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WO 2019/020362 Al 31 January 2019 (31.01.2019) W !P O PCT

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WO 2019/020362 Al 31 January 2019 (31.01.2019) 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 2019/020362 Al 31 January 2019 (31.01.2019) W !P O PCT (51) International Patent Classification: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, C07D 211/42 (2006.01) C07D 211/02 (2006.01) 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. (21) International Application Number: PCT/EP20 18/068648 (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (22) International Filing Date: GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, 10 July 2018 (10.07.2018) UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (25) Filing Language: English 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, (26) Publication Language: English MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (30) Priority Data: TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, 102017000078102 11 July 2017 ( 11.07.2017) IT KM, ML, MR, NE, SN, TD, TG). (71) Applicant: DIPHARMA FRANCIS S.R.L. [IT/IT]; Via Published: Bissone, 5, 20021 Baranzate (MI) (IT). — with international search report (Art. 21(3)) (72) Inventors: ATTOLINO, Emanuele; c/o Dipharma Fran — before the expiration of the time limit for amending the cis S.r.L, Via Bissone, 5, 20021 Baranzate (MI) (IT). SAN- claims and to be republished in the event of receipt of TILLO, Niccolo; c/o Dipharma Francis S.r.L, Via Bissone, amendments (Rule 48.2(h)) 5, 20021 Baranzate (MI) (IT). RAZZETTI, Gabriele; c/o Dipharma Francis S.r.L, Via Bissone, 5, 20021 Baranzate (MI) (IT). (74) Agent: BERTUCCIO, Silvia; Bianchetti Bracco Minoja S.r.L, Via Plinio, 63, 20129 Milano (IT). (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, (54) Title: SYNTHESIS OF AN AZASUGAR AND INTERMEDIATES THEREOF (57) Abstract: The present invention relates to a process for the preparation of migalastat of formula (I) and intermediates useful in the synthesis thereof. The process comprises the double reductive amination reaction of a compound of formula (VI). (I) o © o (VI) SYNTHESIS OF AN AZASUGAR AND INTERMEDIATES THEREOF The present invention relates to a process for the preparation of intermediates useful in the synthesis of the galactosidase inhibitor migalastat. Background of the Invention (2R,3S,4R,5S)-2-(Hydroxymethyl)-3,4,5-trihydroxypiperidine of formula (I), (I) also known as l,5-dideoxy-l,5-imino-D-galactitol, 1-deoxygalactonojirimycin (DGJ) or migalastat, is a potent inhibitor of the alpha and beta-galactosidases, which are important enzymes for the metabolism of complex carbohydrates. Inhibitors of said enzymes have been studied in the treatment of various diseases, including diabetes (U.S. 4,634,765), cancer (U.S. 5,250,545), herpes (U.S. 4,957,926), HIV or Fabry Disease (Fan, J. Q. et al. Nat. Med. 1999, 5, 112). Migalastat is a representative of iminosugars or azasugars, a family of polyhydroxylated heterocycles comprising one endocyclic nitrogen atom. The first synthesis of these compounds was reported in the early 1960s (Paulsen, H., Angew. Chem. Int. Ed. Engl. 1962, 1, 454; Jones, J. K. N . et al, Can. J. Chem. 1963, 41, 636; Hanessian, S. et al, J. Org. Chem. 1963, 28, 2604). In 1966, Inuoye et al. isolated for the first time nojirimycin of formula (II) from strains of Streptomyces (Inuoye et al. J. Antibiot. 1966, 9, 288), in the following year Paulsen et al. reported the first synthesis of 1-deoxynojirimycin of formula (III) (Paulsen et al. Chem. Ber. 1967, 100, 802). (II) (in) Since then, the interest in iminosugars has increased thanks to the discovery of their potent inhibitory activity of glycosidases. At physiological pH value, the nitrogen atom is positively charged and this allows an interaction with the terminal carboxylates present in the active site of the enzyme. In addition, iminosugars are structurally similar to the oxygen analogues present in nature. However, 1-deoxygalactonojirimycin is not present in nature and has thus to be prepared. The first synthetic route was disclosed by Paulsen et al. (Chem. Ber. 1980, 113, 2601) starting from 1,6-anhydro-a-D-galactofuranose. Since then, various synthetic procedures to 1-deoxygalactonojirimycin have been published using as starting materials sugars or analogues of sugars. An interesting approach for the synthesis of galacto-configurated azasugars has been reported by Barili et al. (Tetrahedron 1997, 53, 3407). The authors describe the preparation of 1-deoxy galactonojirimycin by double reductive amination starting from L- arabino-hexos-5-ulose of formula (IVa) (Scheme 1) with benzhydrylamine and a subsequent debenzylation step. The yield in the key reaction step of double reductive amination was found to be 36%. P=H, IVa P=Bn, IVb Scheme 1 The so obtained D-galacto-isomer was then purified by chromatography. Also in the case of the di-protected derivative of formula (IVb) with different amines, the final product had to be purified by chromatography. Moreover, the reported procedure makes use of NaCNBH3 as reducing agent, which is used in excess with respect to compound of formula (IV), in specific 2.2 moles of reducing agent per mole of L-arabino-hexos-5-ulose of formula (IVa). Important precautions have to be taken when using NaCNBH3 in order to prevent the release of toxic and dangerous HCN. Furthermore, the article does not mention how to dispose the wastewater containing cyanide ions, which is a major issue in order to make the process applicable at an industrial scale. Therefore, there is a need for a new method for the preparation of migalastat of formula (I), which overcomes the disadvantages mentioned above and which allows to obtain the desired product in an efficient manner on an industrial scale, safe for human health and the environment and in high yield and purity, in particular stereochemical purity. Brief description of the Figure and Analytical Methods Migalastat HC1 in crystalline form, herein referred to as form I, was characterized by X-ray powder diffraction (XRPD). The XRPD spectra were collected with the automatic powder and liquid diffractometer Bruker D8 Advance with a PSD LynxEye detector at the following operating conditions: Bragg-Brentano geometry, Cu Kd (λ = 1.54 A) radiation filtered with Nickel and scanning from 3 to 40° degrees with 2Θ and an angular step time of 0.02° in 1 sec. Figure 1 shows the XRPD spectrum of migalastat HC1 in crystalline form, herein referred to as form I, characterized by an XRPD pattern having peaks at (expressed in ° in 2Θ) : 12.07; 13.58; 15.81; 16.37; 17.06; 17.53; 20.59; 21.59; 21.75; 22.67; 39.95; 24.92; 26.30; 27.16; 27.67; 28.37; 30.26; 30.81; 32.74; 33.11; 33.46, 33.87 and 34.52 ± 0.2° in 2Θ. Summary of the Invention The object of the present invention is a process for the preparation of a compound of formula (V) or a salt thereof (V) wherein X, equal to each other, is hydrogen or an alcohol protecting group, R is hydrogen, Ci-C6 alkyl, or an amino protecting group; comprising the double reductive amination step of a dicarbonyl compound of formula (VI) (VI) wherein each of Xi, equal to each other, is an alcohol protecting group, with an amine NH2-R or a salt thereof in the presence of a reducing agent and a solvent and, if the case, the conversion of a compound of formula (V) into another compound of formula (V) or a salt thereof, and/or the conversion of a salt of a compound of formula (V) into its free base. Detailed description of the invention The object of the present invention is a process for the preparation of a compound of formula (V) or a salt thereof (V) wherein X, equal to each other, is hydrogen or an alcohol protecting group, R is hydrogen, Ci-C 6 alkyl, or an amino protecting group; comprising the double reductive amination step of a dicarbonyl compound of formula (VI) (VI) wherein each of Xi, equal to each other, is an alcohol protecting group, with an amine of formula (VII) or a salt thereof (VII) wherein R is as defined above, in the presence of a reducing agent and a solvent and, if the case, the conversion of a compound of formula (V) into another compound of formula (V) or a salt thereof, and/or the conversion of a salt of a compound of formula (V) into its free base, and, if the case, the separation of a single isomer from a mixture thereof. The alcohol-protecting group X and Xi are for example a protecting group known from carbohydrate chemistry, for example, benzyl, allyl, acetyl or benzoyl group. A preferred alcohol-protecting group is benzyl.
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