DESC:TITLE: AN IMPROVED PROCESS FOR THE PREPARATION OF MIGLUSTAT

FIELD OF THE INVENTION:
The present invention relates to the field of Imino sugars; particularly relates to the process of preparation of the Imino sugars and the intermediates thereof. The Imino sugars of the present invention has glycosyltransferase inhibitor activity used in the treatment of Gaucher's disease.

BACKGROUND OF THE INVENTION:
Miglustat is a potent inhibitor of glycosyltransferase. It is primarily used in the treatment of Gaucher's disease. Miglustat is chemically known as N-butyl-1,5-dideoxy-1,5-imino-D-glucitol of formula (IV) and is sometimes referred as N-butyl-1-deoxynojirimycin. Miglustat is a white to off-white crystalline solid with a melting point of 125-126° C. It's empirical formula is C10H21NO4 and has a molecular weight of 219.28 g/mol.

Miglustat belongs to the class of azasugars or iminosugars. Ever since the discovery of iminosugars in the 1960s, iminosugars have been subject of extensive studies in both the organic chemistry and biochemistry fields. A well-known member of this extensive family of compounds is 1-deoxynojirimycin.

Various prior arts reported the synthesis of Azasugars. Journal of Organic Chemistry, 1994, 59, 3175 discloses synthesis of Miglustat by double reductive amination of 5-keto-D-glucose.

The prior art reference US 4639436A discloses, in example 2, preparation of N-butyl-1-desoxynojirimycin by reacting 1-desoxynojirimycin with n-Butyraldehyde, Methanolic HCl and NaCNBH3 in Methanol solvent. This process involves column purification (using resin) of the residue obtained followed by crystallization to obtain N-n-butyl-desoxynojirimycin crystals. This reference is silent about preparation of the starting material 1-deoxynojirimycin.

Another reference WO98/35685A1 in example 1 discloses a similar process to that of the above US '436 patent by reacting a solution of 1,5-dideoxy-1,5-imino-D-glucitol, butyraldehyde, Palladium in Methanol under Hydrogen atmosphere to obtain 1,5-(butylimino)-1,5-dideoxy-D-glucitol. However, this reference too is silent about how the starting material 1,5-dideoxy-1,5-imino-D-glucitol is prepared.

The Later developed methods in the literature involve synthesis of Miglustat through the formation of tetra-O-benzyl-glucose intermediate. For instance, the prior art references such as "Journal of medicinal chemistry 53(2), 689-698, 2010"; "Journal of carbohydrate chemistry (2016), 35 (8-9), 445-454"; and patent document "EP 3031800" disclose this approach of preparing Miglustat starting from the tetra-O-benzyl protected 1-deoxynojirimycin. This approach involves introduction of n-butyl side chain on the benzyl protected 1-deoxynojirimycin as first step in order to prepare the benzyl protected Miglustat or its salt. In the subsequent second step, the O-protected Miglustat salt is deprotected to obtain Miglustat salt. In the final step, the Miglustat salt is cleaved with a base such as DBU or by using column chromatography (using Resin).

These approaches mentioned in the prior arts involve serious disadvantages. For instance, the " Journal of medicinal chemistry 53(2), 689-698" approach involves debenzylation at - 70°C and further involves use of column chromatography; whereas the "Journal of carbohydrate chemistry (2016), 35 (8-9), 445-454" process involve use of BCl3 reagent involving temperatures of -78°C and uses flash chromatography purification in the later stage.

Hence, there is/are drawback(s) in the prior art mentioned processes for the preparation of Miglustat and so, there is a need for robust and reproducible process for the preparation of Miglustat with better industrial operability, for better yield and purity.

SUMMARY OF THE INVENTION:
One aspect of the present invention relates to a process for the preparation of Miglustat of formula IV,

comprising:
a) treatment of a salt of 1-deoxynojirimycin of formula II with a base to give 1-deoxynojirimycin of formula III; and

b) converting the 1-deoxynojirimycin of formula III by treating with a suitable reagent to produce Miglustat of formula IV.

Another aspect of the present invention relates to a process for the preparation of Miglustat of formula IV,

comprising:
i. Deprotection of 2,3,4,6-tetra-O-protected 1-deoxynojirimycin of formula I to obtain 1-deoxynojirimycin or its salt;

ii. treatment of the salt of 1-deoxynojirimycin of formula II with a base to produce 1-deoxynojirimycin of formula III; and

iii. converting the 1-deoxynojirimycin of formula III by treating with a suitable reagent to produce Miglustat of formula IV.

DEFINITIONS:
As used herein, the 1-Deoxynojirimycin refers to the structural formula:

Further, as used herein, the 1-Deoxynojirimycin may refer to any of the possible isomers such as (2R, 3R, 4R, 5S); or (2R, 3S, 4R, 5S); or (2S, 3S, 4R, 5R); or (2S, 3R, 4S, 5R) etc.,

As used herein, 2,3,4,6-Tetra-O-protected-1-deoxynojirimycin refers to the following compound of formula:

Further, as used herein, the 2,3,4,6-Tetra-O-protected-1-deoxynojirimycin may refer to any of the possible isomers such as (2R, 3R, 4R, 5S); or (2R, 3S, 4R, 5S); or (2S, 3S, 4R, 5R); or (2S, 3R, 4S, 5R) etc.,

As used herein, Miglustat refers to the following structure:

Further, as used herein, the Miglustat may refer to any of the possible isomers such as (2R, 3R, 4R, 5S); or (2R, 3S, 4R, 5S); or (2S, 3S, 4R, 5R); or (2S, 3R, 4S, 5R) etc and any mixtures thereof.

DETAILED DESCRIPTION:
The inventors of the present invention developed a new alternative approach for the preparation of Miglustat as described here after.
Further, the present invention avoids the use of, tedious and expensive to implement at industrial level, column chromatography anywhere throughout the process of preparation of Miglustat.
Further, the present invention avoids the use of harsh reaction conditions of prior art processes. The invention further provides Miglustat in high purity and with controlled level of impurities such as the N-methyl impurity of Miglustat.

Aspect-I:
One embodiment of the present invention provides a process for the preparation of Miglustat of formula IV

comprising:
a) treatment of a salt of 1-deoxynojirimycin of formula II with a base to produce 1-deoxynojirimycin of formula III; and

b) converting the 1-deoxynojirimycin of formula III by treating with a suitable reagent to produce Miglustat of formula IV.

In the embodiments of step a) of the above Aspect-I, the starting material 1-deoxynojirimycin salt may be prepared as per any of the prior art mentioned processes such as " Chemistry Letters, Issue: 10, Pages: 1881-4, Journal: 1989". Alternatively, this starting material may be procured from the commercially available sources.

In some embodiments, the 1-deoxynojirimycin salt of step a) of Aspect-I may be prepared comprising deprotection of 2,3,4,6-Tetra-O-protected 1-deoxynojirimycin or its salt of formula I.

In the embodiments of step a) of the above Aspect-I, the salt of compound of formula II is typically a mineral acid salt, preferably hydrochloric acid salt.
In the embodiments of step a) of the above Aspect-I, the base used in step a) may be selected from organic bases or inorganic bases. Organic bases may be selected from one or more of the group comprising of triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicycloundec-7-ene (DBU), and 1,5-diazabicyclonon-5-ene. Inorganic bases may be selected from one or more of the group consisting of NH3, NaOH, KOH, Na2CO3, NaHCO3, sodium acetate and LiOH. However, there is no restriction on the type of base used as long as the base is capable of cleaving the salt of compound of formula II.
In the embodiments of step a) of the above Aspect-I, the solvent used in step a) may be any organic solvent and is selected from methanol, acetone, water, and mixtures thereof. However, there is no restriction to the use of solvent as long as the solvent enables the cleaving of salt.
In the embodiments of step b) of the above Aspect-I, the suitable reagent used may be selected from n-butyraldehyde, 1-bromobutane, 1-chlorobutane, butyl methane sulfonate, a mixture of n-butanol and methane sulfonyl chloride or any mixtures thereof. However, there is no restriction on the type of solvent used as long as the solvent enables the conversion of compound of formula III to IV.
In the embodiments of step b) of the above Aspect-I, the suitable solvent used in step b) may be selected from n-butanol, methanol, water, and mixtures thereof.
In the embodiments of the above Aspect-I, both steps a) and b) may be carried one-pot/in situ or separate.

Aspect-II:
Another embodiment of the present invention provides a process for the preparation of Miglustat of formula IV

comprising:
i. Deprotection of 2,3,4,6-Tetra-O-protected 1-deoxynojirimycin of formula I or its salt to obtain 1-deoxynojirimycin or its salt;

ii. treatment of the salt of 1-deoxynojirimycin of formula II with a base to produce 1-deoxynojirimycin of formula III; and

iii. converting the 1-deoxynojirimycin of formula III by treating with a suitable reagent to produce Miglustat of formula IV.
In the embodiments i) of above Aspect-II, the protecting group may be selected from, but not limited to, benzyl protection, Allyl protection, t-Butyl protection, Sillyl protection, ester protection, Acetal protection, tetrahydro Pyranyl protection and alkoxy protection.
In the embodiments i) of the above Aspect-II, the salt of compound of formula I is typically a mineral acid salt, preferably hydrochloric acid salt.
In the embodiments i) of above Aspect-II, the deprotection of 2,3,4,6-Tetra-O-protected 1-deoxynojirimycin may be carried out using any of the deprotection methods known in the literature such as catalytic methods, Hydrogenolysis, reductive cleavage including one or more of the reagents: Hydrogen, HCl, Palladium, Nickle and H2SO4; In a preferred embodiment, the deprotection is carried out by Hydrogenation under acidic conditions.
In the embodiments i) of above Aspect-II, the solvent used may be according to the embodiments as explained above for the embodiments of step a) of Aspect-I.
In the embodiments i) of the above Aspect-II, the salt of compound of formula II is typically a mineral acid salt, preferably hydrochloric acid salt.
In the embodiments ii) of above Aspect-II, the suitable base and the solvent used may be according to the embodiments as explained above for the embodiments of step b) of Aspect-I.
In the embodiments iii) of above Aspect-II, the suitable reagent used for the conversion of compound of formula III to IV may be according to the embodiments as explained above for the embodiments of step b) of Aspect-I.
In the embodiments of above aspect-II, two or more steps of i), ii) and iii) may be carried one-pot or in-situ.
EXAMPLES:
Example 1: Preparation of 2,3,4,6-tetrakis(benzyloxy)hexane-1,5-diol

To a stirred solution of dichloromethane (2500 ml) and 2,3,4,5-tetra-O-benzoyl glucopyranose (250 gms) added NaBH4 (42 gms). Heated the reaction mixture to 33-40 oC. Slowly added methanol (750 ml) and maintained the temperature of the reaction at 33-40° C till the reaction completion. Cooled the reaction mass and acidified the reaction mass with HCl. The layers were separated, and the organic layer was distilled under vacuum to get 2,3,4,6-tetrakis(benzyloxy)hexane-1,5-diol as an oily mass.
Yield: 251 gms
Purity: 99.01%
Example 2: Preparation of 3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl) piperidine HCl (corresponds to compound of formula I)

2,3,4,6-tetrakis(benzyloxy)hexane-1,5-diol (240 gms) and DMSO (1200 ml) were stirred at 25-35 oC to get a homogenous solution. Cooled the reaction mixture to 18-22 oC and charged P2O5 (240 gms) at this temperature under stirring. Slowly added triethyl amine (358 gms) and stirred the reaction till the completion. Cooled the reaction mass and seperated the layers by the addition of toluene and water to the reaction mass.
To the organic layer added methanol (2400 ml), ammonium acetate (340 gm), sodium sulfate (288.2 gms), Acetic acid (360 gms) and Sodium cyano borohydride (105.6 gms) and raised the temperature of the reaction mass to 25-35 oC. Stirred the reaction mass until reaction completion. Cooled the reaction mass and extracted the layers by the addition of toluene and water to the reaction mass. Distilled out the organic layer under vacuum get the residue. To the residue added acetone (1440 ml) and IPA.HCl (64.8 gms) and maintained the temperature of the mixture at 25-35 oC for 2 hours. Filtered the mass to obtain wet cake. Washed the wet cake with Acetone and then with water. Dried the wet material under vacuum to get the purified 3,4,5-tris(benzyloxy)-2-(benzyloxy)methyl) piperidine HCl.
Yield: 113 gms
Purity: 99.86%

Example 3: Preparation of 1-deoxynojirimycin

To an autoclave, added methanol (3000 ml), 3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl) piperidine HCl (150 gms), IPA. HCl (150 ml), Palladium on carbon (45 gms) under H2 pressure at 25-35 oC. Heated the reaction mass to 40-45 oC and maintained the temperature of the reaction mass till the reaction completion. Cooled the reaction mass to 25-30 oC, added water (150 ml) and heated to 40-45 oC for 1 hour. Filtered the reaction mass through hyflo bed. Distill out the filtrate and strip out with toluene and methanol. Charged methanol (150 ml) to the residue, cooled the reaction mass to 0 to 5 oC and stirred the reaction mass for 2 to 3 hours. Filtered the reaction mass, washed with methanol (75 ml) and suck dried the wet cake (1-deoxynojirimycin HCl).
A solution of 1-deoxynojirimycin HCl (wet cake) in methanol (485 ml) and DBU (51.4 gms) were mixed and stirred at 45-50 oC for 2 hours. Cooled the reaction mass to 25-30 oC and stirred the reaction mixture at 25-30 oC for 2 hours. Filtered the mass and washed the wet cake with methanol. Dried the wet cake under vacuum to get 1-deoxynojirimycin.
Yiled: 34.1 gms
Purity: 99.62%

Example 4: Preparation of Miglustat

A solution of n-butanol (425 ml), water (75 ml), 1-deoxynojirimycin (25 gms), n-butyraldehyde (77.3 gms) and Palladium on carbon (2.5 gms) under H2 pressure were mixed and stirred at a temperature of 40-45°C till the reaction completion. Reaction mixture was filtered through hyflo bed and distilled out the filtrate under vacuum to get a residue which is isolated using Acetone. The material is purified using a mixture of Acetone, Methanol, and water. Dried the wet material under vacuum to get the purified Miglustat.
Yield: 20.8 gms
Purity: 99.97%
,CLAIMS:
1. A process for the preparation of Miglustat of formula IV,

comprising:
a) treatment of a salt of 1-deoxynojirimycin of formula II with a base to give 1-deoxynojirimycin of formula III; and

b) converting the 1-deoxynojirimycin of formula III by treating with a suitable reagent to produce Miglustat of formula IV.

2. The process according to claim 1, wherein the base is selected from the group of NH3, NaOH, KOH, Na2CO3, NaHCO3, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicycloundec-7-ene, and 1,5-diazabicyclonon-5-ene.

3. The process according to claim 1, wherein the salt of compound of formula II is selected from mineral acid salt, preferably hydrochloric acid salt.

4. The process according to claim 1, wherein suitable reagent is selected from n-butyraldehyde, 1-bromobutane, 1-chlorobutane, butyl methane sulfonate, a mixture of n-butanol and methane sulfonyl chloride or any mixtures thereof.

5. The process according to claim 1, wherein the salt of 1-deoxynojirimycin compound of formula II is prepared by the deprotection of 2,3,4,6-Tetra-O-protected 1-deoxynojirimycin or its salt of formula I.

6. A process for the preparation of Miglustat of formula IV,

comprising:
i. Deprotection of 2,3,4,6-Tetra-O-protected 1-deoxynojirimycin of formula I or its salt to obtain 1-deoxynojirimycin or its salt;

ii. treatment of the salt of 1-deoxynojirimycin of formula II with a base to produce 1-deoxynojirimycin of formula III; and

iii. converting the 1-deoxynojirimycin of formula III by treating with a suitable reagent to produce Miglustat of formula IV.

7. The process according to claim 6, wherein the base is selected from the group of NH3, NaOH, KOH, Na2CO3, NaHCO3, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, 1,8-diazabicycloundec-7-ene, and 1,5-diazabicyclonon-5-ene.

8. The process according to claim 6, wherein the salt of compound of formula II is selected from mineral acid salt, preferably hydrochloric acid salt.

9. The process according to claim 6, wherein the suitable reagent is selected from n-butyraldehyde, 1-bromobutane, 1-chlorobutane, butyl methane sulfonate, a mixture of n-butanol and methane sulfonyl chloride or any mixtures thereof.

10. The process according to claim 6, wherein the protecting group is selected from benzyl, allyl, t-Butyl, sillyl, ester, acetal, tetrahydro pyranyl and alkoxy.