DE2065462B2 - 7-ISOCYANATO-CEPHALOSPORANIC ACID DERIVATIVES AND THEIR USE FOR THE PRODUCTION OF CEPHALOSPORINES - Google Patents

Description

O C

(I)

CH ₂ i C-CH ₁ -R

COOE

wherein R represents a hydrogen atom, a silylated hydroxy group or an acetoxy group and in which E denotes an easily removable protective group customary in the cephalosporin field, or a lactone according to the following formula

= C = N = CH- CH CH,

ι ι ι

C N C-CH,

O C

30th

O = CO

2. Trimethylsilyl ester of 7-isocyanatocephalosporanic acid.

3. Trimethylsilyl ester of 7-isocyanatodesacetoxycephalosporanic acid.

4. Use of the compounds according to claim 1 for the preparation of cephalosporins general formula

35

4 ° and A represents a group of the general formula R,

r /

in which R2 represents an alkyl, aryl, aralkyl or phenoxy group. R3 is a hydrogen atom or halogen atom, a cyano group or a group of the general formula -NH-COOY ₁ -OY,

-C-NH-Y ₁

Il
O

or -COOY, in which Y is a lower alkyl, aryl or benzyl group or a hydrogen atom and Yi is an alkyl, aryl, sulfonylalkyl or sulfonylaryl group and Rt is a hydrogen atom or a lower alkyl group or in which A is an aryl group which is optionally replaced by a lower alkoxy -, lower alkyl, aryloxy or aralkyl group, by reaction with an organometallic compound of the general formula A-Me ¹ , A-Me "-A or A-Me" -Hai, wherein Me is a metal atom, the number I. or II is its valency and Hal is a halogen atom, in an anhydrous organic solvent medium and, if appropriate, splitting off the protective groups by methods known per se and converting them into a salt.

The invention relates to 7-isocyanatocephalosporanic acid derivatives the general formula

A - CO - NH - CH - CH

i I c

-N \

CH, (111)

i C - CH ₂ R ₁

i COOE ₁

A-CO

NH- -CH
I. - cn
ι /
C.
ι CH; I.
C-
y I.
Kl I.
C- C.
/ \ O IN
\ 2 (I. CH ₁
ι ' I.
-O

45 CH,

i C-CH,

I = C = N-CH-CH

I!

C N

O C

I.
COOE

wherein R represents a hydrogen atom, a silylated hydroxy group or an acetoxy group and wherein E denotes an easily removable protecting group customary in the cephalosporin field, or a lactone according to the following formula

60

wherein Ei has the meaning of E or represents a hydrogen atom or a cation, Ri the Meaning of R or a hydroxy group / '\ O = C = N = CH-CH CH,

I i I

C N C-CH,

, / \ / OCI
O = CO

The group E in the compounds of the general

, _mel i represents an ester group, the general

«• expresses the following conditions: ^! Ie should easily be in the carboxyl group of the "/ Vmino-cephalosporanic acid compounds of the general formula

H ₂ N-CH-CH CH ₂
CN C-

IO

C.
COOH

20th

25th

wherein R 'is a hydrogen atom, a hydroxy group or an acetoxy group means to be introduced so that an undesirable conversion, such as an opening of the 0-lactam ring of the bicyclic Kernes, does not occur;

M it should be easily separable to allow restoration of the carboxyl function without affecting the bicyclic core; c) it should give the compound which carries the group E, especially when it is dissolved in an inert organic solvent, sufficient stability, especially for storage purposes, and d \ it should remain unaffected when the isocyanato group of the compounds of the general formula I is implemented with different compounds.

Suitable groups represented by E of the type mentioned above are, for. B.
1 Silyl groups, such as those of the general formula (R ") 3Si, in which R" denotes a lower-alkyl, phenyl or phenyl-lower alkyl radical. The term "lower" as used herein in connection with alkyl groups indicates that the alkyl group has a maximum of 6 carbon atoms. ...

It should be said that such silyl esters, the all correspond to my formal, light and smooth be hvdrolyzed. Above all, those esters are preferred in which E is a trialkylsilyl group, especially the trimethylsilyl group. the The silyl ester group can easily be added after further processing of the compounds of the general formula Addition of alcohols or water can be hydrolyzed to form the free carboxyl group

Furthermore, the silyl group is not influenced by reactions involving the isocyanato group. In the case When using alcohols, an excess of alcohol is preferred.

2 A phenacyl group that may appear on Benzoiring, preferably in the para position, is substituted by halogen, e.g. B. the p-bromopne or difficult to obtain. The isocyanato group can be so z. B. with Alcohols, thiols, carboxylic acids, amines, amides, water, organometallic compounds such as Gngnard reagents and organolithium compounds, react.

The invention thus also relates to the use of the compounds of the general formula 1 and the formula II for the preparation of cephalosporins of the general formula

/ \ A —CO —NH-CM —CH CH ₂ (UM

1 I!

CN C-CH ₂ R ₁

o ^/ y

COOE ₁

CH ₂

(IV)

Λ- CO-NH-CH-CH

CN C

c / V ^N CH ₂

c ο

35 where E. has the meaning of E or em represents a hydrogen atom or a cation, Ri has the meaning of R or represents a hydroxyl group and A is a group of the general formula

40

R,

represents, in which R2 is an alkyl, aryl, aralkyl or Phenoxy group, R3 is a hydrogen atom or halogen-50 atom, a cyano group or a group of the general formula -NH-COOY, -OY,

-C-NH-Y ₁

nacvlfiruppCt
3. A benzyl or benzhydryl group represented by

mild hydrogenation is separable. The Z-Isocyanatocephalosporansäuredenvate the general Formula 1 and formula II can be obtained according to German patent 20 62 296.

From the y-isocyanatocephalosporan acid derivatives of the general formula 1 and the formula II can, using the known reactivity of the isocyanato group a large number of Cephalosporanäurederivateri, fmH Twar especially those that have not been up to now or -COOY, where Y is a lower alkyl, aryl or benzyl group or a hydrogen atom and Yi is a Alkyl, aryl, sulfonylalkyl or sulfonylaryl group

60 represents and R4 represents a hydrogen atom or a Lower alkyl group or in which A is an aryl group which is optionally substituted by a lower alkoxy, Lower alkyl, aryloxy or aralkyl group is substituted, by reaction with a

65 organometallic compound of the general formula A-Me ¹ , A-Me "-A or A-Me" -Hal, in which Me is a metal atom, the number I or H is its valence and Hai is a halogen atom, in an anhydrous organic

Solvent medium and, if appropriate, cleavage the protective groups according to methods known per se and conversion into a salt.

It has been shown that in the above reaction of the isocyanato compounds with the organometallic compounds mentioned d> e isocyanato function Surprisingly, it is more reactive than other points of attack in the molecule of the isocyanato compounds, which are known to be very sensitive to carbanion-like reactants. ι ο

Suitable salts into which the products obtained can be converted are alkali metal, alkaline earth metal or amine salts. In particular, those from the 7-isocyanato-cephalosporanic acid esters of the general Formula I obtained cephalosporins in the form of sodium, potassium, calcium, cyclohexylamine or N-ethylpiperidine salt can be obtained.

The radical R2 in the compounds of the general formulas III and IV can in particular be a phenyl, Mean halogenophenyl, alkoxyphenyl, naphthyl, alkoxynaphthyl or benzyl group. Y means preferably a phenyl group.

Examples of I ^ RjfaC groups are

O —CH, -

NH-CO-O-CH

35

40

45

CH
CN

Further R2R3R4C groups are the benzyl or naphthylmethyl group, optionally with a Halogen atom or a cyano, CO2Y or OY group, in which Y is a lower alkyl or aryl radical means, or can be replaced by hydrogen after the reaction, is α-substituted

The radical A, if it is an aryl group, can be a phenyl, 1- or 2-naphthyl or biphenyl group be.

The reaction is carried out in an anhydrous organic solvent medium under conditions one reaction of the Grignard kind, the Reformatzky kind or favor an analogous reaction. The organometallic reactant can be, for. B. of l-broiti-2-ethoxynaphthalene, bromobenzene, 4-methoxyphenyl bromide, a-bromophenylacetic acid or its ester, of phenylacetic acid or its ester or of Derive benzyl cyanide. As organometallic compounds can e.g. B. Compounds with a C-Li, C-Na or C-Mg bond can be used.

Particularly good results are obtained in the preparation of 7-AryIcarbonamido-cephalosporanic acid derivatives obtained from the isocyanato compounds and aryl Grignard compounds according to the invention. To this end, the isocyanato compound, dissolved in a suitable solvent, preferably toluene, is added to a very cold solution of the aryl Grignard reagent in a solvent such as tetrahydrofuran, 2,2'-dimethoxy diethyl ether or 1,2-dimethoxyethane, with a predetermined amount of a strongly dipolar aprotic solvents such as tetramethylurea, N-methylpyrrolidone or especially hexamethylphosphonetriamide can be added.

Surprisingly, the selectivity of the process is so high that any acetoxy group in the Cephalospora genes are essentially not decomposed.

Generally, an excess of the Grignard reagent will be used for reaction with the isocyanato compound may be used, the extent of the excess depending on the particular reaction, for example with 2-ethoxynaphthalene-1-magnesium bromide with an excess of the Grignard reagent of about 100% good Results obtained with phenylmagnesium bromide and 4-methoxyphenylmagnesium bromide only a small excess of the Grignard reagent is necessary.

The conversion of the isocyanate residue of a 7-isocyanato-cephalosporanic acid ester of the general formula I or the lactone of the formula II into a group A — CO — NH— can also be carried out by adding the ester or the lactone compound with an acid A-CO-OH, where A is the above The reaction is preferably carried out in an inert organic solvent medium carried out like toluene. A small amount of an organic base, e.g. B. pyridine, can be used as Serve catalyst.

The isocyanato compounds according to the invention with amides become acylureidocephalosporanic acid derivatives implemented, it is usually activated with the help of a metal such as Na or Li necessary to achieve a sufficient reaction rate. The reaction is preferably carried out in an inert organic solvent medium, e.g. B. dichloromethane or toluene, under anhydrous conditions, advantageously in the presence of a catalytic amount of an organic base such as pyridine carried out.

By reacting with hydroxyiischen reactants can from the isocyanato compounds according to the invention 7-cephalosporanyl urethanes are obtained. This reaction can be done without using a Solvents are carried out in those cases in which the hydroxyiischen reactants themselves show good solvent properties with respect to the isocyanato compounds. Is the hydroxylic Compound a phenol, an inert anhydrous organic solvent, e.g. B. toluene, The reaction can be facilitated by the addition of a catalyst such as a dialkylzinii (IV) diacetate will.

The cephalosporanic acid derivatives of the general formulas IH and IV have antibiotic properties, which they are used as medicinal products in the human and veterinary

make medicine usable. The compounds of general formula III become therapeutic For purposes, preferably in the form of a non-toxic salt such as the sodium, potassium or calcium salt used. Other salts that can be used in pharmaceutical compositions include the non-toxic and especially crystallizable salts with organic bases such as amines, ζ. Β. Trialkylamine, cyclohexylamine, procaine, dibenzylamine, and N-alkylpyridines. ι ο

The cephalosporins according to the general formulas Hl and IV or their non-toxic salts can be used for therapeutic purposes can be used as such or in a conventional administration form. So they can e.g. mixed with a solid or liquid diluent in capsules from an absorbable Material such as gelatin can be introduced. They can also be incorporated into a carrier substance in this way be that the active ingredient is released over a prolonged period of time after ingestion. Liquid preparations can be in the form of solutions suitable for parenteral administration are.

The following example illustrates the invention.

example

Preparation of the sodium salt of 7- (2-ethoxynaphthyl) -carbonamido-cephalosporanic acid

S.
O C- -NH-CH CH CH ₂

/ , uu CN C CH ₂ OC CH,

-y

COONn

40

0.49 g (20 millimoles) of magnesium turnings were added to a solution of 4.38 g (17.5 millimoles) of 1-bromo-2-ethoxy-naphthalene in 17.5 ml of anhydrous tetrahydrofuran. Upon careful warming, the reaction started spontaneously. The stirred mixture was then refluxed for 30 minutes while bubbling nitrogen over it. The reaction mixture was cooled to about 10 ° C. and 6.2 ml of hexamethylphosphonic triamide were added. The mixture was further on - cooled 6O ⁰ C Then a solution of 8.71 mmol of trimethylsilyl ester of the 7-Isocyanatocephalosporansäure in 24 ml of toluene was dropwise added to the stirred mixture of the Grignard reagent at such a rate that the temperature in the reaction mixture -40 ° C not exceeded. During this, nitrogen was passed over the reaction mixture. This was stirred for a further 30 minutes at -40 ° C. and then poured into a stirred mixture of 155 ml of ice water and 45 ml of ethyl acetate, the pH being kept at about 2.5 by the simultaneous addition of 1N HCl. After the pH had remained constant for a few moments, it was adjusted to 7 with the aid of dilute NaOH. The resulting precipitate was filtered off, the organic layer was separated from the aqueous layer and washed twice with ice water. The aqueous layer was combined with the wash waters. 45 ml of ethyl acetate was added to the stirred mixture and the pH was adjusted to 3.5 with 1N HCl. The layers were separated and the aqueous layer was extracted with 45 ml of ethyl acetate. Examination of the combined ethyl acetate layers by thin layer chromatography indicated that they contained an additional portion of the same compound as the above-mentioned precipitate. This compound was mixed with a cold mixture of 45 ml of ethyl acetate and 50 ml of water and enough 1N HCl was added to bring the pH to 3.5. The layers were separated and the aqueous layer was extracted with a small amount of ethyl acetate. The combined ethyl acetate solution was washed twice with 20 ml of ice water, treated with a small amount of decolorizing activated charcoal and concentrated in vacuo to a volume of about 50 ml. Then a solution of 8.2 millimoles of sodium a-ethylcaproate in 14 ml of propanol was added to the residue given. A precipitate formed, which was filtered off, washed with ethyl acetate and diethyl ether and dried in vacuo at room temperature. The yield was 3.3 g. The mother liquor contained a further small amount of the end product.

The thin-layer chromatographic investigations showed that the solid obtained from a The only compound containing sulfur was found. The IR and NMR spectra confirmed the configuration the connection. The purity of the final product was about 90%.

Partial analysis of the IR spectrum of the end product "(KBr disk, values in cm - '):
at 3275 NH

around 3050 = C-H

1760 C = O0 lactam

1735 C = O ester

1650 C = O amide

1625 C = O carboxylate ion

1598 C = C aromatic nucleus

1510-1530 NH def.

1369 CH3 acetoxy

1238 C-O-C esters

Claims (1)

20 65 claims: 1. Z-Isocyanatocephaiosporansäurederivate der general formula O == C = Ν — CH-CH I I C N