DESC:
Technical field of invention:

The present invention is relating to a process for the preparation of migalastat and novel intermediates thereof. The invention also comprises migalastat produced according to the method described herein and pharmaceutical compositions and uses thereof.

Background of the invention:

Migalastat is chemically known as (2R,3S,4R,5S)-2-(Hydroxymethyl)-3,4,5-trihydroxypiperidine of formula (I),

also known as l,5-dideoxy-l,5-imino-D-galactitol, 1-deoxygalactonojirimycin (DGJ).

Migalastat indicated for the treatment of Fabry disease (https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208623lbl.pdf). There are several chemical routes to migalastat disclosed in the literature. Santoyo-Gonzalez et al., Synlett 1999 593-595 describes the synthesis of migalastat from D-galactose, by a chemical route comprising eight steps including undesirable azide chemistry. A twelve-step chemical route to migalastat starting from 1,2:5,6-di-o-isopropylidene-a-D-glucofuranose is described by Legler & Pohl, Carbohydr. Res., 155 (1986) 119-129. The final step of this process involves converting galactostatin bisulfite adduct to migalastat. WO2008/045015 describes another chemical process for the preparation of migalastat.

Further, WO2019/020362 also describes process for the preparation of migalastat by double reductive amination starting from L-arabino-hexos-5-ulose with benzhydrylamine and a subsequent debenzylation step.

Problems with the existing processes to migalastat are that they are costly, require at least an eight stage process, and include potentially hazardous azidation chemistry. It would be beneficial if migalastat could be produced by a more cost effective and sustainable process.

The present invention thus provides a simple, effective and industrial feasible process for the preparation of migalastat and intermediates thereof.

Summary of the invention:

In one aspect, the present invention provides a novel process for the preparation of migalastat or pharmaceutically acceptable salts thereof.

In another aspect, the present invention provides a process for the preparation of migalastat or pharmaceutically acceptable salts thereof from novel intermediates.

In another aspect, the present invention provides a process for the preparation of migalastat or a pharmaceutically acceptable salts thereof comprising following steps:

In another aspect, the present invention provides a process of migalastat or pharmaceutically acceptable salts thereof produced according to the above methods.

In another aspect, the present invention provides a pharmaceutical composition comprising
migalastat or pharmaceutically acceptable salts thereof produced according to the above methods.

In another aspect, the present invention provides a method of treatment using migalastat or pharmaceutically acceptable salts thereof produced according to the above methods.

In another aspect, the present invention provides novel intermediate compounds of migalastat.

In another aspect, the present invention provides use of novel intermediate compounds for the preparation of migalastat or pharmaceutically acceptable salts thereof.

Description of the invention:

"Migalastat" refers to 1-deoxygalactonojirimycin (DGJ) which is (2R,3S,4R,5S)-2-(Hydroxymethyl)-3,4,5-trihydroxypiperidine. As used herein, reference to "migalastat", "1-
deoxygalactonojirimycin" or "DGJ" throughout includes both the free base and any salt forms
of the same including the hydrochloride salt unless the context indicates otherwise.

"Protecting group" refers to alcohol-protecting group and/or amino protecting group. The alcohol-protecting group selected from a protecting group known from the carbohydrate chemistry, for example, benzyl, allyl, acetyl or benzoyl group. Preferably, benzyl protecting group. The amino protecting group selected from a protecting group known from the chemistry of peptides for example benzyl, benzhydryl, triphenylmethyl, 1-phenylethyl, benzyloxycarbonyl and trt-butoxycarbonyl. Preferably benzyl, benzyloxycarbonyl and trt-butoxycarbonyl.

According to one aspect, the present invention provides a process for the preparation of migalastat or a pharmaceutical acceptable salt thereof comprising the steps of:

a) reacting galactopyranose (SM) with benzhydryl amine to afford compound of formula MGL-I;

wherein P is a alcohol-protecting group known from the carbohydrate chemistry, for example, benzyl, allyl, acetyl or benzoyl group. Preferably, benzyl protecting group.
b) reacting compound of formula MGL-I with benzyl chloroformate to afford compound of formula MGL-II-a;

c) oxidization of compound of formula MGL-II-a to afford compound of formula MGL-III-a;

d) cyclizing compound of formula MGL-III-a to afford compound of formula MGL-IV; and

e) deprotecting of product of step d) to afford migalastat or a pharmaceutical acceptable salt thereof.

The reaction of Step-(a) can be performed in the presence of reducing agent. The reducing agent may be any reducing agent suitable for use in a reductive amination including various borohydrides and borane reducing agents, such as those in Ellen W. Baxter and Allen B. Reitz, Reductive Aminations of Carbonyl Compounds with Borohydride and Borane Reducing Agents (Carbonyl Compound Reduction Aminations with Borohydride and Borane Reducing Agents), Organic Reactions, Chapter 1, pages 1-57 (Wiley, 2002), which is incorporated herein by reference in its entirety. Non-limiting classes of appropriate reducing agents include borohydrides, cyanoborohydrides, tri (C1-4 acyl) oxyhydroxides (eg, triacetoxyborohydride derivatives), 9-borobicyclo [3.3.1] nonane hydride, tri (C1-4 alkyl) borohydride), and derivatives of disopinocampteylcyanoborohydride, amino borane, borane-pyridine complexes, and alkylamine borane. Non-limiting examples of suitable reducing agents include sodium cyanoborohydride, sodium triacetoxyborohydride, cyano-9-borobicyclo hydride [3.3.1] sodium nonane, tetrabutylammonium cyanoborohydride, solid support cyanoborohydride, sodium tetramethylammonium triacetoxyborohydride, triacetoxyborohydride , lithium triethylborohydride, tri (sec-butyl) lithium borohydride, sodium disopinocampteylcyanoborohydride, catechol borane, borane tetrahydrofuran, sodium borohydride, potassium borohydride, lithium borohydride, palladium in the presence of hydrogen gas 5-ethyl-2-methylpyridine (PEMB - 5-ethyl-2-methylpyridine borane), 2-picoline borane or polymer-supported triacetoxyborohydride.

The reaction of Step-(c) can be performed in the presence of any suitable oxidizing agent known to those skilled in the art may be used. Examples of the oxidizing agent include but not limited to diacetoxy iodobenzene, di (trifluoroacetoxy) iodobenzene, dichloroiodobenzene, potassium persulfate, sodium perborate, sodium bromate, sodium iodate, sodium iodate , Urea hydrogen peroxide, tert-butyl hydroperoxide, N-methylmorpholine-N-oxide, trimethylammonium-N-oxide, sodium dichloroisocyanuric acid, iodosobenzene, N-bromosuccinimide, N (I) tris- (triphenylsulfonyl) amide, N-bromophthalimide, sodium ascorbate, sodium hypobromite, m-chloroperbenzoic acid, 2-iododecibenzoic acid, (I), copper (I) chloride, copper (I) bromide, copper (II) bromide, copper (II) chloride, Tetrapropyl ammonium perruthenate, N-chlorosuccinimide, 1,1, (1 H) -one, trimethylaluminum, aluminum triisopropoxide, dimethylsulfoxide, potassium peroxymonosulfate, nitric acid Ammonium cerium, oxygen, trichloroisocyanuric acid, chromium, iodine, chlorine, bromine, bromine monochloride, 5,5-dimethyl-1,3-dibromohydantoin, pyridinium tribromide, 4,4,6-tetrabromo-2,5-cyclohexadiene, dibromoisocyanuric acid, tribromoisocyanuric acid, N-bromoisocyanuric acid monosodium salt, N- N, N'-dibromo-4-methylbenzenesulfonamide, sodium bromate, lithium bromate, potassium bromate, tetra-n-butylammonium tribromide, trimethylphenylammonium tri Bromide, trimethylammonium tribromide, triethylammonium tribromide, polymer support phase But are not limited to, bromine, 4- (dimethylamino) pyridine tribromide, polymer bound pyridinium tribromide, bromotrichloromethane, sodium hypobromite, lithium hypobromite, potassium hypobromite, beryllium aphosphate , Magnesium hypobromite, calcium hypobromite, N, N-dibromobenzenesulfonamide, sodium ascorbic acid, lithium ascorbate, potassium ascorbate, N-bromoglutarimide, 1,3 -Dibromo-2,4-imidazolidinedione, 3-bromo-1-chloro-5,5-dimethylhydantoin, 1-bromo-5-ethyl- -Imidazolidinedione, 1,3-dibromo-5-ethyl-5-methylhydantoin, 1,3-dibromo-5-isopropyl-5-methylhydantoin and 3- Methyl-5-phenyl-imidazolidin-2,4-dione, dibromo (triphenyl) phosphorane.

The above oxidizing agent can be used in the presence of catalyst. Preferably, nitroxyl radicals 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) and / or derivatives of 2,2,6,6-tetramethylpiperidin-1-oxyl are used substituted at position 4 of the heterocycle, examples of corresponding compounds are 4-methoxy-2,2,6,6-tetramethylpiperidin-1-oxyl (4-MeO-TEMPO), 4-oxo-2,2,6,6-tetramethylpiperidin-1-oxyl (4- oxo-TEMPO), 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (4-hydroxy-TEMPO), 4-benzoyloxy-2,2,6,6-tetramethylpiperidin-1-oxyl (BnO- TEMPO), 4-acetamido-2,2,6,6-tetramethylpiperidin-1-oxyl, 4-acetamino-2,2,6,6-tetramethylpiperidin-1-oxyl (AA-TEMPO), 4-amino-2, 2,6,6-tetramethylpiperidin-1-oxyl, N, N-dimethylamino-2,2,6,6-10 tetramethylpiperidin-1-oxyl (NNDMA-TEMPO), 3,6-dihydro-2,2,6, 6-tetramethyl-1 (2H) -pyridinyl-oxyl (DH-TEMPO) or bis- (2,2,6,6-tetramethylpiperidin-1-oxyl-4-yl) sebacate.

Preferably, the oxidizing agent is trichloroisocyanuric acid in the presence of a catalyst e.g. 1,1 ',6,6'- tetramethyl piperidine-1-oxyl (TEMPO).

The reaction of Step-(d) can be performed at reductive ring closure conditions. The reductive ring closure may be conducted under any suitable reducing conditions known to those skilled in the art, for example in the presence of hydrogen gas and a catalyst such as palladium on carbon e.g. 10% palladium on carbon, in a suitable solvents such as an alcohol, ether, THF, 2-methyl THF, e.g. ethanol or methanol or preferably 2-methyl THF.

The deprotection Step-(e) can be performed according to the person skilled in the art further depends on the specific protecting group, for example, by catalytic hydrogenation. The catalytic hydrogenation can be carried out in the presence of homogeneous or heterogeneous metal catalysts, for example a catalyst based on Pd, Pt, Ni, Rh or Ru. Preferably, the catalyst is based on Pd.

In case of heterogeneous metal catalysts, the catalyst is preferably placed on an inert support, such as, for example, carbon, barium hydroxide, alumina, calcium carbonate; preferably charcoal. The concentration of the metal on the support may vary between about 1% and 30%, preferably between about 10% and 30%.

The employed hydrogen pressure may vary from about 2 kg to 8kg preferably from about 5 kg to 6 kg.

In one embodiment, the reaction products of step-(a), (b), (c) and (d) are optionally isolated.

The reactions of the processes described here can be carried out in suitable solvents that can be easily selected by a person with knowledge in the organic synthesis industry. Suitable solvents may be substantially non-reactive with the starting materials (reactors), intermediatesor products at temperatures at which the reactions are performed, for example, temperatures may vary from the freezing temperature of the solvent and the temperature of boiling of the solvent. A specific reaction can be carried out in a solvent or in a mixture of more than one solvent. Depending on the specific reaction step, suitable solvents for a specific reaction step can be selected.

Suitable solvents usually include halogenated solvents such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride, dichlorobenzene and the like.

Suitable ether solvents include: 2-methyl THF, dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol ethylene dimethyl ether triethylene glycol, anisole, t-butyl metal ether, mixtures thereof and the like.

Suitable protic solvents may include, by way of example and without limitation, water, methanol, ethanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol , 1-butanol, 2- butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3- pentanol, neo-pentolic alcohol, t-pentolic alcohol, diethylene glycol monomethyl ether , diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol.

Suitable aprotic solvents may include, by way of example and without limitation, tetrahydrofuran (THF), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), 1,3-dimethyl-3,4,5, 6-tetrahydro-2 (1H) -pyrimidinone (DMPU), 1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide, acetonitrile, sulfoxide dimethyl, propionitrile , ethyl format, methyl acetate, hexachloroacetone, acetone, ethylmethyl ketone, ethyl acetate, sulfolane, N, N-dimethylpropionamide, tetramethylurea, nitromethane, nitrobenzene.

Suitable hydrocarbon solvents include benzene, cyclohexane, pentane, hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.

In another aspect, the present invention provides following intermediate compounds of migalastat:

Wherein P is a protecting group refers to alcohol-protecting group and/or amino protecting group.
In another aspect, the present invention provides following intermediate compounds of migalastat:

or isomers thereof.

The present invention of intermediate compounds includes all possible isomers. Means that, the absolute configuration at the chiral center of any intermediate compound is (S) or (R) or a stereoisomeric mixture thereof.

In another aspect, the present invention provides use of above intermediate compounds for the preparation of migalastat or pharmaceutically acceptable salts thereof.

In another aspect, the present invention provides a process for the preparation of Migalastat comprising the steps of:
a) reacting 2,3,4,6-Tetra-O-benzyl-D- galactopyranose with benzhydryl amine to afford (2R,3S,4R,5S)-6-(benzhydrylamino)-1,3,4,5-tetrakis(benzyloxy)hexan-2-ol;
b) reacting (2R,3S,4R,5S)-6-(benzhydrylamino)-1,3,4,5-tetrakis(benzyloxy)hexan-2-ol with benzyl chloroformate to afford benzyl benzhydryl((2S,3R,4S,5R)-2,3,4,6-tetrakis(benzyloxy)-5-hydroxyhexyl)carbamate;
c) oxidization of benzyl benzhydryl((2S,3R,4S,5R)-2,3,4,6-tetrakis(benzyloxy)-5-hydroxyhexyl)carbamate to afford benzyl benzhydryl((2S,3R,4R)-2,3,4,6-tetrakis(benzyloxy)-5-oxohexyl)carbamate;
d) cyclizing benzyl benzhydryl((2S,3R,4R)-2,3,4,6-tetrakis(benzyloxy)-5-oxohexyl)carbamate to afford (2R,3S,4R,5S)-1-benzhydryl-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine and (2R,3S,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine; and
e) deprotecting of product of step d) to afford migalastat or a pharmaceutical acceptable salt thereof.

In another aspect, the present invention provides a pharmaceutical composition comprising migalastat produced according to the method of the invention, e.g. for oral administration, by mixing with a pharmaceutically acceptable carrier.

The invention is further illustrated by following examples, which should not be construed as limiting to the scope of invention.

Example 1:
Step-1: Preparation of benzyl benzhydryl((2S,3R,4R)-2,3,4,6-tetrakis(benzyloxy)-5-oxohexyl)carbamate
2,3,4,6-Tetra-O-benzyl-D-galactopyranose (300 gm,1.0 mole ratio), and benzhydryl amine (111.9 gm,1.1 mole ratio) was stirred in methanol (900 ml) for 30-45 min at 20-30°C. To this resultant mixture sodium cyanoborohydride (69.6gm, 2.0 mole ratio) was added in lot wise with controlled temperature 22-30°C. A mixture of methanol (165ml) and acetic acid (129ml) was added in 45 min at 20-30°C. The resultant mixture was heated to 50-55 °C till completion of reaction. After completion of reaction, the reaction mixture was cooled to 15-25°C and aqueous sodium hydroxide solution (1200 ml) was added, then mixture was stirred at 20-30°C. The reaction mixture was extracted with dichloromethane (3x1200 ml) and organic layer was separated. The combined organic layer was washed with DM water (3x1200ml). The organic layer was separated. The resultant organic layer contains (2R,3S,4R,5S)-6-(benzhydrylamino)-1,3,4,5-tetrakis(benzyloxy)hexan-2-ol (in situ intermediate).

To a solution of (2R,3S,4R,5S)-6-(benzhydrylamino)-1,3,4,5-tetrakis(benzyloxy)hexan-2-ol in dichloromethane, aqueous sodium bicarbonate solution (?8.0%), (1350ml) was added. Benzyl chloroformate solution 50% in toluene (195 ml, 1.056 mole ratio) was added slowly over 30 min and the mixture was stirred vigorously for 12-14 hrs at 25-30 °C. After completion of reaction, organic layer was separated. The organic layer was washed with sodium hydroxide solution (1200 ml) followed by dil hydrochloric acid (900 ml). The reaction mixture was stirred, and organic layer was separated. Further organic layer was washed with DM water and followed by ~20% sodium chloride solution. The organic layer was separated and distilled under vacuum to give benzyl benzhydryl((2S,3R,4S,5R)-2,3,4,6-tetrakis(benzyloxy)-5-hydroxyhexyl) carbamate as an oily mass.

The resulting oily mass benzyl benzhydryl benzyl benzhydryl((2S,3R,4S,5R)-2,3,4,6-tetrakis(benzyloxy)-5-hydroxyhexyl) carbamate was diluted with acetone (900 ml) under nitrogen atmosphere and anhydrous sodium acetate (205.2 gm, 4.5 mole ratio) was added and the reaction mixture was cooled at 0-5°C. TEMPO (15.75 gm, 0.18 mole ratio) was added. A solution of acetone (600 ml) and trichloroisocyanuric acid (96 gm, 0.75 mole ratio) was added at 0-5°C in 2-5 hrs and reaction mixture was stirred at 0-5°C for 4 to 10 hrs. After completion of reaction, the reaction mixture was filtered and washed with dichloromethane (900ml). Transferred the combined filtrate in flask then added dichloromethane (1500ml) and DM water (2400 ml). The reaction mixture was stirred at 20-30°C and organic layer was separated. Aqueous layer was extracted with dichloromethane (1200 ml). The combined organic layer was washed with dil hydrochloric acid solution (600ml) and followed by DM water (2400ml). The organic layer was separated and distilled under vacuum at 40-45°C. Isopropyl alcohol (600ml) was added and distilled under vacuum at 40-45°C. To the resultant oily mass, isopropyl alcohol (1200ml) was added and the slurry was stirred at 40-45°C for 45-60 min. The slurry was cooled and stirred at 20-30°C for 120 min. The solid was filtered and washed with isopropyl alcohol (600ml). The isolated wet solid was dissolved in a mixture of isopropyl alcohol (1500 ml) and acetone (150ml) at 60-70°C and mixture was stirred for 45-60 min. The reaction mixture was cooled and stirred at 20-30°C for 120 min. Solid obtained was filtered and washed with acetone (600ml). The material was dried under vacuum at 40-45°C to give benzyl benzhydryl((2S,3R,4R)-2,3,4,6-tetrakis(benzyloxy)-5-oxohexyl)carbamate as a solid (330 gm, 70%).

Step-2: Preparation of Migalastat Hydrochloride (crude)
A solution of benzyl benzhydryl((2S,3R,4R)-2,3,4,6-tetrakis(benzyloxy)-5-oxohexyl)carbamate (300.0 gm,1.0 mole ratio) in 2-methyltetrahydrofuran (6000ml) was subjected to reductive amination in presence of 10% Pd/C(50% wet, 60.0 gm) under hydrogen pressure 5-6 Kg at 18-25°C for 5-6 hrs gave mixture of (2R,3S,4R,5S)-1-benzhydryl-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl) piperidine and (2R,3S,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy) methyl)piperidine in situ intermediates. The resultant mixture of (2R,3S,4R,5S)-1-benzhydryl-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl) piperidine and (2R,3S,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy) methyl)piperidine further subjected to debenzylation in presence of dil 1:1 hydrochloric acid solution (40 ml) and under hydrogen pressure 5-6 Kg at 25-30°C. After completion of reaction, DM water (900 ml) was added and stirred at 25-30°C for 45-60 min. Pd/C was filtered and washed with DM water (300 ml). Aqueous layer was separated containing migalastat hydrochloride. The aqueous layer was washed with dichloromethane (2x1800ml) and aqueous layer was separated. The aqueous layer was subjected to charcoal treatment. The mixture was filtered and washed with DM water. The filtrate was distilled under vacuum at 45-50°C till ~150 volume mass remains in the flask. Isopropyl alcohol was added to the solution and solid obtained was filtered and washed with isopropyl alcohol. The isolated wet solid was added in water (~112.5 ml) and heated to dissolve at 40-45°C for 20-30 min. The solution was cooled to 20-30°C and acetone was added (~675 ml). The slurry was stirred at 20-30°C for 90-120 min. The solid obtained was filtered and washed with acetone(~90ml). The material was dried under vacuum at 40-45°C to give (+)-(2R,3S,4R,5S)-2-(hydroxymethyl)piperidine-3,4,5-triol hydrochloride (Migalastat hydrochloride)(45 gm, 56% yield).

Step-3: Preparation of Pure Migalastat Hydrochloride
The Migalastat Hydrochloride (crude), (45.0 gm,1.0mole ratio) was dissolved in DM water (101.25ml) at 40-45°C and filtered through micron filter to remove undissolved particles and washed with DM water (11.25 ml). The acetone (675ml) was added to filtrate and stirred the slurry at 20-30°C for 90-120 min. The solid was filtered and washed with acetone (~90ml). The material was dried under vacuum at 40-45°C to give (+)-(2R,3S,4R,5S)-2-(hydroxymethyl)piperidine-3,4,5-triol hydrochloride (Migalastat hydrochloride) (42.75 gm, 95% yield)
,CLAIMS:Claim 1: A process for the preparation of migalastat or a pharmaceutical acceptable salt thereof comprising the steps of:

a) reacting galactopyranose (SM) with benzhydryl amine to afford compound of formula MGL-I;

wherein P is an alcohol-protecting group known from the carbohydrate chemistry, for example, benzyl, allyl, acetyl or benzoyl group.
b) reacting compound of formula MGL-I with benzyl chloroformate to afford compound of formula MGL-II-a;

c) oxidization of compound of formula MGL-II-a to afford compound of formula MGL-III-a;

d) cyclizing compound of formula MGL-III-a to afford compound of formula MGL-IV; and

e) deprotecting of product of step d) to afford migalastat or a pharmaceutical acceptable salt thereof.

Claim 2: The process as claimed in claim 1, the reaction of Step-(a) can be performed in the presence of reducing agent selected from sodium cyanoborohydride, sodium triacetoxyborohydride, cyano-9-borobicyclo hydride [3.3.1] sodium nonane, tetrabutylammonium cyanoborohydride, solid support cyanoborohydride, sodium tetramethylammonium triacetoxyborohydride, triacetoxyborohydride , lithium triethylborohydride, tri (sec-butyl) lithium borohydride, sodium disopinocampteylcyanoborohydride, catechol borane, borane tetrahydrofuran, sodium borohydride, potassium borohydride, lithium borohydride, palladium in the presence of hydrogen gas 5-ethyl-2-methylpyridine (PEMB - 5-ethyl-2-methylpyridine borane), 2-picoline borane or polymer-supported triacetoxyborohydride.

Claim 3 : The process as claimed in claim 1, the reaction of Step-(c) can be performed in the presence of any suitable oxidizing agent selected from but not limited to diacetoxy iodobenzene, di (trifluoroacetoxy) iodobenzene, dichloroiodobenzene, potassium persulfate, sodium perborate, sodium bromate, sodium iodate, sodium iodate , Urea hydrogen peroxide, tert-butyl hydroperoxide, N-methylmorpholine-N-oxide, trimethylammonium-N-oxide, sodium dichloroisocyanuric acid, iodosobenzene, N-bromosuccinimide, N (I) tris- (triphenylsulfonyl) amide, N-bromophthalimide, sodium ascorbate, sodium hypobromite, m-chloroperbenzoic acid, 2-iododecibenzoic acid, (I), copper (I) chloride, copper (I) bromide, copper (II) bromide, copper (II) chloride, Tetrapropyl ammonium perruthenate, N-chlorosuccinimide, 1,1, (1 H) -one, trimethylaluminum, aluminum triisopropoxide, dimethylsulfoxide, potassium peroxymonosulfate, nitric acid Ammonium cerium, oxygen, trichloroisocyanuric acid, chromium, iodine, chlorine, bromine, bromine monochloride, 5,5-dimethyl-1,3-dibromohydantoin, pyridinium tribromide, 4,4,6-tetrabromo-2,5-cyclohexadiene, dibromoisocyanuric acid, tribromoisocyanuric acid, N-bromoisocyanuric acid monosodium salt, N- N, N'-dibromo-4-methylbenzenesulfonamide, sodium bromate, lithium bromate, potassium bromate, tetra-n-butylammonium tribromide, trimethylphenylammonium tri Bromide, trimethylammonium tribromide, triethylammonium tribromide.

Claim 4: The process as claimed in claim 1, the reaction of Step-(d) can be performed in the presence of suitable reducing conditions selected from hydrogen gas and a catalyst such as palladium on carbon.

Claim 5: A process for the preparation of migalastat or a pharmaceutical acceptable salt thereof comprising the steps of:

a) reacting 2,3,4,6-Tetra-O-benzyl-D- galactopyranose with benzhydryl amine to afford (2R,3S,4R,5S)-6-(benzhydrylamino)-1,3,4,5-tetrakis(benzyloxy)hexan-2-ol;
b) reacting (2R,3S,4R,5S)-6-(benzhydrylamino)-1,3,4,5-tetrakis(benzyloxy)hexan-2-ol with benzyl chloroformate to afford benzyl benzhydryl((2S,3R,4S,5R)-2,3,4,6-tetrakis(benzyloxy)-5-hydroxyhexyl)carbamate;
c) oxidization of benzyl benzhydryl((2S,3R,4S,5R)-2,3,4,6-tetrakis(benzyloxy)-5-hydroxyhexyl)carbamate to afford benzyl benzhydryl((2S,3R,4R)-2,3,4,6-tetrakis(benzyloxy)-5-oxohexyl)carbamate;
d) cyclizing benzyl benzhydryl((2S,3R,4R)-2,3,4,6-tetrakis(benzyloxy)-5-oxohexyl)carbamate to afford (2R,3S,4R,5S)-1-benzhydryl-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine and (2R,3S,4R,5S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)piperidine; and
e) deprotecting of product of step d) to afford migalastat or a pharmaceutical acceptable salt thereof.

Claim 6: Migalastat intermediates of formula:

or isomers thereof.
wherein P is an alcohol-protecting group known from the carbohydrate chemistry, for example, benzyl, allyl, acetyl or benzoyl group.

Claim 7: Migalastat intermediates of formula:

or isomers thereof.