Title of Invention	PROCESS FOR THE PREPARATION OF N - [2 - [4 - (PIVALOYLOXY) PHENYLSULFONAMIDO] BENZOYL] GLYCINE SODIUM SALT TETRAHYDRATE
Abstract	The present invention relates to an efficient and scaleable synthetic process of N-[2-[4-(pivaloyloxy) phenylsulfonamido] benzoyl] glycine sodium salt tetrahydrate (sivelestat sodium).

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (Seesection l0) 1. Title of the invention: "Process for the preparation of N-[2-[4-(pivaloyloxy) phenylsulfonamido] benzoyl] glycine sodium salt tetrahydrate" 2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India. 3. The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed. Field of the Invention The present invention relates to an efficient and scaleable synthetic process of N-[2-[4- (pivaloyloxy) phenylsulfonamido] benzoyl] glycine sodium salt tetrahydrate (Sivelestat sodium). Background of the Invention Sivelestat sodium hydrate (Ono-5046, Elaspol [TM]) is an injectable selective inhibitor of human neutrophil elastase, was jointly developed by Lilly and Ono for the treatment of acute lung injury associated with systemic inflammatory response syndrome (SIRS). Treatment with this agent has been shown to improve respiratory function that facilitates the early removal of patients from mechanical ventilation, which could reduce the development of ventilator-associated pneumonia and patient stay in intensive care. A new application of elastase inhibitors has been reported (WO 2005084612) in the preparation of anti wrinkle cosmetic composition which includes sivelestat. The anti wrinkle activity is believed to be the result of effective elastase inhibition, reduced hydrolytic rate and the increased content of elastin in derma cortex by the elastase inhibitors. Sivelestat sodium hydrate is chemically known as N-[2-[4-(pivaloyloxy) phenylsulfonamido] benzoyl] glycine sodium salt tetrahydrate 1 (Fig I). Fig I: Sivelestat sodium hydrate A synthesis of sivelestat sodium has been reported by Imaki et al (US5017610 and 1 US5359121).The synthesis has been started from o-nitro benzoic acid 2. o-Nitro benzoic acid was converted to o-nitrobenzoyl chloride and treated with glycine benzyl ester 3 to get (2-amino benzoyl amino) glycine benzyl ester 5. Condensation of 4-(pivaloyloxy) benzene sulfonyl chloride 6 with (2-aminobenzoyl) glycine benzyl ester 5 in pyridine furnished N-[2-[4-(pivaloyloxy) phenylsulfonamido] benzoyl] glycine benzyl ester 7, which on hydrogenation, followed by treatment with sodium hydroxide furnished sivelestat sodium 1 (scheme I) IkA. 0"Na+ /—i .4H20 NH O or COOH N02 Scheme I: (i) Thionyl chloride, Glycine benzyl ester 3 (ii) Fe/ HCl (iii) Pivaloyloxy benzene sulfonyl chloride 6, sodium hydroxide (iv) Pd-C/ H2 gas (v) Sodium hydroxide. Wakatsuka et al (JP9040692) reported the synthesis of sivelestat sodium 1 by condensing anthranillic acid 9 with 4-(pivaloyloxy) benzene sulfonyl chloride 6 to get o-(p-pivaloyloxybenzenesulfonylamino) benzoic acid 8 which on further reaction with trimethylsilyl glycine furnished sivelestat 10 (Scheme II). S02CI NH2 6- 85 S-NH V-NH ,0 OH 10 Scheme II: (i) Sodium Hydroxide (ii) a-picoline, trimethylsilyl glycine. 2 The above two reported processes require reagents such as palladium charcoal, hydrogenation and anthranilic acid. First two of the above reagents are costly, flammable whereas, anthranilic acid comes under narcotic and psychotropic substances, making the process difficult to apply on industrial scale. Therefore, there is a need in the art to develop an alternate process for the synthesis of sivelestat sodium hydrate, with high yield and purity and also suitable to industrial scale up. Thus the present invention provides such an alternate synthetic route to the preparation of sivelestat sodium hydrate. Summary of the Invention In one preferred aspect, the invention provides a process for preparation of Sivelestat sodium hydrate as illustrated in scheme III comprising the steps of: a) Reacting isatoic anhydride 11 with glycine ethyl ester hydrochloride to get (2-aminobenzoylamino) glycine ethyl ester 12. b) Hydrolyzing (2-aminobenzoylamino) glycine ethyl ester 12 with aqueous sodium hydroxide to furnish (2-aminobenzoylamino) acetic acid 13. c) Condensing (2-aminobenzoylamino) acetic acid 13 with 4-(pivaloyloxy) benzene sulfonyl chloride to yield sivelestat 10. CCJT--CC?JU-J- o;u„ 13 0 0 0 11 12 in °^^ ^ ^0 n IV 02S' - ° - o2S^^ ° NHH ° rVHH ° 0 1 0 10 3 Scheme III: (i) Glycine ethyl ester, Triethyl amine (ii) Aq. sodium hydroxide (iii) Trimethylsilyl chloride, Pyridine, Pivaloyloxy benzene sulfonyl chloride (iv) Aqueous, sodium hydroxide. The details of one or more embodiments of the inventions 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 retro synthetic analysis carried out on sivelestat molecule identified isatoic anhydride as the key starting material. The synthesis was designed keeping in mind to eliminate the catalytic hydrogenation as well as the dissolving metal reduction reported in one of the syntheses. °-\ />-fHNH ^NH ° ^ o-( )-§-x + }~irV—V o ° ^—' 0 H2N // NH ° 0 (X=Halogen) H2N ^"NH 0 \#*;^Y' 0 0 Isatoic anhydride 11 was treated with glycine ethyl ester hydrochloride to get (2-aminobenzoylamino) glycine ethyl ester 12, which on hydrolysis with aqueous sodium hydroxide furnished (2-aminobenzoylamino) acetic acid 13. (2-aminobenzoylamino) acetic acid was treated with 4-(pivaloyloxy) benzene sulfonyl chloride 5 in presence of trimethyl silyl chloride to yield sivelestat. 5 on reaction with (2-aminobenzoylamino) acetic acid 13 will not only react with an amino group in 13, but also with the carboxyl group, because of the fairly weak nucleophilicity of the amino group leading to formation of impurities. To avoid the formation of impurities, the carboxyl group in 13 was protected as the trimethylsilyl derivative in situ and treated with pivaloyloxy benzene sulfonyl chloride to get the sivelestat in pure form (scheme III). 4 HNY° ' II0 II0 11 120^ ° C Y'^O-Na-0 1 0 13 IV 0 0 o2s 4H20 ^Y^^OH 0 10 Scheme III: (i) Glycine ethyl ester, Triethyl amine (iii) Aq. sodium hydroxide (iii) Trimethylsilyl chloride, Pyridine, Pivaloyloxy benzene sulfonyl chloride (IV) Aq. sodium hydroxide. In the foregoing section embodiments are described by way of examples to illustrate the process of invention. However, these are not intended by way of examples to illustrate the process of invention. However, these are not intended in any way to limit the scope of the present invention and several variants of these examples would be evident to persons ordinarily skilled in the art. The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention. Examples: Example 1: Preparation of N-(2-aminobenzoyl) glycine ethyl ester Isatoic anhydride (500 gm, 3.06 moles) was added to a solution of glycine ethyl ester hydrochloride (427.8 gm, 3.06 moles), triethylamine (326 gm, 3.2 moles) and acetonitrile (4.0 lits) and heated under reflux for 3 hours. The reaction mass was cooled to room temperature and filtered. The clear filtrate was concentrated under reduced pressure at 40 - 45°C. The residue was dissolved in ethyl acetate (2.0 lits) and washed with water (2 X 2.0 lits). The organic layer was dried over sodium sulfate and concentrated to 1.0 lit and n- 5 hexane (2.0 lits) was added and stirred for 30 minutes at 10 - 15°C. The solids was filtered and dried at 50 - 55°C to get the title compound. (544 gm, 79.8 %) Melting point:78-81°C. IR (KBr) (Vmaxcm1): 3436, 3355, 2985, 1735, 1639, 1577, 1539, 1450, 1404, 1377, 1265, 1218, 1164, 1029, 995, 867, 744; 'H NMR (CDC13) (d ppm): 7.43 (1H, q), 7.24 (1H, m), 6.66 (2H, m), 6.60 (1H, bs), 5.50 (2H, bs), 4.28 (2H, q), 4.19 (2H, d), 1.31 (3H, t); MS (m/z): 223 [M+l] Example 2: Preparation of N-(2-aminobenzoyl) glycine N-(2-aminobenzoyl) glycine ethyl ester (500 gm, 2.24 moles) was added to a solution of sodium hydroxide (125.0 gm, 3.09 moles) in 2.5 lits water and stirred for 30 minutes at 25 -30°C. The reaction mass was washed with 2 X 1.0 lit ethyl acetate and filtered. The reaction mass was neutralized by acetic acid (189 gm). The clear solution was distilled off to complete dryness at 50 - 55°C and 2.0 lits isopropanol was added and stirred at 0 - 5°C for 30 minutes and filtered. The solids were washed with 2 X 500 ml chilled isopropanol and dried at 50 - 55°C to get title compound. (390 gm, 89.31 %); Melting point: 164°C (decomposes); IR (KBr) (vmaxcm-l): 3413, 3328, 3282, 2981, 2349, 1720, 1643, 1527, 1400, 1303, 1245, 1157,1037,999,933,794,752; 1HNMR(DMSO-D6) (5 ppm): 12.56 (1H, bs), 8.51 (1H, t), 7.52 (1H, q), 7.15 (1H, m), 6.7 (1H, d), 6.54 (1H, m), 6.44 (2H,bs), 3.85 (2H,t) MS (m/z): 193 [M-l] Example 3: Preparation of p-pivaloyloxybenzenesulfonyl chloride Sodium salt of p-pivaloyloxybenzenesulfonic acid (prepared by the methods described in Reference Example 4 in the specification of the European Patent Publication No. 347168; 500 gm, 1.733 moles) was charged to toluene (5.0 lits) and toluene (2.5 lits) was distilled out 6 azeotropically at 110 - 115°C. The slurry was cooled to 25 - 30°C and dimethylformamide (440 ml) was added. Phosphorus oxychloride (273.7 gm, 1.73 moles) was added dropwise at 0 - 5°C in 15 minutes and the mixture stirred at 0-5°C till completion of the reaction on TLC. Charge 2.5 lits water at 0 - 5°C and stir for 15 minutes. The layers were separated and the organic layer dried over sodium sulfate and distilled off at 50-55°C. The residue was treated with hexane (500 ml) and cooled to 0-5°C for 1 hour and filtered to get the title compound. (421 gm, 85.22 %); Melting point: 83-87°C; lR(KBr)(vmax cm-'): 2981, 2939, 2318, 1751, 1589, 1458, 1369, 1107,894,844; 'H NMR (CDC13) (5 ppm): 1.37 (s, 9H), 7.34 (dd, 2H), 8.07 (dd, 2H); MS (m/z): 193 [M-l] Example 4: Preparation of N-[o-(p-pivaloyloxybenzenesulfonyl amino) benzoyl] glycine To slurry of N-(2-aminobenzoyl) glycine (500 gm, 2.5 moles), p-pivaloyloxybenzenesulfonyl chloride (712.5 gm, 2.5 moles), pyridine (612.5 gm, 7.5 moles) and methylene chloride (7.5 lits) was added trimethylsilyl chloride (365 gm, 3.25 moles) dropwise at 25 - 30°C for 10 mins. The reaction mixture was stirred at 25 - 30°C till completion of the reaction on TLC. Upon completion of the reaction, water (7.5 lits) is added drop wise at 25 - 30 °C and stirred for 15 mins. The layers were separated and aqueous portion extracted with methylene chloride (5.0 lits). The organic layers are combined and washed with water (5.0 lits). The organic layer was dried over sodium sulfate and distilled off under vacuum completely below 40°C, added ethyl acetate (2.5 lits) and stirred at 10 - 15°C for 1 hour and filtered to get title compound (775 gm, 69.99 %); Melting Point: 213-217°C; IR(KBr) ((vmaxcm'): 2977, 1747, 1720, 1693, 1519, 1454, 1334, 1103, 925, 759; *H NMR (CDCI3 + DMSO-De) (8 ppm): 1.23 (9H, s), 3.87 (2H, d), 7.01 (1H, t), 7.10 (2H, d), 7.33 (1H, t), 7.52 (1H, d), 7.64 (1H, d), 7.74 (2H, d), 8.87 (1H, t), 11.39 (1H, s); MS (m/z): 434 [M]. 7 Example 5: Preparation of N-[o-(p-pivaloyloxybenzenesulfonyl amino) benzoyl] glycine sodium hydrate N-[o-(p-pivaloyloxybenzenesulfonyl amino) benzoyl] glycine (500 gm, 1.15 moles) was dissolved with heating into THF (2.25 lits). 5N aqueous solution of NaOH (242 ml) was added at 0 - 5°C and stirred for 30 mins. The solvents were distilled off completely at 25-30°C under reduced pressure. The residue was dissolved in water (5.0 lits 1) at 35-40°C and cooled to 0-5 °C and filtered and again recrystallised from water (1.725 lits), filtered, dried under reduced pressure at 25-30°C to obtain product as white solid (461.8 gm, 75.9 %); Melting point: 104-108°C; Moisture content (Karl Fischer's method): 13.68 %. IR(KBr) ((vmaxcm'): v 3498, 3440, 2977, 2873, 1755, 1504, 1446, 1392, 1110, 941, 752; NMR (DMSO-d6)(8 ppm): 1.26 (s, 9H), 3.91 (s, 2H), 6.65 (t, IH), 7.10 (m, 3H), 7.23 (d, IH), 7.81 (m,3H), 10.12 (s,lH). MS (m/z): 434 [M]. 8 We Claim: 1. A process for the preparation of N-[o-(p-pivaloyloxybenzenesulfonyl amino) benzoyl] glycine sodium tetrahydrate of the formula 1. p"Na+ .4H20 >JH h— NH 0 0 1 2. A process for the preparation of the compound of formula 1 as claimed in claim 1, comprises a) reacting isatoic anhydride with glycine ethyl ester hydrochloride to get (2-aminobenzoylamino) glycine ethyl ester. b) hydrolyzing (2-aminobenzoylamino) glycine ethyl ester with aqueous sodium hydroxide to furnish (2-aminobenzoylamino) acetic acid. c) condensing (2-aminobenzoylamino) acetic acid with 4-(pivaloyloxy) benzene sulfonyl chloride to yield N-[o-(p-pivaloyloxybenzenesulfonyl amino) benzoyl] glycine. 3. A process for the preparation of N-[o-(p-pivaloyloxybenzenesulfonyl amino) benzoyl] as claimed in claim 2 consists of condensing (2-aminobenzoylamino) acetic acid 4-(pivaloyloxy) benzene sulfonyl chloride using silylating agents and an organic base in halogenated solvents. 4. A process for the preparation of N-[o-(p-pivaloyloxybenzenesulfonyl amino) benzoyl] as claimed in claim 2, wherein the silylating agent used is preferably trimethylsilyl chloride in the molar ratio of 1 to 4 equivalents. 5. The molar ratio of trimethylsilyl chloride as claimed in claim 4, is preferably in the range of 1.1 to 3.5 equivalents. 6. A process for the preparation of N-[o-(p-pivaloyloxybenzenesulfonyl amino) benzoyl] as claimed in claim 2, wherein the base is selected from the organic bases preferably pyridine. 7. A process for the preparation of N-[o-(p-pivaloyloxybenzenesulfonyl amino) benzoyl] as claimed in claim 2, wherein the solvent is selected from the halogenated solvents preferably dichloromethane. 9 Abstract: The present invention relates to an efficient and scaleable synthetic process of N-[2-[4-(pivaloyloxy) phenylsulfonamido] benzoyl] glycine sodium salt tetrahydrate (sivelestat sodium). Dated this 31st day of July, 2007 To 10 The Controller of Patents The patent Office, At Mumbai

Documents:

1508-mum-2007-abstract.doc

1508-mum-2007-abstract.pdf

1508-MUM-2007-CANCELLED PAGES(8-7-2011).pdf

1508-MUM-2007-CLAIMS(AMENDED)-(18-11-2010).pdf

1508-MUM-2007-CLAIMS(AMENDED)-(8-7-2011).pdf

1508-MUM-2007-CLAIMS(GRANTED)-(2-9-2011).pdf

1508-MUM-2007-CLAIMS(MARKED COPY)-(18-11-2010).pdf

1508-mum-2007-claims.doc

1508-mum-2007-claims.pdf

1508-MUM-2007-CORRESPONDENCE(28-5-2009).pdf

1508-MUM-2007-CORRESPONDENCE(3-6-2009).pdf

1508-MUM-2007-CORRESPONDENCE(30-6-2009).pdf

1508-MUM-2007-CORRESPONDENCE(8-7-2011).pdf

1508-MUM-2007-CORRESPONDENCE(IPO)-(2-9-2011).pdf

1508-mum-2007-description (complete).pdf

1508-MUM-2007-DESCRIPTION(GRANTED)-(2-9-2011).pdf

1508-mum-2007-form 13(18-11-2010).pdf

1508-mum-2007-form 18(6-8-2007).pdf

1508-MUM-2007-FORM 2(GRANTED)-(2-9-2011).pdf

1508-MUM-2007-FORM 2(TITLE PAGE)-(3-8-2007).pdf

1508-MUM-2007-FORM 2(TITLE PAGE)-(GRANTED)-(2-9-2011).pdf

1508-mum-2007-form 9(6-8-2007).pdf

1508-mum-2007-form-1.pdf

1508-mum-2007-form-2 (diagram).doc

1508-mum-2007-form-2.doc

1508-mum-2007-form-2.pdf

1508-mum-2007-form-3.pdf

1508-mum-2007-form-5.pdf

1508-MUM-2007-REPLY TO EXAMINATION REPORT(18-11-2010).pdf

1508-MUM-2007-REPLY TO HEARING(8-7-2011).pdf