Title of Invention	AN IMPROVED SYNTHESIS OF (3R,4R)-4-ACETOXY-3-(1"R-TERT-BUTYLDIMETHYLSILYOXYETHY1] AZETIDIN-2-ONE, A KEY INTERMEDIATE FOR PENEM AND CARBAPENEM SYNTHESIS
Abstract	Abstract: The present invention relates to a novel process for stereoselective synthesis of (3R54R)-4-Acetoxy-3-[1,(R)-tert-Butyldimethylsilyloxyethyl] azetidin-2-one (3), which is a key intermediate in the preparation of Penem and Carbapenem type p-lactam antibiotics. According to the present invention the objective compound can be synthesized using the Camphorsultam as a key and recyclable chiral auxiliary.

Title of Invention

AN IMPROVED SYNTHESIS OF (3R,4R)-4-ACETOXY-3-(1"R-TERT-BUTYLDIMETHYLSILYOXYETHY1] AZETIDIN-2-ONE, A KEY INTERMEDIATE FOR PENEM AND CARBAPENEM SYNTHESIS

Abstract

Abstract: The present invention relates to a novel process for stereoselective synthesis of (3R54R)-4-Acetoxy-3-[1,(R)-tert-Butyldimethylsilyloxyethyl] azetidin-2-one (3), which is a key intermediate in the preparation of Penem and Carbapenem type p-lactam antibiotics. According to the present invention the objective compound can be synthesized using the Camphorsultam as a key and recyclable chiral auxiliary.

Full Text	Field of invention: Present invention describes the diastereoselective synthesis of AOSA using the camphorsultam as a key and recyclable chiral auxiliary. Background of the invention: (3R, 4R)-4-Acetoxy-3-[r(R)-tert-Butyldimethylsilyloxyethyl] azetidin-2-one (AOSA) is a highly versatile and important starting material used in the manufacture of many of the new-generation beta-lactams. This includes the marketed and clinical versions of the penems 1 and carbapenems 2 exemplified as ertapenem, meropenem, doripenem, faropenem etc.. AOSA 3, which is their common intermediate and is available on an industrial scale, dominates a considerable proportion of their cost of materials. Therefore, it is highly desirable to achieve an improved synthesis of 3 for development of 1 & 2 penems. Priorart shows a plethora of novel synthetic approaches for the synthesis of (3R, 4R)-4-Acetoxy-3-[l' 5(R)-tert-Butyldimethylsilyloxyethyl] azetidin-2-one (AOSA). US 4861877 by Kanegafochi Chemical Industry Co. Ltd., discloses the process for the preparation of AOSA from methyl 3-hydroxy butyrate US 5204460 by Takasago international corporation, JAPAN describes the process from (2S,3R)-2-aminomethyl3-hydroxy-butyric acid In another method as reported in Tetrahedron Lett. 1998, 39, 7779-7782., hexahydrotriazine has been used for the stereocontrolled synthesis of AOSA 3. However, this too suffers from the formation of the undesired isomer during the crucial cyclisation. The advantage of the present process is cost-effective, scalable through commercially available raw material which is recovered and recycled. Summary of the invention: The objective of the present invention is to prepare AOSA through a novel synthetic and non-infringement route using commercially available raw material Camphorsultam. Camphorsultam is recovered in the process and recycled. The following scheme I depicts the novel synthetic route for the preparation of AOSA. Camphorsultam is converted to N-acryloyl derivative followed by Baylis-Hilmann reaction to form 1,3 dioxane-4-one derivative. During this step camphorsultam is recovered in quantitative yield and recycled for the first step. 1,3 dioxane-4-one derivative is further esterified with methanol followed by silylation step. Thus formed silylated ester compound is reacted with benzylamine to form the silylbenzylamine ester followed by next step debenzylation by hydrogenolysis to form the free amino compound. Free amino group in the compound formed in the previous step is silylated to form Silylaminoester derivative which is cyclised and followed by next step acetoxylation to form the final product AOSA. Detailed Description of the invention: The following scheme I represents a novel synthesis of AOSA 3 using commercially available camphorsutlam 1. (a)acryloyl chloride, THF, CuCl, DIPEA (b) CH3CHO, DABCO, MDC,(c) BF3Et2O, MeOH (d) TBDMSCI, imidazoie, DMF(e) PhCH2NH2, MeOH (f) 20% Pd (OH)2/C, H2(8 Kg/cm2), MeOH (g) (1) HMDS, TMCS, MDC (2) t- BuMgCl, THF(h) RuCl3.3H2O, 40%CH3COOOH,*NaOAc, CH3CN. In one embodiment of the present invention, stereoselective synthesis of the (R)-3-Hydroxy-2-methylene-butyric acid methylester 5 is carried out using commercially available Camphorsultam 1 as chiral auxiliary. Thus camphorsultam 1 was reacted with acryloylchloride at about 5 to -5°C in aprotic solvents like Dichloromethane, Diethylether, Tetrahydrofuran, or acetonitrile in presence of one or combinations of catalysts selected from the group consisting of cuprous chloride, Triethylamine, diisoproylethylamine to yield the N-Acryloylcamphorsultam 2. Subsequent Baylis-Hilman reaction of 2 with acetaldehyde and l,4-diazabicyclo[2.2.2]octane (DABCO) in solvents selected from the group consisting of dichloromethane, THF for about 40 to 60hrs yielded the 1, 3-dioxane-4-one derivative 4.The crude mass obtained from this step was subjected to extraction with solvents like hexane, heptane to recover the camphorsultam 1 in 70% yield for recycle. In the next step the compound 4 was esterified in methanol using catalytic amount of borontrifluoride etherate yielded allylalcoholester 5. The product 5 was isolated and on silylation with t-Butyldimethylsilylchloride (TBDMS-C1) and imidazole in aprotic solvents selected from the group comprising N,N-dimethylformamide, THF, N,N-Dimethylacetamide, Dichloromethane resulted silylatedester 6 in quantitative yield. This was then subjected to diastereoselective Michael addition with benzyl amine in methanol as per literature described in J. Org. Chem. 1995, 60, 6515-6522 ; Tetrahedron Lett. 1988, 29, 949-952 to afford the product 7. Debenzylation of 7 with 20% Pd (OH)2 on carbon or 10% Pd/C in solvents like methanol, ethanol at ambient temperature yielded amino compound 8 which on further silylation with hexamethyldisilazine (HMDS) using catalytic amount of chlorotrimethylsilane followed by reaction with t-Butyl magnesiumchloride yielded compound 9. Compound 9 was converted to the AOSA 3 as per the experimental procedure described in US 5081239 wherein acetoxylation is carried out inpresence of anhydrous sodium acetate in acetonitrile and ruthenium trichloride trihydrate at about -5°C to 0°C and the final compound was characterized by H-NMR and specific rotation. 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. The invention is further illustrated with a few non-limiting examples Example 1: N-Acryloyl (2R)-bornane-10,2-suItam (2). To a solution of camphorsultam 1 (36.0 g, 0.167 mole) in THF (350 ml)5 was added cuprous chloride, (14.90 gm, 0.15 mole) followed by diisopropylethylamine (38.7 g, 0.30 mole) at room temperature over a time period of 15 min. A THF ( 20 ml) solution of acryloyl chloride (18.9 g, 0.209 mole) was then added drop wise to it at about -5°C over 1 hr. The reaction mixture was stirred at the same temperature for 1 hr. After completion of the reaction, the reaction was terminated by addition of saturated NaHCCO3 (300 ml) solution at 0°C followed by dilution with dichloromethane (200 ml). The organic layer was washed with IN HC1 (50 ml) followed by saturated NaHCO3 (100 ml) solution and further by brine (100 ml).The solution was dried (Na2SO4) and concentrated under vacuum. The light brown solid obtained was stirred with hexane (100 ml) at room temperature and filtered to give title compound (2) (42.2 g 94% yield). [a]D20 -94.32° (c = 1.05, CH2C12). mp 189.9-192 °C. 'H NMR (300 MHz, CDC13) 5 0.98 (s, 3H), 1.17 (s, 3H), 1.33-1.47 (m, 2H), 1.8-1.98 (m, 3H), 2.0-2.2 (m, 2H), 3.5 (ABq, 2H, J= 13.8 Hz), 3.9 (dd, 1H, J1 = 5.34 Hz, J2 = 5.31 Hz), 5.8 (d, 1H, J = 10.32 Hz) 6.5 (d, 1H, J = 16.62 Hz), 6.85 (dd, 1H, J1 = 10.32Hz, J2 = 10.32 Hz),MS m/z(M+l)270.1. Example 2: (2R, 6R)-2,6-Dimethyl-5-methylene-l,3-dioxan-4-one (4). To the solution of sultamamide 2 (50.0 g, 0.185 mole) and DABCO (10.41 g, 0.092 mole) in dichloromethane (215 ml) was added CH3CHO (175 ml, 3.12 mole) slowly at 0-5°C and stirred at the same temperature for 48 h. The reaction progress was monitored by TLC, the excess acetaldehyde by distillation at atmospheric pressure and then reaction mass was concentrated under vacuum. The crude product obtained was dissolved in diisopropylether IPE (750 ml) and washed with water (2x100 ml). The IPE layer was dried on sodium sulphate & concentrated to give gummy mass which was stirred with a mixture of heptane (70 ml) and IPE (40 ml) to extract the 1,3-dioxane-4-one 4. Finally the mass was stirred with hexane (200 ml) for 1 hr at room temperature to precipitate the camphorsultam 1 (28.1 g 70% recovery) which was filtered, dried and successfully recycled. The combined organic solvents were evaporated under diminished pressure to yield 4 (24.5 g, yellowish oil). Example 3: Methyl (3R)-hydroxy-2-methylenebutanoate (5). To the solution of crude compound 4 (24.5 g, 0.172 mole) in methanol (215 ml) was added boron trifluoride etherate (8.07 g, 0.056 mole) drop wise at 0°C in 30 min and stirred for 1 hr. The reaction was monitored by TLC and then refluxed for 24 h. Methanol was removed under vacuum and the mass was dissolved in ethyl acetate (200 ml) and washed it with cold sodium bicarbonate solution followed by brine and finally dried with sodium sulphate. Ethyl acetate was removed under vacuum and the oily mass was distilled under high vacuum to afford the title compound 5 (12.5 g), as a yellow oil. [α]D25 +9.8 (c = 0.8, CHC13) reported + 10.2 (c = 0.85 CHC13) ; 'H NMR (300 MHz, CDCI3) 5 1.4 (d, 3H5 J = 6.45 Hz), 2.7 (d, 1H, J = 5.34 Hz), 3.8 (s, 3H), 4.62 (q, 1H), 5.83 (s, 1H), 6.2 (s, 1H). MS m/z (M+l) 131.1. Example 4: Methyl (3R)-3-tert-butyldimethylsilyloxy-2-methylenebutanoate (6). To the mixture of methyl ester 5 as obtained in Example 3 (12.5 g, 0.096 mole) and imidazole (17.0 g, 0.249 mole) in DMF (40 ml) was added t-Butyldimethylsilylchloride (18.2 g, in 40 ml DMF) drop wise at 10-15°C in 30 min and stirred for 4 hr at room temperature. The reaction mass was diluted with water (200 ml) and extracted with hexane (3x100 ml) which was washed with water and dried with sodium sulfate. Hexane was removed under vacuum to afford compound 6 (23.4g) as light yellow oil. 1K NMR (300 MHz, CDCI3) 5 0.08 (s, 6H), 0.9 (s, 9H), 1.25 (d, 3H, J= 6.24 Hz), 3.76 (s, 3H), 4.7 (m, 1H), 5.96 (s, 1H), 6.2 (s, 1H). MS m/z (M-l) 243.2. Example 5: Methyl (2S, 3R)-2-[(benzyIamino)methyIJ-3-tert-butyl dimethyl silyloxybutanoate (7). The mixture of compound (6) (23.4 g, 0.095 mole) and benzyl amine (10.3 g3 0.095 mole) in methanol (190 ml) was stirred for 48 hr at room temperature. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated and diluted with ethyl acetate (300 ml) and washed with 5% acetic acid (50 ml) in cold condition followed by water, sodium bicarbonate and brine. Ethyl acetate was dried on sodium sulphate and concentrated to give compound (7) (30.7 g, 91% yield) as viscous oil after purification by column chromatography .!H NMR (300 MHz, CDC13) 5 0.08 (s, 6H), 0.85 (s, 9H), 1.15 (d, 3H, J = 6.15 Hz), 2.6 (m, 1H), 2.9 (m, 2H), 3.7 (s, 3H), 3.8 (s, 2H), 4.1 (m, 1H), 7.3 (s, 5H). MS m/z (M+l) 352.3. Example 6: Methyl (2S, 3R)-2-aminomethyl-3- tert-butyl dimethyl silyloxybutan--oate (8). To the solution of compound (7) as obtained in example 5(30.7 g, 0.087 mole) in methanol (350 ml) was charged 20% Pd(OH)2 on carbon (1.5 g) and stirred under hydrogen pressure (8.5 kg/cm2) for 4-5 h. The catalyst was filtered and the filtrate was concentrated to give amine compound (8) (22.6 g) as viscous oil. 'H NMR (300 MHz, CDCb) 5 0.1 (s, 6H), 0.85 (s, 9H), 1.2 (d, 3H, J = 6.18 Hz), 2.5 (m, 1H), 3.0 (m, 2H), 3.7 (s, 3H), 4.15 (m, 1H). MS m/z (M+l) 262.2. Example 7: (l'R, 3S)-3-(r-tert-butyldimethylsilyloxy)ethylazetidin-2-one (9). Under nitrogen atmosphere, t-Butyl chloride (33.6 g, 0.362 mole) was added drop wise to the stirred mixture of Mg turnings (7.95 g, 0.326 mole) and pinch of iodine in dry THF (300 ml) at 65-70°C in 1.0-1.5 h and further stirred at 90 °C till complete consumption of Mg for about 1.5 h. In another flask, the amine compound (8) (22.0 g, 0.084 mole) was dissolved in dichloromethane (250 ml) and hexamethyldisilazane (HMDS, 16.7 g,) was added followed by catalytic amount of TMCS (0.34 ml, 0.0013 mole) and refluxed for 3 h. Dichloromethane was distilled and the oily silylated mass was dissolved in THF (100 ML) and the solution was added to the above Grignard Reagent at room temperature in 1 hr and stirred for 30 minutes. The reaction mass was quenched with drop wise addition of saturated NH4C1 at 0-5 °C followed by ethyl acetate (200 ml) extraction. The organic layer was separated, and the aqueous layer was extracted again with ethyl acetate (100 ml). Combined ethyl acetate layer was washed with brine, dried on sodium sulphate, concentrated and purified by column chromatography afforded compound (9) (10.5 g, 54% yield) as white solid, mp 67.5°C.[a]D20 -64.9 (c = 1.02, CHC13), reported -69.8 (c - 1.02, CHC13); lH NMR (300 MHz, CDC13) 8 0.08 (s, 6H), 0.87 (s, 9H), 1.2 (d, 3H, J= 6.24 Hz), 3.2-3.25 (m, 1H), 3.26-3.32 (t, 1H, J1 = 5.1 Hz, J2 = 5.1 Hz), 3.33-3.38 (m, 1H), 4.2 (m, 1H), 5.55 (br s, 1H, -NH). MS m/z (M+l) 230.1. « Example 8: (3R, 4R)-4-Acetoxy-3-[l'(R)-tert-ButyIdimethylsiIyloxyethyl]azetidin-2-one (3). To the suspension of compound (9) (9.5 g, 0.041 mol) and anhydrous Sodium acetate (13.6 g, 0.164 mol) in acetonitrile (200 ml) was added ruthenium trichloride trihydrate (1.3 g) at about -5 to 0 °C. To this 30% peracetic acid (32 ml) was added drop wise in 3 hr, monitored by TLC. Acetonitrile was removed under vacuum at lower temperature and then product was extracted with ethyl acetate and purified by column chromatography (3) (8.5 g,. 72%) as white solid, mp 107.5-108.3 °C. IR (KBr) cm"1 3200.15, 2958.34, 2930.99, 2857.78, 1781.87, 1745.32. [a]D20 +47.5 (c = 0.98, CHC13). 'H NMR (300 MHz, CDCI3) 5 0.06 (s, 3H), 0.075 (s, 3H), 0.85 (s, 9H), 1.25 (d, 3H, J= 6.33 Hz), 3.2 (dd, 1H, J, = 3.3 Hz, J2 = 1.2 Hz), 4.2 (m, 1H), 5.8 (d, 1H, J = 1.27 Hz), 6.4 (br s, 1H, -NH). MS m/z (M+Na) 310.1. We Claim: 1. A Process for the preparation of (3R54R)-4-Acetoxy-3-[l'(R)-tert-Butyl dimethyl silyloxyethyl] azetidin-2-one (AOSA) comprising the following steps of: a. Reaction of camphorsultam with acryloylchloride followed by a reaction with DABCO and acetaldehyde to form a l,3-dioxan-4-one derivative; b. Esterification of l,3-Dioxan-4-one derivative to (R)-3-Hydroxy-2-methylene- butyric acid methylester in presence of a catalyst c. Silylation of Butyricacidmethylester followed by a reaction with benzylamine to get silylated benzylamine ester derivative d. Debenzylation and further silylation of free amino group to form silylated amino ester derivative e. Cyclization of silylated amino ester derivative to get (lR,3S)-3-(l-tert- butyldimethylsilyloxy)ethylazetidinone f. Acetoxylation of (lR?3S)-3-(l-tert-butyldimethylsilyloxy)ethylazetidinone to get AOSA 2. The process as claimed in claim la, wherein camphorsultam is reacted with acryloylchloride at about -10°C to 0°C 3. The process as claimed in claim lb, wherein l,3-Dioxan-4-one derivative is esterified with methanol in presence of a catalyst BF3 etherate 4. The process as claimed in claim lc, wherein silylation of butyric ester is carried out with TBDMSC1 in presence of imidazole 5 .The process as claimed in claim Id, wherein debenzylation is carried out with Pd(OH)2 or Pd/C followed by silylation with hexamethyldisilazane in presence of catalytic amount of chlorotrimethylsilane 6. The process as claimed in claim le, wherein cyclization is carried out in presence of tertiary butyl magnecium chloride 7. A Process for the preparation of (3R,4R)-4-Acetoxy-3-[l'(R)-tert-Butyl dimethyl silyloxyethyl] azetidin-2-one (AOSA) comprising the following steps of: a. Esterification of l,3-Dioxan-4-one derivative to (R)-3-Hydroxy-2- methylene-butyric acid methylester in presence of a catalyst b. Silylation of Butyricacidmethylester followed by a reaction with benzylamine to form silylated benzylamine ester derivative c. Debenzylation and further silylation of free amino group to form silylated amino ester derivative d. cyclization of silylated amino ester derivative to form (lR,3S)-3-(l-tert- butyldimethylsilyloxy)ethyl azetidinone e. Acetoxylation of (lR,3S)73-(i-tert-butyldimethylsilyloxy)ethyIazetidinone to form AOSA ' 8. The process as claimed in claim 7a, wherein l,3-Dioxan-4-one derivative is esterified with methanol in presence of a catalyst BF3 etherate 9. The process as claimed in claim 7b, wherein silylation of butyric ester is carried out with TBDMSC1 in presence of imidazole 10 .The process as claimed in claim 7c, wherein debenzylation is carried out with Pd(OH)2 or Pd/C followed by silylation with hexamethyldisilazane in presence of catalytic amount of chlorotrimethylsilane

Full Text

Field of invention: Present invention describes the diastereoselective synthesis of AOSA using the camphorsultam as a key and recyclable chiral auxiliary.
Background of the invention:
(3R, 4R)-4-Acetoxy-3-[r(R)-tert-Butyldimethylsilyloxyethyl] azetidin-2-one (AOSA) is a highly versatile and important starting material used in the manufacture of many of the new-generation beta-lactams. This includes the marketed and clinical versions of the penems 1 and carbapenems 2 exemplified as ertapenem, meropenem, doripenem, faropenem etc.. AOSA 3, which is their common intermediate and is available on an industrial scale, dominates a considerable proportion of their cost of materials. Therefore, it is highly desirable to achieve an improved synthesis of 3 for development of 1 & 2 penems.

Priorart shows a plethora of novel synthetic approaches for the synthesis of (3R, 4R)-4-Acetoxy-3-[l' 5(R)-tert-Butyldimethylsilyloxyethyl] azetidin-2-one (AOSA).
US 4861877 by Kanegafochi Chemical Industry Co. Ltd., discloses the process for the preparation of AOSA from methyl 3-hydroxy butyrate

US 5204460 by Takasago international corporation, JAPAN describes the process from (2S,3R)-2-aminomethyl3-hydroxy-butyric acid

In another method as reported in Tetrahedron Lett. 1998, 39, 7779-7782., hexahydrotriazine has been used for the stereocontrolled synthesis of AOSA 3. However, this too suffers from the formation of the undesired isomer during the crucial cyclisation.
The advantage of the present process is cost-effective, scalable through commercially available raw material which is recovered and recycled.
Summary of the invention: The objective of the present invention is to prepare AOSA through a novel synthetic and non-infringement route using commercially available raw material Camphorsultam. Camphorsultam is recovered in the process and recycled. The following scheme I depicts the novel synthetic route for the preparation of AOSA. Camphorsultam is converted to N-acryloyl derivative followed by Baylis-Hilmann reaction to form 1,3 dioxane-4-one derivative. During this step camphorsultam is recovered in quantitative yield and recycled for the first step. 1,3 dioxane-4-one derivative is further esterified with methanol followed by silylation step. Thus formed silylated ester compound is reacted with benzylamine to form the silylbenzylamine ester followed by next step debenzylation by hydrogenolysis to form the free amino compound. Free amino group in the compound formed in the previous step is silylated to form Silylaminoester derivative which is cyclised and followed by next step acetoxylation to form the final product AOSA.

Detailed Description of the invention: The following scheme I represents a novel synthesis of AOSA 3 using commercially available camphorsutlam 1.

(a)acryloyl chloride, THF, CuCl, DIPEA (b) CH3CHO, DABCO, MDC,(c) BF3Et2O, MeOH (d) TBDMSCI, imidazoie, DMF(e) PhCH2NH2, MeOH (f) 20% Pd (OH)2/C, H2(8 Kg/cm2), MeOH (g) (1) HMDS, TMCS, MDC (2) t- BuMgCl, THF(h) RuCl3.3H2O, 40%CH3COOOH,*NaOAc, CH3CN.
In one embodiment of the present invention, stereoselective synthesis of the (R)-3-Hydroxy-2-methylene-butyric acid methylester 5 is carried out using commercially available Camphorsultam 1 as chiral auxiliary. Thus camphorsultam 1 was reacted with acryloylchloride at about 5 to -5°C in aprotic solvents like Dichloromethane, Diethylether, Tetrahydrofuran, or acetonitrile in presence of one or combinations of catalysts selected from the group consisting of cuprous chloride, Triethylamine, diisoproylethylamine to yield the N-Acryloylcamphorsultam 2. Subsequent Baylis-Hilman reaction of 2 with acetaldehyde and l,4-diazabicyclo[2.2.2]octane (DABCO)

in solvents selected from the group consisting of dichloromethane, THF for about 40 to 60hrs yielded the 1, 3-dioxane-4-one derivative 4.The crude mass obtained from this step was subjected to extraction with solvents like hexane, heptane to recover the camphorsultam 1 in 70% yield for recycle. In the next step the compound 4 was esterified in methanol using catalytic amount of borontrifluoride etherate yielded allylalcoholester 5. The product 5 was isolated and on silylation with t-Butyldimethylsilylchloride (TBDMS-C1) and imidazole in aprotic solvents selected from the group comprising N,N-dimethylformamide, THF, N,N-Dimethylacetamide, Dichloromethane resulted silylatedester 6 in quantitative yield. This was then subjected to diastereoselective Michael addition with benzyl amine in methanol as per literature described in J. Org. Chem. 1995, 60, 6515-6522 ; Tetrahedron Lett. 1988, 29, 949-952 to afford the product 7. Debenzylation of 7 with 20% Pd (OH)2 on carbon or 10% Pd/C in solvents like methanol, ethanol at ambient temperature yielded amino compound 8 which on further silylation with hexamethyldisilazine (HMDS) using catalytic amount of chlorotrimethylsilane followed by reaction with t-Butyl magnesiumchloride yielded compound 9. Compound 9 was converted to the AOSA 3 as per the experimental procedure described in US 5081239 wherein acetoxylation is carried out inpresence of anhydrous sodium acetate in acetonitrile and ruthenium trichloride trihydrate at about -5°C to 0°C and the final compound was characterized by H-NMR and specific rotation.
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.
The invention is further illustrated with a few non-limiting examples

Example 1: N-Acryloyl (2R)-bornane-10,2-suItam (2).
To a solution of camphorsultam 1 (36.0 g, 0.167 mole) in THF (350 ml)5 was added cuprous chloride, (14.90 gm, 0.15 mole) followed by diisopropylethylamine (38.7 g, 0.30 mole) at room temperature over a time period of 15 min. A THF ( 20 ml) solution of acryloyl chloride (18.9 g, 0.209 mole) was then added drop wise to it at about -5°C over 1 hr. The reaction mixture was stirred at the same temperature for 1 hr. After completion of the reaction, the reaction was terminated by addition of saturated NaHCCO3 (300 ml) solution at 0°C followed by dilution with dichloromethane (200 ml). The organic layer was washed with IN HC1 (50 ml) followed by saturated NaHCO3 (100 ml) solution and further by brine (100 ml).The solution was dried (Na2SO4) and concentrated under vacuum. The light brown solid obtained was stirred with hexane (100 ml) at room temperature and filtered to give title compound (2) (42.2 g 94% yield). [a]D20 -94.32° (c = 1.05, CH2C12). mp 189.9-192 °C. 'H NMR (300 MHz, CDC13) 5 0.98 (s, 3H), 1.17 (s, 3H), 1.33-1.47 (m, 2H), 1.8-1.98 (m, 3H), 2.0-2.2 (m, 2H), 3.5 (ABq, 2H, J= 13.8 Hz), 3.9 (dd, 1H, J1 = 5.34 Hz, J2 = 5.31 Hz), 5.8 (d, 1H, J = 10.32 Hz) 6.5 (d, 1H, J = 16.62 Hz), 6.85 (dd, 1H, J1 = 10.32Hz, J2 = 10.32 Hz),MS m/z(M+l)270.1.
Example 2: (2R, 6R)-2,6-Dimethyl-5-methylene-l,3-dioxan-4-one (4).
To the solution of sultamamide 2 (50.0 g, 0.185 mole) and DABCO (10.41 g, 0.092 mole) in dichloromethane (215 ml) was added CH3CHO (175 ml, 3.12 mole) slowly at 0-5°C and stirred at the same temperature for 48 h. The reaction progress was monitored by TLC, the excess acetaldehyde by distillation at atmospheric pressure and then reaction mass was concentrated under vacuum. The crude product obtained was dissolved in diisopropylether IPE (750 ml) and washed with water (2x100 ml). The IPE layer was dried on sodium sulphate & concentrated to give gummy mass which was stirred with a mixture of heptane (70 ml) and IPE (40 ml) to extract the 1,3-dioxane-4-one 4. Finally the mass was stirred with hexane (200 ml) for 1 hr at room

temperature to precipitate the camphorsultam 1 (28.1 g 70% recovery) which was filtered, dried and successfully recycled. The combined organic solvents were evaporated under diminished pressure to yield 4 (24.5 g, yellowish oil).
Example 3: Methyl (3R)-hydroxy-2-methylenebutanoate (5).
To the solution of crude compound 4 (24.5 g, 0.172 mole) in methanol (215 ml) was added boron trifluoride etherate (8.07 g, 0.056 mole) drop wise at 0°C in 30 min and stirred for 1 hr. The reaction was monitored by TLC and then refluxed for 24 h. Methanol was removed under vacuum and the mass was dissolved in ethyl acetate (200 ml) and washed it with cold sodium bicarbonate solution followed by brine and finally dried with sodium sulphate. Ethyl acetate was removed under vacuum and the oily mass was distilled under high vacuum to afford the title compound 5 (12.5 g), as a yellow oil. [α]D25 +9.8 (c = 0.8, CHC13) reported + 10.2 (c = 0.85 CHC13) ; 'H NMR (300 MHz, CDCI3) 5 1.4 (d, 3H5 J = 6.45 Hz), 2.7 (d, 1H, J = 5.34 Hz), 3.8 (s, 3H), 4.62 (q, 1H), 5.83 (s, 1H), 6.2 (s, 1H). MS m/z (M+l) 131.1.
Example 4: Methyl (3R)-3-tert-butyldimethylsilyloxy-2-methylenebutanoate (6).
To the mixture of methyl ester 5 as obtained in Example 3 (12.5 g, 0.096 mole) and imidazole (17.0 g, 0.249 mole) in DMF (40 ml) was added t-Butyldimethylsilylchloride (18.2 g, in 40 ml DMF) drop wise at 10-15°C in 30 min and stirred for 4 hr at room temperature. The reaction mass was diluted with water (200 ml) and extracted with hexane (3x100 ml) which was washed with water and dried with sodium sulfate. Hexane was removed under vacuum to afford compound 6 (23.4g) as light yellow oil. 1K NMR (300 MHz, CDCI3) 5 0.08 (s, 6H), 0.9 (s, 9H), 1.25 (d, 3H, J= 6.24 Hz), 3.76 (s, 3H), 4.7 (m, 1H), 5.96 (s, 1H), 6.2 (s, 1H). MS m/z (M-l) 243.2.

Example 5: Methyl (2S, 3R)-2-[(benzyIamino)methyIJ-3-tert-butyl dimethyl silyloxybutanoate (7).
The mixture of compound (6) (23.4 g, 0.095 mole) and benzyl amine (10.3 g3 0.095 mole) in methanol (190 ml) was stirred for 48 hr at room temperature. The progress of the reaction was monitored by TLC. The reaction mixture was concentrated and diluted with ethyl acetate (300 ml) and washed with 5% acetic acid (50 ml) in cold condition followed by water, sodium bicarbonate and brine. Ethyl acetate was dried on sodium sulphate and concentrated to give compound (7) (30.7 g, 91% yield) as viscous oil after purification by column chromatography .!H NMR (300 MHz, CDC13) 5 0.08 (s, 6H), 0.85 (s, 9H), 1.15 (d, 3H, J = 6.15 Hz), 2.6 (m, 1H), 2.9 (m, 2H), 3.7 (s, 3H), 3.8 (s, 2H), 4.1 (m, 1H), 7.3 (s, 5H). MS m/z (M+l) 352.3.
Example 6: Methyl (2S, 3R)-2-aminomethyl-3- tert-butyl dimethyl silyloxybutan--oate (8).
To the solution of compound (7) as obtained in example 5(30.7 g, 0.087 mole) in methanol (350 ml) was charged 20% Pd(OH)2 on carbon (1.5 g) and stirred under hydrogen pressure (8.5 kg/cm2) for 4-5 h. The catalyst was filtered and the filtrate was concentrated to give amine compound (8) (22.6 g) as viscous oil. 'H NMR (300 MHz, CDCb) 5 0.1 (s, 6H), 0.85 (s, 9H), 1.2 (d, 3H, J = 6.18 Hz), 2.5 (m, 1H), 3.0 (m, 2H), 3.7 (s, 3H), 4.15 (m, 1H). MS m/z (M+l) 262.2.
Example 7: (l'R, 3S)-3-(r-tert-butyldimethylsilyloxy)ethylazetidin-2-one (9).
Under nitrogen atmosphere, t-Butyl chloride (33.6 g, 0.362 mole) was added drop wise to the stirred mixture of Mg turnings (7.95 g, 0.326 mole) and pinch of iodine in dry THF (300 ml) at 65-70°C in 1.0-1.5 h and further stirred at 90 °C till complete consumption of Mg for about 1.5 h. In another flask, the amine compound (8) (22.0 g, 0.084 mole) was dissolved in dichloromethane (250 ml) and hexamethyldisilazane

(HMDS, 16.7 g,) was added followed by catalytic amount of TMCS (0.34 ml, 0.0013 mole) and refluxed for 3 h. Dichloromethane was distilled and the oily silylated mass was dissolved in THF (100 ML) and the solution was added to the above Grignard Reagent at room temperature in 1 hr and stirred for 30 minutes. The reaction mass was quenched with drop wise addition of saturated NH4C1 at 0-5 °C followed by ethyl acetate (200 ml) extraction. The organic layer was separated, and the aqueous layer was extracted again with ethyl acetate (100 ml). Combined ethyl acetate layer was washed with brine, dried on sodium sulphate, concentrated and purified by column chromatography afforded compound (9) (10.5 g, 54% yield) as white solid, mp 67.5°C.[a]D20 -64.9 (c = 1.02, CHC13), reported -69.8 (c - 1.02, CHC13); lH NMR (300 MHz, CDC13) 8 0.08 (s, 6H), 0.87 (s, 9H), 1.2 (d, 3H, J= 6.24 Hz), 3.2-3.25 (m, 1H), 3.26-3.32 (t, 1H, J1 = 5.1 Hz, J2 = 5.1 Hz), 3.33-3.38 (m, 1H), 4.2 (m, 1H), 5.55 (br s, 1H, -NH). MS m/z (M+l) 230.1.
«
Example 8: (3R, 4R)-4-Acetoxy-3-[l'(R)-tert-ButyIdimethylsiIyloxyethyl]azetidin-2-one (3).
To the suspension of compound (9) (9.5 g, 0.041 mol) and anhydrous Sodium acetate (13.6 g, 0.164 mol) in acetonitrile (200 ml) was added ruthenium trichloride trihydrate (1.3 g) at about -5 to 0 °C. To this 30% peracetic acid (32 ml) was added drop wise in 3 hr, monitored by TLC. Acetonitrile was removed under vacuum at lower temperature and then product was extracted with ethyl acetate and purified by column chromatography (3) (8.5 g,. 72%) as white solid, mp 107.5-108.3 °C. IR (KBr) cm"1 3200.15, 2958.34, 2930.99, 2857.78, 1781.87, 1745.32. [a]D20 +47.5 (c = 0.98, CHC13). 'H NMR (300 MHz, CDCI3) 5 0.06 (s, 3H), 0.075 (s, 3H), 0.85 (s, 9H), 1.25 (d, 3H, J= 6.33 Hz), 3.2 (dd, 1H, J, = 3.3 Hz, J2 = 1.2 Hz), 4.2 (m, 1H), 5.8 (d, 1H, J = 1.27 Hz), 6.4 (br s, 1H, -NH). MS m/z (M+Na) 310.1.

We Claim:
1. A Process for the preparation of (3R54R)-4-Acetoxy-3-[l'(R)-tert-Butyl dimethyl
silyloxyethyl] azetidin-2-one (AOSA) comprising the following steps of:
a. Reaction of camphorsultam with acryloylchloride followed by a reaction with
DABCO and acetaldehyde to form a l,3-dioxan-4-one derivative;
b. Esterification of l,3-Dioxan-4-one derivative to (R)-3-Hydroxy-2-methylene-
butyric acid methylester in presence of a catalyst
c. Silylation of Butyricacidmethylester followed by a reaction with benzylamine to
get silylated benzylamine ester derivative
d. Debenzylation and further silylation of free amino group to form silylated
amino ester derivative
e. Cyclization of silylated amino ester derivative to get (lR,3S)-3-(l-tert-
butyldimethylsilyloxy)ethylazetidinone
f. Acetoxylation of (lR?3S)-3-(l-tert-butyldimethylsilyloxy)ethylazetidinone to
get AOSA
2. The process as claimed in claim la, wherein camphorsultam is reacted with
acryloylchloride at about -10°C to 0°C
3. The process as claimed in claim lb, wherein l,3-Dioxan-4-one derivative is
esterified with methanol in presence of a catalyst BF3 etherate
4. The process as claimed in claim lc, wherein silylation of butyric ester is carried out
with TBDMSC1 in presence of imidazole
5 .The process as claimed in claim Id, wherein debenzylation is carried out with Pd(OH)2 or Pd/C followed by silylation with hexamethyldisilazane in presence of catalytic amount of chlorotrimethylsilane

6. The process as claimed in claim le, wherein cyclization is carried out in presence of
tertiary butyl magnecium chloride
7. A Process for the preparation of (3R,4R)-4-Acetoxy-3-[l'(R)-tert-Butyl dimethyl
silyloxyethyl] azetidin-2-one (AOSA) comprising the following steps of:
a. Esterification of l,3-Dioxan-4-one derivative to (R)-3-Hydroxy-2-
methylene-butyric acid methylester in presence of a catalyst
b. Silylation of Butyricacidmethylester followed by a reaction with
benzylamine to form silylated benzylamine ester derivative
c. Debenzylation and further silylation of free amino group to form silylated
amino ester derivative
d. cyclization of silylated amino ester derivative to form (lR,3S)-3-(l-tert-
butyldimethylsilyloxy)ethyl azetidinone
e. Acetoxylation of (lR,3S)73-(i-tert-butyldimethylsilyloxy)ethyIazetidinone
to form AOSA '
8. The process as claimed in claim 7a, wherein l,3-Dioxan-4-one derivative is
esterified with methanol in presence of a catalyst BF3 etherate
9. The process as claimed in claim 7b, wherein silylation of butyric ester is carried out
with TBDMSC1 in presence of imidazole
10 .The process as claimed in claim 7c, wherein debenzylation is carried out with Pd(OH)2 or Pd/C followed by silylation with hexamethyldisilazane in presence of catalytic amount of chlorotrimethylsilane

Documents:

17-CHE-2007 FORM-1 30-11-2012.pdf

17-CHE-2007 FORM-2 30-11-2012.pdf

175-CHE-2007 AMENDED PAGES OF SPECIFICATION 30-11-2012.pdf

175-CHE-2007 CORRESPONDENCE OTHERS 30-11-2012.pdf

175-CHE-2007 FORM-13 30-11-2012.pdf

175-CHE-2007 CORRESPONDENCE OTHERS 24-07-2012.pdf

175-che-2007-abstract.pdf

175-che-2007-claims.pdf

175-che-2007-correspondnece-others.pdf

175-che-2007-description(complete).pdf

175-che-2007-form 1.pdf

175-che-2007-form 3.pdf

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Patent Number

254947

Indian Patent Application Number

175/CHE/2007

PG Journal Number

02/2013

Publication Date

11-Jan-2013

Grant Date

07-Jan-2013

Date of Filing

29-Jan-2007

Name of Patentee

MYLAN LABORATORIES LTD

Applicant Address

1-1-151/1, IV FLOOR, SAIRAM TOWERS, ALEXANDER ROAD SECUNDERABAD-500 003 INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	DR. GOPALAN BALASUBRAMANIAN	1-1-151/1, IV FLOOR, SAIRAM TOWERS, ALEXANDER ROAD SECUNDERABAD-500 003 INDIA
2	DR. RAVI DHAMJEWAR	1-1-151/1, IV FLOOR, SAIRAM TOWERS, ALEXANDER ROAD SECUNDERABAD-500 003 INDIA
3	DR. SANTOSH KUMAR SINGH	1-1-151/1, IV FLOOR, SAIRAM TOWERS, ALEXANDER ROAD SECUNDERABAD-500 003 INDIA

PCT International Classification Number

C07B61/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA