WO2004011471A1

WO2004011471A1 - Process for the preparation of cephem esters

Info

Publication number: WO2004011471A1
Application number: PCT/IB2003/002967
Authority: WO
Inventors: Yatendra Kumar; Mohan Prasad; Kaptan Singh; Satyananda Misra
Original assignee: Ranbaxy Laboratories Ltd
Current assignee: Ranbaxy Laboratories Ltd
Priority date: 2002-07-25
Filing date: 2003-07-24
Publication date: 2004-02-05
Anticipated expiration: 2005-01-25
Also published as: AU2003249494A1

Abstract

The present invention relates to a process for the preparation of cephem esters.

Description

PROCESS FOR THE PREPARATION OF CEPHEM ESTERS

FIELD OF THE INVENTION

BACKGROUND OF THE INVENTION

Cephem esters having a physiologically labile group are used as prodrugs for oral administration of cephalosporin antibiotics. The preparation of cephem esters from the corresponding cephem free acid or salts thereof results in the formation of undesired Δ² - isomer of the cephem ester of Formula A along with the desired Δ³ - isomer of Formula B.

Formula B

The Δ² - isomer is formed as a result of Δ³ → Δ² isomerization under basic conditions, which are necessary for the completion of the esterification reaction. The removal of the Δ² - isomer from the cephem ester is very difficult due to the structure similarity of Δ² and Δ³- isomers and also entails decrease in yield. Several processes have been reported to overcome this problem in the synthesis of cephem esters by minimizing isomerization. J. Org. Chem. 1986, 51, 4723 and J. antibiotics,

1994, 44 (2), 200 reported the preparation of cephem esters using dioxane as a cosolvent to lower the polarity of the reaction medium. The addition of a cosolvent decrease the basicity of the cephem carboxylate, which is believed to be responsible for the isomerization.

U.S. Patent No. 5,498,787 teaches the use of quaternary ammonium or quaternary phosphonium salts as catalysts for eliminating the formation of Δ² -isomer of cephem esters. PCT patent application WO 02/16372 uses crown ether catalysts to achieve similar results for the preparation of cefuroxime axetil.

The addition of a polarity lowering cosolvent like dioxane often results in sluggish and incomplete reactions thus lowering the yield. Also, crown ether, quaternary ammonium or phosphonium salts are expensive and are not preferred at a commercial scale.

The present invention provides an inexpensive and efficient process for preparing cephem esters while minimizing the concomitant formation of the corresponding Δ² -isomer.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of cephem ester of formula I,

Formula I wherein R is cyano, phenyl, cyclohexadienyl, heterocyclyl, heterocyclylthio, or a heterocyclylamido group, wherein the phenyl or the heterocyclic ring may be further substituted by an alkyl, hydroxy, a ino, aminoalkyl, halo or a carboxyalkyl group; A is mono or disubstituted methylene group, -CH, — -CH- -CH-

I I

OH NH₂

wherein Ri is alkyl, alkoxyalkyl or carboxyalkyl;

R' is hydrogen, alkyl, alkenyl, alkynyl, alkoxymethyl, alkylthiomethyl, alkanoyloxymethyl, carbamoyloxymethyl, or a heterocyclylthiomethyl group, wherein the heterocyclic ring may be further substituted by hydroxy, alkyl, carboxyalkyl, sulfonylalkyl or carbamoyl; and R" is alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, alkoxyalkyl, alkanoyloxyalkyl or alkoxycarbonyloxyalkyl, comprising reacting a compound of Formula II,

Formula II

wherein R and R' are as defined above, with a compound of Formula R" X, wherein X is a halogen and R" is as defined above, in the presence of an amine, an inorganic base and a phosphate buffer to give a compound of Formula I. The heterocyclyl group may be a 5 or 6 membered heterocyclic ring containing up to four hetero atoms independently selected from the group consisting of nitrogen, oxygen and sulfur.

Examples of R include 4-hydroxyphenyl, 2-aminomethylphenyl, 2-amino-4-thiazolyl, 2-furanyl, 2-thienyl, 4-pyridinyl, IH-tetrazolyl, 5-amino-l,2,4-thiadiazol-3-yl, 5-methyl- l,3,4-thiadiazol-2-yl, 5-carboxy-lH-imidazol-4-yl, 4-hydroxy-6-methyl-3-pyridinyl, 3,5- dichloro-4-oxo-l(4H)-pyridinyl, and 4-ethyl-2,3-dioxo-l-piperazinyl.

Examples of R' include methyl, 2-(4-methyl-5-thiazolyl)ethenyl, acetoxymethyl, methoxymethyl, chloro, l-methyl-lH-tetrazol-5-ylthio, lH-l,2,3-triazol-4-ylthio, 5- methyl- 1, 3, 4-thiadiazol-2-yl, l,2,3-thiadiazol-5-ylthio and l,2,5,6-tetrahydro-2-methyl-5,6- dioxo- 1 ,2,4-triazin-3 -ylthio .

Examples of R" include 1-acetoxyethyl, pivaloyl, pivaloyloxymethyl, 1- (isopropoxycabonyloxy)ethyl and 1 -(cyclohexyloxycabonyloxy)ethyl.

Halogen X in R"X is selected from the group consisting of chloro, bromo and iodo.

The reaction can be carried out in the presence of an amine, for example triethylamine, tributylamine, N, N-dimethylaniline, dicyclohexylamine, pyridine, N- methylpiperidine N-methyl pyrrolidine, N-methyl morpholine, collidine, lutidine, picoline, quinoline, isoquinoline, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and mixture(s) thereof.

Suitable inorganic bases which may be used in the process include sodium carbonate, potassium carbonate and sodium bicarbonate.

Suitable phosphate buffers which may be used in the process include disodium hydrogenphosphate, dipotassium hydrogenphosphate and sodium hydrogen phosphate. It is convenient to employ about 0.5 to about 2.5 molar equivalents of the phosphate buffer with respect to the inorganic base.

The reaction can be carried out in the presence of a solvent which is inert under the reaction conditions, for example dimethylformamide, dimethylacetamide, dimethylsulphoxide, hexamethylphosphoric triamide, tetrahydrofuran, dichloromethane, ethylacetate, acetonitrile and mixture(s) thereof. The reaction can be carried out at ambient temperature or with cooling, for example at temperatures ranging from about -10°C to about 0°C.

The process of the present invention consistently gives cephem esters in high yield and purity.

5 DETAILED DESCRIPTION OF THE INVENTION

In the following section one preferred embodiment is described by way of example to illustrate the process of this invention. However, it is not intended in any way to limit the scope of the present invention.

EXAMPLE

0 Preparation of cefpodoxime proxetil

(6R,7R) 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-(methoxymethyl)3- cephem-4-carboxylic acid (cefpodoxime acid, 10. Og) was dissolved in N, N- dimethylacetamide (35ml) and the mixture was cooled to -10°C. A mixture of pulverized disodium hydrogenphosphate(0.8g) and pulverized sodium carbonate(0.5g) was added. 1,8-

15 diazabicylco[5.4.0]undec-7-ene(DBU, 3.35g) was then added slowly followed by the addition of 1-iodoethyl isopropylcarbonate (6.2g) at -10 to -5°C in 10 minutes. The reaction mixture was stirred for about 2 hours at the same temperature and progress of the reaction was monitored by HPLC. Qualitative analysis after 2 hours showed 92.12% cefpodoxime proxetil, 0.56% corresponding Δ² -isomer, and 2.29% cefpodoxime acid.

>0

The reaction mixture was poured into ethylacetate (300ml) followed by the addition of water (300ml). The organic layer was separated and then washed successively with aqueous hydrochloric acid, aqueous sodium thiosulphate and finally with aqueous sodium chloride. The ethyl acetate layer obtained above was concentrated to about 40 ml at 30-35°C

!5 under reduced pressure and added to cyclohexane (300ml) under stirring at 25°C during about 30 minutes. The precipitated solid was then filtered and washed with cyclohexane. The wet product was added to methanol (40ml) at room temperature to obtain a solution and was concentrated at 30-35°C under reduced pressure to about 30ml. It was then added to water (180ml) in 15 minutes at 20-25°C to obtain a solid which was filtered and washed with a cold

.0 mixture of methanol and water (1:6 v/v, 20ml). The filtered solid was dried to obtain 10.5g of l-(isopropoxycabonyloxy)ethyl (6R,7R) 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino- acetamido]-3-(methoxymethyl)3-cephem-4-carboxylate i.e. cefpodoxime proxetil (Yield 80.5%, Assay : 98%, Qualitative HPLC cefpodoxime proxetil: 99%, corresponding Δ²- isomer: 0.5%).

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

WE CLAIM:

1. A process for preparing compounds of Formula T,

Formula I wherein R is cyano, phenyl, cyclohexadienyl, heterocyclyl, heterocyclylthio, or a heterocyclylamido group, wherein the phenyl or the heterocyclic ring may be further substituted by an alkyl, hydroxy, amino, aminoalkyl, halo or a carboxyalkyl group;

A is mono or disubstituted methylene group,

-CH, — -CH- -CH-

I

OH NH,

wherein R¹ is alkyl, alkoxyalkyl or carboxyalkyl;

R' is hydrogen, alkyl, alkenyl, alkynyl, alkoxymethyl, alkylthiomethyl, alkanoyloxymethyl, carbamoyloxymethyl, or a heterocyclylthiomethyl group, wherein the heterocyclic ring may be further substituted by hydroxy, alkyl, carboxyalkyl, sulfonylalkyl or carbamoyl; and

R" is alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, alkoxyalkyl, alkanoyloxyalkyl or alkoxycarboxylalkyl, comprising reacting a compound of Formula II,

Formula II

wherein R and R' are as defined above, with a compound of Formula R" X, wherein X is a halogen and R" is defined above, in the presence of an amine, an inorganic base and a phosphate buffer to obtain compounds of Formula I.

2. The process according to claim 1, wherein R is selected from the group consisting of 4- hydroxyphenyl, 2-aminomethylphenyl, 2-amino-4-thiazoyl, 2-furanyl, 2-thienyl, 4- pyridinyl, IH-tetrazolyl, 5-amino-l,2,4-thiadiazol-3-yl, 5-methyl-l,3,4-thiadiazol-2-yl, 5- carboxy-lH-imidazol-4-yl, 4-hydroxy-6-methyl-3-pyridinyl, 3,5-dichloro-4-oxo-l(4H)- pyridinyl, and 4-ethyl-2,3-dioxo-l-piperazinyl.

3. The process according to claim 1, wherein R' is selected from the group consisting of methyl, 2-(4-methyl-5-thiazolyl)ethenyl, acetoxymethyl, methoxymethyl, chloro, 1- methyl-lH-tetrazol-5-ylthio, lH-l,2,3-triazol-4-ylthio5-methyl-l,3,4-thiadiazol-2-yl, 1,2,3, -thiadiazol-5-ylthio and l,2,5,6-tetrahydro-2-methyl-5,6-dioxo-l,2,4-triazin-3- ylthio.

4. The process according to claim 1, wherein R" is selected from the group consisting of 1- acetoxyethyl, pivaloyl, pivaloyloxymethyl, l-(isopropoxycabonyloxy)ethyl and 1- (cyclohexyloxycabonyloxy) ethyl.

5. The process according to claim 1, wherein X is selected from the group consisting of chloro, bromo and iodo.

6. The process according to claim 1, wherein the amine is selected from the group consisting of triethylamine, tributylamine, N, N-dimethylaniline, cycloexylamine, pyridine, N- methylpiperidine N-methyl pyrrolidine, N-methyl morpholine, collidine, lutidine, picoline, quinoline, isoquinoline, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and mixture(s) thereof.

7. The process according to claim 1 , wherein the inorganic base is selected from the group consisting of potassium carbonate, sodium carbonate and sodium bicarbonate.

8. The process according to claim 1, wherein the phosphate buffer is selected from the group consisting of disodium hydrogenphosphate, dipotassium hydrogenphosphate and sodium hydrogen phosphate.

9. The process according to claim 1, wherein the phosphate buffer is used in an amount from about 0.5 to about 2.5 molar equivalents with respect to the inorganic base.

10. The process according to claim 1, wherein the reaction is performed in the presence of a solvent selected from the group consisting of dimethylformamide, dimethylacetamide, dimethylsulphoxide, tefrahydrofuran, dichloromethane, ethylacetate, acetonitrile and mixture(s) thereof.

11. The process according to claim 1, wherein the reaction is performed at ambient temperature or with cooling.

12. The process according to claim 11, wherein the reaction is performed at about -10°C to about 0°C.