Classifications

• • 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
  • C07D501/02—Preparation
  • C07D501/08—Preparation by forming the ring or condensed ring systems
• • 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
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention provides an improved process to produce the chloromethylcephem derivatives of the formula (I).
• R 1 represents a carboxy-protecting group viz., substituted methyl group, which can be deprotected easily, such as t-butyl group, diphenylmethyl, 4-methoxybenzyl, 2- methoxybenzyl, 2-chlorobenzyl or benzyl group;
• R 2 represents hydrogen, (C ⁇ -C 4 )aJLkyl, substituted or unsubstituted phenyl or substituted or unsubstituted phenoxy.
• chloromethylcephem derivatives of the formula (I) prepared according to the process of the present invention are useful for the preparation of cephalosporin antibiotics of the formula (II)
• R 4 is carboxylate ion or COOR d , where Ra represents hydrogen, esters or a counter ion which forms a salt;
• R 6 represents H, CH 3 , CR a R COOR c where R a and R b independently represent hydrogen or methyl and R c represents hydrogen or (C ⁇ -C 6 )alkyl;
• cephalosporin antibiotics of the formula (II) have wide range of biological activity. Specifically the cephalosporin antibiotics of the formula (LI) have very good antibiotic activity.
• R 3 represents phenyl, (C ⁇ -C )alkylphenyl, ( - C )alkoxyphenyl or a heteroaryl group.
• the main objective of the present invention is to provide a simple and efficient process for producing chloromethyl cephem derivatives of the formula (I) through 3- chloromethyl azetidinone compounds of the formula (Nil).
• Another objective of the present invention is to provide a process for manufacturing chloromethyl azetidinone compounds of the formula (Nil), without employing the hazardous reagents, which are difficult-to-handle in manufacturing scales.
• Another objective of the present invention is to carry out the preparation of the sulfonyl azetidinone in a clean manner, by controlling the formation of the major impurity & also provide a methodology to remove the side product.
• Another objective of the present invention is to provide a process for cyclization of chloromethyl azetidinone compounds of the formula (Nil) while minimizing the formation of the impurities and achieve maximum conversion.
• the present invention provides an improved process to produce the chloromethylcephem derivatives of the formula (I)
• Ri represents a carboxy-protecting group viz., substituted methyl group, which can be deprotected easily, such as t-butyl group, diphenylmethyl, 4-methoxybenzyl, 2- methoxybenzyl, 2-chlorobenzyl, or benzyl group;
• R represents hydrogen, (C ⁇ -C )alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted phenoxy, the said process comprising the steps of
• the heteroaryl group represented by R 7 is selected from 2-mercaptobenzothiazole, 2-mercaptobenzooxazole, 2- mercaptobenzimidazole or 2-mercapto-5-methyltetrazole.
• the conversion in step (i) is carried out using metal salt of aryl sulfinic acid selected from copper (II) p- toluenesulfinate, copper (II) benzenesulfinate, silver (II) p-toluenesulfinate, silver (II) benzenesulf ⁇ nate and the like in the presence of a solvent selected from acetone, THF, dioxane, diglyme, 2-butanone, acetonitrile, alcohols such as methanol, ethanol or iso- propanol, with or without water.
• aryl sulfinic acid selected from copper (II) p- toluenesulfinate, copper (II) benzenesulfinate, silver (II) p-toluenesulfinate, silver (II) benzenesulf ⁇ nate and the like in the presence of a solvent selected from acetone, THF, dio
• the step (i) is carried out while controlling the pH in the range 4-8, more preferably 5-7, by employing the base selected from ammonia, alkali/alkali earth metal carbonate/bicarbonate such as calcium carbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, or the organic bases such as diisopropylethylamine, triethylamine and the like.
• the base selected from ammonia, alkali/alkali earth metal carbonate/bicarbonate such as calcium carbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium hydrogen carbonate, or the organic bases such as diisopropylethylamine, triethylamine and the like.
• chlorinating agent used in step (ii) is selected from chlorine gas, HOCl, Cl 2 O, CH 3 OCl and the like in the presence of a base.
• chlorinating agent used in step (ii) is either used as gas or a solution in a solvent selected from dioxane, carbon tetrachloride, ethyl acetate, acetonitrile, diglyme, dimethylformamide, dimethylacetamide, tetrahydrofuran, methylene chloride, butyl acetate, diphenyl ether, toluene, or mixtures thereof.
• a solvent selected from dioxane, carbon tetrachloride, ethyl acetate, acetonitrile, diglyme, dimethylformamide, dimethylacetamide, tetrahydrofuran, methylene chloride, butyl acetate, diphenyl ether, toluene, or mixtures thereof.
• the base used in step (ii) is selected from alkali/alkali earth metal carbonate/bicarbonate such as calcium carbonate, sodium bicarbonate, sodium carbonate, potassium carbonate, potassium hydrogen carbonate and the like.
• the cyclization in step (iii) is carried out using a base selected from ammonia, ammonium salts like ammonium carbonate, ammonium acetate; organic amines like di-isopropylamine, ethylenediamine, diethylamine, methylamine, ethylamine and the like.
• a base selected from ammonia, ammonium salts like ammonium carbonate, ammonium acetate; organic amines like di-isopropylamine, ethylenediamine, diethylamine, methylamine, ethylamine and the like.
• the cyclization step (iii) is carried out in a solvent selected from DMF, acetonitrile, dimethylacetamide, ethyl acetate, 4-formylmorpholine, 4-acetylmorpholine, dioxane, dimethylsulfoxide, THF, 1- methylpyrrolidine-2-one (NMP), methylene dichloride and the like, or the mixtures thereof.
• the starting material can be prepared from the literature known in the prior art.
• 1,4-Dioxane 150 ml was added to p-methoxybenzyl 2-(p-toluenesulfonylthio)- ⁇ -(l- methylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate (obtained from 25.0 gm of p- methoxybenzyl 6-phenacetamidopencillanate-l -oxide as shown in step-2) above followed by sodium bicarbonate (90 gm) at 26-28°C. C1 2 /CC1 4 (12.5% w/v) (60 ml) added slowly.
• reaction mixture was filtered and washed with dichloromethane (150 ml).
• dichloromethane 150 ml
• cold water 450 ml
• organic layer separated, and washed with a solution of sodium thiosulphate followed by water.
• the organic layer was treated with charcoal, concentrated and worked up as usual to get p- methoxybenzyl 2-(p-toluenesulfonylthio)- ⁇ -(l-chloromethylethenyl)-4-oxo-3- phenacetamido-1-azetidineacetate, which was taken to next step without purification.
• aqueous ammonia solution (25%, 8.8 mL) in l-methylpyrrolidin-2-one (25 mL, 2-5 °C) was added at -50 °C over a period of 2-5 min and the temperature was allowed to raise to -40 °C.
• the reaction mixture was stirred at -A5 to -40 °C for 15-20 min.
• cold dil. HCl (1 : 1; 27 mL; 2-5 °C) was added at -50 to -40 °C in drops over a period of 5 min.
• the reaction mixture was poured into cold water (900 mL) at 2-5 °C. Dichloromethane was added, stirred for 5-10 min and the organic layer was separated.
• 1,4-Dioxane 150 ml was added to p-methoxybenzyl 2-(p-toluenesulfonylthio)- ⁇ -(l- methylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate (obtained from 25.0 gm of p- methoxybenzyl 6-phenacetamidopencillanate-l -oxide as shown in step-2) above followed by sodium bicarbonate (90 gm) at 26-28°C. C1 2 /CC1 4 (12.5% w/v) (60 ml) added slowly.
• reaction mixture was filtered and washed with dichloromethane (150 ml).
• dichloromethane 150 ml
• cold water 450 ml
• organic layer separated, and washed with a solution of sodium thiosulphate followed by water.
• the organic layer was concentrated and worked up as usual to get p-methoxybenzyl 2-(p- toluenesulfonylthio)- ⁇ -(l-chloromethylethenyl)-4-oxo-3-phenacetamido-l- azetidineacetate, which was taken to next step without purification.
• Step-4 Preparation of p-Methoxybenzyl 7-phenyIacetamido-3-chloromethyl-3-cephem-4- carboxylate p-Methoxybenzyl 2-(2-toluenesulfonylthio)- ⁇ -(l-chloromethylethenyl)-4-oxo-3- phenacetamido-1-azetidineacetate (obtained from 25.0 gm of p-methoxybenzyl 6- phenacetamido pencillanate-1 -oxide), obtained according to step-3 of example- 1 above, was added to DMF (125 ml) and cooled to -40 °C.
• Step -3 Preparation of p-Methoxyb enz yl 2-(p-toluenesulfonyIthio - ⁇ -(l- chIoromethylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate (VID
• 1,4-Dioxane 150 ml was added to p-methoxybenzyl 2-(p-toluenesulfonylthio)- ⁇ -(l- methylethenyl)-4-oxo-3-phenacetamido-l-azetidineacetate (obtained from 25.0 gm of p- methoxybenzyl 6-phenacetamidopencillanate-l -oxide as shown in step-2) above followed by sodium bicarbonate (90 gm) at 26-28°C. C1 2 /CC1 4 (12.5% w/v) (60 ml) added slowly.
• reaction mixture was filtered and washed with dichloromethane (150 ml).
• dichloromethane 150 ml
• cold water 450 ml
• organic layer separated, and washed with a solution of sodium thiosulphate followed by water.
• the organic layer was treated with charcoal, concentrated and worked up as usual to get p- methoxybenzyl 2-(p-toluenesulfonylthio)- ⁇ -( 1 -chloromethylethenyl)-4-oxo-3 - phenacetamido- 1-azetidineacetate, which was taken to next step without purification.
• step (ii) increases the purity of 2-(p-toluenesulfonylthio)- ⁇ - ( 1 -methylethenyl)-4-oxo-3 -phenacetamido- 1 -azetidineacetate.
• the use of NMP at cyclization step gives more yields when compared to DMF.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Engineering & Computer Science (AREA)
• Biotechnology (AREA)
• Molecular Biology (AREA)
• Cephalosporin Compounds (AREA)

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• 2003
  • 2003-10-23 WO PCT/IB2003/004721 patent/WO2004039813A1/en not_active Ceased
  • 2003-10-23 KR KR1020057007694A patent/KR20050087791A/ko not_active Withdrawn
  • 2003-10-23 AU AU2003269416A patent/AU2003269416A1/en not_active Abandoned
  • 2003-10-23 JP JP2004547902A patent/JP2006507289A/ja active Pending
  • 2003-10-23 CN CNB2003801023937A patent/CN1315841C/zh not_active Expired - Fee Related

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