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WO2007004028A2 - Processes for the preparation of penems and its intermediate - Google Patents

Processes for the preparation of penems and its intermediate Download PDF

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Publication number
WO2007004028A2
WO2007004028A2 PCT/IB2006/001821 IB2006001821W WO2007004028A2 WO 2007004028 A2 WO2007004028 A2 WO 2007004028A2 IB 2006001821 W IB2006001821 W IB 2006001821W WO 2007004028 A2 WO2007004028 A2 WO 2007004028A2
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WO
WIPO (PCT)
Prior art keywords
formula
azetidinone
group
protecting group
hydroxy
Prior art date
Application number
PCT/IB2006/001821
Other languages
French (fr)
Other versions
WO2007004028A3 (en
Inventor
Parendu Dhirajlal Rathod
Kiran Kumar Ganagakhedkar
Ram Chander Aryan
Original Assignee
Ranbaxy Laboratories Limited
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Publication date
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Publication of WO2007004028A2 publication Critical patent/WO2007004028A2/en
Publication of WO2007004028A3 publication Critical patent/WO2007004028A3/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D205/00Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/06Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D205/08Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
    • YGENERAL 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
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00Technologies relating to chemical industry
    • Y02P20/50Improvements relating to the production of bulk chemicals
    • Y02P20/55Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the field of the invention relates to a process for the preparation of 4-acetoxy azetidinone of Formula I,
  • the compounds of Formula I are important synthetic intermediates of ⁇ -lactam antibiotics that possess the carbapenem and penem ring systems such as imipenem, ertapenem, faroperem, doripenem, meropenem, and the like.
  • the ⁇ -lactam antibiotics are commonly prescribed antimicrobial agents with activity against a wide range of both Gram- positive and Gram-negative bacteria.
  • Ri represents a C 1 . 4 alkyl group and R 2 Js a protective group for ⁇ -lactam ring such as aryl or substituted aryl, particularly 4-methoxyphenyl or 2,4-dimethoxybenzyl.
  • R 2 is p-methoxyphenyl
  • Ri and R' each independently represent Ci -4 alkyl group, by a series of react: ons involving hydrolysis of the ester group at 4- ⁇ osition to carboxyl group followed by oxidation of the carboxyl group to acetoxy group and finally deprotection of the azetidinone ring nirrogen using ozone.
  • R 2 is hydrogen or a suitable amino protecting group and P is suitable hydroxy protecting group.
  • Ri is Ci -4 alkyl group and R 2 is hydrogen or a suitable amino protecting group.
  • Ri is CM alkyl group and R 2 is hydrogen or a suitable amino protecting group.
  • Ri is Ci - 4 alkyl group
  • R 2 is hydrogen or a suitable amino protecting group
  • Ri is CM alkyl
  • P is a hydroxy protecting group
  • R 2 is hydrogen or a suitable amino projecting group
  • R 7 and Rs are same or different and are hydrogen, Q -S alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • a first aspect of the present invention provides a process for the preparation of 4- acetoxy azetidinone of Formula I,
  • tie process comprising: a) stirring a basified reaction mixture comprising L-threonine of Formula H,
  • Suitable hydroxy and amino protecting groups include, but are not limited to, lowertrialkylsilyl groups, lowerdialkylhalosilyl groups, nitrogen containing silyl groups, lower alkoxymethjl groups, aralkyl groups, acyl groups, lower alkoxycarbonyl groups, alkenyloxycarbonyl groups and aralkyloxycarbonyl groups, aryl or substituted aryl group for example, 4-methoxyphenyl or 2,4-dimethoxybenzyl.
  • the silyl groups described above can be introduced using silylating agents.
  • Examples include trimethylchlorosilane, tert- butyldimethylchloiosilane, 1 , 1 ,1 ,3,3,3,-hexamethyl disilazane, ⁇ -trimethylsilylacetamide, tetramethyldisilazane, bis(trimethylsilyl)acetamide, vinyltriacetoxysilane. dimethylchlorosilaie, bromomethyldimethylchlorosilane, diCchloromethy ⁇ te-jamethyldisilazane, vinyltriethoxysilane, and the like.
  • Suitable condensing agents include 1,3-dicyclohexylcarbodiimide (DCC), 1,8- diazabicyclo(5.4.0)undec-7-ene (DBU), and the like.
  • DCC 1,3-dicyclohexylcarbodiimide
  • DBU 1,8- diazabicyclo(5.4.0)undec-7-ene
  • a second aspect of the present invention provides a process for the preparation of (2R,3R)-epoxybutyric acid of Formula III,
  • Formula III the pTocess comprising stirring a basifled reaction mixture comprising L-threonine of Formula I, an acid and an alkali metal nitrite, which is acidified with an acid at a temperature less than 20 0 C.
  • the reaction mixture containing the (2R,3R)-epoxybutyric acid of Formula III may be extracted with an organic solvent comprising one or more of C ⁇ g ethers; Ci -4 alcohols; C$.% ketones; halogenat ⁇ d solvents; polar aprotic solvents, hydrocarbons, or a mixture thereof,' with a proviso that the organic solvent is not an ester.
  • the (2R,3F)-epoxybutyric acid of Formula III can be converted to 4-acetoxy azetidinone of Formula I by the process disclosed in the present invention.
  • the inventors have found that the yield of (2R,3R)-epoxybutyric acid obtained by stirring the reaction mixture for less than 10 hours at 25 0 C after addition of 40% w/v sodium hydroxide is comparable to the yield obtained by practicing Example 1 of WO 98/07691.
  • Examples cf suitable acids include hydrochloric acid, hydrobromic acid, nitric acid, p- toluene sulphonic acid, and the like.
  • suitable alkali metal nitrites include sodium nitrite, potassium citrite, and the like.
  • suitable bases include alkali metal amides, hydrides, hydroxides, metal ulkyls, tertiary amines and bicyclic amines.
  • the tertiary amines may include triethylamitie, pyridine, 4-N,N-dimethylamino pyridine, N-methylmorpholine, and the like.
  • the bicyclic amines may include l,5-Diazabicyclo[4.3.0]non-5-ene (DBN), 1,8- diazabicyclo(5.4.0'undec-7-ene (DBU) 3 and the like.
  • Suitable solvents include C 4 - 8 ethers; Ci -4 alcohols; C 3-8 ketones; halogenated solvents; polar aprotic solvents; and hydrocarbon solvents.
  • halogenated solvents include dichloromethane, cichloroethane, chloroform, carbon tetrachloride, ethylene bromide, and the like.
  • a suitable polar aprotic solvent includes one or more of tetrahydrofuran, dimethylformamid2 ) dimethylacetamide, and the like.
  • Suitable hydrocarbon solvents include benzene, toluene, xylene, and the like. Mixtures of all of these solvents are also contemplated. The solvents described above do not cause undesired side reactions and also can be recovered and reused in the present process without purification.
  • a third aspect of the present invention provides a process for the preparation of glycine ester of formula IV,
  • R] is C M ⁇ lkyl group and R 2 is hydrogen or a suitable amino protecting group, the process comprising reacting a compound of Formula A,
  • X is a leavir g group and Rj is as described above, in the presence of a base at about 80- 100 0 C.
  • the glycine ester of Formula IV can be converted to 4-acetoxy azetidinone of Formula I by the process of the present invention.
  • Suitable bases include alkali metal amides, hydrides, hydroxides, metal alkyls, tertiary amines and bicyclic amines.
  • the tertiary amines may include triethylamine, pyridine, 4-NjN-dimethylamino pyridine, N-methylmorpholine, and the like.
  • the bicyclic amines may include l,5-Diazabicyclo[4.3.0]non-5-ene (DBN), 1,8- diazabicyclo(5.4.0)u ⁇ dec-7-ene (DBU), and the like.
  • Suitable leaving groups represented by X in Formula B above can be chlorine, bromine, iodine, mesyl, tosyl, and the like.
  • the present inventors have found that the process for the preparation of glycine derivative of Formula IV reported in Example 7 of WO 98/07691 failed to initiate at ths reported temperature of 50 0 C leading to consumption of a large amount of ethylchloroacetate. The reaction suddenly got initiated whereby the high exothermicity led to a runaway condition and consequently resulted in low yield of the glycine derivative of Formula IV.
  • a fourth aspect of the present invention provides a process for the preparation of epoxyatnide of Formula V,
  • Ri is C] -4 alkyl group and R 2 is hydrogen or a suitable amino protecting group, the process comprising condensing (2R,3R)-epoxybutyric acid of Formula III with glycine ester of Formula IV in the presence of a condensing agent in a halogenated solvent.
  • Epoxyamide Formula V can be converted to 4-acetoxy azetidinone of Formula I by the process of the present invention.
  • Epoxybutyric acid of Formula III and glycine ester of Formula TV can be prepared by methods known in the art or according to the processes disclosed in the present invention.
  • halogenated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ethylene bromide, and the like.
  • the process of the present invention does not require tedious column chromatography for isolation of the final product and provides good yield of the epoxyamide.
  • the product can be used as such in the subsequent reaction step and the halogenated solvent used can be recovered and reused without purification.
  • a fifth aspect of the present invention provides a process for the preparation of hydroxy azetidinor.e ester of Formula VIa 5
  • R[ and R 2 are as described above, with a base.
  • the hydroxy azetidinone ester of Formula Via can be converted to 4-acetoxy azetidinone of Formula I by the process of the present invention.
  • the epoxyamide of Formula V can be prepared by methods known in the art or according to the processes described in the present invention.
  • the preseni inventors have found that the above cyclization of epoxyamide of Formula V when carried out under reduced quantities of tetrahydrofuran proceeds with nearly 100% conversion ⁇ .s determined by Thin Layer Chromatography.
  • the process of the present invention does not require tedious column chromatography purification, provides good yield of the hydroxy azeiidinone of Formula Via, which can be used as such in the subsequent reaction step.
  • a sixth aspect of the present invention provides a process for the preparation of azetidinone ester or ' Formula VIb,
  • the hydroxy azetidinone ester of Formula Via wherein Ri and R 2 are as described above, can be prep ared by methods known in the art or according to the process disclosed in the present invention.
  • the hydroxy azetidinone ester of Formula Via described above was treated with a hydroxy protecting agent for example, a silylating agent in the absence of a reaction solvent, to obtain O-silyl protected azetidinone ester which can be converted to 4- acetoxy azetidinons of Formula I, by the process of the present invention.
  • a hydroxy protecting agent for example, a silylating agent in the absence of a reaction solvent
  • the present inventors have surprisingly found that the silyl protection of side chain hydroxy group in azetidinone ester of Formula Via, wherein R 1 and R 2 are as described above, can be carried out without solvent with good yield and the product can be used as such in the subsequent reaction step. Further, the present inventors have found that the reaction times are greatly reduced when solvent is not used and the process of the present invention does not require tedious coluir.n chromatography for isolation of the product.
  • 4-acetoxy gwetidinone of Formula I prepared by the process of the present invention can be further converted to ⁇ -lactam compounds of Formula VIII,
  • Formula VHI wherein P] is hydrogen or a cafboxyl protecting group, R$ is hydrogen or C1.5 alkyl and X is C OT S 5 Y is a tetrahydrofuran ring connected via C 2 or Y represents a substituted thiol of Formula S-A wherein A is selected from the group consisting of a)
  • compound of Formula I can be converted to compound of Formula VIII by processes disclosed in U.S. Patent Nos. 4,943,569; 5,478,820; 5,317,016; 5,652,233; 5,856,321; 4,997,829; and 5,998,612.
  • 4- acetoxy azetidinone of Formula I can be converted to ⁇ -lactam compounds of Formula VIII by the following steps: a) reacting 4-acetoxy azetidinone of Formula I
  • Ring B is a benzene ring which may be substituted by one to four group(s) selected from halogen, C ]-6 -alkyl, C 1-6 -alkoxy and phenyl which maybe substituted with Ci-e-alkyl, Ci -6 -alkoxy, halogen or optionally protected amino;
  • X' is O or S;
  • Y' is O, S, CH 2 or an imino group which may be substituted by Ci- 6 -alkyl or an acyl group selected from C 2 .
  • Z is a methylene group which may be substituted by one to two group(s)
  • Fo ⁇ nula XIII wherein P, Pi, R 6 are as described above and OE is an esterified hydroxy group; and d) reacting the compound of Formula XIII with a thiol of Fo ⁇ nula,
  • Tetrahydrofuran was recovered from the combined extracts under vacuum at less than 15°C.
  • dichloromethane 700 ml was added followed by the addition of anhydrous sodium sulfate (100 g). The reaction mixture was stirred for 0.5 to 1 hour and filtered to remove the solids.
  • Dichloromethane (100 ml) washings were added to the above filtrate.; This combined filtrate wa; concentrated under vacuum at less than 15 0 C to obtain the product. Alternatively, the filtrate was concentrated to half its volume and the solution was used as such for the next step.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The present invention relates to a process for the preparation of 4-acetoxy azetidinone of Formula I, wherein R2 is hydrogen or a suitable amino protecting group and P is suitable hydroxy protecting group, and to the use of these compounds as intermediates for the preparation of ß-lactam antibiotics that possess the carbapenem and penem ring systems. 4-acetoxy azetidinone of Formula I is a key intermediate in the synthesis of ß-lactam antibiotics which are commonly prescribed antimicrobial agents having activity against a wide range of both Gram-positive and Gram-negative bacteria.

Description

PROCESSES FORTHEPREPARATION OFPENEMSAND ITS INTERMEDIATE
Field of the Invention
The field of the invention relates to a process for the preparation of 4-acetoxy azetidinone of Formula I,
Figure imgf000002_0001
Formula I wherein R2 is hydrogen or a suitable amino protecting group and P is suitable hydroxy protecting group, and to the use of these compounds as intermediates for the preparation of β- lactam antibiotics that possess the carbapenem and penem ring systems. Background of the Invention
The compounds of Formula I are important synthetic intermediates of β-lactam antibiotics that possess the carbapenem and penem ring systems such as imipenem, ertapenem, faroperem, doripenem, meropenem, and the like. The β-lactam antibiotics are commonly prescribed antimicrobial agents with activity against a wide range of both Gram- positive and Gram-negative bacteria.
Several processes have been reported for the preparation of 4-acetoxy azetidinone for example, in U.S. Patent Nos. 5,081,239; 5,204,460; 4,861,877; Journal of Chemical Society, Chemical Commm.ication, 1991, 662; International (PCT) Publication Nos. WO 98/07691; 98/07690. U.S. Patent Nos. 5,081,239; and 5,204,460 disclose a process for the preparation of 4- acetoxy azetidinone of Formula I by acetoxylation using acetic acid and an oxidizing agent in the presence of Ruchenium compound as catalyst. U.S. 4,861, -i577 discloses a process for the preparation of 4-acetoxy azetidinone by reaction of corresponding O-silyl protected compound with acetic anhydride in an organic solvent in the presence of a base.
Journal of Chemical Society, Chemical Communication, 1991, 662 discloses a process for the preparation of 4-acetoxy azetidinone from (3R)-butane-l ,3-diol by reaction of corresponding enol-fiioether with chlorosulphonyl isocyanate followed by acetoxylation of the azetidinone so formed at 4-position.
International (PCT) Publication No. WO 98/07691 discloses a process for the preparation of 4-alkoxycarbonyl-3-hydroxyethyl azetidinone of Formula VI from L- Threonine of Formula II by a series of reactions depicted in scheme 1 below:
Figure imgf000003_0001
Formula !l Formula Formula IV
Figure imgf000003_0002
Formula V
Figure imgf000003_0003
Formula Vl
Scheme 1 wherein Ri represents a C 1.4 alkyl group and R2Js a protective group for β-lactam ring such as aryl or substituted aryl, particularly 4-methoxyphenyl or 2,4-dimethoxybenzyl.
International (PCT) Publication No. WO 98/07690 discloses a process for preparation of 4-acetoxy azetidimne of Formula X,
Figure imgf000004_0001
Formula X from 4-alkoxycarbonyl azetidinone of Formula VII,
Figure imgf000004_0002
Formula VII wherein R2 is p-methoxyphenyl, and Ri and R' each independently represent Ci-4 alkyl group, by a series of react: ons involving hydrolysis of the ester group at 4-ρosition to carboxyl group followed by oxidation of the carboxyl group to acetoxy group and finally deprotection of the azetidinone ring nirrogen using ozone.
The processes reported in the prior art require extensive column chromatographic purification of inte:τnediates and use of large quantities of solvents and reagents. The present invention provides processes which do not involve tedious and costly chromatographic pαrifϊcation steps and are easily scalable. The yield and quality of the product is greatly improved when made by the processes of the present invention. Summary of the Invention
In one general aspect there is provided a process for the preparation of 4-acetoxy azetidinone of Formula I,
Figure imgf000005_0001
Formula I wherein R2 is hydrogen or a suitable amino protecting group and P is suitable hydroxy protecting group.
In another |,eneral aspect there is provided a process for the preparation of (2R,3R)- epoxybutyric acid of Formula III.
Figure imgf000005_0002
In another general aspect there is provided a process for the preparation of glycine ester of formula IV,
Figure imgf000005_0003
Formula IV
wherein Ri is Ci-4 alkyl group and R2 is hydrogen or a suitable amino protecting group.
In another g.eneral aspect there is provided a process for the preparation of epoxyamide of Formula V,
Figure imgf000006_0001
Formula V
wherein Ri is CM alkyl group and R2 is hydrogen or a suitable amino protecting group.
In another general aspect there is provided a process for the preparation of hydroxy azetidinone ester o f Formula Via,
Figure imgf000006_0002
Formula Via wherein Ri is Ci -4 alkyl group, and R2 is hydrogen or a suitable amino protecting group.
In another general aspect there is provided a process for the preparation of azetidinone ester of Formula VIb,
Figure imgf000006_0003
Formula VIb
wherein Ri is CM alkyl, P is a hydroxy protecting group and R2 is hydrogen or a suitable amino proiecting group.
In another general aspect there is provided a process for the preparation of β-lactam compounds of Formi ila VHI,
Figure imgf000007_0001
Formula VIII wherein Pi is hydrogen or a carboxyl protecting group, R6 is hydrogen or Ci-5 alkyl and X is C or S, Y is a tetrahydrofuran ring connected via C2 or Y represents a substituted thiol of Formula S-A, wherein A is selected from the group consisting of a)
b)
Figure imgf000007_0002
, and
c)
Figure imgf000007_0003
wherein P2 is hydrogen or an amino protecting group, R7 and Rs are same or different and are hydrogen, Q-S alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and claims.
Detailed Description of the Invention
A first aspect of the present invention provides a process for the preparation of 4- acetoxy azetidinone of Formula I,
Figure imgf000008_0001
Formula I wherein R2 is hydrogen or a suitable amino protecting group and P is a suitable hydroxy protecting group, tie process comprising: a) stirring a basified reaction mixture comprising L-threonine of Formula H,
Figure imgf000008_0002
Formula Il an acid and an alk∑ Ii metal nitrite, for 10 hours or less, to obtain (2R,3R)-epoxybutyric acid of Formula III;
Figure imgf000008_0003
Formula HI b) condensing the upoxyacid of Formula III with glycine ester of Formula IV,
Figure imgf000009_0001
Formula IV wherein Ri is CM a kyl group and R2 is as described above, in the presence of a condensing agent in a halogenated solvent to obtain epoxyamide of Formula V,
Figure imgf000009_0002
Formula V wherein R1 and R2 are as described above; c) converting the epoxyamide of Formula V to hydroxy azetidinone ester of Formula Via,
Figure imgf000009_0003
Formula Via wherein Rj, R2 are as described above, by treatment with abase; d) converting the hydroxy azetidinone ester of Formula Via to azetidinone ester of Formula VIb5
Figure imgf000009_0004
Formula VIb wherein Rj, R2 are as described above, and P is a hydroxy protecting group, by treatment with a hydroxy protecting; agent in the absence of a reaction solvent; e) hydrolyzing azetidinone ester of Formula VIb to carboxy azetidinone of Formula Vila,
Figure imgf000010_0001
Formula Vila wherein P and R2 are as described above; and f) oxidizing the caόoxy azetidinone of Formula Vila in the presence of an oxidizing agent to obtain 4-acetoxy azetidinone of Formula I,
Figure imgf000010_0002
Formula I wherein P and R2 see as described above.
Suitable hydroxy and amino protecting groups include, but are not limited to, lowertrialkylsilyl groups, lowerdialkylhalosilyl groups, nitrogen containing silyl groups, lower alkoxymethjl groups, aralkyl groups, acyl groups, lower alkoxycarbonyl groups, alkenyloxycarbonyl groups and aralkyloxycarbonyl groups, aryl or substituted aryl group for example, 4-methoxyphenyl or 2,4-dimethoxybenzyl. The silyl groups described above can be introduced using silylating agents. Examples include trimethylchlorosilane, tert- butyldimethylchloiosilane, 1 , 1 ,1 ,3,3,3,-hexamethyl disilazane, π-trimethylsilylacetamide, tetramethyldisilazane, bis(trimethylsilyl)acetamide, vinyltriacetoxysilane. dimethylchlorosilaie, bromomethyldimethylchlorosilane, diCchloromethy^te-jamethyldisilazane, vinyltriethoxysilane, and the like.
Suitable condensing agents include 1,3-dicyclohexylcarbodiimide (DCC), 1,8- diazabicyclo(5.4.0)undec-7-ene (DBU), and the like. A second aspect of the present invention provides a process for the preparation of (2R,3R)-epoxybutyric acid of Formula III,
Figure imgf000011_0001
Formula III the pTocess comprising stirring a basifled reaction mixture comprising L-threonine of Formula I, an acid and an alkali metal nitrite, which is acidified with an acid at a temperature less than 200C.
The reaction mixture containing the (2R,3R)-epoxybutyric acid of Formula III may be extracted with an organic solvent comprising one or more of C^g ethers; Ci-4 alcohols; C$.% ketones; halogenatυd solvents; polar aprotic solvents, hydrocarbons, or a mixture thereof,' with a proviso that the organic solvent is not an ester.
The (2R,3F)-epoxybutyric acid of Formula III can be converted to 4-acetoxy azetidinone of Formula I by the process disclosed in the present invention. The inventors have found that the yield of (2R,3R)-epoxybutyric acid obtained by stirring the reaction mixture for less than 10 hours at 250C after addition of 40% w/v sodium hydroxide is comparable to the yield obtained by practicing Example 1 of WO 98/07691.
Examples cf suitable acids include hydrochloric acid, hydrobromic acid, nitric acid, p- toluene sulphonic acid, and the like. Examples of suitable alkali metal nitrites include sodium nitrite, potassium citrite, and the like. Suitable bases include alkali metal amides, hydrides, hydroxides, metal ulkyls, tertiary amines and bicyclic amines. The tertiary amines may include triethylamitie, pyridine, 4-N,N-dimethylamino pyridine, N-methylmorpholine, and the like. The bicyclic amines may include l,5-Diazabicyclo[4.3.0]non-5-ene (DBN), 1,8- diazabicyclo(5.4.0'undec-7-ene (DBU)3 and the like.
Suitable solvents include C4-8 ethers; Ci-4 alcohols; C3-8 ketones; halogenated solvents; polar aprotic solvents; and hydrocarbon solvents. Examples of halogenated solvents include dichloromethane, cichloroethane, chloroform, carbon tetrachloride, ethylene bromide, and the like. A suitable polar aprotic solvent includes one or more of tetrahydrofuran, dimethylformamid2) dimethylacetamide, and the like. Suitable hydrocarbon solvents include benzene, toluene, xylene, and the like. Mixtures of all of these solvents are also contemplated. The solvents described above do not cause undesired side reactions and also can be recovered and reused in the present process without purification.
A third aspect of the present invention provides a process for the preparation of glycine ester of formula IV,
Figure imgf000012_0001
Formula IV
wherein R] is CM εlkyl group and R2 is hydrogen or a suitable amino protecting group, the process comprising reacting a compound of Formula A,
R2— NH2
Formula A wherein R2 is as described above, with 2-halo acetic acid ester of Formula B,
Figure imgf000012_0002
wherein X is a leavir g group and Rj is as described above, in the presence of a base at about 80- 1000C.
The glycine ester of Formula IV can be converted to 4-acetoxy azetidinone of Formula I by the process of the present invention. Suitable bases include alkali metal amides, hydrides, hydroxides, metal alkyls, tertiary amines and bicyclic amines. The tertiary amines may include triethylamine, pyridine, 4-NjN-dimethylamino pyridine, N-methylmorpholine, and the like. The bicyclic amines may include l,5-Diazabicyclo[4.3.0]non-5-ene (DBN), 1,8- diazabicyclo(5.4.0)uπdec-7-ene (DBU), and the like.
Suitable leaving groups represented by X in Formula B above can be chlorine, bromine, iodine, mesyl, tosyl, and the like. The present inventors have found that the process for the preparation of glycine derivative of Formula IV reported in Example 7 of WO 98/07691 failed to initiate at ths reported temperature of 500C leading to consumption of a large amount of ethylchloroacetate. The reaction suddenly got initiated whereby the high exothermicity led to a runaway condition and consequently resulted in low yield of the glycine derivative of Formula IV.
A fourth aspect of the present invention provides a process for the preparation of epoxyatnide of Formula V,
Figure imgf000013_0001
Formula V
wherein Ri is C]-4 alkyl group and R2 is hydrogen or a suitable amino protecting group, the process comprising condensing (2R,3R)-epoxybutyric acid of Formula III with glycine ester of Formula IV in the presence of a condensing agent in a halogenated solvent.
The epoxyamide Formula V can be converted to 4-acetoxy azetidinone of Formula I by the process of the present invention. Epoxybutyric acid of Formula III and glycine ester of Formula TV can be prepared by methods known in the art or according to the processes disclosed in the present invention. Examples of halogenated solvents include dichloromethane, dichloroethane, chloroform, carbon tetrachloride, ethylene bromide, and the like.
The presenl inventors have found that this amide coupling reaction when carried out in the presence of a condensing agent DCC in a halogenated solvent at a temperature of about - 2O0C to about 300O proceeds with nearly 100% conversion as determined by Thin Layer
Chromatography, The process of the present invention does not require tedious column chromatography for isolation of the final product and provides good yield of the epoxyamide. The product can be used as such in the subsequent reaction step and the halogenated solvent used can be recovered and reused without purification.
A fifth aspect of the present invention provides a process for the preparation of hydroxy azetidinor.e ester of Formula VIa5
Figure imgf000014_0001
Formula Via wherein Ri is CM ilkyl group, R2 is hydrogen or a suitable amino protecting group, the process comprising treating epoxyamide of Formula V,
Figure imgf000014_0002
Formula V
wherein R[ and R2 are as described above, with a base.
The hydroxy azetidinone ester of Formula Via can be converted to 4-acetoxy azetidinone of Formula I by the process of the present invention. The epoxyamide of Formula V can be prepared by methods known in the art or according to the processes described in the present invention.
The preseni inventors have found that the above cyclization of epoxyamide of Formula V when carried out under reduced quantities of tetrahydrofuran proceeds with nearly 100% conversion ε.s determined by Thin Layer Chromatography. The process of the present invention does not require tedious column chromatography purification, provides good yield of the hydroxy azeiidinone of Formula Via, which can be used as such in the subsequent reaction step.
A sixth aspect of the present invention provides a process for the preparation of azetidinone ester or' Formula VIb,
Figure imgf000015_0001
Formula VIb wherein Ri is C1-4 alkyl, P is a hydroxy protecting group and R2 is hydrogen or a suitable amino protecting group, the process comprising treating hydroxy azetidinone ester of Formula Via,
Figure imgf000015_0002
Formula Via wherein R1 and R2 are as described above, with a hydroxy protecting agent in the absence of a reaction solvent.
The hydroxy azetidinone ester of Formula Via, wherein Ri and R2 are as described above, can be prep ared by methods known in the art or according to the process disclosed in the present invention. The hydroxy azetidinone ester of Formula Via described above was treated with a hydroxy protecting agent for example, a silylating agent in the absence of a reaction solvent, to obtain O-silyl protected azetidinone ester which can be converted to 4- acetoxy azetidinons of Formula I, by the process of the present invention.
The present inventors have surprisingly found that the silyl protection of side chain hydroxy group in azetidinone ester of Formula Via, wherein R1 and R2 are as described above, can be carried out without solvent with good yield and the product can be used as such in the subsequent reaction step. Further, the present inventors have found that the reaction times are greatly reduced when solvent is not used and the process of the present invention does not require tedious coluir.n chromatography for isolation of the product.
4-acetoxy gwetidinone of Formula I prepared by the process of the present invention can be further converted to β-lactam compounds of Formula VIII,
Figure imgf000016_0001
Formula VHI wherein P] is hydrogen or a cafboxyl protecting group, R$ is hydrogen or C1.5 alkyl and X is C OT S5 Y is a tetrahydrofuran ring connected via C2 or Y represents a substituted thiol of Formula S-A wherein A is selected from the group consisting of a)
b)
and
c)
Figure imgf000017_0001
wherein P2 is hydrogen or an amino protecting group, R7 and Rg are same or different and are hydrogen, C1-5 alky], substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, by processes known 10 one skilled in the art. For example, compound of Formula I can be converted to compound of Formula VIII by processes disclosed in U.S. Patent Nos. 4,943,569; 5,478,820; 5,317,016; 5,652,233; 5,856,321; 4,997,829; and 5,998,612. For example, 4- acetoxy azetidinone of Formula I can be converted to β-lactam compounds of Formula VIII by the following steps: a) reacting 4-acetoxy azetidinone of Formula I
Figure imgf000017_0002
Formula I wherein R2 is hydrogen or a suitable amino protecting group and P is a suitable hydroxy protecting group, with α-haloacetamide derivative of Formula IX,
Figure imgf000017_0003
Formula IX wherein R6 is as described above; Ring B is a benzene ring which may be substituted by one to four group(s) selected from halogen, C]-6-alkyl, C1-6-alkoxy and phenyl which maybe substituted with Ci-e-alkyl, Ci-6-alkoxy, halogen or optionally protected amino; X' is O or S; Y' is O, S, CH2 or an imino group which may be substituted by Ci-6-alkyl or an acyl group selected from C2.*- ilkanoyl, (Ci-6alkoxy)carbonyl, oτ phenylcarbonyl or pheny^Q-e- alkoxy)carbonyl, the phenyl group of which each may be substituted with Ci-6-alkyl, Q-e- alkoxy, halogen or optionally protected amino; Z is a methylene group which may be substituted by one to two group(s) selected from C3.7-aIkylene, Ci-2d-alkyl5 C4-7-cycloalkyl, phenyl, each of these substituents may be substituted with Q^-alkyl, Q^-alkoxy, halogen or optionally protected amino, phenyl-Ci-6-alkyl, the phenyl group of which maybe substituted with Ci-s-alkyl, Ci-β-alkoxy, halogen or optionally protected amino, or a heterocyclic group; and L1 is a haloger atom, to obtain a compound of Formula X,
Figure imgf000018_0001
Formula X wherein P, R2, Re, X', Y' and Z' are as described above; b) deprotecting the compound of Formula X wherein R2 is a suitable amino protecting group and reacting the deprotected compound with acetic acid derivative of Formula XI,
L2-CH2-COOP1
Formula XI wherein P1 is as described above and L2 is a leaving group, to obtain N-substituted azetidinone compound of Formula XII,
Figure imgf000018_0002
Formula Xπ wherein P5 P1, Rg, X', Y' and Z' are as described above; c) subjecting the compound of Formula XII to intramolecular cyclization and esterification to obtain a compound of Formula XIII,
Figure imgf000019_0001
Foπnula XIII wherein P, Pi, R6 are as described above and OE is an esterified hydroxy group; and d) reacting the compound of Formula XIII with a thiol of Foπnula,
HS-A wherein A is as described above and deprotecting the hydroxy protecting group P, to obtain the compound of Formu.a VIII,
Figure imgf000019_0002
Formula VHI wherein P1 and R6 ars as described above, X is Carbon and Y represents a thiol of formula wherein A is as described above.
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.
Example 1: Preparation of ethyl N-p-methoxyphenylglvcinate p-Anisidine (100 g) was dissolved in triethylamine (500 ml) at about 5O0C under nitrogen atmosphere. The solution was warmed to 900C and ethylchloroacetate was added slowly over 2-3 hours. The reaction mixture was refluxed for 0.5 hours and cooled to 4O0C and washed with water at the same temperature. The organic layer was cooled to O0C slowly and stirred for 1 hour and filtered to collect the solids. The solids were washed with 2 x 100 ml of 1 :1 of methanol: water mixiure and dried under vacuum to obtain the title compound in high purity. Yield =135 g
Example 2: Preparation of (2R,3R)-eρoxybutyric acid
L-Threonine (100 g) was dissolved in 7.5 NHCl (546 ml) at 0-50C. To this solution, 40% w/v aqueous sodium nitrite (240 ml) was added in 5 hours maintaining temperature at -2 to +20C. The reaction mixture was stirred for 0.5 hours at O0C, warmed to 25°C, vigorously stirred for 2 hours and then cooled to O0C. A 40% w/v solution of sodium hydroxide (504 ml) was added maintaining the temperature at 0-50C and stirred for 1-2 hours at 25°C. pH of the solution of was adjusted to 1-1.2 with concentrated hydrochloric acid at 0-50C. The reaction mass was saturated with sodium chloride and extracted with 3 x 500 ml tetrahydrofuran at pH 1 -1.2.
Tetrahydrofuran was recovered from the combined extracts under vacuum at less than 15°C. To the residue so obtained, dichloromethane (700 ml) was added followed by the addition of anhydrous sodium sulfate (100 g). The reaction mixture was stirred for 0.5 to 1 hour and filtered to remove the solids. Dichloromethane (100 ml) washings were added to the above filtrate.; This combined filtrate wa; concentrated under vacuum at less than 150C to obtain the product. Alternatively, the filtrate was concentrated to half its volume and the solution was used as such for the next step.
Yield =74 g
Example 3: Preparation of f2RJR)-N-fefcoxycarbonyl)methyl-N-p-methoxyphenyl-2,3- epoxybutyric amido
To a stirred solution of (2R,3R)-epoxybutyric acid (50 g) in dichloromethane, was added ethyl N-p-methoxyphenyl glycinate (92.2 g) at 0-50C. A solution of dicyclohexylcarbodiimide (101 g) in dichloromethans (75 ml) was added to the reaction mass in 1.5 hours at 0-50C. To this reaction mixture, waier (75 ml) was added at 0-50C followed by stirring at 20-250C for 1 hour. The reaction mass was filtered to remove solids. The solids were washed with dichloromethane (2 x 75 ml) and the washings added to the filtrate. The filtrate was washed with 2 x 150 ml 3N HCl and 1 x 50 ml saturated sodium bicarbonate solution at 15°C. Dichloromethane was recovered under vacuum to obtain the title compound as a thick oil which can be used as such in the next step. Yield =145 g
Example 4: Preparation of (3S.4SV3-f( 1 'RVl '-hvdroxyethyll-4-ethoxycarbonyli-l-p- methoxyphenyl-2-Ezetidinone
Method 1:
5 To (2R,3R)-N-(ethoxycarbonyl)methyl-N-p-methoxyphenyl-2,3-epoxybutyric amide (100 g), was added tetrahydrcfuran (500 ml) followed by zinc chloride (7 g) at room temperature. The reaction mass was stirred to dissolve the solids and then cooled to -150C. Lithium hexamethyldisilazane solution in tetrahydrofuran (20%, 385 ml) was added at-15°C. The reaction mass was brought to O0C and stirred to completion. The reaction was then quenched in 10 2:1 mixture of dichloromethanerdilute hydrochloric acid. The reaction mass was filtered over HYFLO® and the lavers separated. The organic layer was washed with water and concentrated under reduced pressure to afford the title compound as thick oil, which was used as such in the next step.
Yield = 98 g 15 Method 2: Part i:
To a stirred solution of Lithium amide (14.23 g) in tetrahydrofuran (230 ml), was added hexamethyldisilazano (126.7 g) at 25°C. The resulting solution was refluxed for 3 hours and cooled to 25°C and stored under nitrogen atmosphere.
20 Part H:
To a stirred solution of (2R,3R)-N-(ethoxycarbonyl)methyl-N-p-raethoxyphenyl-2,3- epoxybutyric amide 1115 g) in tetrahydrofuran (345 ml), was added zinc chloride (8.05 g) at 25°C. The reaction mixture was stirred for 10 minutes at 25°C and cooled to -15°C. The solution prepared in part I was slowly added into the above reaction mixture at —10 to -15°C in 25 15 minutes. The resu ltant mass was stirred at O0C till the reaction was complete and quenched in a mixture of dichloromethane:dilute hydrochloric acid (575 ml + 719 ml) at 0-20C and then filtered through HYf LO®. The layers were separated and the organic layer was washed with water and concentrated under vacuum to afford the title compound as a brown solid, which was taken as such to the rext step. Yield =112.7 g
Example 5: Preparation of f3S.4SV3-fr(rRπM-butyldimethylsilyloxy1 ethyll-4-ethoxy carbonyl-l-p-methoxyphenyl-2-azetidinone
To (3S,4S)-3-[(l 'R)-r-hydroxyethyl]-4-ethoxycarbonyl]-l-ρ-methoxyρhenyl-2-azetidinone (10Og), tert-butyldimethylsilylchloride (56.5 g) and imidazole (27.8 g) were added under stirring at 200C. The reaction was exothermic and the temperature rose to about 450C. The reaction mass was slowly warmed to 900C when the reaction was complete. The reaction mass was cooled to room temperature and 400 ml of dichloromethane was added. The separated solids (imidazole hydrochloride) were filtered and the filtrate was washed with water. Dichloromethane was then recovered from the organic layer by distillation and the product was obtained as thick oil, which was used as such in the next step.
Yield =135 g Example 6: Preparation of r3S,4SV3-(r(rRVr-t-butyldimethyl silyloxyiethvU-4-carboxv-l- p-methox vphenyl -2-azetidinone
To (3S,4S)-3- {[(1 'R)-I '-t-butyldimethylsilyloxy] ethyl} -4-ethoxycarbonyl- 1 -p-methoxyphenyl- 2-azetidinone (10Og), methanol (500ml) was added. To the methanolic solution, was added 245 ml of IN sodium hydroxide and the reaction mixture was stirred at room temperature till the starting material was completely consumed as determined by Thin Layer Chromatography. Methanol was then recovered under reduced pressure at 300C. The reaction mass was then diluted with water (1 L), washed with ethyl acetate and further diluted with water (1 L). The pH of the solution was adjusted to 3.5 at 0-50C and the solids obtained were filtered and washed with water. The solic s were then dissolved in 250 ml of acetone at 35°C and 250 ml of water was added slowly. The reaction mass was cooled slowly to 200C and filtered and the solids washed with 1:1 acetone: water. The solids were dried to obtain the product as off-white to light brown powder, whic i was used as such in the next step. Yield =64g Purity -95%
Reference example 1: GR^RI^-acetoxy-S-ffα'RVl'-t-butyldimethylsilyloxyethvβ-l-p-ethoxy phenyl-2-azetidinone
Method 1: To a mixed solution of dimethylformamide and acetic acid (3/1, 300 ml), (3S,4S)-3-
{[(1 'R)-I '-t-butyldimethylsilyloxy]ethyl}-4-carboxy-l-p-methoxyphenyl-2-azetidinone (15 g, 39.5 mmol) was addei followed by tetravalent lead acetate (24.5 g, 55.3 mmol) and the reaction mixture was stirred fcr 2 hours while maintaining the reaction temperature at 6O0C. To the reaction mixture, a mixed solution of ethyl acetate and n-hexane (1:1, 800 ml), and brine (500 ml) were added. The reaction mass was stirred for 30 minutes at room temperature and insoluble materials were filtered off. The filtrate containing the organic layer was washed with brine (400 ml), 10% sodium bicarbonate solution (400 ml) and brine (400 ml) sequentially and concentrated under reduced pressure. The residue was purified by a short column chromatography (eluent: ethyl acetate: hexane = 1:6) to obtain pure title compound as brown oil.
Method 2:
(3S,4S)-3-{[(l'R)-r-:-butyldimethylsilyloxy]ethyl}-4-carboxy-l-p-methoxyphenyl-2- azetidinone) (15 g, 39.5 mmol) was dissolved in glacial acetic acid (100 ml). To this solution, lead tetraoxide (29.4 g, 43 mmol) was added in small portions at the reaction temperature of 600C. The reaction te uperature slowly rose as the reaction was exothermic. The reaction mixture was vigorously stirred for 30 minutes. After completion of reaction, a small amount of ethylene glycol was aided and the solvent removed by evaporation under reduced pressure. The reaction mixture was worked-up as the procedure described in (Method A) to obtain the title compound
Reference example 2: (3R>4R)-4-acetoxy-3-(r(l'RVr-t-butyldimethylsilyloxylethvπ-2- azetidinone Method 1:
(3R,4R)-4-acetoxy-3-(((l'R)- r-t-butyldimethylsilyloxylethyl} -1 -p-ethoxy phenyl-2-azetidinone (26 g, 66 mmol) was dissolved in methanol (500 ml). The internal temperature of the reactor was lowered to -2O0C and the reaction was performed for 3 hours with slowly incorporating ozone. After the reaction was completed, 10% solution of sodium thiosulphate and thiourea were added sequentially and the resultant mixture was vigorously stirred for 30 minutes at room temperature. The reaction mixture was concentrated to 1/3 of the initial volume of the mixture. The concentrate was chilled to — 100C to produce white crystalline powder. The powder was filtered, dried and recrystallized from n-hexane to obtain pure title compound as white crystals.
Method 2:
To lithium perchlora1e solution (0.1 M; 45 ml) in mixed solvent of acetonitrile and distilled water (10:1), (3R,4R)-4-acetoxy-3-(((rR)-l'-t-butyldimethylsilylofylethyl}-l-p-ethoxy phenyl- 2-azetidinone (349 rr.g, 1 mmol) was added and dissolved. The mixture was poured in a non- dividable electrolysis vessel with connecting an amorphous carbon anode and a cathode plate, and a Ag/Ag+ reference electrode to a Potentiostat (EG & G 273). Under 1.8 V constant voltage, the mixture was electrolysed until all the starting material disappeared. The organic solvent was removed by evaporation under reduced pressure and the residue was dissolved in ethyl acetate. The solution was washed with 10% aqueous sodium sulfite solution and saturated brine sequentially and evaporated under reduced pressure. The residue was purified by a short column chromatography (elusnt: ethyl acetate: hexane = 1:4) to obtain pure title compound as white crystals. Method 3: 3R,4R)-4-acetoxy-3-(((l'R)-l'-t-butyldimethylsilyloxyethyl}-l-p-ethoxy phenyl-2-azetidinone (5 g, 12.7 mmol) was; dissolved in acetonitrile (100 ml). After chilling the solution to -150C, a solution of eerie ammonium nitrate (34.8 g, 63.5 mmol) dissolved in water (150 ml) was added dropwise. The resultiint mixture was stirred for 30 minutes. After the completion of the reaction, the mixture was extracted from ethyl acetate (300 ml), and the organic layer was washed with water (200 ml), 10% sodium thiosulphate solution, 10% sodium bicarbonate solution and saturated brine, sequentially and then concentrated under reduced pressure. The brown residue obtained was recryst;ιllized from n-hexane to obtain the title compound as white crystalline powder.
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 1. A process for the preparation of 4-acetoxy azetidinone of Formula I,
Figure imgf000026_0001
3 Formula I
4 wherein R2 is hydrogen or a suitable amino protecting group and P is a suitable hydroxy
5 protecting group, the process comprising:
6 a) stirring a basifieii reaction mixture comprising L-threonine of Formula II,
OH
NH2 η Formula Il
8 an acid and an alkali metal nitrite, for 10 hours or less, to obtain (2R,3R)-epoxybutyric acid of
9 Formula III;
Figure imgf000026_0002
10 Formula III
11 b) condensing the cpoxyacid of Formula HI with glycine ester of Formula F/,
Figure imgf000026_0003
j 2 Formula IV
13 wherein Ri is CM alkyl group, R2 is as described above, in the presence of a condensing agent
14 in a halogenated solvent to obtain epoxyamide of Formula V,
Figure imgf000027_0001
Formula V wherein Ri and R2 are as described above; c) converting the epoxyamide of Formula V to hydroxy azetidinone ester of Formula Via,
Figure imgf000027_0002
Formula Via wherein Rj5 R2 are as described above, by treatment with a base; d) converting the hydroxy azetidinone ester of Formula Via to azetidinone ester of Formula VIb,
Figure imgf000027_0003
Formula VIb wherein Ri , R2 are as described above, and P is a hydroxy protecting group, by treatment with a hydroxy protecting agent in the absence of a reaction solvent; e) hydrolyzing the ;izetidinone ester of Formula VIb to carboxy azetidinone of Formula Vila,
Figure imgf000027_0004
Formula Vila wherein R2 is as described above and P is a hydroxy protecting group; and f) oxidizing the carboxy azetidinone of Formula Vila in the presence of an oxidizing agent to obtain 4-acetoxy az stidinone of Formula I,
Figure imgf000028_0001
Formula I wherein P and R2 are as described above. 2. The process according to claim 1, wherein the basified reaction mixture is acidified with an acid at a temperature less than 2O0C. 3. The process according to claim 2, further comprising extracting with organic solvent comprising one or more of C4-S ethers; Cj-4 alcohol; C3.g ketones; halogenated solvents; polar aprotic solvents, and hydrocarbons with a proviso that the organic solvent is not an ester. 4. The process according to claim 1 step b), wherein the condensation is carried out in the presence of dicyclohexylcarbodiimide in dichloromethane. 5. The process- according to claim 1 step d), wherein the hydroxy azetidinone ester of Formula Via is tre∑.ted with a silylating agent. 6. The process, according to claim 5, wherein the silylating agent comprises one or more of trimethylchlorosilane, tert-butyldimethylchlorosilane, 1,1,1,3,3,3,-hexamethyldisilazane, n. trimethylsilylacetainide, tetramethyldisilazane, bis(trimethylsilyl)acetamide, vinyltriacetoxysilane, dimethylchlorosilane, bromomethyldimethylchlorosilane, di(chloromethyl)te;ra methyldisilazane, and vinyltriethoxysilane. 7. The process for the preparation of 4-acetoxy azetidinone of Formula I according to claim 1, wherein tre process does not employ chromatographic purification. 8. A process for the preparation of 4-acetoxy azetidinone of Formula I,
Figure imgf000029_0001
Formula I wherein R2 is hydrogen or a suitable amino protecting group and P is a suitable hydroxy protecting group, the process comprising: a) stirring a basified reaction mixture of L-threonine of Formula II,
Figure imgf000029_0002
Formula Il an acid and an alkali metal nitrite, to obtain (2R,3R)-epoxybutyric acid of Formula III;
Figure imgf000029_0003
Formula III b) condensing the epoxyacid of Formula m with glycine ester of Formula IV,
Figure imgf000029_0004
Formula IV wherein Ri is Ci-4 alkyl group, R2 is as described above, to obtain epoxyamide of Formula V,
Figure imgf000029_0005
Formula V wherein R| and R2 £.re as described above; c) converting the epoxyamide of Formula V to hydroxy azetidinone ester of Formula Via by treatment with a base,
Figure imgf000030_0001
Formula Via wherein Ri, R2 and P are as described above; d) converting the hydroxy azetidinone ester of Formula Via to azetidinone ester of Formula VIb,
Figure imgf000030_0002
Formula VIb wherein Rj, R2 are £.s described above, and P is a hydroxy protecting group, by treatment with a hydroxy protecting agent; e) hydrolyzing the hydroxy azetidinone of Formula VIb to carboxy azetidinone of Formula Vila,
Figure imgf000030_0003
Formula Vila wherein P and R2 ars as described above; and f) oxidizing the cart oxy azetidinone of Formula VTIa in the presence of an oxidizing agent to obtain 4-acetoxy azetidinone of Formula I,
Figure imgf000031_0001
Formula I wherein P and R2 are as described above, wherein the process does not employ chromatographic purification at any stage. 9. A process for the preparation of glycine ester of formula IV,
Figure imgf000031_0002
Formula IV wherein Rj is CM a'kyl group and R2 is hydrogen or a suitable amino protecting group, the process comprising reacting a compound of Formula A,
R2— NH2 Formula A wherein R2 is as described above, with 2-halo acetic acid ester of Formula B,
Figure imgf000031_0003
Formula B wherein X is a leaving group and Rt is as described above, in the presence of a base at about SO-IOO0C. 10. The process according to claim 9 further comprising converting the glycine ester of Formula FV to 4-acetoxy azetidinone of Formula I by the process of claim 1. 11 The process according to claims 1, 8 or 9 wherein the base comprises one or more of alkali metal amides, hydrides, hydroxides, metal alkyls, tertiary amines and bicyclic amines.
12. A process for the preparation of β-lactam compounds of Formula VIII,
Figure imgf000032_0001
Formula VIII wherein Pi is hydrogen or a carboxyl protecting group, R^ is hydrogen or Ci-S alkyl and X is C or S, Y is a tetrahycrofuran ring connected via C2 or Y represents a substituted thiol of Formula S-A, whennn A is selected from the group consisting of a)
,NH π W ^:'N1 H
b)
Figure imgf000032_0002
and c)
Figure imgf000032_0003
wherein P2 is hydrogen or an amino protecting group, R? and R8 are same or different and are hydrogen, C1-S alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, the process comprising: a) reacting 4~acetoxy azetidinone of Formula I prepared by the process of claim 1 or 8,
Figure imgf000033_0001
Formula I wherein R2 is hydrogen or a suitable amino protecting group and P is a suitable hydroxy protecting group, with α-haloacetamide derivative of Formula IX,
Figure imgf000033_0002
Formula IX wherein R6 is as described above; Ring B is a benzene ring which may be substituted by one to four group(s) se ected from halogen,
Figure imgf000033_0003
and phenyl which may be substituted with Ci -β-alkyl, Ci-β-alkoxy, halogen or optionally protected amino; X' is O or S; Y' is O, S, CH2 or an imino group which may be substituted by Ci-6-alkyl or an acyl group selected from C2-8-alkanoyl} (Cj.6-alkoxy)carbonyl, or phenylcarbonyl or phenyl(Ci.6~ alkoxy)carbonyl, the phenyl group of which each may be substituted with
Figure imgf000033_0004
Ci .6- alkoxy, halogen or optionally protected amino; Z is a methylene group which may be substituted by one to two group(s) selected from C3.7-alky.ene, Ci-20-alkyl, C4-7-cycloalkyl, phenyl, each of these substituents may be substituted with Ci-6-alkyl, Cj-β-alkoxy, halogen or optionally protected amino, phenyl-Ci-6-alkyl, the phenyl group of which may be substituted with Ci-6-alkyl, C] g-alkoxy, halogen or optionally protected amino, or a heterocyclic group; and Li is a haloger atom, to obtain a compound of Formula X,
Figure imgf000034_0001
Formula X wherein P, R2, R6, X\ Y' and Z' are as described above; b) deprotecting the compound of Formula X wherein R2 is a suitable amino protecting group and reacting the deprotected compound with acetic acid derivative of Formula XI,
Figure imgf000034_0002
Formula XI wherein P] is as described above and L2 is a leaving group, to obtain N-substituted azetidinone compound of Formula XII,
Figure imgf000034_0003
Formula Xn wherein P, Pi, R6, X', Y' and Z' are as described above; c) subjecting the compound of Formula XE to intramolecular cyclization and esterification to obtain a compound of Formula XHI,
Figure imgf000034_0004
Formula XIII wherein P, Pi, Re are as described above and OE is an esterified hydroxy group; and d) reacting the cornpo und of Formula XIII with a thiol of Formula, HS-A wherein A is as described above and deprotectϊng the hydroxy protecting group P, to obtain the compound of Formula VIII,
Figure imgf000035_0001
Formula VIII wherein P1 and Rg are as described above, X is Carbon and Y represents a thiol of formula
, wherein A if as described above.
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CN101747250B (en) * 2008-12-16 2012-09-05 上海医药工业研究院 Method for preparing 4 - acyloxo heterocyclic ketone compounds
CN102827199A (en) * 2012-08-28 2012-12-19 三峡大学 Synthetic method for penem and carbapenem antibiotic type key intermediate 4AA
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US9079901B2 (en) 2010-07-02 2015-07-14 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
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Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2642586T3 (en) 2009-07-27 2017-11-16 Gilead Sciences, Inc. Condensed heterocyclic compounds as ion channel modulators

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0126587A1 (en) * 1983-05-09 1984-11-28 Sumitomo Pharmaceuticals Company, Limited Carboxylic thio-pyrrolidinyl beta-lactam compounds and production thereof
EP0367722A1 (en) * 1988-11-04 1990-05-09 Ciba-Geigy Ag Process for preparing optically active acyloxyazetidinones
EP0371875A2 (en) * 1988-11-29 1990-06-06 Takasago International Corporation Process for preparing 4-acetoxyazetidinones
EP0528678A1 (en) * 1991-08-20 1993-02-24 SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI & CO. LTD. A pyrrolidylthiocarbapenem derivative
WO1998007690A1 (en) * 1996-08-24 1998-02-26 Choongwae Pharmaceutical Co., Ltd. Process for stereoselective preparation of 4-acetoxyazetidinones

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0126587A1 (en) * 1983-05-09 1984-11-28 Sumitomo Pharmaceuticals Company, Limited Carboxylic thio-pyrrolidinyl beta-lactam compounds and production thereof
EP0367722A1 (en) * 1988-11-04 1990-05-09 Ciba-Geigy Ag Process for preparing optically active acyloxyazetidinones
EP0371875A2 (en) * 1988-11-29 1990-06-06 Takasago International Corporation Process for preparing 4-acetoxyazetidinones
EP0528678A1 (en) * 1991-08-20 1993-02-24 SHIONOGI SEIYAKU KABUSHIKI KAISHA trading under the name of SHIONOGI & CO. LTD. A pyrrolidylthiocarbapenem derivative
WO1998007690A1 (en) * 1996-08-24 1998-02-26 Choongwae Pharmaceutical Co., Ltd. Process for stereoselective preparation of 4-acetoxyazetidinones
WO1998007691A1 (en) * 1996-08-24 1998-02-26 Choongwae Pharmaceutical Co., Ltd. Process for stereoselective preparation of trans-azetidinones

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CAINELLI, GIANFRANCO ET AL: "Stereocontrolled total synthesis of the chiral building block (3S,4R)-3-Ä(R)-1-hydroxyethylÜ-4-acetyloxy -azetidin-2-one: a useful synthon for the synthesis of (+)-thienamycin, carbapenems and penems" TETRAHEDRON LETTERS, vol. 26, no. 7, 1985, pages 937-940, XP002406363 *
COZZI, FRANCO ET AL: "A short, stereoselective synthesis of (3R,4R)-4-acetoxy-3-Ä(R)-1'((t- butyldimethylsilyl)oxy)ethylÜ-2-azetidinon e, key intermediate for the preparation of carbapenem antibiotics" CHIRALITY, vol. 10, no. 1/2, 1998, pages 91-94, XP002406364 *
LAURENT, MATHIEU ET AL: "A new method of N-benzhydryl deprotection in 2-azetidinone series" SYNTHESIS, vol. 4, 2003, pages 570-576, XP002406359 *
LAURENT, MATHIEU ET AL: "Regioselective Baeyer-Villiger Oxidation in 4-Carbonyl-2-azetidinone Series: A Revisited Route toward Carbapenem Precursor" JOURNAL OF ORGANIC CHEMISTRY, vol. 69, no. 9, 2004, pages 3194-3197, XP002406360 *
SHIOZAKI, MASAO ET AL: "Stereocontrolled syntheses of chiral intermediates of thienamycin from threonines" TETRAHEDRON LETTERS, vol. 22, no. 51, 1981, pages 5205-5208, XP002406361 *
SHIOZAKI, MASAO ET AL: "Stereospecific synthesis of chiral precursors of thienamycin from L-threonine" TETRAHEDRON, vol. 40, no. 10, 1984, pages 1795-1802, XP002406362 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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WO2011048583A1 (en) 2009-10-23 2011-04-28 Ranbaxy Laboratories Limited Process for the preparation of carbapenem compounds
US9079901B2 (en) 2010-07-02 2015-07-14 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9682998B2 (en) 2011-05-10 2017-06-20 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9598435B2 (en) 2011-07-01 2017-03-21 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9695192B2 (en) 2011-07-01 2017-07-04 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
US9676760B2 (en) 2011-07-01 2017-06-13 Gilead Sciences, Inc. Fused heterocyclic compounds as ion channel modulators
CN102432632A (en) * 2011-09-16 2012-05-02 上海悦昂化学有限公司 Method for preparing (3R,4R)-3-[(1R)tert-butyl-dimethyl-silyloxyethyl]-4-acetoxyl-2-azetidinone
CN102827199A (en) * 2012-08-28 2012-12-19 三峡大学 Synthetic method for penem and carbapenem antibiotic type key intermediate 4AA
WO2014071565A1 (en) * 2012-11-07 2014-05-15 凯莱英医药集团(天津)股份有限公司 Preparation method for intermediate 4aa of imipenem drugs
CN102936262A (en) * 2012-11-07 2013-02-20 凯莱英医药集团(天津)股份有限公司 Preparation method for imipenem medicine intermediate 4AA
CN103242361A (en) * 2013-05-23 2013-08-14 浙江海翔川南药业有限公司 Preparation method of penem antibiotic intermediate
CN109721521A (en) * 2018-11-26 2019-05-07 广东药科大学 A kind of preparation method of optical activity clausenamide ketone and its derivative
CN115385950A (en) * 2022-10-27 2022-11-25 天津凯莱英医药科技发展有限公司 System and method for preparing 4-acetoxyazetidinone through continuous ozone oxidation

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