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WO 2016/147132 Al 22 September 2016 (22.09.2016) P O P C T

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WO 2016/147132 Al 22 September 2016 (22.09.2016) P O P C T (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2016/147132 Al 22 September 2016 (22.09.2016) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07C 227/32 (2006.01) C07D 405/04 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/IB20 16/05 14 1 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 17 March 2016 (17.03.2016) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (25) Filing Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 895/MUM/2015 18 March 2015 (18.03.2015) (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: PIRAMAL ENTERPRISES LIMITED GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, [IN/IN]; Piramal Tower, Ganpatrao Kadam Marg, Lower TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, Parel, Mumbai 400 013 (IN). TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (72) Inventors: RAJAPPA, Murali; Digwal Village, Kohir LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Mandal, Medak 502321 (IN). ROY, Arnab; Digwal Vil SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, lage, Kohir Mandal, Medak 502321 (IN). MANDAL, GW, KM, ML, MR, NE, SN, TD, TG). Amit Kumar; Plot # 18, Pharmaceutical Special Economic Zone Village Matoda, Sarkhej Bawla N H # 8A., Taluka - Declarations under Rule 4.17 : Sanand, Ahmedabad 382213 (IN). KRISHNAMURTHY, — as to the identity of the inventor (Rule 4.1 7(Ϊ)) Dhileepkumar; 1, Nirlon Complex, Off Western Express Highway, Goregaon (East), Mumbai 400063 (IN). — as to applicant's entitlement to apply for and be granted a KULKARNI, Mahesh Ramrao; Plot # 18, Pharmaceutic patent (Rule 4.1 7(H)) al Special Economic Zone Village Matoda, Sarkhej Bawla — of inventorship (Rule 4.17(iv)) N H # 8A., Taluka - Sanand, Ahmedabad 382213 (IN). CHAVAN, Kamlesh Harichandra; Plot # 18, Pharma Published: ceutical Special Economic Zone Village Matoda, Sarkhej — with international search report (Art. 21(3)) Bawla N H # 8A., Taluka - Sanand, Ahmedabad 382213 (IN). SYTHANA, Suresh Kumar; Digwal Village, Kohir — before the expiration of the time limit for amending the Mandal, Medak 502321 (IN). AAVULA, Sanjeev Kumar; claims and to be republished in the event of receipt of Digwal Village, Kohir Mandal, Medak 502321 (IN). PA- amendments (Rule 48.2(h)) TEL, Chirag Navinchandra; Plot # 18, Pharmaceutical Special Economic Zone Village Matoda, Sarkhej Bawla N H # 8A., Taluka - Sanand, Ahmedabad 382213 (IN). (54) Title: A PROCESS FOR THE PREPARATION OF DROXIDOPA (57) Abstract: The present invention provides a novel process for the preparation of droxidopa, a synthetic amino acid precursor of norepinephrine. The process is a stereoselective process for the preparation of droxidopa using asymmetric induction and thus avoids synthetic process involving chiral resolution. The present invention also provides novel intermediates of formula V and formula VI. A PROCESS FOR THE PREPARATION OF DROXIDOPA Field of the invention The present invention relates to a process for the preparation of (2S,37?)-2-amino-3-(3,4- dihydroxyphenyl)-3-hydroxypropanoic acid, which is known as Droxidopa, a synthetic amino acid precursor of norepinephrine. The present invention also relates to novel intermediates for the preparation of Droxidopa. Background of the invention Droxidopa is chemically known as (2S,37?)-2-amino-3-(3,4-dihydroxyphenyl)-3- hydroxypropanoic acid and it is structurally represented by the following formula I. It is also known as L-i/zreo-dihydroxyphenylserine. Droxidopa is available in the market as Northera® capsules with dosages of 100 mg, 200 mg and 300 mg for oral administration. Droxidopa (Formula I) Droxidopa is an orally active, synthetic norepinephrine precursor that was originally launched in 1989 in Japan by Sumitomo Dainippon Pharma for the oral treatment of frozen gait or dizziness associated with Parkinson's disease and for the treatment of orthostatic hypotension, syncope or dizziness associated with Shy-Drager syndrome and familial amyloidotic polyneuropathy. In 2011, the product was filed for approval in the U.S. and in 2014 Northera® was approved for the treatment of orthostatic dizziness, light headedness, or the "feeling that you are about to black out" in adult patients with symptomatic neurogenic orthostatic hypotension caused by primary autonomic failure, dopamine beta- hydroxylase deficiency, and non-diabetic autonomic neuropathy. Droxidopa is a synthetic amino acid analog that is directly metabolized to norepinephrine by dopadecarboxylase, which is extensively distributed throughout the body. Chirality has acquired increasing importance for the pharmaceutical industry, as evidenced by the fact that more than 80% of the drugs developed hitherto have chiral properties. The various enantiomers may develop completely different effects in the body, so that only one of two or more enantiomeric forms administered may be effective. In the case of droxidopa, the compound of formula I, it has been observed that the h-threo enantiomer is the desired isomer having desired activity. Administration of the active h-threo enantiomer of the compound of formula I, substantially free of its other isomers, would essentially enable a reduction in the dose of drug. Due to the importance of the h-threo enantiomer of the compound of formula I as an oral, synthetic norepinephrine precursor, there exists a need to develop an economical and efficient synthetic process for its production. Droxidopa is disclosed in US Patent No. 3,920,728 (hereinafter referred to as US'728 patent). The US'728 patent also provides a process for the preparation of droxidopa comprising the steps of (i) reaction of 3,4-dibenzyloxybenzaldehyde with glycine, followed by treatment with sodium acetate trihydrate and diethylamine to obtain racemic- i/zreo/eryi/zro-3-(3,4-dibenzyloxyphenyl)-serine; (ii) treatment of the compound obtained in step (i) with carbobenzoxy chloride to obtain racemic-threo/erythro-3-(3,4- dibenzyloxyphenyl)-N-carbobenzoxyserine; (iii) treatment of the compound obtained in step (ii) with freshly distilled dicyclohexylamine to obtain racemic-i/zreo-3-(3,4- dibenzyloxyphenyl)-N-carbobenzoxyserinedicyclohexylamine salt, which on treatment with HC1 gas in the presence of ethyl acetate yields racemic-threo-3-(3,4- dibenzyloxyphenyl)-N-carbobenzoxyserine; (iv) treatment of the compound obtained in step (iii) with (+)-ephedrine to yield (+)-ephedrine salt of h-threo-3-(3,4- dibenzyloxyphenyl)-N-carbobenzoxyserine; (v) hydrolysis of the compound obtained in step (iv) to yield L-i/zreo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine and (vi) reduction of the compound obtained in step (v) over Pd/C to yield h-threo-3-(3,4- dibenzyloxyphenyl)-serine. The process disclosed in US'728 patent is an elaborate and tedious process for commercial manufacturing. Also, the chiral resolution to obtain threo/erythro isomer results into 50% loss of the undesired isomer, which affects the overall yield of the process. The US Patent No. 4,319,040 discloses a process for preparation of droxidopa comprising reaction of racemic threo-3-(3,4-dibenzyloxyphenyl)-N-carbobenzoxyserine with resolving agent of formula A, followed by decomposition using hydrochloric acid to yield (-)-3-(3,4- dibenzyloxyphenyl) -N-carbobenzoxyserine. Formula A wherein R is methyl, isopropyl or isobutyl. The US Patent No. 4,562,263 (hereinafter referred to as US'263 patent) discloses a process for preparation of droxidopa comprising optical resolution of N-phthaloyl-3-(3,4- methylenedioxyphenyl) serine using optically active amine selected from the group consisting of strychinine, cinconidine, L-norephedrine, S-2-amino-l,l-diphenyl-l-propanol and L-3-hydroxy-3-(4-nitrophenyl)-2-amino-l-propanol to yield L-N-phthaloyl-3-(3,4- methylenedioxyphenyl) serine, reacting the resulting compound with a Lewis acid selected from the group consisting of aluminium trichloride, aluminium tribromide, boron trichloride and boron tribromide to form N-phthaloyl-3-(3,4-dihydroxyphenyl)-serine; which is then deprotected by removal of phthaloyl group with hydrazine to yield L-threo- 3-(3,4-dihydroxyphenyl)-serine. The process involves use of complex agents for isomer separation, which also results in < 50 % of desired isomer. Also, the hydrazine used for the deprotection of phthaloyl group is known to be genotoxic and thus it is required to remove traces of hydrazine from the final product, droxidopa. However, the limitation of the process described in US'263 patent is that it is unable to remove traces of hydrazine. The prior art processes for the preparation of droxidopa involve a resolution method involving significant processing. The use of resolving agent renders the process costly. Partial recycling of the resolving agent is feasible but such recycling is costly as it requires additional processing and is also associated with waste generation. The undesired enantiomer cannot be recycled and is discarded. The maximum theoretical yield of the key intermediate obtained is just 50 % on a laboratory scale synthesis due to loss of half of the racemate. This yield may be further reduced due to the need for high chiral purity (> 95% enantiomeric excess).
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