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WO 2019/002407 Al 03 January 2019 (03.01.2019) W !P O PCT

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WO 2019/002407 Al 03 January 2019 (03.01.2019) W !P O PCT (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 2019/002407 Al 03 January 2019 (03.01.2019) W !P O PCT (51) International Patent Classification: Near Gangotri Circle, Nikol, Ahmedabad Gujarat 382350 C07D 403/06 (2006.01) A61K 31/513 (2006.01) (IN). SAVALIYA, Bhavesh Laljibhai; At: Itali, Men- A61P 35/00 (2006.01) darda, Junagadh Gujarat 362260 (IN). KOILPILLAI, Joseph Prabahar; H-56, TNHB Phase-II, Perumalpu- (21) International Application Number: ram, Tirunelveli, Tamil Nadu 627007 (IN). AGARW- PCT/EP20 18/067322 AL, Virendra Kumar; A14, Vishal residency, Anandna- (22) International Filing Date: gar charrasta, Satellite, Ahmedabad Gujarat 380015 (IN). 27 June 2018 (27.06.2018) CHAVAN, Rahul Baburao; 525, Manisha Nivas, Nanded road, Ahmedpur, Maharashtra 4135 15 (IN). ARABIANI, (25) Filing Language: English Mohsin Razakbhai; 32A Gulzar Park Gate No. 1, Opp. Es- (26) Publication Language: English sar Petrol Pump, Sarkhej Juhapura Road, Ahmedabad Gu jarat 380055 (IN). HEDAPARA, Kalpesh Ratilal; B-205, (30) Priority Data: Shreenidhi apartment, Haridarshan road, Ahmedabad Gu 201721022621 28 June 2017 (28.06.2017) jarat 382350 (IN). KATARIYA, Lalit Keshav; D-102, 201721022621 26 June 2018 (26.06.2018) Garden Residency 2, Behind Shyam villa, Ahmedabad Gu (71) Applicant: AMNEAL PHARMACEUTICALS COM¬ jarat 380058 (IN). PATEL, Vijay Premajibhai; A-20, PANY GMBH [CH/CH]; Turmstrasse 30, 63 12 Stein- Shivalik society, Patel street, Bayad Gujarat 383335 (IN). hausen (CH). THUMMAR, Mahesh Kurajibhai; L-204, Nilkanth or chid, Sterling city, Bopal, Ahmedabad Gujarat 380058 (IN). (72) Inventors: MAHETA, Abhay Subodhbhai; F-302, Bi- BHALODIYA, Rahul Harsukhlal; 1-504, Prathna lavish, nori sonnet, , Near Govt. Tubewell,Opp., Rangsagar so Gota, Jagatpur, Ahmedabad Gujarat 382481 (IN). ciety, Bopal, Ahmedabad Gujarat 380058 (IN). KAN- ERIA, Ankur Amrutlal; 603, Mansi Residency, Opp. (74) Agent: FRKELLY; 27 Clyde Road, Dublin, D04 F838 Jain Nagar Society, Ghuma, Ahmedabad Gujarat 380058 (IE). (IN). BHESANIYA, Kapil Dhanjibhai; H-302, Sarovar-5, (54) Title: PROCESS FOR THE PREPARATION OF TIPIRACIL HYDROCHLORIDE (I) o ©o Figure 1 (57) Abstract: The present invention relates to a process for preparation of tipiracil of formula (I) or salt thereof. o [Continued on nextpage] WO 2019/002407 Al llll II II 11III II I II II 11II II II III II I II (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 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. (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, 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, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3)) — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) Process for the preparation of tipiracil hydrochloride Field of Invention The present invention relates to the novel polymorphs of tipiracil hydrochloride and process for the preparation thereof. The present invention also relates to the process for preparation of tipiracil of formula (I) or salt thereof which involves novel intermediates. Background of Invention Tipiracil is an anticancer molecule and indicated for the treatment of patients with metastatic colorectal cancer. Tipiracil is known by chemical name 5-chloro-6-[(2- iminopyrrolidin- 1-yl) methyl]pyrimidine-2,4-(lH,3H)-dione monohydrochloride or 2,4(1H,3H)- Pyrimidinedione, 5-chloro-6-[(2-imino-l-pyrrolidinyl)methyl]-, hydrochloride (1:1). Tipiracil is marketed in USA by Taiho Pharmaceutical Co., Ltd. under trade name LONSURF® which is a combination of tipiracil HC1 and trifiuridine in the form of oral tablet of EQ 6.14MG BASE; 15MG and EQ 8.19MG BASE; 20MG strength. It is represented by following structure. U.S. patent no. 5,744,475 first disclosed tipiracil HCI and process for its preparation. Reference example 1 and example 6 of the said patent disclose a method for producing a 5- chloro-6-chloromethyluracil intermediate and tipiracil HCI respectively as shown in scheme 1. Nucleosides, Nucleotides, and Nucleic Acids, 2005, Vol 24 (5-7), page 367-373, discloses process for the preparation of 6-chloromethyluracil which can be used for the preparation of tipiracil as shown in scheme 2. However, the first step in the route of the oxidation reaction use toxic selenium dioxide, which is a strong irritant. Synthetic Communications, 2002, Vol 32(6), page 851-855, provides process for the preparation of 6-chloromethyluracil starting from β-diketone as shown in Scheme 3. Various processes for the preparation of tipiracil HC1 and its intermediates were disclosed in CN103980253, CN104945384, CN1063 17028, CN104725324, CN105906573 and CN106366073. The above synthetic processes suffer from one or more drawbacks. For this reason, there is need for the development of novel methods for producing tipiracil hydrochloride. The present application covers novel processes for preparation of tipiracil of formula (I) or salt thereof involving novel intermediates. The occurrence of different solid forms is possible for some compounds. A single compound can give rise to a variety of solid forms having distinct physical properties. This variation in solid forms can be significant and can result in differences in pharmaceutical products with respect to solubility, bioavailability, stability and other properties. Because solid forms can vary in their physical properties, regulatory authorities require that efforts shall be made to identify all possible solid forms, e.g., crystalline, amorphous, solvated, etc., of new drug substances. The existence and possible number of solid forms for a given compound cannot be predicted, and there are no "standard" procedures that can be used to prepare solid forms of a substance. However, new forms of a pharmaceutically useful compound can provide an opportunity to improve the performance characteristics of pharmaceutical products. For example, in some cases, different forms of the same drug can exhibit very different solubility and dissolution rates. The discovery of new solid forms enlarges selection of materials with which formulation scientists can design a pharmaceutically acceptable dosage form of a drug with a targeted release profile or other desired characteristics. U.S. patent no. 9,527,833 discloses three crystalline form of tipiracil HCl namely Crystal I, Crystal II and Crystal III. It has been reported in the patent that Crystal II of tipiracil HCl is unstable. CN103788075, CN104744443, CN104945385, CN105859691, CN107216314 are the applications disclosing different polymorphic form of tipiracil HCl and the process for its preparation. Discovering new polymorphic forms of a pharmaceutical product may provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, dissolution rate, ease of purification. Such properties may significantly influence the processing, shelf life, and commercial acceptance of a polymorph. There remains a need to provide new polymorphic forms of Tipiracil HCl and processes for making the new polymorphic forms. Brief description of the drawings Figure 1 is an X-ray powder diffraction (XRPD) pattern of a dimethyl sulfoxide (DMSO) solvate of tipiracil HCl. Figure 2 is a differential scanning calorimetry (DSC) curve of a dimethylsulfoxide (DMSO) solvate of tipiracil HCl. Figure 3 is a thermogravimetric analysis (TGA) curve of a dimethylsulfoxide (DMSO) solvate of tipiracil HCl. Figure 4 is an X-ray powder diffraction (XRPD) pattern of a N, N-dimethylacetamide (DMAc) solvate of tipiracil HCl. Figure 5 is an X-ray powder diffraction (XRPD) pattern of a N-methyl-2-pyrrolidone (NMP) solvate of tipiracil HCl. Figure 6 is an X-ray powder diffraction (XRPD) pattern of crystalline form-A of tipiracil HCl. Figure 7 is an X-ray powder diffraction (XRPD) pattern of a Crystal II of tipiracil HCl produced as per example 14. Figure 8 is an X-ray powder diffraction (XRPD) pattern of amorphous tipiracil HCl. Figure 9 is an X-ray powder diffraction (XRPD) pattern of amorphous solid dispersion of tipiracil HCl together with polyvinylpyrrolidone (PVP). Figure 10 is an X-ray powder diffraction (XRPD) pattern of amorphous solid dispersion of tipiracil HC1 together with hydroxypropylmethylcellulose (HPMC). Summary of the Invention The present invention relates to the novel polymorphs of tipiracil hydrochloride and process for the preparation thereof. The present invention also relates to the process for preparation of tipiracil of formula (I) or salt thereof which involves novel intermediates. In first embodiment, the present invention relates to tipiracil HC1 solvate and process for the preparation thereof. In second embodiment, the present invention relates to tipiracil HC1 dimethylsulfoxide (DMSO) solvate. In third embodiment, the present invention relates to tipiracil HC1 dimethylsulfoxide (DMSO) solvate characterized by X-ray diffraction pattern having characteristic peaks at about 8.0°, 11.6°, 16.0°, 17.0°, 22.5°, 22.7°, 24.0°, 24.3°, 26.4°, 27.5°, 27.9°, 30.1°, 31.6° and 38.1 ± 0.2° 2Θ.
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