WO2015059679A1

WO2015059679A1 - Improved process for the preparation of eliglustat

Info

Publication number: WO2015059679A1
Application number: PCT/IB2014/065631
Authority: WO
Inventors: Iqbal Javed; Vilas Hareshwar Dahanukar; Srinivas ORUGANTI; Bhaskar KANDAGATLA
Original assignee: Dr. Reddy's Laboratories Limited
Priority date: 2013-10-25
Filing date: 2014-10-27
Publication date: 2015-04-30

Abstract

The present invention provides an improved process for the preparation of eliglustat to salts thereof. Present invention also provides a crystalline eliglustat free base form R1.

Description

IMPROVED PROCESS FOR THE PREPARATION OF ELIGLUSTAT

INTRODUCTION

The present application relates to an improved process for the preparation of eliglustat to salts thereof.

Eliglustat tartrate (Genz-1 12638) is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of gaucher disease and other lysosomal storage disorders, which is currently under development.

Eliglustat is chemically known as 1 R, 2R-Octanoic acid [2-(2', 3'-dihydro- benzo [1 , 4] dioxin-6'-yl)-2-hydroxy-1 -pyrrolidin-1 -ylmethyl]-ethyl]-amide, having a structural formula I depicted here under.

Formula I

Eliglustat hemitartrate (Genz-1 12638) development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is orally active with potent effects on the primary identified molecular target for type 1 Gaucher disease and other glycosphingolipidoses, appears likely to fulfill high expectations for clinical efficacy. Gaucher disease belongs to the class of lysosomal diseases known as glycosphingolipidoses, which result directly or indirectly from the accumulation of glycosphingolipids, many hundreds of which are derived from glucocerebroside. The first step in glycosphingolipid biosynthesis is the formation of glucocerebroside, the primary storage molecule in Gaucher disease, via glucocerebroside synthase (uridine diphosphate [UDP] - glucosylceramide glucosyl transferase). Eliglustat hemitartrate is based on improved inhibitors of glucocerebroside synthase. U.S. patent No. 7,196,205 (herein described as US'205) discloses a process for the preparation of eliglustat or a pharmaceutically acceptable salt thereof. In this patent, eliglustat was synthesized via a seven-step process involving steps in that sequence: (i) coupling S-(+)-2-phenyl glycinol with phenyl bromoacetate followed by column chromatography for purification of the resulting intermediate, (ii) reacting the resulting (5S)-5-phenylmorpholin-2-one with 1 , 4-benzodioxan-6-carboxaldehyde to obtain a lactone, (iii) opening the lactone of the oxazolo-oxazinone cyclo adduct via reaction with pyrrolidine, (iv) hydrolyzing the oxazolidine ring, (v) reducing the amide to amine to obtain sphingosine like compound, (vi) reacting the resulting amine with octanoic acid and N-hydroxysuccinimide to obtain crude eliglustat, (vii) purifying the crude eliglustat by repeated isolation for four times from a mixture of ethyl acetate and n-heptane.

U.S. patent No. 6855830, 7265228, 7615573, 7763738, 8138353, U.S. patent application publication No. 2012/296088 disclose processes for preparation of eliglustat and intermediates thereof.

U.S. patent application publication No. 2013/137743 discloses (i) a hemitartrate salt of eliglustat, (ii) a hemitartrate salt of eliglustat, wherein at least 70% by weight of the salt is crystalline, (iii) a hemitartrate salt of Eliglustat, wherein at least 99% by weight of the salt is in a single crystalline form.

It is also an objective of the present application to provide an improved process for the preparation of eliglustat and a pharmaceutically acceptable salt thereof which is high yielding, simple, cost effective, environment friendly and commercially viable by avoiding repeated cumbersome and lengthy purification steps. It is a further objective of the present application to provide crystalline forms of eliglustat free base and its salts.

SUMMARY

In first embodiment, the present application provides an improved process for the preparation of eliglustat free base, which comprises: a) reacting S-(+)-phenyl glycinol with phenyl-a-bromoacetate to obtain a compound of formula II,

Formula II

wherein HA is an acid residue,

b) converting a compound of Formula II in one or more steps in to eliglustat.

In second embodiment, the present application provides a crystalline eliglustat free base form R1 having powder x-ray diffraction (PXRD) pattern with peaks located at about 6.06, 16.29, 18.96, 21 .77 and 24.03 ± 0.2 degrees 2Θ. An aspect of the present application provides a crystalline eliglustat free base form R1 having PXRD pattern with additional peaks located at about 13.07, 16.93 and 28.30 ± 0.2 degrees 2Θ. Another aspect of the present application provides a crystalline eliglustat free base form R1 having PXRD pattern with further peaks located at about 12.65 and 26.41 ± 0.2 degrees 2Θ.

In third embodiment, the present application provides a crystalline eliglustat free base form R1 having PXRD pattern substantially as illustrated by figurel .

In fourth embodiment, the present application provides a crystalline eliglustat free base form R1 having thermal events at about 71 .98 in differential scanning calorimetry (DSC) thermogram.

In fifth embodiment, the present application provides a crystalline eliglustat free base form R1 having differential scanning calorimetry (DSC) thermogram as illustrated by figure 2.

In sixth embodiment, the present application provides a process for preparation of crystalline eliglustat free base form R1 , which comprises: a) providing a solution of eliglustat free base in a solvent;

b) adding an anti-solvent to the solution obtained in step (a); and

c) isolating crystalline eliglustat free base form R1 .

In seventh embodiment, the present application provides a process for the preparation of crystalline eliglustat free base form R1 , which comprises:

a) reacting S-(+)-phenyl glycinol with phenyl-a-bromoacetate to obtain a compound of formula II,

Formula II

wherein HA is an acid residue;

b) converting a compound of Formula II in one or more steps in to eliglustat; c) providing a solution of eliglustat free base in a solvent; and

d) isolating crystalline eliglustat free base form R1 by adding an anti-solvent.

In eighth embodiment, the present application provides crystalline eliglustat oxalic acid salt having PXRD pattern with peaks located at about 5.58, 6.90, 14.84, 18.71 and 28.98 ± 0.2 degrees 2Θ. An aspect of the present application provides crystalline eliglustat oxalic acid salt having PXRD pattern with additional peaks located at about 8.13, 21.08 and 23.96 ± 0.2 degrees 2Θ. Another aspect of the present application provides crystalline eliglustat oxalic acid salt having PXRD pattern with further peaks located at about 15.24 and 21 .60 ± 0.2 degrees 2Θ.

In ninth embodiment, the present application provides crystalline eliglustat oxalic acid salt having PXRD pattern substantially as illustrated by figure 3.

In tenth embodiment, the present application provides a process for the preparation of crystalline oxalic acid salt of eliglustat, which comprises:

d) providing a solution of eliglustat oxalic acid salt in a solvent, and

e) isolating crystalline eliglustat oxalic acid salt. BRIEF DESCRIPTION OF THE DRAWING

Figure 1 is an illustration of a PXRD pattern of crystalline form R1 of eliglustat free base as obtained from example 6.

Figure 2 is an illustration of a DSC thermogram of crystalline form R1 of eliglustat free base as obtained from example 6.

Figure 3 is an illustration of a PXRD pattern of crystalline oxalic acid salt of eliglustat as obtained from example 7.

DETAILED DESCRIPTION

The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 1 1 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1 .

Any process known in the art may be followed for providing crude eliglustat free base. For example, the process that is reported in example-2 of the US patent document No. 7,196,205 may be followed to obtain crude eliglustat freebase.

In first embodiment, the present application provides an improved process for the preparation of eliglustat free base, which comprises:

Formula II

wherein HA is an acid residue; and

b) converting a compound of Formula II in one or more steps in to eliglustat.

Step (a) of the first embodiment involves reacting S-(+)-phenyl glycinol with phenyl-a-bromoacetate in the presence of a base to obtain 5-phenyl morpholine-2- one. 5-phenyl morpholine-2-one was isolated as a solid as per the procedure described in the US patent No 7,196,205 using column chromatography which is tedious and commercially not viable. In the process of the present application 5- phenyl morpholine-2-one was isolated as an acid addition salt thereby providing a process which is simple, cost effective and commercially viable.

The base that can be used for the said reaction includes, organic base such as DBU (1 ,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1 ,5-Diazabicyclo[4.3.0]non-5- ene), DABCO (1 ,4-diaza-bicyclo[2.2.2]octane), ABCO (1 -azabicyclo [2,2,2]octane), TBD (1 ,5,7-Triazabicyclo[4.4.0]dec-5-ene) or DMAP (4-dimethylaminopyridine), TEA (Triethylamine), DIPEA (Ν,Ν-diisopropylethylamine), DIEA (Diethylamine), N-methyl morpholine, lutidine, pyridine or collidine; inorganic base like hydroxides of alkali metals such as sodium hydroxide, lithium hydroxide or potassium hydroxide; carbonates of alkali metals such as sodium carbonate or potassium carbonate; bicarbonates of alkali metals such as sodium bicarbonate or potassium bicarbonate.

HA of formula II is an acid residue, which includes, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, phosphorous acid, hypophosphorous acid, propionic acid, butyric acid, formic acid and the like, and organic acids such as p-toluenesulfonic acid, methane sulfonic acid, trifluoromethane sulphonic acid, succinic acid, citric acid, benzoic acid, acetic acid, trifluoroacetic acid and the like.

An aspect of the present application is to convert 5-phenyl morpholine-2-one in to an acid addition salt to obtain a compound of formula II. Suitable acids that can be used to form acid addition salts are from HA described above.

Step (b) of the first embodiment involves converting a compound of Formula II in one or more steps in to eliglustat to provide a solution of crude eliglustat free base. Any process known in the art may be followed for providing a solution of crude eliglustat free base. For example, the process that is reported in example-2 of the US patent document No 7,196,205 may be followed to obtain crude eliglustat free base except that instead of free base of formula II, the acid addition salt of formula II is used.

In second embodiment, the present application provides a crystalline eliglustat free base form R1 having powder x-ray diffraction pattern (PXRD) peaks located at about 6.06, 16.29, 18.96, 21 .77 and 24.03 ± 0.2 degrees 2Θ. The aspect of the present application provides a crystalline eliglustat free base form R1 having powder x-ray diffraction pattern (PXRD) having additional peaks located at about 13.07, 16.93 and 28.30 ± 0.2 degrees 2Θ. The aspect of the present application provides a crystalline eliglustat free base form R1 having powder x-ray diffraction pattern (PXRD) having further peaks located at about 12.65 and 26.41 ± 0.2 degrees 2Θ.

In third embodiment, the present application provides a crystalline eliglustat free base form R1 having powder x-ray diffraction pattern (PXRD) substantially as illustrated by fig.1 .

In fourth embodiment, the present application provides a crystalline eliglustat free base form R1 having thermal events at about 71 .98^°C in differential scanning calorimetry (DSC) thermogram.

In fifth embodiment, the present application provides a crystalline eliglustat free base form R1 having differential scanning calorimetry (DSC) thermogram as illustrated by fig.2.

In sixth embodiment, the present application provides a process for the preparation of crystalline eliglustat free base form R1 , which comprises:

a) providing a solution of eliglustat free base in a solvent;

b) adding an anti-solvent to the solution obtained in step (a); and

c) isolating crystalline eliglustat free base form R1 .

The processes described above for step (b) and step (c) of the first embodiment, all the disclosures of which are incorporated herein by reference, can be used for step (a) and step (b) respectively of the sixth embodiment.

Step (a) of the sixth embodiment involves providing a solution of eliglustat free base in a solvent. A solution of crude eliglustat free base may be obtained during the course of its synthesis, for example by a process described above from the US patent document No 7,196,205 or alternatively a solution of crude eliglustat free base may be obtained by dissolving crude eliglustat free base in a suitable solvent.

Suitable solvent that may be used for providing a solution of crude eliglustat free base includes, but not limited to: ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, dimethylfuran, 1 ,2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, 1 ,4-dioxane, or the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate or the like; aliphatic or alicyclic hydrocarbons such as hexanes, heptane, pentane, cydohexane, methylcydohexane or the like; nitromethane; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, 1 ,2- dichloroethene or the like; aromatic hydrocarbons toluene, xylene, chlorobenzene, 1 ,2-dichlorobenzene or the like.

Step (b) of sixth embodiment involves adding an anti-solvent to the solution obtained in step (a). US patent No 7,196,205 involves repeated dissolution of eliglustat free base in 5% ethyl acetate in heptane under reflux condition and isolates pure eliglustat free base on cooling thereby resulting in 39% yield. In the present application the crude eliglustat free base is dissolved in a solvent and isolated by adding an antisolvent there by resulting in high yield.

Anti-solvent as used herein refers to a solvent in which eluglustat is poorly soluble when compared to a solvent that is used in step (a) for providing a solution of eliglustat.

Suitable anti-solvent include, but not limited to: aliphatic or alicyclic hydrocarbons such as hexanes, heptane, pentane, cydohexane, methylcydohexane or the like; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, dimethylfuran, 1 ,2- dimethoxyethane, 2- methoxyethanol, 2-ethoxyethanol, anisole, 1 ,4-dioxane or the like; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate or the like; nitromethane; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, 1 ,2-dichloroethene or the like; aromatic hydrocarbons such as toluene, xylene, chlorobenzene, 1 ,2-dichlorobenzene or the like, or mixtures thereof.

Step (c) of the sixth embodiment involves isolating crystalline eliglustat free base form R1 . The separated crystalline eliglustat free base form R1 can be isolated by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the recovery of solids. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under a reduced pressure, at temperatures less than about 55°C, or less than about 45°C, or less than about 35°C, or less than about 25°C, or any other suitable temperatures.

In seventh embodiment, the present application provides a process for the preparation of crystalline eliglustaxt free base form R1 , which comprises:

Formula II

wherein HA is an acid residue;

The process that can be used for steps (a) through (d) of the seventh embodiment may be similar to the similar processes described for first and sixth embodiments, which are incorporated herein by reference.

The separated crystalline eliglustat free base form R1 can be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the recovery of solids. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under a reduced pressure, at temperatures less than about 55°C, or less than about 45°C, or less than about 35°C, or less than about 25°C, or any other suitable temperatures.

In eighth embodiment, the present application provides crystalline oxalic acid salt of eliglustat having powder x-ray diffraction pattern (PXRD) peaks located at about 5.58, 6.90, 14.84, 18.71 and 28.98 ± 0.2 degrees 2Θ. The aspect of the present application provides crystalline oxalic acid salt of eliglustat having powder x- ray diffraction pattern (PXRD) having additional peaks located at about 8.13, 21 .08 and 23.96 ± 0.2 degrees 2Θ. The aspect of the present application provides crystalline oxalic acid salt of eliglustat having powder x-ray diffraction pattern (PXRD) having further peaks located at about 15.24 and 21 .60 ± 0.2 degrees 2Θ.

In ninth embodiment, the present application provides a crystalline oxalic acid salt of eliglustat having powder x-ray diffraction pattern (PXRD) substantially as illustrated by figure 3.

a) providing a solution of eliglustat oxalic acid salt in a solvent, and

b) isolating crystalline eliglustat oxalic acid salt.

Suitable solvents that may be used for the preparation of eliglustat oxalate include, but not limited to esters, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and the like; ethers, such as, for example, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, dimethylfuran, 1 ,2- dimethoxyethane, 2-methoxyethanol, 2- ethoxyethanol, anisole, 1 ,4-dioxane, and the like; aliphatic or alicyclic hydrocarbons, such as, for example, hexane, heptane, pentane, cydohexane, methylcydohexane, and the like; nitromethane; halogenated hydrocarbons, such as, for example, dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, 1 ,2-dichloroethene, and the like; aromatic hydrocarbons, such as, for example, toluene, xylene, and any mixtures of two or more thereof. The isolation of crystalline eliglustat oxalic acid salt can be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other techniques for the recovery of solids. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under a reduced pressure, at temperatures less than about 55°C, or less than about 45°C, or less than about 35°C, or less than about 25°C, or any other suitable temperatures.

Thus, the present invention addresses the short comings of the prior art by providing an improved process for preparing pure eliglustat (1 R, 2R)-2-amino -1 -(2, 3-dihydro-benzo [1 , 4] dioxin-6-yl)-3-pyrrolidin-1 -yl-propan-1 -ol) in high yield. The present application also provides alternate forms of eliglustat and its pharmaceutically acceptable salt.

Solid states of eliglustat or oxalic acid salt there of the present application are characterized by its PXRD pattern. All PXRD data reported herein were obtained using Cu Ka radiation, having the wavelength 1.541 A, and were obtained using a PanAlytical, Powder X-ray Diffractometer. DSC was taken using PanAlytical instrument.

DEFINITIONS

The following definitions are used in connection with the present application unless the context indicates otherwise.

An "alcohol" is an organic compound containing a carbon bound to a hydroxyl group. "C1 -C6 alcohols" include, but are not limited to, methanol, ethanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1 - butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1 -, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, isoamyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.

An "aliphatic hydrocarbon" is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called "aromatic." Examples of "C5-C8 aliphatic or aromatic hydrocarbons" include, but are not limited to, isopentane, neopentane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, isoheptane, 3- methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3- dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3- methylheptane, neooctane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.

An "ester" is an organic compound containing a carboxyl group -(C=0)-0- bonded to two other carbon atoms. "C3-C6 esters" include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like.

An "ether" is an organic compound containing an oxygen atom -O- bonded to two other carbon atoms. "C2-C6 ethers" include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2- methyltetrahydrofuran, 1 ,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.

A "halogenated hydrocarbon" is an organic compound containing a carbon bound to a halogen. Halogenated hydrocarbons include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1 ,1 ,1 - trichloroethane, 1 ,1 ,2-trichloroethane, chloroform, carbon tetrachloride, or the like.

A "ketone" is an organic compound containing a carbonyl group -(C=0)- bonded to two other carbon atoms. "C3-C6 ketones" include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, or the like.

A "nitrile" is an organic compound containing a cyano -(C≡N) bonded to another carbon atom. "C2-C6 Nitriles" include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like. All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range "between" two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

EXAMPLES

Example 1 : Preparation of 5-phenyl morpholine-2-one hydrochloride

To a (S) + phenyl glycinol (100g) add N, N-diisopropylethylamine (314ml) and acetonitrile (2000ml) under nitrogen atmosphere at room temperature. It was cooled to 10- 15° C. Phenyl bromoacetate (172.4g) dissolved in acetonitrile (500ml) was added to the above solution at 15° C over a period of 30 min. The reaction mixture is allowed to room temperature and stirred for 16-20h. Progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction mixture was concentrated under reduced pressure at a water bath temperature less than 25^° C to get a residue. The residue was dissolved in ethyl acetate (1000ml) and stirred for 1 h at 15-20°C to obtain a white solid. The solid material obtained was filtered and washed with ethyl acetate (200ml). The filtrate was dried over anhydrous sodium sulphate (20g) and concentrated under reduced pressure at a water bath temperature less than 25° C to give crude compound (1000g) as brown syrup. The Crude brown syrup is converted to HCI salt by using HCI in ethyl acetate to afford 5-phenyl morpholine-2-one hydrochloride (44g) as a white solid. Yield: 50%, Mass: m/z = 177.6; HPLC (% Area Method): 90.5%

Example 2: Preparation of (1 R,3S,5S,8aS)-1 ,3-Bis-(2',3'-dihydro-benzo[1 ,4] dioxin-6'-yl)-5-phenyl-tetrahydro-oxazolo[4,3-c][1 ,4]oxazin-8-one.

5-phenyl morpholine-2-one hydrochloride (100g) obtained from above stage 1 is dissolved in toluene (2500ml) under nitrogen atmosphere at 25-30^°C. 1 ,4- benzodioxane-6-carboxaldehyde (185.3g) and sodium sulphate (400g) was added to the above solution and the reaction mixture was heated at 100-105^°C for 72h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was concentrated under reduced pressure at a water bath temperature less than 25^° C to get a residue. The residue was cooled to 10°C, ethyl acetate (2700ml) and 50% sodium bisulphate solution (1351 ml) was added to the residue and stirred for 1 h at 10^°C to obtain a white solid. The obtained white solid was filtered and washed with ethyl acetate. The separated ethyl acetate layer was washed with water (1000ml), brine (1000ml) and dried over anhydrous sodium sulphate. The organic layer was concentrated under reduced pressure at a water bath temperature of 45-50°C to get a crude material. The obtained crude material is triturated with diethyl ether (1500ml) to get a solid material which is filtered and dried under vacuum at room temperature for 2-3h to afford (1 R,3S,5S,8aS)-1 ,3-Bis-(2',3'-dihydro-benzo[1 ,4]dioxin-6'-yl)-5-phenyl-tetrahydro- oxazolo[4,3-c][1 ,4]oxazin-8-one (148g) as a yellow solid. Yield: 54%, Mass: m/z = 487.7; HPLC (% Area Method): 95.4 % Example 3: Preparation of (2S,3R,1 "S)-3-(2',3'-(Dihydro-benzo[1 ,4]dioxin-6'-yl)- 3-hydroxy-2-(2"-hydroxy-1 ''^henyl-ethy^

(1 R,3S,5S,8aS)-1 _!3-Bis-(2'_!3'-dihydro-benzo[1 ,4]dioxin-6'-yl)-5-phenyl-tetrahydro- oxazolo[4,3-c][1 ,4]oxazin-8-one (70g) obtained from above stage 2 was dissolved in chloroform (1400ml) at room temperature. It was cooled to 0-5°C and pyrrolidone (59.5ml) was added at 0-5°C over a period of 30 minutes. The reaction mixture was allowed to room temperature and stirred for 16-18h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was concentrated under reduced pressure at a water bath temperature of 40-45°C to obtain a crude. The obtained crude was dissolved in methanol (1190ml) and 1 N HCI (1 190ml) at 10-15° C, stirred for 10 minutes and heated at 80-85°C for 7h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, methanol was concentrated under reduced pressure at a water bath temperature of 50-55°C.The aqueous layer was extracted with ethyl acetate and the organic layer was washed with 1 N HCI (50ml). The aqueous layer was basified with saturated sodium bicarbonate solution up to p^H 8-9 and extracted with ethyl acetate (3x70ml). The combined organic layers was washed with brine (100ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure at a water bath temperature of 50-55^°C to afford (2S,3R,1"S)-3-(2',3'- (Dihydro-benzo[1 ,4]dioxin-6'-yl)-3-hydroxy-2-(2"-hydroxy-1 "-phenyl-ethylamino)-1 - pyrrolidin-1 -yl-propan-1 -one (53g) as a yellow foamy solid. Yield: 90%, Mass: m/z = 412.7, HPLC (% Area Method): 85.1 %

Example 4: Preparation of (1 R,2R,1 "S)-1-(2',3'-(Dihydro-benzo[1 ,4]dioxin-6'- yl)2-hydroxy-2-(2"-hydroxy-1 '-phenyl-ethylamino)-3-pyrrolidin-1-yl-propan-1-ol.

(2S,3R,1 "S)-3-(2',3'-(Dihydro-benzo[1 ,4]dioxin-6'-yl)-3-hydroxy-2-(2"-hydroxy-1 "- phenyl-ethylamino)-1 -pyrrolidin-1 -yl-propan-1 -one (2.5g) obtained from above stage 3 dissolved in Tetrahydrofuran (106ml) was added to a solution of Lithium aluminium hydride (12.2g) in tetrahydrofuran (795ml) at 0°C and the reaction mixture was heated at 60-65°C for 10h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 5- 10°C and quenched in saturated sodium sulphate solution (100ml) at 5-10°C. Ethyl acetate was added to the reaction mass and stirred for 30-45 min. The obtained solid is filtered through celite bed and washed with ethyl acetate. Filtrate was dried over anhydrous sodium sulphate and concentrated under reduced pressure at a water bath temperature of 50^°C to afford (1 R,2R, 1"S)-1 -(2',3'-(Dihydro- benzo[1 ,4]dioxin-6'-yl)2-hydroxy-2-(2"-hydroxy-1 '-phenyl-ethylamino)-3-pyrrolidin-1 - yl-propan-1 -ol (43.51 g) as a yellow gummy liquid. The crude is used for the next step without further purification. Yield: 85%, Mass: m/z = 398.7, HPLC (% Area Method): 77 %

Example 5: Preparation of (1 R, 2R)-2-Amino-1-(2', 3'-dihydro-benzo [1 , 4] dioxin-6'-yl)-3-pyrrolidin-1 -yl-propan-1 -ol.

(1 R,2R,1 "S)-1 -(2',3'-(Dihydro-benzo[1 ,4]dioxin-6'-yl)2-hydroxy-2-(2"-hydroxy-1 '- phenyl-ethylamino)-3-pyrrolidin-1 -yl-propan-1 -ol (40g) obtained from above stage 4 was dissolved in methanol (400ml) at room temperature in a 2L hydrogenation flask. Trifluoroacetic acid (15.5ml) and 20% Pd (OH) ₂ (40g) was added to the above solution under nitrogen atmosphere. The reaction mixture was hydrogenated under H₂, 10Opsi for 16-18h at room temperature. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was filtered through celite bed and washed with methanol (44ml) and water (44ml). Methanol was concentrated under reduced pressure at a water bath temperature of 50-55°C and the aqueous layer was washed with ethyl acetate. The aqueous layer was basified with 10M NaOH till the P^H reaches 12-14 and then extracted with dichloromethane (2x125ml). The organic layer was dried over anhydrous sodium sulphate (3gm) and concentrated under reduced pressure at a water bath temperature of 45°C to obtain a gummy liquid. The gummy liquid was triturated with methyl tertiary butyl ether for 1 h to get a white solid, which is filtered and dried under vacuum at room temperature to afford (1 R, 2R)-2-Amino-1 -(2', 3'- dihydro-benzo [1 , 4] dioxin-6'-yl)-3-pyrrolidin-1 -yl-propan-1 -ol (23g) as a white solid. Yield: 82.3%, Mass (m/zj: 278.8, HPLC (% Area Method): 99.5%, Chiral HPLC (% Area Method): 97.9% Example 6: Preparation of Eliglustat {(1 R, 2R)-Octanoic acid[2-(2',3'-dihydro- benzo [1 , 4] dioxin-6'-yl)-2-hydroxy-1 -pyrrolidin-1-ylmethyl-ethyl]-amide}.

(1 R, 2R)-2-Amino-1 -(2', 3'-dihydro-benzo [1 , 4] dioxin-6'-yl)-3-pyrrolidin-1 -yl-propan- 1 -ol (15g) obtained from above stage 5 was dissolved in dry dichloromethane (150ml) at room temperature under nitrogen atmosphere and cooled to 10-15^° C. Octanoic acid N-hydroxy succinimide ester (13.0 g)was added to the above reaction mass at 10-15^° C and stirred for 15 min. The reaction mixture was stirred at room temperature for 16h-18h. Progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the reaction mixture was cooled to 15°C and diluted with 2M NaOH solution (100 ml_) and stirred for 20 min at 20 °C. The organic layer was separated and washed with 2M sodium hydroxide (3x90ml).The organic layer was dried over anhydrous sodium sulphate (30g) and concentrated under reduced pressure at a water bath temperature of 45^°C to give the crude compound (20g).The crude is again dissolved in methyl tertiary butyl ether (25 ml_) and precipitated with Hexane (60ml). It is stirred for 10 min, filtered and dried under vacuum to afford Eliglustat as a white solid (16g). Yield: 74%, Mass (m/zj: 404.7 HPLC (% Area Method): 97.5 %, ELSD (% Area Method): 99.78%, Chiral HPLC (% Area Method): 99.78 %.

Example 7: Preparation of Eliglustat oxalate.

Eliglustat (5g) obtained from above stage 6 is dissolved in Ethyl acetate (5ml) at room temperature under nitrogen atmosphere. Oxalic acid (2.22g) dissolved in ethyl acetate (5ml) was added to the above solution at room temperature and stirred for 14h. White solid observed in the reaction mixture was filtered and dried under vacuum at room temperature for 1 h to afford Eliglustat oxalate as a white solid (4g). Yield: 65.46%, Mass (m/zj: 404.8 [M+H] ^+> HPLC (% Area Method): 95.52 %, Chiral HPLC (% Area Method): 99.86 %

Claims

Claims:

1 . A crystalline eliglustat free base (Form R1 ) having an X-ray powder diffraction pattern comprising peaks, located at about 6.06, 16.29, 18.96, 21.77 and 24.03 ± 0.2 degrees 2Θ.

2. The crystalline eliglustat free base (Form R1 ) according to claim 2, further comprising peaks, located at about 13.07, 16.93 and 28.30 ± 0.2 degrees 2Θ.

3. The crystalline eliglustat free base (Form R1 ) according to claim 1 and 2, further comprising peaks, expressed in 2Θ, located at about 12.65 and 26.41 ± 0.2 degrees 2Θ.

4. A crystalline eliglustat free base (Form R1 ) having PXRD pattern substantially as illustrated by figurel .

5. A crystalline eliglustat free base (Form R1 ) having thermal events at about 71 .98°C in differential scanning calorimetry (DSC) thermogram.

6. A crystalline eliglustat free base (Form R1 ) having differential scanning calorimetry (DSC) thermogram as illustrated by figure 2.

7. An improved process for the preparation of eliglustat free base, which comprises:

Formula II

wherein HA is an acid residue such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, phosphorous acid, hypophosphorous acid, propionic acid, butyric acid, formic acid and the like, and organic acids such as p-toluenesulfonic acid, methane sulfonic acid, trifluoromethane sulphonic acid, succinic acid, citric acid, benzoic acid, acetic acid, or trifluoroacetic acid; and

b) converting a compound of Formula II in one or more steps in to eliglustat.

8. The process of claim 7, wherein S-(+)-phenyl glycinol is reacted with phenyl- a-bromoacetate in the presence of a base.

9. A process for the preparation of crystalline eliglustat free base (form R1 ), which comprises:

a. providing a solution of eliglustat free base in a solvent;

b. adding an anti-solvent to the solution obtained in step (a); and c. isolating crystalline eliglustat free base (form R1 ).

10. The process of claim 9, wherein solvent is ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, dimethylfuran, 1 ,2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or 1 ,4-dioxane; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, or ethyl butanoate; aliphatic or alicyclic hydrocarbons such as hexanes, heptane, pentane, cydohexane, or methylcydohexane; nitromethane; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, or 1 ,2-dichloroethene; aromatic hydrocarbons such as toluene, xylene, chlorobenzene, or 1 ,2- dichlorobenzene; or mixture thereof.

1 1 . The process of claim 9, wherein anti-solvent is aliphatic or alicyclic hydrocarbons such as hexanes, heptane, pentane, cydohexane, or methylcydohexane; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, dimethylfuran, 1 ,2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or 1 ,4- dioxane; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, or ethyl butanoate; nitromethane; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, or 1 ,2-dichloroethene; aromatic hydrocarbons such as toluene, xylene, chlorobenzene, or 1 ,2- dichlorobenzene; or mixtures thereof.

12. A process for the preparation of crystalline eliglustat free base (form R1 ), which comprises: a) reacting S-(+)-phenyl glycinol with phenyl-a-bromoacetate to obtain a compound of formula II,

Formula II

13. The process of claim 12, wherein S-(+)-phenyl glycinol is reacted with phenyl-a-bromoacetate in the presence of a base.

14. The process of claim 12, wherein solvent is ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, dimethylfuran, 1 ,2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or 1 ,4-dioxane; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, or ethyl butanoate; aliphatic or alicyclic hydrocarbons such as hexanes, heptane, pentane, cydohexane, or methylcydohexane; nitromethane; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, or 1 ,2-dichloroethene; aromatic hydrocarbons such as toluene, xylene, chlorobenzene, or 1 ,2- dichlorobenzene; or mixtures thereof.

15. The process of claim 12, wherein anti-solvent is aliphatic or alicyclic hydrocarbons such as hexanes, heptane, pentane, cydohexane, or methylcydohexane; ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, dimethylfuran, 1 ,2- dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or 1 ,4- dioxane; esters such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, or ethyl butanoate; nitromethane; halogenated hydrocarbons such as dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, or 1 ,2-dichloroethene; aromatic hydrocarbons such as toluene, xylene, chlorobenzene, or 1 ,2- dichlorobenzene; or mixtures thereof.

16. Eliglustat oxalic acid salt.

17. Crystalline eliglustat oxalic acid salt.

18. A crystalline oxalic acid salt of eliglustat having an X-ray powder diffraction pattern comprising peaks, located at about 5.58, 6.90, 14.84, 18.71 and 28.98 ± 0.2 degrees 2Θ.

19. The crystalline oxalic acid salt of eliglustat according to claim 18, further comprising peaks, located at about 8.13, 21 .08 and 23.96 ± 0.2 degrees 2Θ.

20. The crystalline oxalic acid salt of eliglustat according to claim 18 and 19, further comprising peaks, expressed in 2Θ, located at about 15.24 and 21 .60 ± 0.2 degrees 2Θ.

21 . A crystalline oxalic acid salt of eliglustat having PXRD pattern substantially as illustrated by figure 3.

22. A process for the preparation of crystalline oxalic acid salt of eliglustat, which comprises:

a) providing a solution of eliglustat oxalic acid salt in a solvent, and

b) isolating crystalline eliglustat oxalic acid salt.

23. The process of claim 22, wherein solvent is esters, such as, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, or ethyl butanoate; ethers, such as, diethyl ether, diisopropyl ether, tert-butyl methyl ether, dibutyl ether, tetrahydrofuran, dimethylfuran, 1 ,2-dimethoxyethane, 2-methoxyethanol, 2- ethoxyethanol, anisole, or 1 ,4-dioxane; aliphatic or alicyclic hydrocarbons, such as, hexane, heptane, pentane, cydohexane, or methylcydohexane; nitromethane; halogenated hydrocarbons, such as, dichloromethane, chloroform, 1 ,1 ,2-trichloroethane, or 1 ,2-dichloroethene; aromatic hydrocarbons, such as, toluene, xylene; or any mixtures thereof.