synthesizing a compound of structural formula 6: S S S S. S. S 5S5* S 'YR 2 is disclosed wherein R' represents H or a suitable protecting group for an alcohol; R 2 represents a benzyl, C 1 -6 alkyl or aryl; Y represents C 1 3 alkyl, 0, NH or S; X represents O, NH, or S and R 5 represents a carboxy protecting group, comprising reacting a compound of formula OR 1 H 3 C HH O AYR 2 N 0 0 S O-R wherein R 2 R 5 X and Y are as previously described with a phosphite or phosphonite reagent to produce a compound of formula 6. 22 4. A process of synthesizing a carbapenem compound of formula 6: 0 0* *0 9 9 9. 9 9 9 9 9 9* 9 wherein R' represents H or a suitable protecting group for an alcohol; R 2 represents a benzyl, Ci-6 alkyl or aryl; Y represents C 1 -3 alkyl, 0, NH or S; X represents O, NH, or S and R 5 represents a carboxy protecting group, comprising reacting a compound of formula 2: OR 1 X H 3 ,C H H 0 YR2 NH 0 O 2 2 2 wherein R R 2 X and Y are as previously described, with an activated protected oxalic acid agent in the presence of a base to produce a compound of formula OR 1 x H 3 C HH0 -YR 10 O O-R and reacting a compound of formula 5, wherein R 2 R 5 X and Y are as previously described with a phosphite or phosphonite reagent to produce a compound of formula 6. 5. A process of synthesizing a carbapenem compound of formula 6: OR 1 HH H 3 C HT YR 2 0 N CO 2 R 6 wherein R' represents H or a suitable protecting group for an alcohol; R 2 represents a benzyl, C.-6 alkyl or aryl; Y represents C 1 .3 alkyl, 0, NH or S; X represents O, NH, or S and R 5 represents a carboxy protecting group, comprising reacting a compound of formula 1: [l:\DAYLIB\LIBXX]03085.docaak 0 1 wherein R' is described above and R 4 represents C1- 1 5 alkyl, aryl or C1- 6 aralkyl; with a compound of formula 3: O YR 2 x 3 wherein R 2 X and Y are as previously defined in the presence of WZ 4 and an amine to produce a compound of formula 2: OR 1 H 3 C HH o YR2 NH O O 2 wherein W is a titanium, zirconium or hafnium metal and Z represents halo, sulfonate, alkoxy, aryloxy or combination thereof, and R 2 X and Y are as previously described, 10 reacting a compound of formula 2 with an activated protected oxalic acid agent in the 'presence of a base to produce a compound of formula OR O H 3 C H oYR 2 O O-R and reacting a compound of formula 5, wherein R 2 R 5 X and Y are as previously 6. A process of synthesizing a carbapenem compound of formula OR 1 H 3 C HH 0 YR 2 N O O 0 O O-R wherein R' represents H or a suitable protecting group for an alcohol; R 2 represents a AL benzyl, C 1 -6 alkyl or aryl; Y represents CI- 3 alkyl, 0, NH or S; X represents O, NH, or S [I:\DAYLIB\LDXX]03085.doc:aak 24 and R 5 represents a carboxy protecting group, comprising reacting a compound of formula 1: OR 1 O H 3 C HH o R 4 NH 0 1 wherein R' is described above and R 4 represents Cl- 15 alkyl, aryl or CI- 6 aralkyl; with a compound of formula 3: x 3 wherein R 2 X and Y are as previously defined in the presence of WZ 4 and an amine to produce a compound of formula 2: OR 1 X H 3 C HH o YR 2 NH O 10 2 S. wherein W is a titanium, zirconium or hafnium metal and Z represents halo, sulfonate, alkoxy, aryloxy or combination thereof, and R 2 X and Y are as previously described, and reacting a compound of formula 2 with a pNB oxalimide forming agent in the presence of a base to produce a compound of formula 7. A process in accordance with any one of claims 1-6 wherein R' represents a member selected from the group consisting of: H, TES, TMS, TBDMS, pNB, p- nitrobenzyloxycarbonyl, allyl and alloxycarbonyl; R 5 represents a carboxylic acid protecting group selected from the group consisting of: p-nitrobenzyl (PNB), benzyl, trimethysylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), allyl, p-methoxybenzyl, trichloroethyl, and 2 -trimethylsilylethyl; R 2 represents C1- 6 alkyl and R 4 represents a C-s 1 5 alkyl, aryl or aralkyl. 8. A process in accordance with any one of claims 1-7 wherein X represents O. 9. A process in accordance with any one of claims 1-8 wherein Y represents O or CH 2 10. A process in accordance with claim 9 wherein Y represents O. 11. A process in accordance with any one of claims 1, 5 and 6 wherein W L/ represents zirconium metal. S12. A process in accordance with claim 11 wherein W represents titanium metal. [1:\DAYLIB\LIBXX]03085.doc:aak 13. A process in accordance with claim 11 wherein W represents hafnium metal. 14. A process in accordance with any one of claims 1, 5 and 6 wherein Z represents a halogen. A process in accordance with claim 14 wherein Z represents chloride. 16. A process in accordance with claim 1 or 6 wherein the amine represents triethylamine, tributylamine, trimethylamine, ethyldimethylamine, tri-n-propylamine, di- isopropylethylamine, aniline, and N,N-dialkylanilines. 17. A process in accordance with claim 7 wherein R' represents a member selected from the group consisting of: H, TES, TMS, TBDMS, and pPNB; R 5 represents p-nitrobenzyl (pNB) or benzyl; R 2 represents ethyl or isobutyl; and R 4 represents CI- 1 alkyl, aryl or C1- 6 aralkyl. 18. A process in accordance with claim 1 wherein said compound of formula 2 is further reacted with an acid to produce a compound of formula 2a: ORla H3C H* -1 YR 2 r•o• NHO O 2 2a S 15 wherein R a represents H, TES, TMS, TBDMS, or pNB, provided that R' and Ria are not the same. 19. A process in accordance with claim 18 wherein the acid represents hydrofluoric acid or fluorosilicic acid or HC1. 20. A process of synthesizing a compound of formula 2: OR 1 H 3 C HH -YR 2 NH 0 20 2 is disclosed wherein R' represents a member selected from the group consisting of: H, TES, TMS, TBDMS, and pNB; R 2 represents ethyl or isobutyl; Y represents 0; and X represents O comprising reacting a compound of formula 1: OR 1 O H 3 C H H R 4 NH 0 1 wherein R' is described above and R 4 represents CI- 5 alkyl, aryl or CI- 6 aralkyl; LL xi with a compound of formula 3: [I:\DAYLIB\LIBXX]03085.doc:aak .J 26 O YR 2 x 3 wherein R 2 X and Y are as previously defined in the presence of WZ 4 and an amine to produce a compound of formula 2, wherein W is a titanium and Z represents chloride. 21. A process in accordance with claim 20 wherein the said compound of formula 2 is further reacted with an acid to produce a compound of formula 2a: ORla H 3 C H H OYR 2 NH O 0 2a wherein R la represents H, TES, TMS, TBDMS, or pNB, provided that R' and R l a are not the same and the acid represents hydrofluoric acid, hydrochloric acid or fluorosilicic acid.
22. A process in accordance with claim 20 wherein the amine represents 0t triethylamine, tributylamine, trimethylamine, ethyldimethylamine, tri-n-propylamine, di- isopropylethylamine, aniline, and N,N-dialkylanilines.
23. A process in accordance with claim 2 or 4 wherein the base represents triethylamine, trimethylamine, ethyldimethylamine, tri-n-propylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, imidazole, lutidine, collidine, 15 4 -dimethylaminomethylpyridine, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, potassium sodium tartrate, potassium tartrate, potassium bitartrate, sodium tartrate or sodium bitartrate and the oxalic acid agent represents pNB oxalyl chloride or benzyl oxalyl chloride.
24. A process according to claim 2 or 4 wherein the base in pyridine, lutidine or 20 collidine.
25. A process according to claim 3 wherein the phosphites are trialkylphosphites such as triethyl phosphite, tributyl phosphite, triisopropyl phosphite, and trimethyl phosphite.
26. A process according to claim 3 wherein the phosphonites represent P(ORe)(OR')(Rg), wherein Re and Rr independently represent CI-4 alkyl, allyl, benzyl or phenyl, optionally substituted with CI-3 alkyl or C-. 3 alkoxy and R9 presents C-4 alkyl, trifluoromethyl or phenyl, which is optionally substituted with C 1 -3 alkyl or CI-3 alkoxy.
27. A process of synthesizing a carbapenem compound of formula 6: [1:\DAYLIB\LIBXX]03085.doc:aak H 3 C O O YR2 CO 2 R5 6 wherein R' represents a member selected from the group consisting of H, TES, TMS, TBDMS, and pNB; R 2 represents ethyl or isobutyl; Y represents 0; and X represents O; and R 5 represents p-nitrobenzyl (PNB) or benzyl comprising reacting a compound of formula 1: OR 1 H 3 C H H 0 R 4 NH 0 1 wherein R' is described above and R 4 represents C 1 1 5 alkyl, aryl or C 1 6 aralkyl; with a compound of formula 3: YR 2 x 3 I X 3 0 wherein R 2 X and Y are as previously defined, in the presence of WZ 4 and amine to produce a compound of formula 2, wherein W is a titanium and Z represents chloride to produce a compound of formula 2: OR 1 H3C HHH YR 2 SNHO *o 2 reacting a compound of formula 2 with a pNB oxalyl chloride in the presence of a base 15 such as pyridine, lutidine or collidine to produce a compound of formula OR' X H 3 C H H 0 YR 2 N 0 O O-R 5 and reacting a compound of formula 5, wherein R 2 R 5 X and Y are as previously described with triethylphosphite to produce a compound of formula 6. [I:\DAYLIB\LIBXX]03085.doc:aak *I ir 28
28. A process according to claim 27 wherein the amine represents triethylamine, tributylamine, trimethylamine, ethyldimethylamine, tri-n-propylamine, di- isopropylethylamine, aniline, or N,N-dialkylanilines.
29. A process in accordance with claim 27 or 28 wherein said compound of formula 2 is further reacted with an acid to produce a compound of formula 2a: ORla H3C HH 0 YR NH O 0 2a wherein R 1 represents H, TES, TMS, TBDMS, or pNB, provided that R' and R'a are not the same and the acid represents hydrofluoric acid, HC1 or fluorosilicic acid. A process of synthesizing a compound of formula 2, said process being 0o substantially as hereinbefore described with reference to any one of the examples 1 to 3.
31. A process of synthesizing a compound of formula 5, said process being substantially as hereinbefore described with reference to example 4.
32. A process of synthesizing a comound of formula 6, said process being e substantially as hereinbefore described with reference to example S 15 33. The compound of formula 2: 1 O R2 H 3 C H YR 2 H *NH 0" 2 produced in accordance to process of any one of claims 1, 20 and
34. The compound of formula 2a: SORla 1 **H 3 C H H YR NH 0O 0 2a produced in accordance to the process of claim 18 or 21. The compound of formula OR 1 X H 3 C H H l2 H3C YR 2 N O O0 GD 4 Oc O-R- [1:\DAYLIB\LIBXX]03085.doc:aak 29 produced in accordance to the process of any one of claims 2, 6 and 3 1.
36. The compound of formnula 6: OR 1 H 3 C HH IJYR N 7 C0 2 R 6 produced in accordance to the process of any one of claims 3, 4, 5, 27 and 32. Dated 8 February, 2002 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 0O 0SO 0 S. 0 S. 0 OS 0 OSOS0 6000 S S. 00 S 0000 S 0005 05 0 0 C 0 S 0O 0 50 00 S 0600 0 *055 0S S So S. @560 S S OBOe S 0050 0 0e00 0 660006 0 [I:\DAYL1B\L1BXX]03085.doc:aak