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WO 2014/183211 Al 20 November 2014 (20.11.2014) WIPOIPCT (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 2014/183211 Al 20 November 2014 (20.11.2014) WIPOIPCT (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 307/32 (2006.01) C07D 493/22 (2006.01) kind of national protection available)·. AE, AG, AL, AM, C07D 307/28 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (21) International Application Number: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/CA2014/050438 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (22) International Filing Date: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, 9 May 2014 (09.05.2014) 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, (25) Filing Language: English SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (26) Publication Language: English TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 61/823,579 15 May 2013 (15.05.2013) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available)·. ARIPO (BW, GH, (71) Applicant: ALPHORA RESEARCH INC. [CA/CA]; GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 2395 Speakman Drive, Suite 2001, Mississauga, Ontario UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, L5K 1B3 (CA). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, (72) Inventors: SOUZA, Fabio E.s.; 3889 Stardust Drive, Mis­ MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, sissauga, Ontario L5M 7Z9 (CA). BEXRUD, Jason A.; TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, 13-130 MacPherson Avenue, Toronto, Ontario M5R 1W8 KM, ML, MR, NE, SN, TD, TG). (CA). ORPRECIO, Richard; 21 Redwater Drive, Eto­ bicoke, Ontario M9W 1Z5 (CA). GORIN, Boris; 2313 Published: Grand Ravine Drive, Oakville, Ontario L6H 6A8 (CA). — with international search report (Art. 21(3)) (74) Agent: RIDOUT & MAYBEE LLP; 5th Floor, 250 Uni­ versity Avenue, Toronto, Ontario M5H 3E5 (CA). (54) Title: 3-((2S,5S)-4-METHYLENE-5-(3-OXOPROPYL)TETRAHYDROFURAN-2-YL)PROPANOL DERIVATIVES, THEIR = PREPARATION AND INTERMEDIATES USEFUL THEREOF CHO Al (57) Abstract: Discloses is a process for preparation of a compound of formula 11, or a derivative thereof, wherein PG1 is an alcohol 2014/183211 protecting group. Also, disclosed are intermediates and processes for their preparation. The compound of formula 11 can be useful in the preparation ofhalinchondrin analogs. WO WO 2014/183211 PCT/CA2014/050438 - 1 - 3-((2S,5S)-4-METHYLENE-5-(3- OXOPROPYL)TETRAHYDROFURAN-2-YL)PROPANOL DERIVATIVES, THEIR PREPARATION AND INTERMEDIATES USEFUL THEREOF 5 CROSS-REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of and priority to US provisional patent application serial number 61/823,579 filed May 15, 2013, under the title 3-((2S,5S)-4-METHYLENE-5-(3-OXOPROPYL)TETRAHYDROFURAN-2- YL)PROPANOL DERIVATIVES, THEIR PREPARATION AND INTERMEDIATES 10 USEFUL THEREOF. The content of the above patent application is hereby expressly incorporated herein by reference into the detailed description hereof. FIELD [0002] This specification relates to a process for preparation of 3-((2S, 5S)-4-methylene-5-(3-oxopropyl)tetrahydrofuran-2-yl)propanol derivatives and 15 intermediates useful thereof. BACKGROUND [0003] Halichondrins have been disclosed as having anti-cancer and antimitotic activity (Chem. Rev. 2009, 109, 3044-3079, incorporated herein by reference). In particular, Halichondrin B has been reported as a potent 20 anticancer agent that was first isolated from the marine sponge Halichondria okadai (US 5,436,238; Tetrahedron Lett. 1994, 35, 9435 and WO 1993/017690 Al, all incorporated herein by reference). It was further reported that analogs of Halichondrin B bearing only macrocyclic fragment of its molecule (Cl - C30 fragment) and having a ketone function instead of ester at Cl position 25 demonstrate anticancer activity similar to Halichondrin B (Bioorg. Med. Chem. Lett., 2000, 10, 1029 and Bioorg. Med .Chem. Lett., 2004, 14, 5551). It was established that such macrocyclic fragment is responsible for induction of mitotic blocks in cancer cells via disruption of tubulin polymerization process that triggers apoptosis of cancerous cells and stops their proliferation (Cancer Res., 30 2004, 64, 5760 and Mol. Cane. Ther., 2008, 7, 2003). Eribulin mesylate, a macrocyclic Cl-keto analog of Halichondrin B, has been reported as having WO 2014/183211 PCT/CA2014/050438 - 2 - potent anticancer properties (WO 1999/065894 Al, incorporated herein by reference). Eribulin is marketed under the trade name Halaven, and it is also known as E7389, B1939 and ER-086526. Halichondrin B Eribulin mesylate WO 2014/183211 PCT/CA2014/050438 - 3 - [0004] 2,5-disubstituted (2S,5S)-3-methylene-tetrahydrofurans, such as the compound of formula 11a, can be an important building block for the synthesis of the halichondrin natural products and derivatives, as described in US Patents 6,214,865 and 5,436,238, and incorporated herein by reference. 5 lla wherein Piv is (CH3)3C-C(=O)-. [0005] The synthesis of compounds, similar to the compound of formula lla, has been described by Kishi (Pure Appl. Chem. 2003, 75, 1-17; J. Am. Chem. Soc. 2009, 131, 15642-15646; J. Am. Chem. Soc. 2009, 131, 15636­ 10 15641), Phillips (Angew. Chem., Int. Ed. 2009, 48, 2346) and Burke (Org. Lett. 2002, 4, 3411-3414,7. Org. Chem. 2003, 68, 1150-1153), all incorporated herein by reference. However, these methods can be undesirable for commercial manufacturing. For example, all these routes rely on asymmetric reactions that, despite their high degree of selectivity, can give rise to epimers, 15 which are of particular concern in cases where the intended use of the molecule is in the manufacture of an active pharmaceutical ingredient. Furthermore, many of these asymmetric reactions employ chiral ligands that are not necessarily easily commercially available, and which can be a hindrance for large scale production. 20 [0006] A number of concerns were addressed in PCT/CA2012/050897 (filed December 14, 2012, and incorporated herein by reference) that provided a route for synthesis of the compound of formula lla. However, further improvements to improve scalability of the process, such as by improving yields of one or more synthetic steps, improving overall synthetic yield or avoiding or reducing the WO 2014/183211 PCT/CA2014/050438 - 4 - number of chromatographic purifications, by providing an alternate route to the synthesis of the compound of formula 11a can be desirable. [0007] There is a need in the art for a process for preparation of 3- ((2S,5S)-4-methylene-5-(3-oxopropyl)tetrahydrofuran-2-yl)propanol (11a), and 5 its analogs (11), that can be used in the preparation of halichondrin natural products, its derivatives and analogs. In addition, there is a need in the art for a process for preparation of 3-((2S,5S)-4-methylene-5-(3- oxopropyl)tetrahydrofuran-2-yl)prop-l-yl pivaloate (11a), and its analogs (11), that can be prepared from commercially available starting material. Moreover, 10 there is a need in the art for a process for the preparation of 3-((2S,5S)-4- methylene-5-(3-oxopropyl)tetrahydrofuran-2-yl)prop-l-yl pivaloate (11a), and its analogs (11), that can avoid the use of asymmetric reactions, including chiral ligands. In addition, there is a need in the art for a process for preparation of 3- ((2S,5S)-4-methylene-5-(3-oxopropyl)tetrahydrofuran-2-yl)prop-l-yl pivaloate 15 (Ha), and its analogs (11), where the process is scalable and can lead to a product having high stereochemical purity. SUMMARY OF THE INVENTION [0008] In one aspect, the specification discloses a process for preparation of a compound of formula 11, or a derivative thereof, 20 [0009] the process comprising: [0010] reduction of the compound of formula 8, followed by protection of the resulting alcohol functional group, to form the compound of formula 9, and WO 2014/183211 PCT/CA2014/050438 - 5 - [0011] oxidation of the compound of formula 9 to form the compound of formula 11 5 9 [0012] wherein PG1 is an alcohol protecting group, and R1 is H or a hydrocarbon. [0013] In another aspect, the specification discloses a compound of 10 formula 8 [0014] wherein R1 is H or a hydrocarbon. [0015] In a further aspect, the specification discloses a compound of formula 7 WO 2014/183211 PCT/CA2014/050438 [0016] wherein R1 is H or a hydrocarbon. [0017] In still another aspect, the specification discloses a compound of formula 6, [0018] wherein R1 is H or a hydrocarbon. [0019] In a still further aspect, the specification discloses a process for the preparation of compounds of formula 6, 7 and 8. DESCRIPTION [0020] As described above, in one aspect, the specification discloses a process for preparation of a compound of formula 11, or a derivative thereof, WO 2014/183211 PCT/CA2014/050438 - 7 - [0021] the process comprising: [0022] reduction of the compound of formula 8, followed by protection of the resulting alcohol functional group, to form the compound of formula 9, and 5 [0023] oxidation of the compound of formula 9 to form the compound of formula 11 9 10 [0024] wherein PG1 is an alcohol protecting group, and R1 is H or a hydrocarbon.
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