Synthesis of azasugars and intermediates thereof

Abstract

The present invention relates to a process for the preparation of migalastat of formula (I) and intermediates useful in its synthesis. The process comprises a double reductive amination reaction of a compound of formula (VI).

Description

[0001] This invention relates to a method for preparing an intermediate that can be used to synthesize the galactosidase inhibitor migalastat. Background Technology

[0002] (2R,3S,4R,5S)-2-(hydroxymethyl)-3,4,5-trihydroxypiperidine of formula (I),

[0003]

[0004] Also known as 1,5-dideoxy-1,5-imino-D-galactitol, 1-deoxygalactonojirimycin (DGJ), or migasstat, it is a potent inhibitor of α-galactosidase and β-galactosidase, which are important enzymes in complex carbohydrate metabolism. Inhibitors of these enzymes have been investigated for the treatment of various diseases, including diabetes (US4,634,765), cancer (US5,250,545), herpes (US4,957,926), HIV, and Fabry disease (Fan, JQ et al., *Nature Medicine*, 1999, 5, 112).

[0005] Migast is representative of iminosaccharides or azasaccharides, a family of polyhydroxylated heterocycles containing a nitrogen atom within a ring. 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. first isolated nojirimycin of formula (II) from Streptomyces strain (Inuoye et al., Journal of Antibiotics, 1966, 9, 288). The following year, Paulsen et al. reported the first synthesis of 1-deoxynojirimycin of formula (III) (Paulsen et al., Chem. Ber., 1967, 100, 802).

[0006]

[0007] Since then, interest in iminosugars has increased due to the discovery of their strong inhibitory activity against glycosidases. At physiological pH, the nitrogen atom carries a positive charge, which allows for interaction with the terminal carboxylate group present at the active site of the enzyme. Furthermore, iminosugars are structurally similar to naturally occurring oxygen analogs.

[0008] However, 1-deoxygalactosinosin does not exist in nature and therefore must be prepared. Paulsen et al. (Chemical Reports 1980, 113, 2601) disclosed the first synthetic route starting from 1,6-dehydro-α-D-galactofuranose. Since then, various synthetic procedures for 1-deoxygalactosinosin using sugars or sugar analogs as starting materials have been disclosed.

[0009] Barili et al. (Tetrahedron, 1997, 53, 3407) have reported an interesting method for synthesizing galactose-configured azathoses. The authors describe the preparation of 1-deoxygalactosylnojirimycin via a double reductive amination of L-arabino-hexos-5-ulose of formula (IVa) with diphenylmethylamine (procedure 1), followed by a debenzylation step. The yield was found to be 36% in the key reaction step of the double reductive amination.

[0010]

[0011] The D-galactose isomer thus obtained is then purified by chromatography. Similarly, in the case of double-protected derivatives of formula (IVb) with different amines, the final product must also be purified by chromatography. Furthermore, the reported procedure uses NaCNBH3 as a reducing agent, in excess of NaCNBH3 relative to the compound of formula (IV), specifically 2.2 moles of reducing agent per mole of L-arabino-hex-5-ketose of formula (IVa). Important precautions must be taken when using NaCNBH3 to prevent the release of toxic and hazardous HCN. Moreover, the article does not address how to treat wastewater containing cyanide ions, which is a major problem hindering the industrial-scale applicability of this method.

[0012] Therefore, there is a need for a new method for preparing migastrol of formula (I) that overcomes the aforementioned drawbacks and allows the desired product to be obtained efficiently on an industrial scale, safely for human health and the environment, and with high yield and high purity (especially stereochemical purity).

[0013] Brief description of the attached figures and analytical methods

[0014] The crystalline form (referred to herein as Form I) of migastate hydrochloride was characterized by X-ray powder diffraction (XRPD). XRPD spectra were collected using an automated powder and liquid diffractometer, Bruker D8 Advance, equipped with a PSD LynxEye detector, under the following operating conditions: Bragg-Brentano geometry, Cu Kd filtered by nickel. The radiation is emitted and scanned at 2θ from 3 to 40°, with an angle step time of 1 second and 0.02°.

[0015] Figure 1 The XRPD spectrum of migastrol hydrochloride in crystalline form (referred to herein as form I) is shown, characterized by peaks at the following locations in 2θ (expressed in °): 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°. Summary of the Invention

[0016] The object of this invention is a method for preparing compounds of formula (V) or salts thereof.

[0017]

[0018] Where X is equal to all others, and is a hydrogen or alcohol protecting group.

[0019] R is a hydrogen, C1-C6 alkyl, or amino protecting group;

[0020] The method involves, in the presence of a reducing agent and a solvent, the dicarbonyl compound of formula (VI)

[0021]

[0022] Each X1 is equal to the others, and is an alcohol protecting group, reacting with an amine NH2-R or its salt.

[0023] The double reductive amination step, and if this is the case,

[0024] To convert a compound of formula (V) into another compound of formula (V) or a salt thereof, and / or to convert a salt of a compound of formula (V) into its free base. Detailed Implementation

[0025] The object of this invention is a method for preparing compounds of formula (V) or salts thereof.

[0026]

[0027] Where X is equal to all others, and is a hydrogen or alcohol protecting group.

[0028] R is a hydrogen, C1-C6 alkyl, or amino protecting group;

[0029] The method involves, in the presence of a reducing agent and a solvent, the dicarbonyl compound of formula (VI)

[0030]

[0031] Each X1 is equal to the others and is an alcohol protecting group, reacting with an amine of formula (VII) or its salt.

[0032] NH2-R

[0033] (VII)

[0034] Where R is defined as above

[0035] The double reductive amination step, and if this is the case,

[0036] Converting a compound of formula (V) to another compound of formula (V) or a salt thereof, and / or converting a salt of a compound of formula (V) to its free base, and if this is the case,

[0037] To isolate a single isomer from its mixture.

[0038] The alcohol protecting groups X and X1 are, for example, protecting groups known from carbohydrate chemistry, such as benzyl, allyl, acetyl, or benzoyl.

[0039] The preferred alcohol protecting group is benzyl.

[0040] C1-C6 alkyl groups, which can be straight-chain or branched, are typically C1-C4 alkyl groups, such as methyl, ethyl, propyl, isopropyl, or butyl, isobutyl, tert-butyl. C1-C6 alkyl groups may optionally be substituted with one or more substituents, which may be the same or different, preferably one to three substituents, such as halogens, particularly chlorine or fluorine.

[0041] The amino protecting group is, for example, a protecting group known from peptide chemistry, such as benzyl, diphenylmethyl, triphenylmethyl, 1-phenylethyl, benzyloxycarbonyl and tert-butyloxycarbonyl, preferably benzyl, diphenylmethyl, triphenylmethyl or 1-phenylethyl.

[0042] In the amine of formula (VII) or its salts, R is preferably benzyl, diphenylmethyl, triphenylmethyl, or 1-phenylethyl. In the case of 1-phenylethyl, the amine of formula (VII) may be optically active in the absolute configuration (S) ((1S)-1-phenylethylamine or (S)-PhEA) or (R) ((1R)-1-phenylethylamine or (R)-PhEA), or in mixtures of their stereoisomers.

[0043] The preferred amino protecting group is benzyl.

[0044] A further preferred amino protecting group is diphenylmethyl.

[0045] A further preferred amino protecting group is triphenylmethyl.

[0046] A further preferred amino protecting group is 1-phenylethyl, wherein the corresponding amine has an absolute configuration (S) or (R) or a mixture of its stereoisomers.

[0047] A further preferred amino protecting group is 1-phenylethyl, wherein the corresponding amine has an absolute configuration (S).

[0048] A further preferred amino protecting group is 1-phenylethyl, wherein the corresponding amine has an absolute configuration (R).

[0049] The reducing agent used in the reductive amination reaction can be, for example, NaCNBH3.

[0050] In another embodiment, the reducing agent used in the reductive amination reaction can be, for example, NaBH4.

[0051] In another embodiment, the reducing agent used in the reductive amination reaction may be, for example, NaBH(OAc)3.

[0052] In yet another embodiment, the reducing agent used in the reductive amination reaction may be, for example, a complex of borane and amine of formula (VIII).

[0053] BH3·NY3

[0054] (VIII),

[0055] Each substituent Y may be the same or different and may be hydrogen, an optionally substituted C1-C6 alkyl or aryl group, or two Ys together with the nitrogen atom attached thereto form a C5-C6 heterocyclic ring optionally containing an oxygen atom or an NRa group, wherein Ra is hydrogen, an amino protecting group or a C1-C4 alkyl group.

[0056] In yet another embodiment, the reducing agent used in the reductive amination reaction may be, for example, a complex of borane and pyridine of formula (IX).

[0057]

[0058] Each W substituent may be the same or different, and may be hydrogen, an optionally substituted C1-C6 alkyl group, or a halogen atom.

[0059] The preferred amine of formula (VIII) is piperidine.

[0060] A further preferred amine of formula (VIII) is morpholine.

[0061] Further preferred amines of formula (VIII), wherein the C5-C6 heterocyclic ring contains an NRa group, which is a piperazine, wherein Ra is hydrogen or a C1-C4 alkyl group, and wherein the C1-C4 alkyl group is preferably methyl, ethyl or propyl.

[0062] The aryl group can be, for example, phenyl. The phenyl group can optionally be substituted with one to three substituents, which can be the same or different and are independently selected from straight-chain or branched C1-C4 alkyl groups, which can in turn optionally be substituted with: one to three halogen atoms, typically fluorine; hydroxyl group; C1-C4 alkoxy group, such as methoxy group; halogen atom, such as bromine or chlorine group; cyano group; and nitro group.

[0063] The reducing agents of formula (VIII) or formula (IX) are commercially available.

[0064] Alternatively, the reducing agent of formula (VIII) or formula (IX) can be prepared in situ from a borane solution complexed with THF or Me2S by treatment with an amine of the corresponding formula (VIIIa) or a pyridine of the corresponding formula (IXa), wherein Y and W are as defined above.

[0065]

[0066] In a preferred aspect of the invention, the amine of formula (VIIIa) is a secondary amine, more preferably one of the Y atoms is H, and the remaining two Y atoms, together with the nitrogen atom attached to them, form a morpholine, piperidine, or piperazine ring. Preferably, the reducing agent of formula (VIII) is prepared in situ.

[0067] Further reducing agents suitable for this invention are boranes complexed with THF or Me2S. These reducing agents are commercially available or can be prepared in situ using known methods.

[0068] The reducing agents of formula (VIII) or (IX) result in extremely efficient, economical, and safe processes, and are therefore particularly advantageous at the industrial level. Similarly, the treatment of separating the product and wastewater from the reaction mixture becomes much easier compared to other known dual-reductive amination processes.

[0069] The reductive amination reaction can optionally be carried out in the presence of a solvent selected from, for example, dipolar aprotic solvents, typically dimethylformamide, dimethylacetamide, acetonitrile, or dimethyl sulfoxide; ethers, typically tetrahydrofuran, dioxane, or methyl tert-butyl ether; chlorinated solvents, typically dichloromethane; nonpolar solvents, typically toluene or hexane; esters, such as ethyl acetate, isopropyl acetate, or butyl acetate; polar protic solvents, typically C1-C4 alcohols, preferably methanol or water, or mixtures of two or more (preferably two or three) of the solvents.

[0070] Salts of compounds of formula (V) or (VII) are generally pharmaceutically acceptable salts.

[0071] Reductive amination can be performed by treating a dicarbonyl compound of formula (VI) with at least a stoichiometric amount of an amine of formula (VII) and at least 2 moles of a reducing agent of formula (VIII) or (IX) per mole of the compound of formula (VI).

[0072] Reductive amination can advantageously be carried out at a reaction temperature between about -20°C and about 40°C, preferably between about 0°C and about 40°C, more preferably at about 25°C, and generally at a pH of about 8 to about 4 in the reaction mixture.

[0073] The pH of the reaction mixture can be adjusted by adding acetic acid.

[0074] The double reductive amination step of the compound of formula (VI) may result in the formation of two diastereomers:

[0075]

[0076] Barili et al. (Tetrahedron 1997, 53, 3407) have observed the formation of two diastereomers. The authors performed double reductive amination with an unprotected dicarbonyl compound (the compound of formula (IVa)) and diphenylmethylamine and found that only the D-galactose isomer was formed, in a yield of 36%. Reductive amination with the double-protected dicarbonyl compound of formula (IVb) yielded a mixture of 70:30 D-galactose:L-arzose diastereomers in a yield of 38%. Therefore, the method starting with the double-protected compound of formula (IVb) provides imino sugars in almost the same yield as the unprotected dicarbonyl compound of formula (IVa). Furthermore, partial protection resulted in a mixture of two diastereomers that could not be separated from several elution systems by thin-layer chromatography (TLC), even with further protection of the free hydroxyl group using an acetyl protecting group.

[0077] The inventors of this invention have surprisingly discovered that the reaction of the tetraprotected benzyloxy compound of formula (VI), wherein X1 is benzyl, not only provides imino sugars in significantly higher yields (68%), but also provides higher quantities of the D-galactose isomer. Furthermore, both diastereomers can be separated by chromatography.

[0078]

[0079] Where Bn = benzyl and R = diphenylmethyl

[0080] *After acetylation of the free hydroxyl group, the resulting product can only be purified and isolated as a mixture of two diastereomers. Yield refers to the diacetylated compound.

[0081] The inventors of this invention also surprisingly discovered that the choice of reducing agent and amine has an effect on the formation of diastereomeric mixtures.

[0082] For example, the diastereomeric mixture produced by double reductive amination using benzylamine and NaCNBH3 as reducing agents has a D-galactose:L-adarose ratio of 2:1, while the diastereomeric mixture produced using boran morpholine (the reducing agent of the present invention, formula (VIII)) has a D-galactose:L-adarose ratio of 1:2.

[0083] According to the present invention, the reaction of the tetrabenzyloxy compound of formula (VI) with (1S)-1-phenylethylamine and boranemorpholine provides a diastereomeric mixture of D-galactose:L-astragose of 24:76, while the method using (1R)-1-phenylethylamine and boranemorpholine provides a diastereomeric mixture of D-galactoside:L-astragose of 80:20.

[0084] After the reaction is complete, the mixture can optionally be washed with water, and the compound of formula (V) can be extracted using methods known to those skilled in the art. For example, the compound of formula (V), optionally washed with water and extracted with an organic solvent, can be purified by crystallization or chromatography.

[0085] In a preferred embodiment, the mixture can be purified by crystallization, including separating the D-galactose and / or L-azorose isomers from the mixture.

[0086] In another preferred embodiment, the mixture can be purified by chromatography, including separating D-galactose and / or L-azolidinose isomers from the mixture.

[0087] Diasteremeric mixtures can be purified, for example, by normal-phase liquid chromatography (NPLC), such as by normal-phase rapid column chromatography, using a solvent as the eluent. Purification can be performed in isocratic or gradient elution modes.

[0088] Preferred eluents are selected from dichloromethane, ethyl acetate, hexane or acetone, more preferably a mixture of hexane and ethyl acetate, for example, in a ratio of 9:1 (v:v).

[0089] Optionally, the compound of formula (V) can be converted into its pharmaceutically acceptable salt according to known methods.

[0090] Another embodiment of the present invention is a method for preparing L-arzose isomers of compounds of formula (V) as defined above.

[0091] Another embodiment of the invention is a method for preparing a mixture of a compound of formula (V) and its L-arzose isomer as defined above.

[0092] If the alcohol protecting group is allyl, such groups can be removed by known methods, such as isomerization followed by hydrolysis or hydrogenation in the presence of Pd / C.

[0093] If the alcohol protecting group is acetyl or benzoyl, it can be removed by known methods, such as hydrolysis under acidic or alkaline conditions.

[0094] When the alcohol protecting group is benzyl, such groups can be removed by catalytic hydrogenation.

[0095] If the amino protecting group is benzyl, diphenylmethyl, phenethyl, or benzyloxycarbonyl, the protecting group can be removed by catalytic hydrogenation.

[0096] If the amino protecting group is tert-butoxycarbonyl, the protecting group can be removed by treatment with an acid such as trifluoroacetic acid or hydrochloric acid.

[0097] A compound of formula (V) (where R is an amino protecting group, specifically benzyl, diphenylmethyl, triphenylmethyl, 1-phenylethyl or benzyloxycarbonyl, and each X is an alcohol protecting group, specifically benzyl) can be converted into another compound of formula (V) (where X and R are hydrogen), namely migastartane of formula (I) or a salt thereof, by known methods, such as by catalytic hydrogenation or by removing protecting groups.

[0098] A compound of formula (V) (where R is hydrogen and each X is an alcohol protecting group, specifically benzyl) can be converted into another compound of formula (V) (where X and R are hydrogen), namely migastrol of formula (I) or its salts, by known methods, such as by catalytic hydrogenation or by removing protecting groups.

[0099] Catalytic hydrogenation can be carried out in the presence of homogeneous or heterogeneous metal catalysts, such as catalysts based on Pd, Pt, Ni, Rh, or Ru. Preferably, the catalyst is Pd-based.

[0100] In the case of heterogeneous metal catalysts, it is preferable to place the catalyst on an inert support, such as carbon, barium hydroxide, alumina, or calcium carbonate; charcoal is preferred. The concentration of the metal on the support can vary between about 1% and 30%, preferably between about 5% and 20%.

[0101] The hydrogen pressure used can vary between about 1 atm and 40 atm, preferably between about 1 atm and 10 atm.

[0102] The molar amount of the catalyst used relative to the compound of formula (V) is between about 0.1% and 10%, preferably between about 0.5% and 5%.

[0103] The reaction can be carried out in the presence of an organic solvent, such as a polar aprotic solvent, like dimethylformamide, dimethylacetamide, acetonitrile, or dimethyl sulfoxide; an acyclic or cyclic ether solvent, typically tetrahydrofuran or methyl tert-butyl ether; a chlorinated solvent, typically dichloromethane; a nonpolar aprotic solvent, such as toluene or hexane; a polar protic solvent, such as straight-chain or branched C1-C6 alcohols, specifically methanol, ethanol, isopropanol, or butanol; water; esters, such as ethyl acetate, isopropyl acetate, or butyl acetate; straight-chain or branched C3-C7 ketones, such as acetone, methyl ethyl ketone, or methyl isobutyl ketone; carboxylic acids, such as acetic acid or propionic acid; or a mixture of two or more (usually two or three) of the above solvents.

[0104] Alternatively, hydrogenation can be carried out in a solution or mixture of one, two, or more indicated organic solvents (containing inorganic acids or bases, such as hydrochloric acid or sulfuric acid, or sodium hydroxide or potassium hydroxide).

[0105] The hydrogenation reaction can be carried out at a temperature between about 0°C and the reflux temperature of the solvent or the benzyloxycarbonyl group in the solvent system, preferably between about 25°C and the reflux temperature.

[0106] Another object of the present invention is a method for preparing migastrol of formula (I) or a pharmaceutically acceptable salt thereof, comprising a compound of formula (V) obtained using the method according to the invention.

[0107] According to another aspect, the present invention provides migastrol hydrochloride in crystalline form (referred to herein as form I), characterized in that the XRPD plot has peaks at the following locations in 2θ (expressed in °): 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°.

[0108] Preparation of dicarbonyl compounds of formula (VI)

[0109]

[0110] Each of the groups X1 is identical to the others and is an alcohol protecting group, which can be oxidized by oxidation of the diol of formula (X) in the presence of an oxidizing agent and optionally a solvent.

[0111]

[0112] Each X1 is defined as above.

[0113] The oxidation reaction can be carried out by methods known to those skilled in the art, such as by using activated dimethyl sulfoxide (DMSO), chromium-based reagents (CrO3·Py2, PDC, PCC), pentavalent iodine-based oxidants (Dess-Martin periodinane, IBX), TEMPO, or NaOCl. Preferably, the oxidation reaction can be carried out using activated dimethyl sulfoxide (DMSO).

[0114] The oxidation reaction can be carried out by treating the compound of formula (X) with at least a stoichiometric amount of activated DMSO (per mole of the compound of formula (X), for example, with about 2 moles of DMSO).

[0115] DMSO can be activated by methods known to those skilled in the art, for example using activators such as oxalyl chloride (COCl)₂ at temperatures ranging from -78°C to -60°C; cyanuric chloride or trifluoroacetic anhydride at temperatures ranging from -45°C to -30°C; or Py·SO₃ or P₂O₅ at temperatures ranging from 0°C to 30°C. The molar ratio between the activator and the compound of formula (X) is typically between about 2:1 and 8:1, preferably between about 2:1 and 5:1. The reaction mixture is stirred at a temperature suitable for activating the reagent for about 10 minutes to 2 hours. Then, a base is added, and the mixture is allowed to react for a sufficient time to complete the oxidation, typically in less than 5 hours. The base can be an organic or inorganic base. Preferably, the base is an organic base, such as a tertiary amine, specifically triethylamine, diisopropylethylamine, diazabicycloundecene, or diazabicyclooctane.

[0116] The oxidation reaction can optionally be carried out in the presence of a solvent, such as a dipolar aprotic solvent, typically dimethylformamide, dimethylacetamide, acetonitrile, or DMSO; or an ether, typically tetrahydrofuran, or dioxane or methyl tert-butyl ether; a chlorinating solvent, typically dichloromethane; a nonpolar solvent, typically toluene or hexane; an ester, such as ethyl acetate, isopropyl acetate, or butyl acetate; a polar protic solvent, typically C1-C4 alcohol, preferably methanol, or water, or a mixture of two or more (preferably two or three) of the solvents; or dimethyl sulfoxide in an amount also used as a reaction solvent. Preferably, the solvent is DMSO.

[0117] The compound of formula (VI) can be isolated from the reaction mixture at the end of the reaction using methods known to those skilled in the art. The compound of formula (VI), once extracted after washing with water, is preferably used as is in a subsequent reductive amination reaction to give the compound of formula (V), and then migastrol of formula (I) or a pharmaceutically acceptable salt thereof.

[0118] Another object of the present invention is a method for preparing migastrol of formula (I) or a pharmaceutically acceptable salt thereof, comprising using a compound of formula (V) or (VI).

[0119] Compounds of formula (X) can be prepared by reducing compounds of formula (XI), as reported, for example, in *Organic Chemistry Letters*, 2007, 9, 879.

[0120]

[0121] Each X1 is as defined above. The reducing agent and optional solvent are known to those skilled in the art.

[0122] The compound of formula (XI) is a derivative of D-galactose, which is commercially available or can be prepared from galactose by methods known to those skilled in the art, for example as described in Bulletin of the Chemical Society of Japan (Bull. Chem. Soc. Jpn.) 1976, 49(9), 2639.

[0123] The following examples further illustrate the present invention.

[0124] Example 1: Synthesis of 2,3,4,6-tetra-O-benzyl-D-arabino-hexos-5-ulose of formula (VI)

[0125] Under a nitrogen atmosphere, 2.03 mL (23.8 mmol) of (COCl)₂ was dissolved in 5 mL of CH₂Cl₂, and the solution was cooled to -75 °C. Over 15 minutes, while maintaining the temperature below -60 °C, 2.12 mL (29.9 mmol) of DMSO in 5 mL of CH₂Cl₂ was added dropwise, and the reaction mixture was stirred for another 35 minutes. Then, over 15 minutes, while maintaining the temperature below -60 °C, 3.0 g (5.5 mmol) of 2,3,4,6-tetra-O-benzyl-D-galactitol of formula (X) (Organic Chemistry Communications 2007, 9, 879) was added to the mixture, and the reaction mixture was stirred for another 2 hours. Then, over 20 minutes, while maintaining the temperature below -45 °C, 7.78 mL (55.9 mmol) of triethylamine (TEA) was added dropwise. Then, the 2,3,4,6-tetra-O-benzyl-D-arabino-hex-5-ulose solution of formula (VI) is brought to room temperature and can be used in the next step without further purification.

[0126] Example 2: Synthesis of (2R,3S,4R,5S)-2-[(phenylmethoxy)methyl]-3,4,5-tris-(phenylmethoxy)-piperidine of formula (V)

[0127] At 0 °C, 55.9 mmol of an appropriate amine of formula (VII), 5 mL (87.4 mmol) of acetic acid, and 0.9 g (14.4 mmol) of NaCNBH3 were dissolved in 20 mL of methanol. A solution of 2,3,4,6-tetra-O-benzyl-D-arabino-hex-5-ketose of formula (VI) obtained as described in Example 1 was added to the above solution, and the reaction mixture was stirred at 0 °C for 1.5 hours, then allowed to reach room temperature. The mixture was then cooled back to 0 °C, and 10 mL of H2O and 10 mL of 30% NaOH were slowly added. 30 mL of CH2Cl2 was added to separate the phases, and the aqueous phase was further extracted with CH2Cl2. The combined organic phases were washed with 20 mL of 3M HCl, 30 mL of 11% NaOCl solution, 20 mL of 10% Na2S2O3 solution, 40 mL of a saturated solution of NaHCO3, and H2O (2 × 25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude reaction mixture was purified by rapid chromatography (hexane / ethyl acetate 9:1, v:v) to give a mixture of two diastereomers (D-galactose and L-azorose).

[0128] For diphenylmethylamine, the two diastereomers can be separated by rapid chromatography (hexane / ethyl acetate 9:1, v:v).

[0129]

[0130] Example 3: Comparison of the procedure of Barili et al. (Tetrahedron, 1997, 53, 3407) with the method of this invention.

[0131] The authors of this invention have applied the reaction conditions of Barili et al. (Tetrahedron 1997, 53, 3407) for the compound of formula (VI), where X1 is benzyl, using diphenylmethylamine and NaCNBH3 as reducing agents. Surprisingly, the product of formula (V) was obtained in 66% yield, significantly higher than the reported 36% for the unprotected dicarbonyl compound of formula (IVa) (where P = H). Reductive amination of the 2,6-dibenzyl-dicarbonyl group of formula (IVb) where P = Bn, followed by an acetylation step, yielded a mixture of 70:30 of 3,4-O-acetyl-N-diphenylmethylamine D-galactose and L-arzose derivatives, in 38% yield. The acetyl group was then deprotected with a methanolic solution of sodium methoxide, yielding 92%.

[0132]

[0133] Example 4: Synthesis of (2R,3S,4R,5S)-2-[(phenylmethoxy)methyl]-3,4,5-tris-(phenylmethoxy)piperidine of formula (V)

[0134] At 0 °C, an appropriate amine of formula (VII) (55.9 mmol), acetic acid (5 mL, 87.4 mmol), and boranemorpholine (1.45 g, 14.4 mmol) were dissolved in 20 mL of methanol. A solution of the compound of formula (VI) prepared as described in Example 1 was added to the mixture, which was stirred at 0 °C for 1.5 hours and then allowed to reach room temperature overnight. The mixture was then cooled to 0 °C, and H₂O (10 mL) and 30% NaOH (10 mL) were slowly added. 30 mL of CH₂Cl₂ was added to separate the phases, and the aqueous phase was extracted with CH₂Cl₂. The organic phases were combined and washed with 3 M HCl, 11% NaOCl solution, 10% Na₂S₂O₃ solution, saturated NaHCO₃ solution, and finally washed with water. The organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The crude reaction mixture was purified by rapid chromatography (hexane / ethyl acetate 9:1, v:v) to give a mixture of diastereomers with two absolute configurations, namely D-galactose and L-adarose.

[0135]

[0136] Example 5: Synthesis of migastrol of formula (I)

[0137] Under a nitrogen atmosphere, 1.95 g (2.83 mmol) of formula (V) (2R,3S,4R,5S)-1-diphenylmethyl-2-[(phenylmethoxy)methyl]-3,4,5-tris-(phenylmethoxy)-piperidine was dissolved in a mixture of 20 mL MeOH and 1 mL 6M HCl. 300 mg Pd / C (20%) was added, and the suspension was stirred at room temperature under a hydrogen atmosphere. At the end of the reaction, the suspension was filtered through a perlite plate and concentrated. The obtained solid was stirred in MeOH, filtered through a Buchner funnel, and washed with methanol. After vacuum drying at 50 °C, 429 mg of migastart hydrochloride in crystalline form (referred to herein as form I) was obtained, characterized by XRPD plots with peaks at the following locations in 2θ (expressed in °): 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 °, with a yield of 76% and a purity greater than 98%.

Claims

1. A method for preparing a compound of formula (V) or a salt thereof, Each X is identical and is either a hydrogen or an alcohol protecting group, wherein the alcohol protecting group is benzyl. R is an amino protecting group, which is selected from benzyl, diphenylmethyl and (R)-1-phenylethyl; The method involves, in the presence of a reducing agent and a solvent, the compound of formula (VI). Each X1 is identical and represents an alcohol protecting group, which is a benzyl group. With amines or their salts of formula (VII), NH2-R(VII) Where R is an amino protecting group selected from benzyl, diphenylmethyl, and (R)-1-phenylethyl. The double reductive amination reaction, wherein the reducing agent is NaCNBH3, in which case, converts the compound of formula (V) into another compound of formula (V) or a salt thereof, wherein X and R are hydrogen, and in which case, To isolate a single isomer from its mixture.

2. The method according to claim 1, wherein R is (R)-1-phenylethyl.

3. The method according to claim 2, wherein the reaction is carried out at a temperature between about -20°C and about 40°C.

4. The method according to claim 2, wherein the compound of formula (V) or its salt is further purified by crystallization or chromatography.

5. The method according to claim 2, wherein the compound of formula (VI) It is prepared by oxidizing the diol of formula (X) in the presence of an oxidizing agent. Each X1 group is defined as in claim 1.

6. The method according to claim 5, wherein the compound of formula (X) It is prepared by reducing the compound of formula (XI) in the presence of a reducing agent. Each X1 group is defined as in claim 1.

7. The method according to claim 6, comprising removing the protecting group from the compound of formula (V), wherein X is benzyl and R is benzyl or (R)-1-phenylethyl, to obtain the compound of formula (V), wherein X and R are hydrogen, thus obtaining migastrol of formula (I).

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