WO2005100367A1 - Intermediates useful in the synthesis of 3-(2-substituted vinyl) cephalosporins - Google Patents

Intermediates useful in the synthesis of 3-(2-substituted vinyl) cephalosporins Download PDF

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WO2005100367A1
WO2005100367A1 PCT/IB2005/000978 IB2005000978W WO2005100367A1 WO 2005100367 A1 WO2005100367 A1 WO 2005100367A1 IB 2005000978 W IB2005000978 W IB 2005000978W WO 2005100367 A1 WO2005100367 A1 WO 2005100367A1
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formula
aryl
aralkyl
residue
protecting group
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PCT/IB2005/000978
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French (fr)
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Yatendra Kumar
Mohan Prasad
Kaptan Singh
Ashok Prasad
Santosh Richhariya
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Ranbaxy Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

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  • the present invention relates to crystalline intermediates useful in the synthesis of 3-(2-substituted vinyl) cephalosporins and processes for their preparation.
  • the present invention relates to crystalline ylides of Formula I, processes for their preparation, and their use as an intermediate in the preparation of 3-(2-substituted vinyl) cephalosporins.
  • Cephalosporin antibiotics belonging to the class of 3-(2-substituted vinyl) cephalosporins have a very broad spectrum of antimicrobial activity.
  • Cefditoren pivoxil which belongs to this class, is highly active not only against a variety of gram-positive and gram-negative bacteria but also against some resistant strains of bacteria (see, e.g., European Patent No. 175,610).
  • European Patent No. 175,610 describes a process for preparing Cefditoren and its pharmaceutically acceptable salts and esters. The process described is non-selective and gives more than 20% of the unwanted E-isomer, which is then separated by means of column chromatography.
  • R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt.
  • Ri and R 2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally a substituted amino acid residue or a group of Formula A.
  • FORMULA A In Formula A, 4 is an optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4, and R 5 is selected from d to C straight or branch chain alkyl, alkenyl, alkynyl or C 6 to C 10 cycloalkyl, aryl or aralkyl.
  • This crystalline solid of Formula I when used as an intermediate in the synthesis of cefditoren pivoxil, can lead to a significant reduction in the consumption of 4- methylthiazole-5-carboxaldehyde of Formula II.
  • R 3 CHO
  • R 3 is 4-methylthiazole-5-yl, which is also an intermediate. This may advantageously result in significant improvement of process economics as some of the prior art processes reported use of about 6 to 25 moles of 4-methylthiazole-5- carboxaldehyde per mole of the ylide of Formula I. The present inventors have found that this consumption can be reduced to 1.0 to 2.0 moles of 4-methylthiazole-5-carboxaldehyde per mole of ylide of Formula I when the ylide is isolated from the reaction mixture as a crystalline solid.
  • a crystalline ylide of Formula I :
  • R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt
  • Ri and R 2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A
  • n is an integer 2, 3 or 4
  • R 5 is selected from d to C 7 straight or branch chain alkyl, alkenyl, alkynyl or C 6 to Cio cycloalkyl, aryl or aralkyl.
  • 4 is an optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur.
  • substituent groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur.
  • FORMULA I In Formula I, R is diphenylmethyl, one of the Ri and R 2 is hydrogen and other is phenylacetamido group, Y is absent, R 5 is phenyl, and n is an integer having a value of 3.
  • Embodiments of the crystalline ylide may include a powdered X-Ray Diffraction pattern depicted in Figure I.
  • FORMULA I In another general aspect there is provided a process for the preparation of a crystalline ylide of Formula I.
  • R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt
  • Ri and R 2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A
  • n is an integer 2, 3 or 4
  • R 5 is selected from Ci to C 7 straight or branch chain alkyl, alkenyl, alkynyl or C 6 to Cio cycloalkyl, aryl or aralkyl.
  • R is an optionally substituted lower alkyl wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur.
  • the process includes the steps of a) treating a compound of Formula III
  • R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt
  • X is chloro or bromo
  • Ri and R 2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A,
  • FORMULA A wherein is an optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, and heterocyclic containing one or more heteroatoms or halo, with a compound of Formula IN, P(YR 5 )n
  • Y is absent or oxygen or sulphur
  • n is an integer 2
  • R 5 is selected from Ci to C 7 straight or branch chain alkyl, alkenyl, alkynyl or C 6 to Cio cycloalkyl, aryl or aralkyl; b) optionally isolating the product of Formula N,
  • the compound of Formula IN may be selected from trimethylphosphine, triethylphosphine, tributylphosphine, triphenylphosphine, triethyl phosphite, triphenylphosphite, triethylorthophosphite or triphenylorthophosphite.
  • the base may be selected from an inorganic or an organic base.
  • the base may be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminium hydroxide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium t-butoxide, sodium ethoxide, triethylamine, dicyclohexylamine or diphenylamine.
  • R is hydrogen, esterified residue or a metal cation capable of forming a salt
  • R 3 is hydrogen, halo, substituted C ⁇ - 8 alkyl, aryl, aralkyl, substituted heterocyclic residue containing one or more heteroatoms selected from nitrogen, oxygen, sulphur; or SR 6 wherein R 6 is straight or branched chain C ⁇ - alkyl, C ⁇ - 3 alkenyl, aryl, aralkyl, substituted aralkyl, or a heterocyclic residue,
  • Ri and R 2 are independently selected from hydrogen, amino protecting group or combine together to form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A, FORMULA A wherein I is an optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo, wherein the process includes the steps of a) reacting the crystalline ylide of Formula I,
  • R is a hydrogen atom, esteri ying residue or a metal cation capable of forming a salt
  • Ri and R 2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A
  • n is an integer 2, 3 or 4
  • R 5 is selected from Ci to C 7 straight or branch chain alkyl, alkenyl, alkynyl or C 6 to Cio cycloalkyl, aryl or aralkyl,
  • R 4 is an optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur, with a compound of Formula II or a suitable chemical equivalent thereof in an organic solvent at a temperature of about -50 to 35°C, R 3 CHO
  • FORMULA II wherein R 3 is hydrogen, halo, substituted C ⁇ - 8 alkyl, aryl, aralkyl, substituted heterocyclic residue containing one or more heteroatoms selected from nitrogen, oxygen, sulphur; or SR 6 wherein R 6 is straight or branched chain C ⁇ - alkyl, C ⁇ - 3 alkenyl, aryl, aralkyl, substituted aralkyl or a heterocyclic residue; and b) isolating the compound of Formula VI from the reaction mass.
  • a process that includes using the crystalline ylides above for the preparation of 3-(2-substituted vinyl) cephalosponn.
  • Embodiments of the process may include one or more of the following features.
  • the 3-(2-substituted vinyl) cephalosporin maybe cefditoren of Formula VII or pharmaceutically acceptable salts and esters thereof.
  • the 3-(2-substituted vinyl) cephalosporin may be cefdinir of Formula VIII or pharmaceutically acceptable salts and esters thereof.
  • the 3-(2-substituted vinyl) cephalosporin may be cefixime of Formula IX or pharmaceutically acceptable salts and esters thereof.
  • the 3-(2-substituted vinyl) cephalosporin may be cefprozil of Formula X or pharmaceutically acceptable salts and esters thereof.
  • Figure 1 is a powdered X-Ray Diffraction pattern of a crystalline ylide.
  • a first aspect of the present invention provides crystalline ylides of Formula I.
  • R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt.
  • Ri and R 2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A.
  • 1 ⁇ is an optionally substituted lower alkyl wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4, and R 5 is selected from Ci to C 7 straight or branch chain alkyl, alkenyl, alkynyl or C 6 to Cio cycloalkyl, aryl or aralkyl.
  • a second aspect of the present invention provides a crystalline ylide of Formula I.
  • R is diphenylmethyl and one of the Ri and R 2 is hydrogen and the other is a phenylacetamido group; Y is absent; R 5 is phenyl and n is integer having value 3 (herein onwards referred to as GCLH-ylide) having a powder X-Ray Diffraction pattern depicted in Figure I as shown in the accompanied drawings.
  • GCLH-ylide a powder X-Ray Diffraction pattern depicted in Figure I as shown in the accompanied drawings.
  • R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt and Ri and R 2 are independently hydrogen, monovalent amino protecting i group or together form a divalent amino protecting group, optionally' substituted amino acid residue or a group of Formula A.
  • R is an optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4, and R 5 is selected from Ci to C 7 straight or branch chain alkyl, alkenyl, alkynyl or C 6 to Cio cycloalkyl, aryl or aralkyl.
  • the process includes the steps of a) treating a compound of Formula III
  • R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt
  • X is chloro or bromo
  • Ri and R 2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A, K
  • R 4 is a optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo, with a compound of Formula IV, P(YR 5 )n
  • Y is absent or oxygen or sulphur
  • n is an integer 2, 3 or 4
  • R 5 is selected from Ci to C 7 straight or branch chain alkyl, alkenyl, alkynyl or C 6 to Cio cycloalkyl, aryl or aralkyl; b) optionally isolating the product of Formula V,
  • R, Ri, R 2 , Y, R 5 , X and n are as defined above; c) treating the product of step a) or b) with a base; and d) isolating the crystalline ylide of Formula I from the reaction mass.
  • the compound or compounds of Formula III are treated with alkali or alkaline earth metal iodide or bromide and a phosphorous containing compound of Formula III in an organic solvent at a temperature of -10 to 50°C.
  • the alkali or alkaline earth metal iodide or bromide can be selected from sodium i dide, potassium iodide, sodium bromide, potassium bromide and such similar metal iodides or bromides.
  • the compound of Formula IV wherein Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4, and R 5 is selected from Ci to C 7 straight or branch chain alkyl, alkenyl, alkynyl or C 6 to Cio cycloalkyl, aryl or aralkyl, can be selected from trimethylphosphine, triethylphosphine, tributylphosphine, triphenylphosphine, triethyl phosphite, triphenylphosphite, triethylorthophosphite or triphenylorthophosphite.
  • the organic solvent can be one or more of chlorinated hydrocarbons such as ⁇ xethylene chloride, chloroform, ethylene chloride or ethylene bromide; polar aprotic solvents such as dimethylformamide, dimethylacetamide or dimethylsulphoxide; ethers such as tefrahydrofuran, diisopropyl ether, 1,4-dioxane or diethyl ether; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone; esters such as ethyl acetate, methyl acetate, ethyl formate, methyl formate, isopropyl acetate, n-butyl acetate, isobutyl acetate and n-propyl acetate; and lower alcohols such as methanol, ethanol, propanol, isopropanol, bi tanol or mixtures thereof.
  • chlorinated hydrocarbons such
  • the compound or compounds of Formula V can be isolated from the reaction mass by suitable aqueous workup, however, the reaction mass can, as such, be taken in the next step.
  • the reaction mass is treated with a base at a temperature between -20 to 50°C. It is also possible to cool the organic layer obtained in step a) to -5 to 25°C and slowly add a solution of base in water or suitable organic solvent over a period of 15 minutes to 1 hour by maintaining the temperature.
  • Ylides of Formula I start separating out from the reaction mass as a crystalline solid. After complete precipitation of the crystalline product it is filtered and optionally dried under vacuum to get an almost quantitative yield.
  • the base used in this step can be an inorganic compound such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminium hydroxide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; one or more organic salts such as sodium methoxide, potassium t-butoxide, sodium ethoxide; or organic ammonium compounds such as triethylamine, dicyclohexylamine or diphenylamine.
  • a solution of base can be made in a suitable solvent such as water.
  • R is hydrogen, estenfied residue or a metal cation capable of forming a salt
  • R 3 is hydrogen, halo, substituted C ⁇ - 8 alkyl, aryl, aralkyl, substituted heterocyclic residue containing one or more heteroatoms selected from nitrogen, oxygen, sulphur; or SR 6 wherein R 6 is straight or branched chain C ⁇ - 4 alkyl, C ⁇ - 3 alkenyl, aryl, aralkyl, substituted aralkyl, or a heterocyclic residue
  • Ri and R 2 are independently selected from hydrogen, amino protecting group or combine together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A, FORMULA A wherein R 4 is an optionally substituted lower alkyl wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo.
  • the process includes the steps of a) reacting the crystalline crystalline phase,
  • R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt and Ri and R are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A,
  • R 4 is an optionally substituted lower alkyl wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur
  • n is an integer 2, 3 or 4
  • R 5 is selected from Ci to C 7 straight or branch chain alkyl, alkenyl, alkynyl or C 6 to Cio cycloalkyl, aryl or aralkyl, with a compound of Formula II or a suitable chemical equivalent thereof, R 3 CHO FORMULA II wherein R 3 is hydrogen, halo, substituted C ⁇ - 8 alkyl, aryl, aralkyl, substituted heterocyclic residue containing one or more heteroatoms selected from nitrogen, oxygen, sulphur; or SR 6 wherein R 6 is straight or branched chain C ⁇ - 4 alkyl, C ⁇ - 3 alkenyl, aryl, aralkyl, substituted aral
  • the compound of Formula I is treated with a compound of Formula II or a suitable chemical equivalent thereof, wherein R 3 is as defined above, in the presence of an organic solvent at a temperature of about -50 to 35°C.
  • the suitable chemical equivalents include orttioesters, orthoformates, and polymeric forms of compound of Formula II. After completion of the reaction, it is quenched by addition of water followed by washing of the organic layer with sodium bisulphite solution to eliminate aldehydic and related impurities generated during reaction.
  • the compound of Formula VI can then be isolated from the organic layer by suitable methods of isolation, which include evaporation of the organic solvent to get the product, precipitation of the product from the organic solvent by addition of anti-solvent, and the like.
  • the organic solvent can be one or more of chlorinated hydrocarbons such as chloroform or methylene chloride; lower alkanols such as methanol, ethanol, n-propanol, isopropanol and n-butanol; ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane; esters such as ethyl acetate, n-butyl acetate, isopropyl acetate, etc.; or ketones such as acetone, ethyl methyl ketone or mixtures thereof.
  • a chlorinated hydrocarbon containing a lower alkanol is a preferred solvent mixture.
  • a fifth aspect of the present invention provides use of crystalline ylides of Formula I as intermediates in the synthesis of 3-(2-substituted vinyl) cephalosporin commercially used as antimicrobials for the treatment of infectious diseases caused by gram positive, gram negative, and resistant strains of bacteria.
  • 3-(2-substituted vinyl) cephalosporins include cefditoren of Formula VII, cefdinir of Formula VIII, cefixime of Formula IX, cefprozil of Formula X or pharmaceutically acceptable salts and esters thereof.
  • Example 1 Preparation of 1,1 -diphenylmethyl 7-(phenylacetamido -3- r(triphenylphoshoranylidene)methyll-3-cepheme-4-carboxylate To a stfrred mixture of dimethylformamide (20 ml) and methylene chloride (10 ml) at ambient temperature was added 4-diphenylmethyl 7-phenylacetamido-3-chloromethyl- 3-cephem-4-carboxylate (10 g) followed by addition of triphenylphosphine (0.51 g) and sodium bromide (0.23 g).
  • Step A) Preparation of 7-Amino-3-[2-(4-MethyIthiazoI-5-Yl)VinyI]-3-Cepheme-4- Carboxylic Acid l,l-diphenylmethyl 7-(phenylacetamido)-3-[(triphenylphoshoranylidene)methyl]- 3-cephem-4-carboxylate (16 g) was mixed with methylene chloride (120 ml) and 1- propanol (40 ml) followed by addition of 4-methylthiazol-5-carboxaldehyde (3 g). The resultant heterogeneous mixture was stirred at 20 to 25°C for 20 to 22 hours. Progress of the reaction was monitored by HPLC.
  • the organic portion was extracted with sodium bicarbonate solution (0.17 Molar, 2 x 150 ml).
  • the aqueous layer was washed with n-butyl acetate (2 x 150 ml) to remove traces of phenol.
  • Pen-G amidase 8 g wet
  • the pH of the reaction was intermittently adjusted to 7.5 to 7.7 by slow addition of 5% sodium carbonate solution.
  • the enzyme was filtered and washed with de-ionized water. The filtrate was treated with activated carbon and then filtered at 30-35°C.

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  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

The present invention relates to crystalline intermediates useful in the synthesis of 3-(2-substituted vinyl) cephalosporins and processes for their preparation. In particular, the present invention relates to crystalline ylides of Formula I, processes for their preparation, and their use as an intermediate in thepreparation of 3-(2-substituted vinyl) cephalosporins.

Description

INTERMEDIATES USEFUL IN THE SYNTHESIS OF 3-(2-SUBSTITUTED VINYL) CEPHALOSPORINS Field of the Invention
The present invention relates to crystalline intermediates useful in the synthesis of 3-(2-substituted vinyl) cephalosporins and processes for their preparation. In particular, the present invention relates to crystalline ylides of Formula I, processes for their preparation, and their use as an intermediate in the preparation of 3-(2-substituted vinyl) cephalosporins.
Figure imgf000002_0001
Background of the Invention Cephalosporin antibiotics belonging to the class of 3-(2-substituted vinyl) cephalosporins have a very broad spectrum of antimicrobial activity. Cefditoren pivoxil, which belongs to this class, is highly active not only against a variety of gram-positive and gram-negative bacteria but also against some resistant strains of bacteria (see, e.g., European Patent No. 175,610). European Patent No. 175,610 describes a process for preparing Cefditoren and its pharmaceutically acceptable salts and esters. The process described is non-selective and gives more than 20% of the unwanted E-isomer, which is then separated by means of column chromatography. The yield of cefditoren or its sodium salt or its pivaloxymethyl ester is reported to be very low. U.S. Patent No. 6,288,223 describes a process for the selective preparation of the Z-isomer of 3-2 (substituted vinyl) cephalosporins. In this process, reaction conditions as well as solvent system are selected in such a manner that during formation of the vinyl group, selectively the Z-isomer is obtained without formation of E-isomer. The process, however, still generates about 4 to 5% of unwanted E-isomer, which needs to be separated in order to get the desired purity of the finished product. The process uses lower temperature of about -50 to 5°C when the vinyl group is formed by reaction between an ylide and an aldehyde. Stringent conditions are adopted for deprotection of the protected amino and carboxyl functionalities. The process isolates every intermediate followed by its purification and therefore is very time consuming. It gives a reduced yield of Cefditoren pivoxil. U.S. Patent No. 5,616,703 describes a process for separating cephalosporin isomers by forming amine salts. The process described therein produces the intermediates in which the xmwanted E isomer is more than 20%, which is then depleted by forming amine salts. In this process the yield of the intermediate is reduced and the unwanted E-isomer, after separation, is removed from the process. Our pending PCT patent application WO 2005/016936 describes a process for selective preparation of Z-isomer of cefditoren or pharmaceutically acceptable salts and esters thereof. The process selectively prepares Z-isomer of cefditoren pivoxil having less than 1% of the E-isomer. Summary of the Invention The present inventors have surprisingly found that while preparing cefditoren pivoxil by processes described in co-pending PCT patent application WO 2005/016936, they are able to modify the reaction conditions and isolate as a crystalline solid the ylide of Formula I.
Figure imgf000003_0001
FORMULA I In Formula I, R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt. Ri and R2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally a substituted amino acid residue or a group of Formula A.
Figure imgf000004_0001
FORMULA A In Formula A, 4 is an optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4, and R5 is selected from d to C straight or branch chain alkyl, alkenyl, alkynyl or C6 to C10 cycloalkyl, aryl or aralkyl. This crystalline solid of Formula I, when used as an intermediate in the synthesis of cefditoren pivoxil, can lead to a significant reduction in the consumption of 4- methylthiazole-5-carboxaldehyde of Formula II. R3CHO
FORMULA II In Formula II, R3 is 4-methylthiazole-5-yl, which is also an intermediate. This may advantageously result in significant improvement of process economics as some of the prior art processes reported use of about 6 to 25 moles of 4-methylthiazole-5- carboxaldehyde per mole of the ylide of Formula I. The present inventors have found that this consumption can be reduced to 1.0 to 2.0 moles of 4-methylthiazole-5-carboxaldehyde per mole of ylide of Formula I when the ylide is isolated from the reaction mixture as a crystalline solid. Thus, in one general aspect there is provided a crystalline ylide of Formula I:
Figure imgf000004_0002
FORMULA I In Formula I, R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt, and Ri and R2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A, n is an integer 2, 3 or 4, and R5 is selected from d to C7 straight or branch chain alkyl, alkenyl, alkynyl or C6 to Cio cycloalkyl, aryl or aralkyl.
Figure imgf000005_0001
FORMULA A
In Formula A, 4 is an optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur. In another general aspect there is provided a crystalline ylide of Formula I.
Figure imgf000005_0002
FORMULA I In Formula I, R is diphenylmethyl, one of the Ri and R2 is hydrogen and other is phenylacetamido group, Y is absent, R5 is phenyl, and n is an integer having a value of 3. Embodiments of the crystalline ylide may include a powdered X-Ray Diffraction pattern depicted in Figure I. In another general aspect there is provided a process for the preparation of a crystalline ylide of Formula I.
Figure imgf000006_0001
FORMULA I
In Formula I, R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt, and Ri and R2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A, n is an integer 2, 3 or 4, and R5 is selected from Ci to C7 straight or branch chain alkyl, alkenyl, alkynyl or C6 to Cio cycloalkyl, aryl or aralkyl.
Figure imgf000006_0002
FORMULA A In Formula A, R is an optionally substituted lower alkyl wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur.
The process includes the steps of a) treating a compound of Formula III
Figure imgf000006_0003
FORMULA III wherein, R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt, X is chloro or bromo, and Ri and R2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A,
Figure imgf000007_0001
FORMULA A wherein is an optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, and heterocyclic containing one or more heteroatoms or halo, with a compound of Formula IN, P(YR5)n
FORMULA IV wherein,
Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4 and R5 is selected from Ci to C7 straight or branch chain alkyl, alkenyl, alkynyl or C6 to Cio cycloalkyl, aryl or aralkyl; b) optionally isolating the product of Formula N,
Figure imgf000007_0002
FORMULA V wherein R, Ri, R2, Y, R5, X and n are as defined above; c) treating the product of step a) or b) with a base; and d) isolating the crystalline ylide of Formula I from the reaction mass. Embodiments of the process may include one or more of the following features. For example, the compound of Formula IN may be selected from trimethylphosphine, triethylphosphine, tributylphosphine, triphenylphosphine, triethyl phosphite, triphenylphosphite, triethylorthophosphite or triphenylorthophosphite. The base may be selected from an inorganic or an organic base. The base may be selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminium hydroxide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium t-butoxide, sodium ethoxide, triethylamine, dicyclohexylamine or diphenylamine. h another general aspect there is provided a process for the preparation of a compound of Formula VI.
Figure imgf000008_0001
FORMULA VI wherein,
R is hydrogen, esterified residue or a metal cation capable of forming a salt,
R3 is hydrogen, halo, substituted Cι-8 alkyl, aryl, aralkyl, substituted heterocyclic residue containing one or more heteroatoms selected from nitrogen, oxygen, sulphur; or SR6 wherein R6 is straight or branched chain Cι- alkyl, Cι-3 alkenyl, aryl, aralkyl, substituted aralkyl, or a heterocyclic residue,
Ri and R2 are independently selected from hydrogen, amino protecting group or combine together to form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A,
Figure imgf000009_0001
FORMULA A wherein I is an optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo, wherein the process includes the steps of a) reacting the crystalline ylide of Formula I,
Figure imgf000009_0002
FORMULA I wherein, R is a hydrogen atom, esteri ying residue or a metal cation capable of forming a salt, Ri and R2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A, n is an integer 2, 3 or 4, and R5 is selected from Ci to C7 straight or branch chain alkyl, alkenyl, alkynyl or C6 to Cio cycloalkyl, aryl or aralkyl,
Figure imgf000009_0003
FORMULA A wherein R4 is an optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur, with a compound of Formula II or a suitable chemical equivalent thereof in an organic solvent at a temperature of about -50 to 35°C, R3CHO
FORMULA II wherein R3 is hydrogen, halo, substituted Cι-8 alkyl, aryl, aralkyl, substituted heterocyclic residue containing one or more heteroatoms selected from nitrogen, oxygen, sulphur; or SR6 wherein R6 is straight or branched chain Cι- alkyl, Cι-3 alkenyl, aryl, aralkyl, substituted aralkyl or a heterocyclic residue; and b) isolating the compound of Formula VI from the reaction mass. In another general aspect there is provided a process that includes using the crystalline ylides above for the preparation of 3-(2-substituted vinyl) cephalosponn. Embodiments of the process may include one or more of the following features. For example, the 3-(2-substituted vinyl) cephalosporin maybe cefditoren of Formula VII or pharmaceutically acceptable salts and esters thereof.
Figure imgf000010_0001
FORMULA VII The 3-(2-substituted vinyl) cephalosporin may be cefdinir of Formula VIII or pharmaceutically acceptable salts and esters thereof.
Figure imgf000011_0001
FORMULA VIII The 3-(2-substituted vinyl) cephalosporin may be cefixime of Formula IX or pharmaceutically acceptable salts and esters thereof.
Figure imgf000011_0002
FORMULA IX The 3-(2-substituted vinyl) cephalosporin may be cefprozil of Formula X or pharmaceutically acceptable salts and esters thereof.
Figure imgf000011_0003
FORMULA X Brief Description of the Drawings Figure 1 is a powdered X-Ray Diffraction pattern of a crystalline ylide.
Detailed Description of the Invention A first aspect of the present invention provides crystalline ylides of Formula I.
Figure imgf000012_0001
FORMULA I
In. Formula I, R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt. Ri and R2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A.
Figure imgf000012_0002
FORMULA A
In. Formula A, 1^ is an optionally substituted lower alkyl wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4, and R5 is selected from Ci to C7 straight or branch chain alkyl, alkenyl, alkynyl or C6 to Cio cycloalkyl, aryl or aralkyl. A second aspect of the present invention provides a crystalline ylide of Formula I.
Figure imgf000013_0001
FORMULA I
In Fomiula I, R is diphenylmethyl and one of the Ri and R2 is hydrogen and the other is a phenylacetamido group; Y is absent; R5 is phenyl and n is integer having value 3 (herein onwards referred to as GCLH-ylide) having a powder X-Ray Diffraction pattern depicted in Figure I as shown in the accompanied drawings. A third aspect of the present invention provides a process for preparation of crystalline ylides of Formula I.
Figure imgf000013_0002
FORMULA I
In Formula I, R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt and Ri and R2 are independently hydrogen, monovalent amino protecting i group or together form a divalent amino protecting group, optionally' substituted amino acid residue or a group of Formula A. K
Figure imgf000013_0003
FORMULA
In Formula A, R is an optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4, and R5 is selected from Ci to C7 straight or branch chain alkyl, alkenyl, alkynyl or C6 to Cio cycloalkyl, aryl or aralkyl. The process includes the steps of a) treating a compound of Formula III
Figure imgf000014_0001
FORMULA III wherein R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt; X is chloro or bromo; and Ri and R2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A, K
Figure imgf000014_0002
FORMULA A wherein R4 is a optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo, with a compound of Formula IV, P(YR5)n
FORMULA IV wherein Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4, and R5 is selected from Ci to C7 straight or branch chain alkyl, alkenyl, alkynyl or C6 to Cio cycloalkyl, aryl or aralkyl; b) optionally isolating the product of Formula V,
Figure imgf000015_0001
FORMULA V wherein R, Ri, R2, Y, R5, X and n are as defined above; c) treating the product of step a) or b) with a base; and d) isolating the crystalline ylide of Formula I from the reaction mass. The compound or compounds of Formula III are treated with alkali or alkaline earth metal iodide or bromide and a phosphorous containing compound of Formula III in an organic solvent at a temperature of -10 to 50°C. The alkali or alkaline earth metal iodide or bromide can be selected from sodium i dide, potassium iodide, sodium bromide, potassium bromide and such similar metal iodides or bromides. The compound of Formula IV, wherein Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4, and R5 is selected from Ci to C7 straight or branch chain alkyl, alkenyl, alkynyl or C6 to Cio cycloalkyl, aryl or aralkyl, can be selected from trimethylphosphine, triethylphosphine, tributylphosphine, triphenylphosphine, triethyl phosphite, triphenylphosphite, triethylorthophosphite or triphenylorthophosphite. The organic solvent can be one or more of chlorinated hydrocarbons such as πxethylene chloride, chloroform, ethylene chloride or ethylene bromide; polar aprotic solvents such as dimethylformamide, dimethylacetamide or dimethylsulphoxide; ethers such as tefrahydrofuran, diisopropyl ether, 1,4-dioxane or diethyl ether; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone; esters such as ethyl acetate, methyl acetate, ethyl formate, methyl formate, isopropyl acetate, n-butyl acetate, isobutyl acetate and n-propyl acetate; and lower alcohols such as methanol, ethanol, propanol, isopropanol, bi tanol or mixtures thereof. After completion of the reaction, the compound or compounds of Formula V can be isolated from the reaction mass by suitable aqueous workup, however, the reaction mass can, as such, be taken in the next step. The reaction mass is treated with a base at a temperature between -20 to 50°C. It is also possible to cool the organic layer obtained in step a) to -5 to 25°C and slowly add a solution of base in water or suitable organic solvent over a period of 15 minutes to 1 hour by maintaining the temperature. Ylides of Formula I start separating out from the reaction mass as a crystalline solid. After complete precipitation of the crystalline product it is filtered and optionally dried under vacuum to get an almost quantitative yield. The base used in this step can be an inorganic compound such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminium hydroxide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate; one or more organic salts such as sodium methoxide, potassium t-butoxide, sodium ethoxide; or organic ammonium compounds such as triethylamine, dicyclohexylamine or diphenylamine. For the practical utility a solution of base can be made in a suitable solvent such as water. -A fourth aspect of the present invention provides a process for the preparation of compound of Formula VI,
Figure imgf000016_0001
FORMULA VI wherein R is hydrogen, estenfied residue or a metal cation capable of forming a salt; R3 is hydrogen, halo, substituted Cι-8 alkyl, aryl, aralkyl, substituted heterocyclic residue containing one or more heteroatoms selected from nitrogen, oxygen, sulphur; or SR6 wherein R6 is straight or branched chain Cι-4 alkyl, Cι-3 alkenyl, aryl, aralkyl, substituted aralkyl, or a heterocyclic residue; and Ri and R2 are independently selected from hydrogen, amino protecting group or combine together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A,
Figure imgf000017_0001
FORMULA A wherein R4 is an optionally substituted lower alkyl wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo. The process includes the steps of a) reacting the crystalline ylide of Formula I,
Figure imgf000017_0002
FORMULA I wherein, R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt and Ri and R are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A,
Figure imgf000017_0003
FORMULA A wherein R4 is an optionally substituted lower alkyl wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4, and R5 is selected from Ci to C7 straight or branch chain alkyl, alkenyl, alkynyl or C6 to Cio cycloalkyl, aryl or aralkyl, with a compound of Formula II or a suitable chemical equivalent thereof, R3CHO FORMULA II wherein R3 is hydrogen, halo, substituted Cι-8 alkyl, aryl, aralkyl, substituted heterocyclic residue containing one or more heteroatoms selected from nitrogen, oxygen, sulphur; or SR6 wherein R6 is straight or branched chain Cι-4 alkyl, Cι-3 alkenyl, aryl, aralkyl, substituted aralkyl or a heterocyclic residue in an organic solvent at a temperature of about -50 to 35°C; and b) isolating the compound of Formula VI from the reaction mass. The compound of Formula I is treated with a compound of Formula II or a suitable chemical equivalent thereof, wherein R3 is as defined above, in the presence of an organic solvent at a temperature of about -50 to 35°C. The suitable chemical equivalents include orttioesters, orthoformates, and polymeric forms of compound of Formula II. After completion of the reaction, it is quenched by addition of water followed by washing of the organic layer with sodium bisulphite solution to eliminate aldehydic and related impurities generated during reaction. The compound of Formula VI can then be isolated from the organic layer by suitable methods of isolation, which include evaporation of the organic solvent to get the product, precipitation of the product from the organic solvent by addition of anti-solvent, and the like. The organic solvent can be one or more of chlorinated hydrocarbons such as chloroform or methylene chloride; lower alkanols such as methanol, ethanol, n-propanol, isopropanol and n-butanol; ethers such as tetrahydrofuran, diethyl ether, 1,4-dioxane; esters such as ethyl acetate, n-butyl acetate, isopropyl acetate, etc.; or ketones such as acetone, ethyl methyl ketone or mixtures thereof. A chlorinated hydrocarbon containing a lower alkanol is a preferred solvent mixture. A fifth aspect of the present invention provides use of crystalline ylides of Formula I as intermediates in the synthesis of 3-(2-substituted vinyl) cephalosporin commercially used as antimicrobials for the treatment of infectious diseases caused by gram positive, gram negative, and resistant strains of bacteria. Examples of 3-(2-substituted vinyl) cephalosporins include cefditoren of Formula VII, cefdinir of Formula VIII, cefixime of Formula IX, cefprozil of Formula X or pharmaceutically acceptable salts and esters thereof.
Figure imgf000019_0001
FORMULA VII
Figure imgf000019_0002
FORMULA VIII
Figure imgf000019_0003
FORMULA IX
Figure imgf000020_0001
FORMULA X While the present inventions have been described in terms of their 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 inventions. EXAMPLES
Example 1 : Preparation of 1,1 -diphenylmethyl 7-(phenylacetamido -3- r(triphenylphoshoranylidene)methyll-3-cepheme-4-carboxylate To a stfrred mixture of dimethylformamide (20 ml) and methylene chloride (10 ml) at ambient temperature was added 4-diphenylmethyl 7-phenylacetamido-3-chloromethyl- 3-cephem-4-carboxylate (10 g) followed by addition of triphenylphosphine (0.51 g) and sodium bromide (0.23 g). This mixture was stirred for 2 to 3 hours and cooled to 10 to 15°C, followed by addition of sodium carbonate (16 ml, 10% aqueous solution). The temperature was raised to 20 to 25°C and stirring was continued for 1.5 hours. The title compound was filtered as crystalline solid (16 g) under suction.
Example 2: Preparation of Cefditoren Acid Sodium Salt
Step A) Preparation of 7-Amino-3-[2-(4-MethyIthiazoI-5-Yl)VinyI]-3-Cepheme-4- Carboxylic Acid l,l-diphenylmethyl 7-(phenylacetamido)-3-[(triphenylphoshoranylidene)methyl]- 3-cephem-4-carboxylate (16 g) was mixed with methylene chloride (120 ml) and 1- propanol (40 ml) followed by addition of 4-methylthiazol-5-carboxaldehyde (3 g). The resultant heterogeneous mixture was stirred at 20 to 25°C for 20 to 22 hours. Progress of the reaction was monitored by HPLC. After completion, the reaction mixture was sequentially washed with 3% sodium bisulfite (100 ml) and water (100 ml). The organic layer was concentrated under reduced pressure to get an oily residue of 1 , 1 ,- diphenylmethyl 7-(phenylacetamido)-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cepheme-4- carboxylate. To this oily residue phenol (60 ml) was added to the residue to get a clear solution. This solution was stirred at 40 to 50°C for 10 to 12 hours and n-butyl acetate (150 ml) was added to the reaction mass followed by cooling to 5 to 10°C. The organic portion was extracted with sodium bicarbonate solution (0.17 Molar, 2 x 150 ml). The aqueous layer was washed with n-butyl acetate (2 x 150 ml) to remove traces of phenol. To the clear aqueous layer was added Pen-G amidase (8 g wet) at 20 to 25°C. The pH of the reaction was intermittently adjusted to 7.5 to 7.7 by slow addition of 5% sodium carbonate solution. After completion of the reaction, the enzyme was filtered and washed with de-ionized water. The filtrate was treated with activated carbon and then filtered at 30-35°C. The filtrate was cooled to 20-25°C and to it was added dilute HC1 (2 Molar) to adjust the pH to 3.0 to 3.5 in order to effect complete precipitation of the title compound. The product was filtered and sequentially washed with water and acetone and finally dried under vacuum to get 5.5 g of off-white title compound. Step B) Preparation of cefditoren acid sodium salt
A suspension of product obtained in Step A) (5.0 g, 15.4 mmol) and 2-methoxyimino-2- (2-amino thiazol-4-yl)acetic acid, S-2-benzothiazole ester (6.7 g, 18.6 mmol) in aqueous tetrahydrofuran (60 ml) was stirred at 0 to 5°C. Triethylamine (2.3 ml) was added slowly at 0-5°C over 15 to 20 minutes. The mixture was stirred at 0-5°C for 2-3 hours. The reaction was quenched by addition of dichloromethane followed by layer separation. The aqueous layer was diluted with acetone to 50 ml. Sodium 2-ethylhexanoate (3.3 g, 19.8 mmol) was added to the aqueous acetone solution at 20-25°C. After stirring the mixture for sufficient time for crystallization of sodium salt of Cefditoren, acetone (50 ml) was slowly added to the reaction mass in order to complete the crystallization. The crystallized product was filtered under suction and washed with acetone (2 x 10 ml). The product was vacuum dried to get 6.5 g of off-white title compound (Yield = 75%). 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 included within the scope of the present invention.

Claims

We claim:
1. A crystalline ylide of Formula I,
Figure imgf000022_0001
FORMUL I wherein,
R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt, and Ri and R are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A,
Figure imgf000022_0002
FORMULA A wherein,
R is an optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4, and
R5 is selected from Ci to C7 straight or branch chain alkyl, alkenyl, alkynyl or C6 to Cio cycloalkyl, aryl or aralkyl.
2. A crystalline ylide of Formula I,
FORMULA I wherein,
R is diphenylmethyl, one of the Ri and R2 is hydrogen and other is phenylacetamido group,
Y is absent,
R5 is phenyl, and n is an integer having a value of 3.
3. The crystalline ylide of claim 2 having a powdered X-Ray Diffraction pattern depicted in Figure I.
4. A process for the preparation of a crystalline ylide of Formula I,
Figure imgf000023_0002
FORMULA I wherein,
R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt, and
Ri and R2 are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A,
Figure imgf000024_0001
FORMULA A wherein R4 is an optionally substituted lower alkyl wherein the substituents groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4, and
R5 is selected from Ci to C7 straight or branch chain alkyl, alkenyl, alkynyl or C6 to Cio cycloalkyl, aryl or aralkyl, wherein the process comprises the steps of" a) treating a compound of Formula III
Figure imgf000024_0002
FORMULA III wherein, R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt, X is chloro or bromo, and Ri and R are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A, K
Figure imgf000024_0003
FORMULA A wherein R4 is an optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, and heterocyclic containing one or more heteroatoms or halo, with a compound of Formula IV, P(YR5)n FORMULA IV wherein, Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4 and R5 is selected from Ci to C straight or branch chain alkyl, alkenyl, alkynyl or C6 to Cio cycloalkyl, aryl or aralkyl; b) optionally isolating the product of Formula V,
Figure imgf000025_0001
FORMULA V wherein R, Ri, R2, Y, R5, X and n are as defined above; c) treating the product of step a) or b) with a base; and d) isolating the crystalline ylide of Formula I from the reaction mass.
5. The process of claim 4 wherein the compound of Formula IV is selected from trimethylphosphine, triethylphosphine, tributylphosphine, triphenylphosphine, triethyl phosphite, triphenylphosphite, triethylorthophosphite or triphenylorthophosphite.
6. The process of claim 4 wherein the base is selected from an inorganic or an organic base.
7. The process of claim 6 wherein base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminium hydroxide, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium t-butoxide, sodium ethoxide, triethylamine, dicyclohexylamine or diphenylamine.
8. A process for the preparation of a compound of Fomiula NI,
Figure imgf000026_0001
FORMULA VI wherein,
R is hydrogen, esterified residue or a metal cation capable of forming a salt,
R3 is hydrogen, halo, substituted Cι-8 alkyl, aryl, aralkyl, substituted heterocyclic residue containing one or more heteroatoms selected from nitrogen, oxygen, sulphur; or SR6 wherein R6 is straight or branched chain Cι- alkyl, Cι- alkenyl, aryl, aralkyl, substituted aralkyl, or a heterocyclic residue,
Ri and R2 are independently selected from hydrogen, amino protecting group or combine together to form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A,
Figure imgf000026_0002
FORMULA A wherein R4 is an optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo, wherein the process comprises the steps of a) reacting the crystalline ylide of Formula I,
Figure imgf000027_0001
FORMULA I wherein, R is a hydrogen atom, esterifying residue or a metal cation capable of forming a salt, Ri and R are independently hydrogen, monovalent amino protecting group or together form a divalent amino protecting group, optionally substituted amino acid residue or a group of Formula A,
Figure imgf000027_0002
FORMULA A wherein Rt is an optionally substituted lower alkyl wherein the substituent groups are selected from carboxyl, hydroxy, aryl, heterocyclic containing one or more heteroatoms or halo and Y is absent or oxygen or sulphur, n is an integer 2, 3 or 4, and R5 is selected from C to C7 straight or branch chain alkyl, alkenyl, alkynyl or C6 to Cio cycloalkyl, aryl or aralkyl, with a compound of Formula II or a suitable chemical equivalent thereof in an organic solvent at a temperature of about -50 to 35°C, R3CH° FORMULA II wherein R is hydrogen, halo, substituted Cι-8 alkyl, aryl, aralkyl, substituted, heterocyclic residue containing one or more heteroatoms selected from nitrogen, oxygen, sulphur; or SR6 wherein Re is straight or branched chain Cι-4 alkyl, Cι-3 alkenyl, aryl, aralkyl, substituted aralkyl or a heterocyclic residue; and b) isolating the compound of Formula VI from the reaction mass.
9. A process comprising using the crystalline ylide of claims 1 or 2 for the preparation of 3-(2-substituted vinyl) cephalosporin.
10. The process according to claim 9 wherein the 3-(2-substituted vinyl) cephalosporin is cefditoren of Formula VII or pharmaceutically acceptable salts and esters thereof.
Figure imgf000028_0001
FORMULA VII
11. The process according to claim 9 wherein the 3-(2-substituted vinyl) cephalosporin is cefdinir of Formula VIII or pharmaceutically acceptable salts and esters thereof.
Figure imgf000028_0002
FORMULA VIII
12. The process according to claim 9 wherein the 3-(2-substiruted vinyl) cephalosporin is cefixime of Formula IX or pharmaceutically acceptable salts and esters thereof.
Figure imgf000029_0001
FORMULA IX
13. The process according to claim 9 wherein the 3-(2-substituted vinyl) cephalosporin is cefprozil of Formula X or pharmaceutically acceptable salts and esters thereof.
Figure imgf000029_0002
FORMULA X
PCT/IB2005/000978 2004-04-13 2005-04-13 Intermediates useful in the synthesis of 3-(2-substituted vinyl) cephalosporins WO2005100367A1 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7459550B2 (en) 2003-07-04 2008-12-02 Orchid Chemicals & Pharmaceuticals Ltd. Process for the preparation of Cefditoren
CN102911187A (en) * 2012-10-11 2013-02-06 南通康鑫药业有限公司 Recovery method of cefprozil
US8445476B2 (en) 2007-10-25 2013-05-21 Achaogen, Inc. Carbacephem β-lactam antibiotics
CN104693217A (en) * 2015-02-28 2015-06-10 浙江华方药业有限责任公司 Method for preparing cefixime
CN109180704A (en) * 2018-11-19 2019-01-11 齐鲁安替制药有限公司 A kind of synthetic method of Cefditoren pivoxil Cephalosporins

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0175610A2 (en) * 1984-09-07 1986-03-26 Meiji Seika Kaisha Ltd. New cephalosporin compounds and the production thereof
EP1016665A1 (en) * 1997-06-24 2000-07-05 Meiji Seika Kaisha, Ltd. Process for the selective preparation of z-isomers of 3-(2-substituted vinyl)cephalosporins
WO2002083692A1 (en) * 2001-04-18 2002-10-24 Hanmi Pharm. Co., Ltd. Process for the selective preparation of 3-(z) propenyl-cephem compound

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0175610A2 (en) * 1984-09-07 1986-03-26 Meiji Seika Kaisha Ltd. New cephalosporin compounds and the production thereof
EP1016665A1 (en) * 1997-06-24 2000-07-05 Meiji Seika Kaisha, Ltd. Process for the selective preparation of z-isomers of 3-(2-substituted vinyl)cephalosporins
WO2002083692A1 (en) * 2001-04-18 2002-10-24 Hanmi Pharm. Co., Ltd. Process for the selective preparation of 3-(z) propenyl-cephem compound

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SAKAGAMI K ET AL: "SYNTHESIS AND ORAL ACTIVITY OF PIVALOYLOCYMETHYL7-Ä(Z)-2-(2-AMINOTHIA ZOL-4-YL)-2-METHOXYIMINOACETAMIDOÜ-3-(Z)-(4-METHYLTHIAZOL-5-YL)VINYL- 3-CEPHEM-4-CARBOXYLATE (ME1207) AND ITS RELATED COMPOUND", September 1991, CHEMICAL AND PHARMACEUTICAL BULLETIN, PHARMACEUTICAL SOCIETY OF JAPAN, TOKYO, JP, PAGE(S) 2433-2436, ISSN: 0009-2363, XP009042230 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7459550B2 (en) 2003-07-04 2008-12-02 Orchid Chemicals & Pharmaceuticals Ltd. Process for the preparation of Cefditoren
US8445476B2 (en) 2007-10-25 2013-05-21 Achaogen, Inc. Carbacephem β-lactam antibiotics
CN102911187A (en) * 2012-10-11 2013-02-06 南通康鑫药业有限公司 Recovery method of cefprozil
CN104693217A (en) * 2015-02-28 2015-06-10 浙江华方药业有限责任公司 Method for preparing cefixime
CN109180704A (en) * 2018-11-19 2019-01-11 齐鲁安替制药有限公司 A kind of synthetic method of Cefditoren pivoxil Cephalosporins

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