Patent SG-11201810245W-A (SG)
Title: Preparation of (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y l)-3-hydroxypyrrolidine-1-carboxamide
Inventor: REYNOLDS MARK
IPC: A61K31/5025
Filed: 2017-05-18
Abstract: INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property 11111111111111111111011111 110 11E111110 11111111110 11111111110 11111111111 Organization International Bureau (10) International Publication Number (43) International Publication Date ......0\"\" WO 2017/201241 Al 23 November 2017 (23.11.2017) WIPO I PCT (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CO7D 487/04 (2006.01) A61P 35/00 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, A61K 31/5025 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (21) International Application Number: HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, KP, KR, PCT/US2017/033257 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, (22) International Filing Date: PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, 18 May 2017 (18.05.2017) 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. (25) Filing Language: English (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, 62/338,359 18 May 2016 (18.05.2016) US UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventors; and EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicants: REYNOLDS, Mark [US/US]; 281 Tresser MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, Blvd., Stamford, Connecticut 06901 (US). EARY, Charles TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Todd [US/US]; 281 Tresser Blvd., Stamford, Connecticut KM, ML, MR, NE, SN, TD, TG). 06901 (US). SPENCER, Stacey [US/US]; 873 Stagecoach Trail, Lyons, Colorado 80540 (US). JUENGST, Derrick Published: [US/US]; 4529 Canterbury Drive, Boulder, Colorado 80301 — with international search report (Art. 2 I (3)) (US). HACHE, Bruno [US/US]; 281 Tresser Blvd., Stam- ford, Connecticut 06901 (US). JIANG, Yutong [US/US]; — = 3200 Walnut St., Boulder, Colorado 80301 (US). HAAS, = Julia [US/US]; 3200 Walnut St., Boulder, Colorado 80301 — — (US). ANDREWS, Steven W. [US/US]; 3200 Walnut St., Boulder, Colorado 80301 (US). = Agent: DORIGO, Andrea et al.; Fish & Richardson P.C., = (74) = P.O. Box 1022, Minneapolis, Minnesota 55440-1022 (US). Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, = (81) = = = (54) Title: PREPARATION OF (S)-N-(5-((R)-2-(2,5-DIFLUOROPHENYL)PYRROLIDIN-1-YL)PYRAZOLO[1,5-A]PYRIMI = DIN -3-Y L)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDE = (57) : Process for preparing (S)-N-(5-((R)-2-(2,5-d ifluorophenyl)pyrrolidin-l- yl)pyrazolo[1,5-a] pyrimidin-3-y1)-3-hydrox- F = = ypyrrolidine-l-carboxamide (formula I) or a salt thereof = OH by reacting phenyl(5-((R)-2-(2,5- difluorophenyppyrrolidin-l-y1)-3,3a- 10 N1 =F (s) \ dihydropyrazolo[1,5-a]pyrimidin-3- yl)carbamate or a similar deriva- _ (R) N -. ---- tive (formula 13) with (S)-pyrrolidin-3- of (formula 14). Process - = HN for preparing phenyl(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l- y1)-3,3a- O Formula I dihydropyrazolo[1,5-a]pyrimidin-3-yl)carbamate (formula 13) or a sim- ilar derivative by reduction of (R)-5-(2-(2,5-difluorophenyl) pyrro- 1-1 lidin-l-y1)-3-nitropyrazolo[1,5-a]pyrimidine (formula 11) to (R) -54242,5- .4 1-1 difluorophenyppyrrolidin-l-yppyrazolo[1,5-a]pyrimidin-3- amine (formu- la 12). Process for preparing (R)-2-(2,5-difluorophenyl)pyrrolidine(R) ll• -2-hydroxysuccinate (formula 10) by treating (R)-N-((R)-1-(2,5- difluo- ei ropheny1)-3-(1,3-dioxan-2-yppropyl)-2-methylpropane-2- sulfinamide (for- mula 19) with an acid and a reducing agent. (S)-N-(54(R)-2-(2,5- 0 ei difluoropheny1)-pyrrolidin-l-y1)-pyrazolo [1,5- a]pyrimidin-3-y1)-3-hydrox- IN ypyrrolidine-l-carboxamide, is a tyrosin kinase (TRK) inhibitor for trearing 1-1 e.g. cancer. 0 ei C