The present invention provides a diastereoselective processes for the preparation of 4-(P)-alkylsubstituted azetidinone derivatives of Formula 1(a) and 4-(a)-alkylsubstituted azetidinone derivatives of Formula 1(b),
(Formula Removed)

Formula 1(a) Formula 1(b)
wherein R1 represents an alkyl group, which may be substituted by an optionally protected hydroxyl group or halogen; R2 represents an alkyl group; P is hydrogen or suitable amine protecting group. )
The compounds of Formula 1(a) or 1(b) are important synthetic intermediates of p-lactam antibiotics that possess the carbapenem and penem ring systems such as ertapenem, doripenem, meropenem, faropenem and the like. The p-lactam antibiotics are commonly prescribed antimicrobial agents due to their excellent activity against a wide range of both Gram-positive and Gram-negative bacteria, and their stabilities in the human body.
There have been several methods proposed for the preparation of compounds of Formula 1(a) or 1(b).
JS Patent No 5,231,179 discloses a process for preparation of 4-substituted azetidinone amide derivative of Formula C by reaction of 4-acetoxyazetidinone derivative of Formula A (herein after 4-AAZ) and a-bromopropionyloxazolidinone of rormula B in a Reformatsky-type reaction using Zinc powder as depicted in the Scheme 1 below:
(Formula Removed)

Scheme 1
The a-bromopropionamide starting material is difficult to synthesize and requires additional steps for manufacture. The separation of the p-alkyl and a-alkyl isomers requires the use of expensive and time consuming chromatographic techniques.
Japanese Patent Publication Nos. 63-188662, 63-010765 and 02-178262 and Andrew et al., Tetrahedron, 52(2), 331-375 (1996) disclose similar processes using Zinc dust in a Reformatsky-type coupling with 4-AAZ whereas in US Patent No. 6,340,751 alkyl magnesium halides are used for coupling with 4-AAZ.
In the processes for the preparation of 4-substituted azetidinone amide derivative, using Zinc dust mediated Reformatsky-type coupling, the p-alkyl group cannot be selectively introduced. Consequently the separation of the p-alkyl and a-alkyl isomers requires the use of expensive and time consuming chromatographic techniques.
Shih et al. Heterocycles, 21, 29 (1984) discloses a process for preparation of 4-[(P)-methylacetic acid]-azetidinone derivative comprising deprotonating the alpha hydrogen of acetic acid residue at 4-position of azetidinone ring of the demethylated compound using a strong base and introducing a methyl group therein. The said process is carried out at very low temperatures (-78°C) and results in a mixture of p:a = 50:50. The separation of the p-alkyl and a-alkyl isomers requires the use of expensive and time consuming chromatographic techniques.
US Patent Nos. 4,791,207 and 5,104,984 and Robert et al., Tetrahedron Letters, 27, 5687-90 (1986) disclose a process wherein the coupling with 4-AAZ uses divalent tin
enolates of 3-propanoyl thiazolidine and oxazolidine-2-thiones derivatives. Japanese Patent Publication No. 62-7252786 discloses boron triflate mediated coupling with 4-AAZ. Use of boron triflates or tin triflates is not economical as these are expensive and the coupling with 4-AAZ using these reagents is industrially unfavoured. Moreover these processes require expensive and time consuming chromatographic techniques for separation of the p-alkyl and a-alkyl isomers.
US Patent No. 5,731,431 discloses a process wherein substituted thio-oxazolidinones are coupled with 4-AAZ, which produces a mixture of a-methyl and p-methyl isomers of the amide derivative whose ratio is influenced by the type of thio-oxazolidinone auxiliary. The use of substituted oxazolidinones results in a-alkyl: p-alkyl isomer ratio of 68:32. Use of thio-oxazolidinone auxiliaries involves additional steps to manufacture, as these are not commercially available.
US Patent Nos. 5,442,055, 5,847,115 and 6,011,150 and Organic Process Res. & Dev., 5, 186-88 (2001) disclose a process wherein a non-chiral 6-membered benzo fused 2-halopropionamide derivative is coupled with 4-AAZ in the presence of Zinc or Magnesium to obtain the 4-substituted azetidinone amide derivative. The amide derivative is then hydrolyzed using H2O2 and LiOH at low temperature to afford compounds of Formula I having p-alkyl :a-alkyl ratio of 92:8 at a yield of 55 to 58% after cumbersome workup.
US Patent No. 5,792,861 discloses a process wherein a non-chiral 6-membered benzo fused 2-halopropionamide derivatives is coupled with 4-AAZ to obtain the 4-substituted azetidinone amide derivative. The bulky non-chiral auxiliaries reported in the '861 and the '055 patents are not commercially available and require additional steps for manufacture.
The processes known in the art for preparation of 4-substituted azetidinone amide derivative lead to a mixture of p-alkyl and a-alkyl isomers in a ratio ranging from 32:68
to 98.5:1.5. The separation of the p and a isomers requires the use of expensive and time consuming chromatographic techniques.
The present inventors have developed a diastereoselective process for preparation of 4-(P)-alkylsubstituted azetidinone deR1vatives of Formula l(a) (herein after 4-BAA) and 4-(a)-alkylsubstituted azetidinone deR1vatives of Formula l(b) (herein after 4-AAA),
(Formula Removed)
wherein R1 represents an alkyl group, which may be substituted by an optionally protected hydroxyl group or halogen; R2 represents an alkyl group; P is hydrogen or suitable amine protecting group, using chiral (R)- and (S)-4-aryl-2-oxazolidinones or imidazolidinones (herein after 4R-AZ or 4S-AZ respectively).
The present invention also provides 4-BAA of Formula l(a) and 4-AAA of Formula l(b) in high puR1ty. The present process enables preparation of 4-BAA of Formula l(a) having 1% or less of the corresponding a-alkyl isomer and 4-AAA of Formula l(b) having 10% or less of the corresponding a-alkyl isomer. The present process is cost effective, easily scalable, does not employ expensive and time consuming chromatographic puR1fication. The starting chiral oxazolidinones are cheaply available raw mateR1als, can be recovered in-process and reused without further puR1fication.
A first aspect of the present invention provides a diastereoselective process for preparation of 4-BAA of Formula l(a),
Formula 1(a)
or salts, esters and other active deR1vatives thereof, wherein R1 represents an alkyl group which may be substituted by an optionally protected hydroxyl group or halogen; R2 represents an alkyl group and P is hydrogen or suitable amino protecting group, said process compR1ses of, a) reacting 4S-AZ of Formula ll(a),
FORMULA(Formula Removed)
wherein R3 is hydrogen; substituted or unsubtituted alkyl, Ar is substituted or unsubstituted aryl and Y is oxygen or nitrogen substituted by alkyl or aryl, with a carboxylic acid deR1vative of Formula III,
R2CH2COX FORMULA III wherein R2 is as descR1bed above and X is a leaving group, in the presence of a base to obtain N-acyl-4S-AZ of Formula IV(a),
(Formula Removed)

FORMULA IV(a)
wherein R2, R3> Ar and Y are as descR1bed above
b) reacting N-acyl-4S-AZ of Formula IV(a) obtained in step a) with 4-substituted
azetidinone deR1vative of Formula V
(Formula Removed)

FORMULA V
wherein R1 and P are as descR1bed above and L is a suitable leaving group, in the presence of a base to get a compound of Formula Vl(a),
(Formula Removed)

Formula Vl(a)
wherein R1, R2, R3, Ar, Y and P are as descR1bed above
c) hydrolyzing the compound of Formula Vl(a) in the presence of a base
d) isolating 4-BAA of Formula l(a) from the reaction mass thereof
4-BAA of Formula l(a) can be converted to salts, esters or other active deR1vatives thereof. The active deR1vatives of 4-BAA of Formula l(a) compR1se of amides, anhydR1des or compounds of Formula l(a) wherein the carboxyl group is protected by a removable protecting group and are known to a person having ordinary skills in the art. 4-Substituted azetidinone deR1vatives of Formula V can be prepared by processes well-known in the art. 4S-AZ of Formula ll(a) is treated with carboxylic acid deR1vative of Formula III in the presence of a base to obtain N-acyl-4S-AZ of Formula IV(a), which is then reacted with 4-substituted azetidinone deR1vative of Formula V in the presence of a base and a Lewis acid leading to in situ formation of 4-substituted azetidinone amide deR1vative of the formula Vl(a). The reaction mixture compR1sing 4-substituted azetidinone amide deR1vative of the formula Vl(a) is hydrolysed in the presence of a base and the pH of the reaction mixture is adjusted to about 9.0
whereby 4S-AZ of Formula 11(a) separates from the reaction mass, which is then filtered. The pH of the filtrate so obtained is adjusted to about 3.0 whereby 4-BAA of Formula 1(a) isolates from the reaction mass and it can then be suitably worked up. 4-BAA of Formula 1(a) thus obtained has 1% or less of the corresponding a-alkyl isomer. The recovered 4S-AZ of Formula ll(a) can be recycled for the preparation of 4-BAA of Formula l(a).
Suitable leaving group L is known to a person having ordinary skills in the art and can be selected from the group compR1sing of substituted or unsubtituted lower alkylcarbonyloxy; substituted or unsubtituted arylcarbonyloxy; lower alkylsulfonyl; arylsulfonyl; lower alkylsulfonyloxy; arylsulfonyloxy; halogen; lower alkylthio; arylthio and the like.
Suitable bases can be selected from the group compR1sing of alkali metal amides, hydR1des, hydroxides, metal alkyls, tertiary amines and bicyclic amines. Tertiary amines can be selected from the group compR1sing of tR1ethylamine, pyR1dine, 4-N.N-dimethylamino pyR1dine, N-methylmorpholine and the like. Bicyclic amines can be selected from the group compR1sing of DBN, DBU and the like.
Suitable Lewis acids can be represented by the formula M(Hal)a(Z)b wherein M is a metal atom, Hal is halogen, Z is a lower alkyl group, lower alkoxy group, substituted or unsubstituted phenoxy group or a cyclopentadienyl group and a and b each are integers selected from 0, 1, 2, 3, 4 and 5 provided that a+b represents the valence of M. The Lewis acid of formula M(Hal)a(Z)b can be selected from the group compR1sing of TiCU, TiCI3(OCH3), TiCI3(OC2H5), TiCI3(OC3H7), TiCI3(OC4H9), TiCI2(OCH3)2, TiCI2(OC2H5)2, TiCI2(OC3H7)2, TiCI2(OC4H9)2> ZrCI4, ZrCI3(OCH3), ZrCI3(OC2H5), ZrCI3(OC3H7), ZrCI3(OC4H9), AICI3, AI(OCH3)3, AI(OC2H5)3, AI(OC3H7)3, AICI2(C2H5), AICI(C2H5)2, AI(C2H5)3, AICI2(CH3), AICI(CH3)2, AI(CH3)3, SnCI4and the like.
A second aspect of the present invention provides a diastereoselective process for preparation of 4-AAA of Formula l(b),
(Formula Removed)

Formula 1(b)
or salts, esters and other active deR1vatives thereof, wherein R1 represents an alkyl group, which may be substituted by an optionally protected hydroxyl group or halogen; R2 represents an alkyl group and P is hydrogen or suitable amino protecting group, said process compR1ses of, a) reacting 4R-AZ of Formula ll(b),
(Formula Removed)

FORMULA ll(b)
wherein R3 is hydrogen; substituted or unsubtituted alkyl, Ar is substituted or unsubstituted aryl and Y is oxygen or nitrogen substituted by alkyl or aryl, with a carboxylic acid deR1vative of Formula III,
R2CH2COX
FORMULA III wherein R2 is as descR1bed above and X is a leaving group, in the presence of a base to obtain N-acyl-4R-AZ of Formula IV(b),
(Formula Removed)

FORMULA IV(b)
wherein R2, R3, Ar and Y are as descR1bed above
b) reacting N-acyl-4R-AZ of Formula IV(b) obtained in step a) with 4-substituted
azetidinone deR1vative of Formula V
(Formula Removed)
wherein R1 and P are as descR1bed above and L is a suitable leaving group, in the presence of a base to get a compound of Formula Vl(b),
(Formula Removed)

Formula Vl(b)
wherein R1, R2, R3, Ar, Y and P are as descR1bed above
c) hydrolyzing the compound of Formula Vl(b) in the presence of a base
d) isolating 4-AAA of Formula l(b) from the reaction mass thereof
4-AAA of Formula l(b) can be converted to salts, esters or other active deR1vatives thereof. The active deR1vatives of 4-AAA of Formula l(b) compR1se of amides, anhydR1des or compounds of Formula l(b) wherein the carboxyl group is protected by a removable protecting group, which are known to a person having ordinary skills in the art. 4-Substituted azetidinone deR1vatives of Formula V can be prepared by processes well-known in the art. 4R-AZ of Formula ll(b) is treated with carboxylic acid deR1vative of Formula III in the presence of a base to obtain N-acyl-4R-AZ of Formula IV(b), which is then reacted with 4-substituted azetidinone deR1vative of Formula V in the presence of a base and a Lewis acid leading to in situ formation of 4-substituted azetidinone amide deR1vative of the formula Vl(b). The reaction mixture compR1sing 4-substituted azetidinone amide deR1vative of the formula Vl(b) is hydrolysed in the
presence of a base and the pH of the reaction mixture is adjusted to about 9.0 whereby 4R-AZ of Formula 11(b) separates from the reaction mass, which is then filtered. The pH of the filtrate so obtained is adjusted to about 3.0 whereby 4-AAA of Formula 1(b) isolates from the reaction mass, which and can then be suitably worked up. 4-AAA of Formula 1(b) thus obtained has 10% or less of the corresponding p-alkyl isomer. The recovered 4R-AZ of Formula ll(b) can be recycled for the preparation of 4-AAA of Formula l(b).
Suitable leaving groups, bases and Lewis acids have already been descR1bed in the first aspect of the present invention.
A third aspect of the present invention provides 4-BAA of Formula l(a),
Formula l(a) wherein R: represents an alkyl group, which may be substituted by an optionally protected hydroxyl group or halogen; R2 represents an alkyl group; P is hydrogen or suitable amine protecting group, having 1% or less of 4-AAA isomer of Formula l(b),
(Formula Removed)
wherein R1 R2 and P are as descR1bed above.
A fourth aspect of the present invention provides 4-AAA of Formula l(b),
11

Formula 1(b) wherein R1 represents an alkyl group, which may be substituted by an optionally protected hydroxyl group or halogen; R2 represents an alkyl group; P is hydrogen or suitable amine protecting group, having 10% or less of 4-BAA isomer of Formula l(a).
ruimuid(Formula Removed)
wherein R1, R2 and P are as descR1bed above.
Preferably 4-AAA of Formula l(b) has 5% or less of 4-BAA of Formula l(a). More preferably 4-AAA of Formula l(b) has 1% or less of 4-BAA of Formula l(a). Most preferably 4-AAA of Formula l(b) has no detectable 4-BAA of Formula l(a).
The compounds, 4-BAA of Formula l(a) and 4-AAA of Formula l(b) can be converted to p- lactam antibiotics that possess the carbapenem and penem R1ng systems such as ertapenem, doR1penem, meropenem etc. by processes known in the art.
While the present invention has been descR1bed 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 N-PROPIONYL-(S)-4-PHENYL-2-OXAZOLIDINONE
(S)-4-phenyl-2-oxazolidinone (100 g) was suspended in toluene (500 ml) and to this suspension propionyl chloR1de (96.4 g) was added at 20-25°C. To the resultant slurry tR1ethylamine (111.5 g) was added dropwise and the resultant mixture was stirred for 60 minutes. After the completion of the reaction, the reaction mixture was washed with sodium bicarbonate solution and water. Toluene was evaporated under reduced pressure and the residue was crystallized from isopropyl alcohol to obtain the title compound. Yield = 110 g
EXAMPLE 2
PREPARATION OF N-PROPIONYL-(R)-4-PHENYL-2-OXAZOLIDINONE
(R)-4-Phenyl-2-oxazolidinone (100 g) was suspended in toluene (500 ml) and to this suspension propionyl chloR1de (96.4 g) was added at 20-25°C. To the resultant slurry tR1ethylamine (112 g) was added dropwise and the resultant mixture was stirred for 60 minutes. After the completion of the reaction, the reaction mixture was washed with sodium bicarbonate solution and water. Toluene was evaporated under vacuum and the residue was crystallized from isopropyl alcohol to obtain the title compound. Yield = 115 g
EXAMPLE 3 PREPARATION OF 0-METHYL CARBAPENEM INTERMEDIATE
(S)-4-Phenyl-2-oxazolidinone (92 g) was dissolved in dichloromethane (700 ml) and the resultant solution cooled to about -20°C to -25°C. To the cooled solution titanium tetrachloR1de (86 g) was added dropwise and the resultant mixture was stirred for 30 minutes. To this stirred mixture tR1ethylamine (42 g) was added dropwise and the reaction mixture was stirred further for 40-60 minutes at about -20°C to -25°C. The stirred mixture was diluted with dichloromethane (300 ml) and 4-AAZ (100 g) was added at -10°C to -5°C. The reaction mixture was stirred for 60 minutes at -10°C to -5°C and the reaction temperature gradually raised to 20°C to 25°C. At this point stirR1ng was continued for 2-3
hours and the reaction mixture was cooled to 5-10°C and washed with water. The dichloromethane layer was separated and concentrated under reduced pressure to obtain a residue. The residue was dissolved in acetone (700 ml) and water (350 ml). To the resultant mixture hydrogen peroxide (30% w/v; 118 g) was added followed by dropwise addition of sodium hydroxide solution (-3.5 N) at 20°-30°C The basified mixture was stirred for 60 minutes and diluted with water (2.0 L) and the pH adjusted to 8.5-9.0 with 6 N hydrochloR1c acid when (S)-4-Phenyl-2-oxazolidinone separates from the reaction mass, which is then filtered. The pH of the filtrate so obtained was adjusted to 2.5-3.0 by treatment with 6 N hydrochloR1c acid, when a solid separates. The solid so obtained was filtered, washed with water and ethyl acetate and dR1ed to obtain the title compound. Yield = 65 g PuR1ty (by HPLC) =99% Chiral puR1ty (by HPLC) p:a =99:0.5
EXAMPLE 4 PREPARATION OF p-METHYL CARBAPENEM INTERMEDIATE
(S)-4-Phenyl-2-oxazolidinone (95 g) was dissolved in dichloromethane (700 ml) and the resultant solution cooled to about -10°C to -15°C. To the cooled solution titanium tetrachloR1de (87 g) was added dropwise and the resultant mixture was stirred for 30-40 minutes. To this stirred mixture diisopropylethylamine (56 g) was added and the reaction mixture was stirred further for 40-50 minutes. The stirred mixture was diluted with dichloromethane (300 ml) and 4-AAZ (100 g) was added at -10°C to -5°C. The reaction mixture was stirred for 60 minutes at -10°C to -5°C and the reaction temperature gradually raised to 20°C to 25°C. At this point stirR1ng was continued for 2-3 hours and the reaction mixture was washed with water. The dichloromethane layer was separated and concentrated under reduced pressure to obtain a residue. The residue was dissolved in acetone (700 ml) and water (350 ml). To the resultant mixture hydrogen peroxide (30% w/v; 118 g) was added followed by dropwise addition of sodium hydroxide solution (~3.5 N) at 20°-25°C After the completion of reaction, the reaction mixture was diluted with water (2.5 L) and the pH adjusted to 8.5. The resultant mixture was filtered when (S)-4-Phenyl-2-oxazolidinone separated. The pH of the filtrate so obtained was adjusted to 2.5-3.0 when a
solid separated, which was filtered. The solid so obtained was filtered, washed with water
and hexane and dR1ed under vacuum to obtain the title compound.
Yield = 75 g
PuR1ty (by HPLC) >= 99%
Chiral puR1ty (by HPLC) p:a =99:0.5
EXAMPLE 5 PREPARATION OF a-METHYL CARBAPENEM INTERMEDIATE
(R)-4-Phenyl-2-oxazolidinone (92 g) was dissolved in dichloromethane (500 ml) and the resultant solution cooled to about -20°C to -25°C. To the cooled solution titanium tetrachloR1de (86 g) was added dropwise and the resultant mixture was stirred for 30 minutes. To this stirred mixture diisopropylethylamine (54 g) was added and the reaction mixture was stirred further for 30 minutes. The stirred mixture was diluted with dichloromethane (300 ml) and 4-AAZ (-100 g) was added at -15°C to -10°C. The reaction mixture was stirred for 60 minutes at -10°C to -5°C and the reaction temperature gradually raised to 20°C to 25°C. At this point stirR1ng was continued for 3-4 hours and the reaction mixture was washed with water. The dichloromethane layer was separated and concentrated under reduced pressure to obtain a residue. The residue was dissolved in acetone (700 ml) and water (350 ml). To the resultant mixture hydrogen peroxide (30% w/v; 118 g) was added followed by dropwise addition of sodium hydroxide solution (~3.5 N) at 20°-25°C After the completion of reaction, the reaction mixture was diluted with water (2.0 L) and the pH adjusted to 8.5-9.0 when (R)-4-Phenyl-2-oxazolidinone separates from the reaction mass, which is then filtered. The pH of the filtrate so obtained was adjusted to 2.5-3.0 when a solid separates. The solid so obtained was filtered, washed with water and hexane and dR1ed to obtain the title compound. Yield = 70 g
PuR1ty (by HPLC) >= 99% Chiral puR1ty (by HPLC) p:a =0:100
REFERENCE EXAMPLE 1

1,1'-Carbonyldiimidazole (1.10 mmol) is added in one portion to a solution of 2-[(2S,3S)-1-[tert-butyl(dimethyl)silyl]-3-(1-hydroxyethyl)-4-oxoazetidin-2-yl]-2-methyl propanoic acid (1.0 mmol) in anhydrous tetrahydrofuran (5 ml) at room temperature. The resulting solution is stirred at room temperature for 6 hours. In a second flask, magnesium ethoxide (5 mmol) is added in one portion to a solution of the mono-p-nitrobenzyl ester of malonic acid (10 mmol) in anhydrous tetrahydrofuran (25 ml). The resulting mixture is stirred at room temperature for 1 hour, then the tetrahydrofuran is removed at the pump and the residue is tR1turated with ether to yield the magnesium salt. This magnesium salt is then added to the first reaction flask and the resulting mixture is stirred at room temperature for 18 hrs. The reaction mixture is then poured into 50 ml of ether, washed with 0.5 N hydrochloR1c acid solution (20 ml), water (20 ml), saturated aqueous sodium bicarbonate solution (20 ml), bR1ne and dR1ed over magnesium sulfate. Removal of solvents in vacuo gives crude product which is chromatographed on silica gel (ether) to yield 4-nitrobenzyl 4-[(2S,3S)-1-[tert-butyl(dimethyl)silyl]-3-(1-hydroxyethyl)-4-oxoazetidin-2-yl]-4-methyl-3-oxopentanoate.
REFERENCE EXAMPLE 2
A solution of the product of reference example 1 (1.0 mmol) in 20 ml of 9:1 (v/v) methanol-water is cooled to 0°C Concentrated hydrochloR1c acid (0.34 ml) is added and the resulting solution is stirred at 0°C for 15 minutes, then allowed to warm to room temperature. After 2.5 hours, at room temperature the reaction mixture is diluted with ethyl acetate (25 ml), washed with water (10 ml) and bR1ne, dR1ed over magnesium sulfate and concentrated in vacuo to yield 4-nitrobenzyl 4-[(2S,3S)-3-(1-hydroxyethyl)-4-oxoazetidin-2-yl]-4-methyl-3-oxopentanoate.
REFERENCE EXAMPLE 3
TR1ethylamine (263 mg) is added by syR1nge to a mixture of the product of reference example 2 (253 mg) and p-toluenesulfonylazide (196 mg) in dry acetonitR1le (6 ml) at 0°C. When addition is complete the cooling bath is removed and the reaction mixture is stirred at room temperature for 1 hour. The mixture is then diluted with ethyl acetate (50 ml) and filtered. The filtrate is concentrated in vacuo and the residue is
chromatographed on a short silica gel column (ethyl acetate) to yield the corresponding diazo deR1vative.
REFERENCE EXAMPLE 4
A suspension of the product of reference example 3 (56.4 mg) and rhodium (II) acetate (0.1 mg) in cyclohexane (3 ml) is deoxygenated by bubbling through nitrogen for 10 minutes. The mixture is then heated to 78°C for 1 hour. DuR1ng heating the solid starting mateR1al gradually goes into solution. The mixture is then cooled, filtered to remove the catalyst, and the filtrate is concentrated in vacuo to yield 4-nitrobenzyl(5S,6S)-6-(1-hydroxyethyl)-4,4-dimethyl-3,7-dioxo-1-azabicyclo[3.2.0] heptane-2-carboxylate.
REFERENCE EXAMPLE 5 (4R,5R,6S,8R)-p-nitrobenzyl-4-methyl-6-(1 -hydroxyethyl)-1 -azabicyclo[3,2,0 ]-hept-3,7-dione-2-carboxylate (53 mg) was dissolved in 5 ml of dry acetonitR1le, and 57 mg of diisopropylethylamine and then 43 mg of diphenylchlorophosphate were added thereto. After stirR1ng for 2.5 hours, 57 mg of [2S,4S]-1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine was added to the mixture, followed by stirR1ng for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water, dR1ed over magnesium sulfate and the solvent was distilled off. The residue was puR1fied by silica gel thin layer chromatography to obtain 35 mg of (4R, 5S,6S, BR,2'S,4,S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl) pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo [3,2,0]-hept-2-ene-7-one-2-carboxylate.
(4R,5S,6S,8R,2'S,4'S)-p-nitrobenzyl-3-[4-(1-p-nitrobenzyloxycarbonyl-2-dimethyl aminecarbonyl)pyrrolidinylthio]-4-methyl-6-(1 -hydroxyethyl)-1 -azabicyclo [3,2,0]hept-2-ene-7-one-2-carboxylate (25 mg) was dissolved in a mixture of 1.9 ml of :etrahydrofuran and 0.3 ml of ethanol, and the mixture was hydrogenated in a morpholinopropanesulfonic acid buffer solution (pH=7.0, 1.9 ml) under atmospheR1c pressure of hydrogen for 3 hours at room temperature in the presence of 30 mg of 10% palladium-carbon, which had been activated in hydrogen atmosphere for 1 hour fllowed by washing with water. After filteR1ng off the catalyst, tetrahydrofuran and
ethanol were distilled off under reduced pressure, and the residual solution was washed with ethyl acetate. The aqueous layer was again distilled under reduced pressure to remove organic solvents, and the residual solution was subjected to polymer chromatography (CHP-20P) to obtain (4R,5S,6S,8R,2'S,4,S)-3-[ 4-(2-dimethylaminecarbonyl)pyrrolidinylthio]-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo [3,2,0]hept-2-ene-7-one-2-carboxylic acid from the fraction eluted with water.

WE CLAIM:

1. A diastereoselective process for preparation of 4-BAA of Formula l(a),
(Formula Removed)
or salts, esters and other active derivatives thereof, wherein R\ represents an alkyl group which may be substituted by an optionally protected hydroxyl group or halogen; R2 represents an alkyl group and P is hydrogen or suitable amino protecting group, said process comprises of, a) reacting 4S-AZ of Formula ll(a),

(Formula Removed)
FORMULA ll(a)
wherein R3 is hydrogen; substituted or unsubtituted alkyl, Ar is substituted or unsubstituted aryl and Y is oxygen or nitrogen substituted by alkyl or aryl, with a carboxylic acid derivative of Formula III,
R2CH2COX
FORMULA III wherein R2 is as described above and X is a leaving group, in the presence of a base to obtain N-acyl-4S-AZ of Formula IV(a),
R3
O
FORMULA IV(a)
wherein R2, R3, Ar and Y are as described above
b) reacting N-acyl-4S-AZ of Formula IV(a) obtained in step a) with 4-substituted
azetidinone derivative of Formula V
(Formula Removed)
FORMULA V
wherein R1 and P are as described above and L is a suitable leaving group, in the presence of a base to get a compound of Formula Vl(a),
(Formula Removed)
Formula Vl(a)
wherein R1, R2, R3, Ar, Y and P are as described above
c) hydrolyzing the reaction mixture of step b) in the presence of a base
d) isolating 4-BAA of Formula l(a) from the reaction mass thereof
2. The process according to claim 1 wherein recovered 4S-AZ of Formula ll(a),
FORMULA 11(a)
wherein R3, Ar and Y are as described therein, is employed in step (a).
3. A diastereoselective process for preparation of 4-AAA of Formula 1(b),
(Formula Removed)
Formula 1(b)
or salts, esters and other active derivatives thereof, wherein Ri represents an alkyl group which may be substituted by an optionally protected hydroxyl group or halogen; R2 represents an alkyl group and P is hydrogen or suitable amino protecting group, said process comprises of, a) reacting 4R-AZ of Formula ll(b),
(Formula Removed)
FORMULA ll(b)
wherein R3 is hydrogen; substituted or unsubtituted alkyl, Ar is substituted or unsubstituted aryl and Y is oxygen or nitrogen substituted by alkyl or aryl, with a carboxylic acid derivative of Formula III,
FORMULA III
wherein R2 is as described above and X is a leaving group, in the presence of a base to obtain N-acyl-4R-AZ of Formula IV(b),
FORMULA IV(b)
wherein R2, R3, Ar and Y are as described above
b) reacting N-acyl-4R-AZ of Formula IV(b) obtained in step a) with 4-substituted
azetidinone derivative of Formula V
(Formula Removed)
FORMULA V
wherein R1 and P are as described above and L is a suitable leaving group, in the presence of a base to get a compound of Formula Vl(b),
(Formula Removed)
Formula Vl(b)
wherein R1, R2, R3, Ar, Y and P are as described above
c) hydrolyzing the reaction mixture of step b) in the presence of a base
d) isolating 4-AAA of Formula l(b) from the reaction mass thereof
4. The process according to claim 3 wherein recovered 4R-AZ of Formula ll(b),
(Formula Removed)
FORMULA 11(b)
wherein R3, Ar and Y are as described therein, is employed in step (a).
5. The process according to claims 1, 2, 3 and 4 wherein the leaving group L in compound of Formula V is selected from the group comprising of substituted or unsubtituted lower alkylcarbonyloxy; substituted or unsubtituted arylcarbonyloxy; lower alkylsulfonyl; arylsulfonyl; lower alkylsulfonyloxy; arylsulfonyloxy; halogen; lower alkylthio; arylthio.
6. The process according to claims 1,2,3 and 4 wherein the base used in steps a), b) and c) is selected from the group comprising of alkali metal amides, hydrides, hydroxides, metal alkyls, tertiary amines and bicyclic amines.
7. The process according to claims 1, 2, 3 and 4 wherein step b) is carried out in the presence of a Lewis acid of the formula M(Hal)a(Z)b wherein M represents a metal ion, Hal represents halogen and a+b is 4.
8. 4-BAA of Formula l(a),
Formula l(a) wherein R1 represents an alkyl group, which may be substituted by an optionally protected hydroxyl group or halogen; R2 represents an alkyl group; P is hydrogen or suitable amine protecting group, having 1% or less of 4-AAA isomer of Formula l(b),
(Formula Removed)
wherein Ri, R2 and P are as described above.
9. 4-AAA of Formula l(b),
(Formula Removed)
Formula l(b) wherein Ri represents an alkyl group, which may be substituted by an optionally protected hydroxyl group or halogen; R2 represents an alkyl group; P is hydrogen or suitable amine protecting group, having 10% or less of 4-BAA isomer of Formula l(a),
(Formula Removed)
wherein Ri, R2 and P are as described above.
10. A process for preparation of penem compounds of Formula VII,
(Formula Removed)

Formula VII
wherein Ri represents an alkyl group, which may be substituted by an optionally protected hydroxyl group or halogen; R2 represents an alkyl group; Het represents a substituted or unsubstituted five, six or seven membered heterocyclic ring wherein one
or more ring carbons is replaced by N, 0 or S and G represents hydrogen, halogen, substituted or unsubsituted alkyl, acyl, substituted or unsubstituted amine, a metal ion or a removable protecting group, said process comprises of preparation of compounds of 4-BAA of Formula 1(a) or 4-AAA of Formula 1(b) according to any of claims 1, 2, 3 or