DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
IMPROVED PROCESS FOR THE PREPARATION OF ELIGLUSTAT AND ITS SALTS

INTRODUCTION
The present application relates to an improved process for the preparation of Eliglustat or its pharmaceutically acceptable salts thereof. Further relates to isolation of intermediates in the form of solid and their use for preparation of Eliglustat or its pharmaceutically acceptable salts thereof.
Eliglustat is chemically known as 1R, 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.

Eliglustat hemitartrate (Genz-112638) development by Genzyme, is a glucocerebroside (glucosylceramide) synthase inhibitor for the treatment of Gaucher disease and other lysosomal storage disorders. Eliglustat hemitartrate is an 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.
The processes for the preparation of Eliglustat or its salts described in the prior art discussed above suffer from various disadvantages, such as tedious and cumbersome work-up procedures, use of not so environment friendly solvents, reactions under pressure and high temperature, longer reaction times, column chromatographic purifications and thus resulting in low overall yields of the product.
Therefore there remains a need to prepare Eliglustat of high purity and in good yield while overcoming the drawbacks presented by the processes described in the art.
The inventors of the present application have surprisingly found that when intermediates of Eliglustat are isolated in the form of solid, purity of Eliglustat got increased. For example, isolation of a compound of Formula VI, an intermediate of Eliglustat, in the form of a solid avoided the carryover of related impurities to the final stage leading to highly pure Eliglustat. Inventors of the present application further found that when one or more stages of the synthesis are done in one-pot without isolation of intermediates then overall yield is improved.
Therefore, present application provides an improved process for the preparation of Eliglustat or a pharmaceutically acceptable salt thereof which is simple, cost effective, environment friendly and commercially viable by avoiding repeated cumbersome and lengthy purification steps. It is a further an objective of the present application to provide intermediate compounds involved therein in the form of a solid and their use for preparation of highly pure Eliglustat or a pharmaceutically acceptable salt thereof.
SUMMARY
In first embodiment, the present application provides an improved process for preparation of eliglustat or a pharmaceutically acceptable salt thereof, which comprises:
a) obtaining a compound of Formula II,

b) in-situ reacting a compound of Formula II with 1,4-benzodioxan-6 carboxaldehyde to afford a compound of Formula III,

c) converting the compound of Formula III to Eliglustat or a pharmaceutically acceptable salt thereof.
In second embodiment, the present application provides an improved process for the preparation of Eliglustat or a pharmaceutically acceptable salt thereof, which comprises:
a) reducing a compound of Formula IV in presence of borohydride reducing agent to afford a compound of Formula V,

b) converting the compound of Formula V to Eliglustat or a pharmaceutically acceptable salt thereof.
In third embodiment, the present application provides an improved process for preparation of Eliglustat or a pharmaceutically acceptable salt thereof, which comprises:
a) converting a compound of Formula V under catalytic hydrogenation conditions to afford a compound of Formula VI,

b) converting the compound of Formula VI to Eliglustat or a pharmaceutically acceptable salt thereof.
In fourth embodiment, the present application provides one or more intermediate compounds as crystalline solids and their use for preparation of Eliglustat or a pharmaceutically acceptable salt thereof. In a preferred embodiment, compounds of Formula III, Formula IV and Formula VI are isolated in the form of solid and further employed for preparation of Eliglustat or its pharmaceutically acceptable salts.
In fifth embodiment of the present application provides a process for preparation of Eliglustat or a pharmaceutically acceptable salt thereof wherein compounds of Formulae II, V and VI are not isolated.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an illustration of a PXRD pattern of compound as obtained from example 1.
Figure 2 is an illustration of a PXRD pattern of compound as obtained from example 2.
Figure 3 is an illustration of a PXRD pattern of compound as obtained from example 4.
Figure 4 is an illustration of a PXRD pattern of compound as obtained from example 5.
Figure 5 is an illustration of a PXRD pattern of compound as obtained from example 16.
Figure 6 is an illustration of a PXRD pattern of compound as obtained from example 17.

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 11, 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.
In first embodiment, the present application provides an improved process for the preparation of Eliglustat or a pharmaceutically acceptable salt thereof, which comprises:
a) obtaining a compound of Formula II,

The said step a) can be materialized by reaction of S-(+)-phenyl glycinol with phenyl-a-bromoacetate in the presence of a suitable base in a solvent. Suitable bases that can be employed include, but are not limited to: organic bases such as triethylamine, diisopropylethylamine, morpholine, N-methyl Morpholine, DABCO (1,4-diazabicyclo[2.2.2]octane). In a preferred embodiment, diisopropyl ethylamine is employed.
Suitable solvents inert to the reaction conditions can be chosen from the list provided in the application. In a preferred embodiment, acetonitrile is employed.
b) in-situ reacting the compound of Formula II with 1,4-benzodioxan-6 carboxaldehyde to afford compound of Formula III,

The compound of Formula II from step a) is reacted with 1,4-benzodioxan-6 carboxaldehyde under suitable temperature in a suitable solvent to afford compound of Formula III.
The in-situ reaction may also involve removal of solvent from step a) before proceeding for step b).
In a preferred embodiment, the step b) is carried out in non-polar solvents. In yet another preferred embodiment, the step b) is carried out in cyclohexane at elevated temperature for overnight.
The step b) is performed with concomitant azeotropic distillation to increase the efficiency of the reaction.
c) converting the compound of Formula III to Eliglustat or a pharmaceutically acceptable salts.
The said conversion can be done by using an adaptation of literature methods, such as described in US7196205 or the method further described in the instant application.
In second embodiment, the present application provides an improved process for the preparation of Eliglustat or a pharmaceutically acceptable salt thereof, which comprises:
a) reducing a compound of Formula IV in presence of borohydride reducing agent to afford a compound of Formula V,

The said reduction is carried out in the presence of a borohydride based reducing agents such as sodium borohydride, sodium cyanoborohydride, lithium borohydride, and the like. In a preferred embodiment, said reduction is done in the presence of an acid selected from organic acid but not limited to, acetic acid, trifluoroacetic acid, a sulfonic acid such as methanesulfonic acid, p-toluenesulfonic, acid and the like. In preferred embodiments, trifluoroacetic acid, acetic acid are employed.
Suitable solvents inert to the reaction conditions can be chosen from the list provided in the application. In preferred embodiment, tetrahydrofuran (THF), toluene, dimethoxy ethane or mixtures thereof is employed.
Optionally, the compound of Formula V is not isolated and is converted to Eliglustat in one or more steps.
b) converting the compound of Formula VI to Eliglustat or a pharmaceutically acceptable salts thereof.
The said conversion can be done by using an adaptation of literature methods, such as described in US7196205 or the method further described in the instant application.
In third embodiment, the present application provides an improved process for the preparation of Eliglustat or a pharmaceutically acceptable salt thereof, which comprises: a) converting the compound of Formula V under catalytic hydrogenation conditions to afford a compound of Formula VI,

The said catalytic hydrogenation of Formula V may be achieved by techniques known in the art. For example, it may be achieved in the presence of a catalyst such as, for example, palladium on carbon, Raney nickel, or by transfer hydrogenation using ammonium formate, hydrazine, formic acid, and the like as a source of hydrogen.
This can optionally be done in presence of acid selected but not limited to hydrochloric acid, sulphuric acid, trifluoroacetic acid and like. The hydrogenation reaction of step a) may be carried out using hydrogen gas or a hydrogen source, e.g., ammonium formate, ammonium acetate, hydrazine, cyclohexadiene, or any other hydrogen source, and a catalyst, such as, for example, Raney nickel, platinum oxide, platinum on activated carbon, palladium hydroxide, palladium on barium sulfate, palladium on activated carbon, and palladium carbonate. The amount of catalyst employed may be about 1–100%, or about 5–50%, or about 5–25%, of the weight of the compound of Formula V.
Suitable solvents inert to the reaction conditions can be chosen from the list provided in the application. In a preferred embodiment, aqueous methanol is employed.The compound obtained after deprotection in step (a) may optionally be isolated and/or further reacted with an acid to afford a an acid addition salt of Formula VI. Alternatively, hydrogenation can be done under the conditions that directly lead to preparation of an acid addition salt of Formula VI. For example hydrogenation can be conducted using palladium on charcoal and hydrogen gas, in the presence of hydrochloric acid or benzyl chloride, or use of a catalytic amount of palladium on charcoal in the presence of an excess of ammonium formate or formic acid.
In a yet preferred embodiment, compound of Formula VI or its salt is subjected to purification by known methods of recrystallization, acid-base neutralizations, solvent-anti-solvent approach and like. For example, when solvent-anti-solvent approach is employed, esters were used as solvents and aliphatic hydrocarbons as anti-solvent. Ethyl acetate is employed as a solvent and cyclohexane as an anti-solvent. In yet another process, crude compound of Formula VI or its salt is taken up in water and subjected to washings with suitable aromatic hydrocarbon followed by pH adjustment of aqueous layer to about 12-14 and then re-extraction of the desired compound from aqueous layer in suitable aromatic hydrocarbon. Preferably, the suitable aromatic hydrocarbon is toluene and the said organic layer can be used as such for the next step.
b) converting the compound of Formula VI to Eliglustat or a pharmaceutically acceptable salt thereof.
The said conversion can be done by using an adaptation of literature methods, such as described in US7196205 or the method further described in the instant application.
In yet another preferred embodiment, during said conversion the compound of Formula VI is reacted with in situ prepared N-succinimidyl caprylate. More specifically, N-succinimidyl caprylate is generated by reaction of N-hydroxy succinimide with n-octanoyl chloride in a suitable solvent to afford N-succinimidyl caprylate in the mixture which is used without isolation for next step of reaction with compound of Formula VI to afford Eliglustat or a pharmaceutically acceptable salt thereof.
In fourth embodiment, the present application provides an improved process for the preparation of Eliglustat or a pharmaceutically acceptable salt thereof, which comprises a) preparing an acid addition salt of compound of Formula VI’, optionally purifying the said salt using suitable purification technique

wherein HX is an acid moiety such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, oxalic acid, acetic acid, formic acid, succinic acid, mandelic acid, fumaric acid, benzoic acid, or the like;
The compound of Formula VI’ can be prepared either by treating compound of formula VI with a suitable acid under suitable reaction conditions or can be obtained by conducting the deprotection of the compound of Formula V under suitable conditions resulting directly in a compound of Formula VI’.
In a preferred embodiment, compound of Formula VI’ is prepared by performing reduction reaction of compound of Formula IV to the compound of Formula V, optionally without isolation employing it for the next reaction i.e. conversion to compound of Formula VI and then salt preparation to afford the compound of Formula VI’.
Suitable acid addition salts in step a) include, but are not limited to, inorganic acids such as hydrochloric acid, sulphuric acid, and phosphoric acid, and organic acids such as oxalic acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, propionic acid, etc. In a preferred embodiment, oxalic acid salt was prepared.
Suitable solvents inert to the reaction conditions can be chosen from the list provided in the application. In a preferred embodiment, ethyl acetate is employed.
Undissolved particles from a mixture of step a) can be removed suitably by filtration, centrifugation, decantation, or other techniques, such as passing the solution through paper, glass fiber, a particulate bed, or a membrane material.
The compound of Formula VI’ is isolated by conventional techniques and may optionally be subjected to purification.
b) converting the compound of Formula VI’ in one or more steps to Eliglustat or a pharmaceutically acceptable salt thereof.
The said conversion can be done by using an adaptation of literature methods, such as described in US7196205 or the method further described in the instant application. The said conversion may involve generation of compound of Formula VI from compound of Formula VI’ before proceeding for the next chemical conversion.
In fifth embodiment, the present application provides a one or more intermediate compounds as solids, preferably as crystalline solids and their use for preparation of Eliglustat or its pharmaceutically acceptable salts. In a preferred embodiment, compounds of Formula III, Formula IV, Formula VI and Formula VI’ are isolated in the form of solid, preferably crystalline solids and further employed for preparation of Eliglustat or its pharmaceutically acceptable salts.
In sixth embodiment, the present application provides an improved process for the preparation of Eliglustat or a pharmaceutically acceptable salt thereof, which comprises:
a) treating the compound of Formula VI with octanoic acid under suitable reaction conditions to afford Eliglustat of Formula I,
b) optionally converting Eliglustat to its pharmaceutically acceptable acid addition salt.
Step a) can be materialized under amide forming reaction conditions which comprises reaction of compound of Formula VI with octanoic acid in presence of suitable base, coupling agent and activating agent.
In a preferred embodiment, octanoic acid is freshly distilled prior to being employed in step a).
Amide coupling agents that can be used comprise agents such as N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide as well as its hydrochloride salt (EDI or EDCI), 1,1’-Carbonyldiimidazole (CDI), N,N,N’,N’-tetramethyl-O-(7-azabenzotriazol-1-yl)uranium hexafluorophosphate (HATU), benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (commercially available asPyBOP), 1,3-diisopropylcarbodiimide,O-benzotriazole-N,N,N’,N’-tetramethyl-uronium-hexafluoro-phosphate (HBTU) and the like.
A catalyst may optionally be added. The said catalyst includes 1-hydroxybenzotriazole (HOBt), its monohydrate or 4-dimethylaminopyridine (DMAP).
Suitable base employed that can be employed in step a) include, but are not limited to: organic bases such as triethylamine, diisopropylethylamine, morpholine, N-methyl Morpholine, and like. In preferred embodiments, diisopropyl ethylamine is employed.
Suitable solvents inert to the reaction conditions can be chosen from the list provided in the application. In preferred embodiment, toluene is employed.
Step b) involves conversion of Eliglustat of Formula I to its pharmaceutically acceptable acid addition salt under suitable reaction conditions.
Optionally, Eliglustat i.e. compound of Formula I is not isolated and is converted directly without isolation to its pharmaceutically acceptable acid addition salt.
Pharmaceutically acceptable acid in step b) can be selected by a person skilled in the art. A suitable acid that can be employed in step b) is a mineral or organic acid. Suitable mineral acids for salt formation include hydrochloric, hydrobromic, phosphoric acid and sulphuric acid. Suitable organic acids include tartaric acid, para-toluenesulfonic acid, acetic, oxalic, succinic acid and formic acid. In a preferred embodiment, L-tartaric acid is the pharmaceutically acceptable acid.
In seventh embodiment, the present application provides a process for preparation of Eliglustat or its pharmaceutically acceptable salts thereof wherein one or more steps do not employ isolation of intermediate compounds.
a) obtaining a compound of Formula II,

b) in-situ reacting the compound of Formula II with 1,4-benzodioxan-6 carboxaldehyde,

c) reacting compound of Formula III with pyrrolidine under suitable reaction conditions,

d) reducing the compound of Formula IV in presence of borohydride reducing agent to afford a compound of Formula V,

e) converting the compound of Formula V under catalytic hydrogenation conditions to afford a compound of Formula VI,

f) treating compound of Formula VI with octanoic acid under suitable reaction conditions and isolating Eliglustat free base of Formula I,
g) reacting Eliglustat with suitable amount of L-tartaric acid under suitable reaction conditions to afford Eliglustat hemitartrate.
The reaction conditions employed in each step can be referred from above embodiments. For example, compound of Formula III can be prepared without isolation of compound of Formula II. Similarly, compound of Formula I can be prepared without isolation of compound of Formula V and Formula VI.
In eighth embodiment, the present application provides an improved process for the preparation of crystalline Eliglustat hemitartrate, which comprises:
a) treating Eliglustat free base of Formula I with L-tartaric acid in a suitable solvent and refluxing the mixture for at least 30 minutes,
b) cooling the reaction mixture,
c) isolating the crystalline Eliglustat hemitartrate.
The suitable solvent employed in step a) can be chosen from the list provided in the application. In a preferred embodiment acetone is employed.
The mixture in step a) may be prepared either by treating a solution of eliglustat free base with a solution of L-tartaric acid or by addition of L-tartaric acid to a solution of Eliglustat free base. The mixture can be refluxed for about 30 minutes to 4 hours or longer duration. Preferably, refluxing is done for 2 hours.
Optionally, seed crystals of eliglustat hemitartrate can be added during stage a) or b) to facilitate crystallization. In a preferred embodiment, seed crystals are added to a solution of eliglustat free base. The amount of seed crystals added in step a) or step b) can be 0.5-15% (w/w) to the starting material i.e. Eliglustat free base.
Suitable temperatures in step b) may be less than about 40°C, or less than about 20°C, or less than about 5°C, or any other suitable temperatures.
Suitable times employed in step b) may be from about 30 minutes to about 10 hours, or longer. Optionally, step-wise cooling can be done to ease the filtration by improving the morphology of crystalline particles.
The crystalline eliglustat hemitartrate obtained can optionally be further subjected to purification processes by employing solvents reported in the application. In a preferred embodiment, ketones and polar aprotic solvents are employed.
The chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification, may be carried out at ambient temperatures, but particular reactions may require the use of higher or lower temperatures, depending on reaction kinetics, yields, and the like. Furthermore, any of the chemical transformations may employ one or more compatible solvents, which may influence the reaction rates and yields. Depending on the nature of the reactants, the one or more solvents may be polar protic solvents, polar aprotic solvents, non-polar solvents, water or any of their combinations.
Suitable solvents inert to the reaction conditions include but are not limited to: alcohols, such as methanol, ethanol, 2-propanol, n-butanol, isoamyl alcohol and ethylene glycol; ethers, such as diisopropyl ether, dimethoxyethane, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), methyl THF, and diglyme; esters, such as ethyl acetate, isopropyl acetate, and t-butyl acetate and like; ketones, such as acetone and methyl isobutyl ketone and like; aliphatic hydrocarbons like n-hexane, cyclohexane, iso-octane and like; aromatic hydrocarbons like toluene, xylene and like; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and like; nitriles, such as acetonitrile; polar aprotic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, and the like; water; and any mixtures of two or more thereof.
The compounds obtained by the chemical transformations of the present application can be used for subsequent steps without further purification, or can be effectively separated and purified by employing a conventional method well known to those skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt followed by optionally washing with an organic solvent or with an aqueous solution, and eventually adjusting pH. Compounds at various stages of the process may be purified by precipitation or slurrying in suitable solvents, or by commonly known recrystallization techniques. The suitable recrystallization techniques include, but are not limited to, steps of concentrating, cooling, stirring, or shaking a solution containing the compound, combination of a solution containing a compound with an anti-solvent, seeding, partial removal of the solvent, or combinations thereof, evaporation, flash evaporation, or the like. An anti-solvent as used herein refers to a liquid in which a compound is poorly soluble. Compounds can be subjected to any of the purification techniques more than one time, until the desired purity is attained.
Compounds may also be purified by slurrying in suitable solvents, for example, by providing a compound in a suitable solvent, if required heating the resulting mixture to higher temperatures, subsequent cooling, and recovery of a compound having a high purity. Optionally, precipitation or crystallization at any of the above steps can be initiated by seeding of the reaction mixture with a small quantity of the desired product. Suitable solvents that can be employed for recrystallization or slurrying include, but are not limited to: alcohols, such as, for example, methanol, ethanol, and 2-propanol; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), and methyl THF; esters, such as, for example, ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; hydrocarbons, such as toluene, xylene, and cyclohexane; nitriles, such as acetonitrile and the like; water; and any mixtures of two or more thereof.
The compounds at various stages of the process may be recovered using conventional techniques known in the art. For example, useful techniques include, but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, and the like. The isolation may be optionally carried out at atmospheric pressure or under a reduced pressure. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher than desired percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor. Evaporation as used herein refers to distilling a solvent completely, or almost completely, at atmospheric pressure or under a reduced pressure. Flash evaporation as used herein refers to distilling of solvent using techniques including, but not limited to, tray drying, spray drying, fluidized bed drying, or thin-film drying, under atmospheric or a reduced pressure.
A recovered solid may optionally be dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 150°C, less than about 100°C, less than about 60°C, or any other suitable temperatures, in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, from about 1 hour to about 15 hours, or longer.
Eliglustat and its salts, such as the hemitartrate salt, and drug-related impurities may be analysed using high performance liquid chromatography (HPLC), for example by a method using a Poroshell column, with the following parameters:
Flow rate 0.8 mL/minute
Detector 210 nm
Column oven temp. 40°C
Injection volume 5 ?L
Run time 75 minutes
Elution Gradient
Mobile phase Mobile Phase A: Buffer:Acetonitrile::950:50 (v/v)
Mobile phase B: Acetonitrile:methanol::800:200 (v/v)
Buffer: 20 mM potassium phosphate with pH adjusted to 7
Diluent Water:Acetonitrile (1:1)

Eliglustat or its pharmaceutically acceptable salts obtained by above process is substantially free from impurities. Typically, the Eliglustat or its pharmaceutically acceptable salts is of high purity, such as at least about 99%, 99.5%, or 99.9%, by weight pure. Correspondingly, the level of impurities may be less than about 1%, 0.5%, or 0.1%, by weight, as determined using high performance liquid chromatography (HPLC).
The present invention includes Eliglustat or its pharmaceutically acceptable salts, substantially free from below impurities.
S.No. Impurity RRT
1
0.56
2
0.52
2
0.89
3
2.25
4
0.22
5
1.12
6
0.95

The presence of impurities in Eliglustat or its pharmaceutically acceptable salts may pose a problem for pharmaceutical product formulation, in that impurities often affect the safety and shelf life of a formulation. The present invention provides a method for ameliorating the effect of an impurity present in formulations of Eliglustat or its pharmaceutically acceptable salts by reducing the amount of the impurities during synthesis.
Solid states of compounds 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.
The solid compounds of this application are best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. PXRD data reported herein was obtained using CuK? radiation, having the wavelength 1.5418 Å and were obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer. For a discussion of these techniques see J. Haleblain, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sci. 1969 58:911-929.
Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ± 0.2?. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ± 0.20. Accordingly, the present application includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ± 0.20. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2? ± 0.20) of 7.9?" means "having a diffraction peak at a diffraction angle (2?) of 7.7? to 8.1?”. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the PXRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of PXRD is meant to encompass that peak assignments can vary by ± about 0.2 degrees. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not).

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.
A “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, cyclohexane, methylcyclohexane, cycloheptane, petroleum ethers, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, or any mixtures thereof.
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.
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- 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, dimethoxy ethane, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- 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 “polar aprotic solvent” has a dielectric constant greater than 15 and includes: amide-based organic solvents, such as hexamethyl phosphoramide (HMPA), hexamethyl phosphorus triamide (HMPT), and N-methylpyrrolidone, nitro-based organic solvents, such as nitromethane, nitroethane, nitropropane, and nitrobenzene; ester-based organic solvents, such as ?-butyrolactone, ethylene carbonate, propylene carbonate, butylene carbonate, dimethyl carbonate, and propiolactone; pyridine-based organic solvents, such as pyridine and picoline; and sulfone-based solvents, such as dimethylsulfone, diethylsulfone, diisopropylsulfone, 2-methylsulfolane, 3-methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethylsulfolane, 3-sulfolane, and sulfolane.
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.
Any organic solvents may be used alone, or any two or more may be used in combination, or one or more may be used in combination with water in desired ratios.
Acid addition salts are typically pharmaceutically acceptable, non-toxic addition salts with “suitable acids,” including, but not limited to: inorganic acids such as hydrohalic acids (for example, hydrofluoric, hydrochloric, hydrobromic, and hydroiodic acids) or other inorganic acids (for example, nitric, perchloric, sulfuric, and phosphoric acids); organic acids, such as organic carboxylic acids (for example, xinafoic, oxalic, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, 2- or 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 2- or 4-chlorobenzoic, salicylic, succinic, malic, hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, oleic, and glutaric acids), organic sulfonic acids (for example, methanesulfonic, trifluoromethanesulfonic, ethanesulfonic, 2-hydroxyethanesulphonic, benzenesulfonic, toluene-p-sulfonic, naphthalene-2-sulphonic, and camphorsulfonic acids), and amino acids (for example, ornithinic, glutamic, and aspartic acids).
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.
Terms such as "about," "generally," "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at the very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material has 99% purity or higher, as determined using methods conventional in the art such as high performance liquid chromatography (HPLC), gas chromatography (GC), or spectroscopic methods. In general, this refers to purity with regard to unwanted residual solvents, reaction by-products, impurities, and unreacted starting materials. In the case of stereoisomers, "pure" also means 99% of one enantiomer or diastereomer, as appropriate. "Substantially pure” refers to the same as "pure,” except that the lower limit is about 98% purity or higher and, likewise, "essentially pure” means the same as "pure" except that the lower limit is about 97% purity.
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 (1R,3S,5S,8aS)-1,3-bis(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-phenyltetrahydro-3H,8H-oxazolo[4,3-c][1,4]oxazin-8-one (Formula III)
A flask was charged with (S)-2-amino-2-phenylethanol (25 g) and acetonitrile (400 mL), diisopropylethyl amine (47.1g) at room temperature. The mixture was allowed to cool to about 16oC followed by slow addition of a solution of phenylbromoacetate (43.1g) in acetonitrile (125 mL) over a period of 30 minutes. The reaction mixture is stirred at the same temperature for about 2 hours at which point completion of the reaction was checked by HPLC. Then, 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (59.8 g) was added to the mixture and temperature was increased to reflux point. The reaction mixture was stirred at reflux temperature for about 4 hours. The solvent was completely distilled and the obtained mixture was maintained at 110oC for about 2 hours and then cooled to room temperature followed by addition of ethyl acetate (250 mL) and water (250 mL). The organic layer was separated and washed with 5% aqueous sodium hydroxide solution (250 mL), then water (250 mL). The organic layer was subjected to complete distillation under vacuum at 55oC. To the obtained crude compound, toluene (37.5 mL) was added and mixture was cooled to 5oC under stirring. Then methanol (60 mL) was added at the same temperature, the solid obtained was filtered and washed with chilled methanol (25 mL), dried under vacuum to afford the title compound.
Example 2: Preparation of (2S,3R)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxy-2-(((S)-2-hydroxy-1-phenylethyl)amino)-1-(pyrrolidin-1-yl)propan-1-one (Formula IV)
A flask is charged with (1R,3S,5S,8aS)-1,3-bis(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-phenyltetrahydro-3H,8H-oxazolo[4,3-c][1,4]oxazin-8-one (10g), toluene (100 mL) and pyrrolidine (7.29 g) and mixture is stirred at room temperature for 1.5 hours. Then conc. HCl (25 mL) is slowly added over a period of about 35 minutes and mixture is further stirred for about 6 hours, completion of the reaction is monitored by TLC. The layers were separated and aqueous layer was sequentially washed with toluene (50 mL), then with saturated sodium bicarbonate solution (200 mL). Then aqueous layer is separated and further extracted with ethyl acetate (100 mL and 50 mL). The organic layers are combined and subjected to complete distillation under vacuum followed by addition of toluene (10 mL) and its distillation. Again toluene (25 mL) was added and stirred for dissolution followed by cooling to about 28oC. The solid obtained was filtered and washed with toluene (10 mL) followed by drying under vacuum at about 50oC to afford the title compound having HPLC purity as 98.89% in 72% yield.
Example 3: Preparation of (1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(((S)-2-hydroxy-1-phenylethyl)amino)-3-(pyrrolidin-1-yl)propan-1-ol (Formula V)
A flask was charged with (2S,3R)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxy-2-(((S)-2-hydroxy-1-phenylethyl)amino)-1-(pyrrolidin-1-yl)propan-1-one (50 g) in tetrahydrofuran (250 mL) followed by sodium borohydride (22.93 g) at the room temperature. Then trifluoroacetic acid (69.1 g) was slowly added to the above mixture over a period of about 1 hour. The mixture was stirred at about 50oC for about 1.5 hours at which point TLC was checked for completion of reaction. The mixture was then cooled to about 30oC followed by addition of aqueous HCl solution (200 mL conc. HCl in 200 mL of water) over a period of about 45 minutes. The reaction mixture was stirred at about 50oC for about 2 hours, reaction was monitored by TLC. Then mixture was cooled to room temperature followed by addition of 40% sodium hydroxide solution (300 mL) and then toluene (300 mL). The layers were separated. The aqueous layer was extracted with toluene (150 mL). The organic layers were combined and washed with 10% sodium chloride solution (300 mL) followed by complete distillation of toluene under vacuum at about 50oC to afford the title compound.
Example 4: Preparation of (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (Formula VI)
A flask was charged with (1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(((S)-2-hydroxy-1-phenylethyl)amino)-3-(pyrrolidin-1-yl)propan-1-ol (48g), methanol (480 mL) followed by addition of water (96 mL), trifluoroacetic acid (41.2 g) and Pd/C (14.42 g). The mixture was stirred under hydrogen gas pressure of 6 kg/cm2 and at temperature of about 50oC for about 12 hours. After completion of reaction, the mixture was cooled to room temperature and then filtered through hyflow, the bed was washed with methanol (96 mL). The filtrate was subjected to complete distillation under vacuum at about 50oC. To the obtained compound, water (96 mL) was added followed by addition of 1N hydrochloric acid solution (24 mL). Then aqueous layer was subjected to washings with 60% ethyl acetate in n-hexane (720 mL). The aqueous layer was cooled to about 7-9oC at which point 10 M sodium hydroxide solution (48 mL) is added over a period of 20 minutes and the mixture was stirred for about 1 hour at the same temperature. Then solid obtained was filtered, then washed with water (144 mL) and n-hexane (96 mL) and subjected to drying under vacuum at about 50oC for about 4 hours to afford the title compound having HPLC purity of 99.09%.
Example 5: Preparation of Eliglustat
A flask was charged with N-hydroxysuccinimide (0.5 g), dichloromethane (20 mL) and triethyl amine (0.9 mL). The mixture was cooled to 0-5oC under stirring followed by slow addition of a solution of n-octanoyl chloride (0.9 mL) in dichloromethane (10 mL) over a period of 30 minutes. The mixture was stirred at room temperature for about 2 hours for completion of reaction. To this mixture, a solution of (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (1.2 g) in dichloromethane (10 mL) was added over a period of 15 minutes and mixture was stirred for 10-14 hours at 25-35oC. After completion of the reaction as monitored by TLC, the mixture was cooled to 0-5oC followed by addition of 1M sodium hydroxide solution (15 mL) at 0-5oC and stirring for 30 minutes. The layers were separated, and the organic layer was sequentially washed with water (5 mL), sodium chloride solution (20 mL). The organic layer was subjected to complete distillation under vacuum followed by addition of 20% MTBE in n-hexane (10 mL) to the resulting crude compound. The mixture was stirred for 2-3 hours followed by complete distillation of solvent under vacuum to afford the title compound.
Example 6: Preparation of (1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(((S)-2-hydroxy-1-phenylethyl)amino)-3-(pyrrolidin-1-yl)propan-1-ol (Formula V)
A flask was charged with (2S,3R)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxy-2-(((S)-2-hydroxy-1-phenylethyl)amino)-1-(pyrrolidin-1-yl)propan-1-one (3 g) in a mixture of dimethoxyethane (6 mL) and toluene (15 mL) followed by addition of sodium borohydride (1.37 g) at the room temperature. Then reaction mixture was allowed to cool to about 13oC at which point solution of acetic acid (2.18 mL) in toluene (9mL) was added. The mixture is allowed to attain 58oC temperature with continuous stirring of mixture and one more lot of dimethoxy ethane (30 mL) was added. The mixture was stirred at 58oC for about 5 hours. After completion of reaction as monitored by TLC, mixture is allowed to cool at about 14oC at which point 20% sodium hydroxide solution (30 mL) was added. The mixture is heated to about 67-73oC and stirred for about 3.5 hours. The mixture was allowed to cool to about 28oC, the layers were separated. The aqueous layer was extracted with toluene (15 mL). The combined organic layer was again washed with water (30 mL). The organic layers were combined and subjected to complete distillation under vacuum to afford the title compound.
Example 7: Preparation of (S)-5-phenylmorpholin-2-one
A flask was charged with (S)-2-amino-2-phenylethanol (100 g), acetonitrile (2000mL) and stirred for 10 minutes followed by addition of N-ethyl-diisopropyl amine (236 mL) and further stirring for 5-10 minutes. Then a mixture of phenyl 2-bromoacetate (180 g) in acetonitrile (500 mL) was slowly added to the above reaction mixture at room temperature over a period of about 75 minutes. The mixture was maintained at room temperature for about 2.5 hours and then kept under cold conditions for further experimentation purpose.
Example 8: Preparation of (1R,3S,5S,8aS)-1,3-bis(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-phenyltetrahydro-3H,8H-oxazolo[4,3-c][1,4]oxazin-8-one (Formula III)
A flask was charged with a reaction mixture containing (S)-5-phenylmorpholine-2-one (6.45 g) in acetonitrile prepared according to above example. To this 1,4-benzodioxane-6-carboxaldehyde (11.95 g) was added. The solvent was subjected to distillation under vacuum below 45oC followed by cooling of the mass to 25-35oC. To this, cyclohexane (100 mL) was added and mixture was heated to 75-80oC, collected 25 mL of cyclohexane by azeotropic distillation, and the maintained the mixture at the same temperature for 21 hours followed by cooling to 25oC. To this mixture then ethyl acetate (50 mL) and water (50 mL) were added. The layers were separated and organic layer was subjected to distillation under vacuum at below 45oC followed by cooling of the mass. Then methanol (50 mL) and toluene (10 mL) was added into crude at 25oC, stirred for about 2 hours. Then mixture was cooled to about 15oC and maintained for about 1 hour followed by filtration of the obtained solid and its washing with methanol (10 mL). The solid was subjected to drying under vacuum at about 55oC for 12-14 hours to afford the title compound having HPLC purity as 99.05%.
Example 9: Preparation of (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (Formula VI)
A flask was charged with (1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(((S)-2-hydroxy-1-phenylethyl)amino)-3-(pyrrolidin-1-yl)propan-1-ol (40g), methanol (200 mL) followed by addition aqueous hydrochloric acid (7.33 g, 35%) and Pd/C (4.01 g). The reaction mixture was flushed with nitrogen followed by hydrogen gas pressure of 6.5 kg/cm2. The mixture was heated to about 50-55oC and maintained for 8 hours for completion of the reaction as monitored by TLC. The reaction mixture was cooled to about 25-30oC, then filtered through hyflowbed, washed with methanol (40 mL), then water (40 mL). Then the filtrate was subjected to distillation under vacuum at below 55oC to afford the crude compound. The crude compound was dissolved in water (120 mL) followed by addition of 1N HCl solution (20 mL). The mixture was subjected to washing with 60% ethyl acetate in hexane (2x240 mL), then cooled to 10-15oC at which point 10% sodium hydroxide (50 mL) was added. The mixture was stirred at about 15oC for 1 hour and then solid obtained was filtered and sequentially washed with water (80 mL), n-hexane (80 mL) and then suck dried followed by drying in vacuum oven at 25-30oC for about 22 hours to afford the title compound.
Example 10: Preparation of (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (Formula VI)
A flask was charged with (1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(((S)-2-hydroxy-1-phenylethyl)amino)-3-(pyrrolidin-1-yl)propan-1-ol (5g), methanol (40 mL) followed by addition of aqueous solution of sulphuric acid (2.46 g in 2.5 mL) and Pd/C (1 g). The reaction mixture was flushed with nitrogen followed by hydrogen gas pressure of 2.6 kg/cm2. The mixture was heated to about 50-55oC and maintained for 5.5 hours for completion of the reaction as monitored by TLC. The reaction mixture was cooled to about 25-30oC, then filtered through hyflowbed, washed with methanol (5 mL), then water (5 mL). Then the filtrate was subjected to distillation under vacuum at below 55oC to afford the crude compound. The crude compound was dissolved in water (15 mL) followed by addition of 1N HCl solution (2.5 mL). The mixture was subjected to washing with 60% ethyl acetate in hexane (60 mL), then cooled to 10-15oC at which point pH was adjusted to about 12 with 10% sodium hydroxide (50 mL) was added. The mixture was stirred at about 15oC for 25 minutes and then the solid obtained was filtered and sequentially washed with methanol (5mL), water (5 mL) and then suck dried followed by drying in vacuum oven at 25-30oC for about 10 hours to afford the title compound.
Example 11: Preparation of Eliglustat
A flask was charged with (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (82 g) in toluene (15 mL) and heated to about 52-54oC followed by addition of 2,5-dioxopyrrolidin-1-yl octanoate (71.1g). The mixture was maintained at the same temperature for about 4.5 hours, completion of the reaction is monitored by TLC. Then the mixture was cooled to about 15oC at which point 1M sodium hydroxide solution (410 mL) was slowly added over a period of 15 minutes and mixture was stirred at about 28oC for another 15-20 minutes. The organic layer was separated and washed with 10% aqueous sodium chloride (2x492 mL), then subjected to vacuum distillation at below 55oC to afford the crude compound. Then 20% MTBE in n-hexane (656 mL) was added to the crude material and mixture was stirred at 26-28oC for about 3.5 hours followed by filtration of the solid and its washing with n-hexane (246 mL). The obtained solid was dried under vacuum at about 40oC for 4.5 hours to afford the title compound.
Example 12: Preparation of Eliglustat hemitartrate
A flask was charged with Eliglustat (85 g) in acetone (1020 mL) to afford a clear solution. To this, a solution of (2R, 3R)-tartaric acid (15.77 g) in acetone (510 mL) was added and mixture was maintained at about 28oC for 2 hours. Then the mixture was heated to about 50-55oC and maintained for about 1 hour followed by cooling to about 25oC and further maintenance for another 12 hours. The obtained solid was filtered and washed with acetone (85 mL), followed by vacuum drying in oven at 50oC for about 3 hours to afford the title compound in about 85% yield.
Example 13: Preparation of Eliglustat hemitartrate
A flask was charged with Eliglustat hemitartrate (135 g), methyl isobutyl ketone (1620 mL), acetonitrile (1620 mL) and the mixture was heated to about 84oC for about 45 minutes followed by filtration. The filtrate was transferred to a different flask and then mixture was stirred at about 30-40oC for about 40 minutes. The solid is filtered and washed with a mixture of methyl isobutyl ketone (270 mL) and acetonitrile (270 mL), then suck dried followed by vacuum drying at about 50-55oC for about 7-8 hours to afford the title compound having HPLC purity of 99.57% in about 92% yield.
Example 14: Preparation of Oxalate salt of (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (Formula VI’)
A flask was charged with (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (4 g), and ethyl acetate (40 mL), heated to 40-45oC. The clear solution so obtained is maintained for 15-20 minutes and then filtered through hyflow followed by washing with ethyl acetate (8mL). In a separate flask, oxalic acid (1.81 g) was dissolved in ethyl acetate (8mL) by heating to about 40-45oC. The instant oxalic acid solution was added to first solution over a period of 15 minutes at 40-45oC and maintained for about 40 minutes followed by filtration and washing with ethyl acetate (8mL). The obtained compound was subjected to drying under vacuum at 50-55oC for about 20 hours to afford the title compound in about 86% yield having HPLC purity of 99.59%.
Example 15: Preparation of (2S,3R)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxy-2-(((S)-2-hydroxy-1-phenylethyl)amino)-1-(pyrrolidin-1-yl)propan-1-one (Formula IV)
A flask is charged with (1R,3S,5S,8aS)-1,3-bis(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-phenyltetrahydro-3H,8H-oxazolo[4,3-c][1,4]oxazin-8-one (10g), toluene (70 mL) and Pyrrolidine (7.29 g) and mixture is heated to about 50oC and stirred at the same temperature for about 3 hours. Then mixture was cooled to room temperature followed by addition of water (100 mL) and toluene (30 mL). The layers were separated and toluene layer was washed with water (50 mL) followed by slow addition of conc. hydrochloric acid (5.3 mL) over a period of 15 minutes at about 15oC. The mixture was maintained at room temperature for 1.5 hours followed by separation of layers. The aqueous layer was separated and washed with toluene (50 mL). Then to the aqueous layer, ethyl acetate (100 mL) and saturated sodium bicarbonate solution (50 mL) were added. Then aqueous layer is separated and further extracted with ethyl acetate (50 mL). The organic layer were combined and solvent was removed under vacuum followed by addition of ethyl acetate (30 mL) and cyclohexane (30 mL) to the obtained crude compound. The mixture was maintained at room temperature for about 2 hours, followed by filtration of the solid and its washing with cyclohexane (30 mL). The solid was dried under vacuum at below 50oC for about 2 hours to afford the title compound having HPLC purity as 99.50% in 78% yield.
Example 16: Preparation of Oxalate salt of (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (Formula VI’)
A flask was charged with (2S,3R)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxy-2-(((S)-2-hydroxy-1-phenylethyl)amino)-1-(pyrrolidin-1-yl)propan-1-one (50 g) in 1,2-dimethoxyethane (250 mL), toluene (350 mL) and mixture was stirred at room temperature for 15-30 minutes followed by addition of sodium borohydride (27.51 g). The mixture was cooled to 15-20oC and then mixture of acetic acid (43.63 g) in toluene (150 mL) was slowly added at 10-20oC. Then reaction mixture was allowed to attain room temperature and then was heated to 70-75oC at which point it was maintained for 2-4 hours. The mixture was then cooled to 10-20oC followed by addition of 20% sodium hydroxide (300 mL). The mixture was again heated to 70-75oC for 6-8 hours followed by cooling to the room temperature. The organic layer was separated and aqueous layer was extracted with toluene (250 mL). The organic layers were combined and sequentially washed with water (250 mL), 5% aqueous sodium chloride (125 mL) followed by complete distillation of organic layer at 50-55oC under vacuum to afford the crude. Then methanol (150 mL) was added to the above crude and again the solvent was completely distilled under vacuum. Then methanol (500 mL) was added to above crude and mixture was stirred for 25-30 minutes at 25-35oC for dissolution. This mixture was transferred to autoclave hydrogenation vessel and then aqueous sulphuric acid (11.9 g in 50 mL water) was added followed by 10% Pd/C (7.5 g) under nitrogen atmosphere and mixture was stirred for 10-15 minutes. The mixture was flushed with nitrogen atmosphere followed by hydrogen gas pressure 5-7 Kg/cm2. The mixture was heated to about 50-55oC and maintained for 8-10 hours for completion of the reaction as monitored by TLC. The reaction mixture was cooled to about 25-30oC, then mixture was flushed with nitrogen gas and then filtered through celite bed, washed with methanol (100 mL). The filtrate was completely distilled under reduced pressure at 50-55oC followed by addition of water (150 mL) to the resultant crude. Then ethyl acetate (250 mL) was also added and mixture was stirred. The aqueous layer was separated and washed with ethyl acetate (250 mL). Then aqueous layer was cooled to 5-15oC and followed by pH adjustment to 11-14 with 10 M aqueous sodium hydroxide solution (~30 mL). Then ethyl acetate (500 mL) was added and temperature of the mixture was raised to 25-35oC at which point it was maintained for 25-30 minutes. The organic layer was separated and aqueous layer was extracted with ethyl acetate (250 mL). The organic layers were combined and subjected to distillation under vacuum at 50-55oC to afford the crude compound. To the crude compound, ethyl acetate (500 mL) was added and mixture was heated to 40-45oC followed by addition of a solution of oxalic acid in ethyl acetate (7.64 g in 250 mL). The mixture was maintained at 40-45oC for about 3-4 hours followed by filtration of the solid and its washing with ethyl acetate (100 mL). The obtained solid was subjected to drying under vacuum at 50-55oC for about 2 hours to afford the title compound.
Example 17: Purification of (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (Formula VI)
A flask was charged with (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (5 g) and ethyl acetate (20 mL), heated to 55oC for dissolution. Then cyclohexane (80 mL) was added to above solution at 45oC over a period of 10 minutes. The mixture was then cooled to 15-25oC, the obtained solid was filtered and washed with cyclohexane (20mL). The solid obtained was dried under vacuum to afford the title compound.
Example 18: Preparation of Eliglustat (Formula I)
A flask was charged with (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (10 g), ethyl acetate (15 mL) and N-methylmorpholine (10.9 g) at room temperature followed by addition of 2,5-dioxopyrrolidin-1-yl octanoate (8.6 g). The mixture was maintained at the same temperature for about 16 hours, completion of the reaction is monitored by TLC. Then 20% sodium hydroxide solution (50 mL) was added and organic layer is separated, further washed with 20% sodium hydroxide solution (50 mL). Then organic layer was washed with water (100 mL & 50 mL) followed by distillation of organic layer under vacuum at below 50oC. The crude obtained after distillation was chased with ethyl acetate (50 mL). Then ethyl acetate (10 mL) and cyclohexane (40 mL) were added to the residue and mixture was cooled to about 5oC. The solid obtained is filtered and washed with cyclohexane (10 mL) followed by drying to afford the title compound.
Example 19: Preparation of Eliglustat (Formula I)
A flask was charged with (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (10 g) and ethyl acetate (15 mL) at room temperature followed by addition of 2,5-dioxopyrrolidin-1-yl octanoate (8.6 g). The mixture was maintained at the same temperature for about 16 hours, completion of the reaction is monitored by TLC. Then 20% sodium hydroxide solution (50 mL) was added and organic layer is separated, further washed with 20% sodium hydroxide solution (50 mL). Then organic layer was washed with water (100 mL & 50 mL) followed by distillation of organic layer under vacuum at below 50oC. The crude obtained after distillation was chased with ethyl acetate (50 mL). Then ethyl acetate (10 mL) and cyclohexane (40 mL) were added to the residue and mixture was cooled to about 5oC. The solid obtained is filtered and washed with cyclohexane (10 mL) followed by drying to afford the title compound.
Example 20: Preparation of Eliglustat hemitartrate
A flask was charged with (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (5 g) and ethyl acetate (50 mL) at room temperature followed by addition of EDC-HCl (3.7 g), HOBt (243 mg), DIPEA (3.48 g) and octanoic acid (2.59 g). The mixture was maintained at the same temperature for about 6-7 hours, completion of the reaction was monitored by TLC. Then water (50 mL) was added and organic layer was separated, further washed with water (5 mL). Then organic layer was subjected to complete distillation under vacuum at below 55oC. To the obtained crude compound, acetonitrile (25 mL) was added and heated to about 85oC followed by further addition of acetonitrile (125 mL) and L-tartaric acid (1.348 g). The mixture was maintained at the same temperature for about 25 minutes. Then solution was subjected to cooling at about 30oC and maintained for about 2 hours. The solid obtained was filtered and washed with acetonitrile (10 mL) followed by vacuum drying at 50oC for 2 hours to afford the title compound having HPLC purity of 99.64%, N-oxide impurity: 0.021%.
Example 21: Preparation of Eliglustat hemitartrate
A flask was charged with (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (10 g) and ethyl acetate (150 mL) at room temperature followed by addition of EDC-HCl (7.58 g), HOBt (485 mg), DIPEA (6.96 g) and octanoic acid (5.18 g). The mixture was maintained at the same temperature for about 4 hours, completion of the reaction was monitored by TLC. Then water (100 mL) was added and organic layer was separated, further washed with water (10 mL). Then organic layer was subjected to complete distillation under vacuum at below 55oC. The obtained residue is further chased with ethyl acetate (50 mL) followed by further addition of ethyl acetate (100 mL). The organic layer is divided into two parts viz., Part A and Part B and subjected to following procedure.
Part A: This part was distilled under vacuum followed by addition of ethyl acetate (10 mL) at room temperature. Then cyclohexane (40 mL) was added and mixture was cooled to about 5oC at which point it was maintained for about 20 minutes. Then mixture was brought to room temperature and the solvent was completely distilled. To the crude, ethyl acetate (10 mL) and cyclohexane (40 mL) were added and mixture was again cooled and maintained at 2-5oC for about 1.5 hours. The obtained solid was filtered and washed with cyclohexane (10 mL) followed by drying under vacuum at 50oC for about 3-4 hours. To this, acetonitrile (50 mL) was added at room temperature followed by addition of L-tartaric acid (2.7 g). The mixture was maintained at about 75oC for 20 minutes followed by stirring at room temperature for about 2.5 hours. The solid obtained is filtered and washed with acetonitrile (250 mL) followed by drying under vacuum at 50oC for about 4 hours to afford the title compound.

Part B: The ethyl acetate was completely distilled under vacuum at 50oC, then acetonitrile (150 mL) was charged at room temperature. The mixture was heated to about 75oC at which point L-tartaric acid was added, the obtained clear solution was maintained at the same temperature for about 15-20 minutes followed by maintenance at room temperature for 30 minutes. The solid separated was filtered and washed with acetonitrile (10 mL), dried under vacuum at 50oC to afford the title compound.
Example 22: Preparation of Eliglustat
A flask was charged with (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (20 g) and toluene (400 mL) at room temperature followed by addition of octanoic acid (9.73 g), EDC-HCl (14.23 g), HOBt (912 mg), DIPEA (13.08 g). The mixture was maintained at the same temperature for about 28 hours, completion of the reaction was monitored by TLC. Then water (300 mL) was added and organic layer was separated, further washed twice with water (200 mL, 100 mL). Then organic layer was separated and then subjected to complete distillation under vacuum at below 50oC. To the crude obtained was further chased with ethyl acetate (60 mL) followed by addition of ethyl acetate (40 mL). To the ethyl acetate layer, cyclohexane (160 mL) was added. The clear solution obtained was allowed to stir at about 10-12oC for about 2.5 hours. The solid obtained was filtered and washed with cyclohexane (60 mL). The solid was subjected to drying under vacuum at about 50oC for 5 hours to afford the title compound having HPLC purity of ~99.25%.
Example 23: Preparation of Eliglustat
A flask was charged with (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (10 g) and dimethyl formamide (30 mL) at room temperature followed by addition of octanoic acid (5.18 g), EDC-HCl (8.26 g), HOBt (971 mg) and N-methyl morpholine (5.45 g). The mixture was maintained at the same temperature for about 7 hours, completion of the reaction was monitored by TLC. Then toluene (150 mL) and water (150 mL) were added and organic layer was separated. The aqueous layer was extracted with toluene (100 mL), the total organic layer were combined and washed with water (2x100 mL) followed by distillation of organic layer. Then toluene (100 mL) was added to the crude obtained and it was divided into two parts viz., Part A and Part B. Part A was subjected to complete distillation followed by dissolution of the obtained crude in toluene (20 mL) and then subsequent addition of cyclohexane (70 mL). The mixture was maintained at 5oC for 30 minutes and then solvents were distilled off completely under vacuum at 45oC. Then toluene (10 mL) and cyclohexane (50 mL) were added and mixture was maintained at room temperature for about 1.5 hours. The solid obtained was filtered and washed with cyclohexane (20 mL) followed by drying under vacuum at 55oC for about 12 hours to afford the title compound.
Example 24: Preparation of Eliglustat
A flask was charged with (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (10 g) and dimethyl formamide (5 mL) at room temperature followed by addition of octanoic acid (5.18 g), EDC-HCl (8.26 g), HOBt (971 mg) and N-methyl morpholine (5.45 g). The mixture was maintained at about 50oC for about 1.5 hours, then mixture was brought to attain room temperature at which point it was maintained for 2 hours, completion of the reaction was monitored by TLC. 10 mL of DMF was added each during the reaction and after completion of reaction making the total of 30 mL of DMF in the reaction mixture. Then water (100 mL) was added and organic layer was separated. The aqueous layer was extracted with toluene (100 mL). The total organic layer was combined and washed with water (50 mL, 50 mL). The organic layer was then subjected to complete distillation under vacuum and then crude obtained was chased with toluene (20 mL). The residue was again dissolved in toluene (100 mL) and then mixture was divided into two parts. One part having 50 mL of toluene was completely distilled under vacuum at 50oC. The residue was dissolved in toluene (10 mL) followed by cyclohexane (75mL). The mixture was maintained at room temperature for about 30 minutes. The solid obtained was filtered and washed with cyclohexane (10 mL) followed by drying under vacuum at about 55oC for about 10-11 hours to afford the title compound.

Example 25: Preparation of (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (Formula VI)
A flask was charged with (1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2-(((S)-2-hydroxy-1-phenylethyl)amino)-3-(pyrrolidin-1-yl)propan-1-ol (13 g), methanol (143 mL) followed by addition of Pd/C (1.95 g) and aqueous solution of sulphuric acid (3.52 g in 13 mL). The reaction mixture was flushed with hydrogen gas pressure. The mixture was heated to about 50-55oC and maintained for about 6 hours for completion of the reaction as monitored by TLC. The reaction mixture was then cooled to about 25-30oC, then filtered. The filtrate was subjected to distillation under vacuum at below 55oC to afford the crude compound. The crude compound was taken in water (15 mL) followed by addition of toluene (65mL). The aqueous layer was washed with toluene (2x65mL). The aqueous layer was cooled and its pH was adjusted to ~13 with 20% sodium hydroxide (14 mL) followed by addition of toluene (65 mL). The mixture was heated to ~45oC ad then additional quantity of toluene (65mL) was added followed by separation of layers. The aqueous layer was extracted with toluene (65mL). The combined toluene layers were used for next stage.
Example 26: Preparation of Eliglustat
A flask was charged with toluene layer containing (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1-ol (13 g) followed by addition of octanoic acid (6.74 g), EDC-HCl (8.95 g), HOBt (1.789 g) and di-isopropyl ethylamine (9.05 g). The mixture was maintained at room temperature for overnight, completion of the reaction was monitored by TLC. Then reaction mixture was sequentially washed with water (130 mL) and aqueous 20% sodium hydroxide solution (65mL). The organic layer was again sequentially washed with aqueous 20% sodium hydroxide solution (13 mL) and water (65mL). The organic solvent was then distilled under vacuum followed by addition of toluene (26 mL) to the obtained residue. Then cyclohexane (195mL) was slowly added to above solution followed by filtration and washing of the solid with cyclohexane (26mL). The solid was again dissolved in toluene (26mL) at 45oC followed by slow addition of cyclohexane (210 mL). The mixture was maintained at room temperature for overnight. The solid obtained is filtered and washed with cyclohexane (30 mL) and then dried under vacuum to afford the title compound having HPLC purity of 99.57%.
Example 27: Preparation of Eliglustat hemitartrate
A flask was charged with Eliglustat free base (85 g), acetone (1020 mL) and stirred for dissolution followed by addition of L-tartaric acid (15.77 g). The heterogenous mixture was stirred at room temperature for 2 hours followed by heating to reflux and further maintenance at the same temperature for 1hour. Then mixture was cooled to room temperature and stirred for about 11 hours followed by filtration of solid and its washing with acetone (85 mL) and subsequent drying to afford the title compound.
Example 28: Purification of Eliglustat hemitartrate
A flask was charged with eliglustat hemitartrate (135 g) in a mixture of acetonitrile (1620 mL) and methyl isobutyl ketone (1620 mL). The mixture was refluxed for about 45 minutes followed by gradual cooling to room temperature and further maintenance for about 3 hours. The solid is filtered and washed with a mixture of acetonitrile (270 mL) and methyl isobutyl ketone (270 mL) followed by drying under vacuum to afford the title compound having HPLC purity of 99.5%.
Example 29: Preparation of Eliglustat hemitartrate
A flask was charged with Eliglustat free base (3 g), acetone (24 mL) and stirred for dissolution and filtered to make it particle free. To the filtrate, eliglustat hemitartrate seed crystals (15 mg) was added and stirred at room temperature. Then to this mixture a solution of L-tartaric acid (557 mg) in acetone (30 mL) was added over a period of 60-120 minutes. The reaction mixture was stirred for 30-60 minutes at room temperature followed by maintenance at reflux for 2-3 hours. Then reaction mixture was cooled to room temperature and further stirred for 2-3 hours followed by filtration of solid and its washing with acetone (6 mL) and subsequent drying to afford the title compound.
Example 30: Preparation of Eliglustat
A flask is charged with Eliglustat free base (10 g) and toluene (15 mL) then heated to ~50oC. To this mixture cyclohexane (90 mL) was added and then temperature was reduced to 40oC and eliglustat seed (50 mg) was added, followed by maintenance for 10 minutes followed by further addition of cyclohexane (30 mL), then cooled to 25-15oC and maintained for ~1 hour. The solid was filtered, washed with cyclohexane (20 mL) and dried to afford the title compound.

,CLAIMS:CLAIMS:
We Claim:
Claim 1: An improved process for preparation of Eliglustat or pharmaceutically acceptable salts thereof, comprising:
a) reducing the compound of Formula IV in presence of borohydride reducing agent to afford a compound of Formula V,

Claim 2: The process of claim 1, comprising:
a) obtaining a compound of Formula II,

b) reacting the compound of Formula II with 1,4-benzodioxan-6-carboxaldehyde to afford a compound of Formula III,

c) reacting the compound of Formula III with pyrrolidine to afford a compound of Formula IV,

d) reducing the compound of Formula IV in presence of borohydride reducing agent to afford a compound of Formula V,

e) converting the compound of Formula V to a compound of Formula VI,

f) converting the compound of Formula VI to Eliglustat or pharmaceutically acceptable salts thereof.

Claim 3: The process of claim 2, wherein the process do not employ isolation of intermediate compounds in one or more of steps (a), (d) and (e).

Claim 4: The process of claim 2, wherein the compound of Formula VI in step e) is isolated in the form of a crystalline solid.
Claim 5: The process of claim 2, wherein the compound of Formula VI is reacted with octanoic acid or its ester to afford Eliglustat or pharmaceutically acceptable salts thereof.

Claim 6: The process of claim 2, wherein Eliglustat is converted to Eliglustat hemitartrate by treating Eliglustat with L(+)-tartaric acid.

Claim 7: An improved process for the preparation of eliglustat or pharmaceutically acceptable salts thereof, comprising:
a) obtaining a compound of Formula II,

b) in-situ reacting the compound of Formula II with 1,4-benzodioxan-6-carboxaldehyde to afford a compound of Formula III,

c) converting the compound of Formula III to Eliglustat or pharmaceutically acceptable salts thereof.

Claim 8: The process of claim 4, wherein the solvent employed in step b) comprises polar aprotic solvents and aliphatic hydrocarbons.

Claim 9: The process of claim 1 or claim 2, wherein borohydride reducing agent is selected from sodium borohydride, sodium cyanoborohydride, potassium borohydride and lithium borohydride.

Claim 10: A process for the preparation of Eliglustat or pharmaceutically acceptable salts thereof, comprising: reacting the compound of Formula VI with octanoic acid to obtain Eliglustat or pharmaceutically acceptable salts thereof.

Claim 11: The process of claim 10, wherein the reaction additionally employs a coupling agent and an organic base.

Claim 12: A process for the synthesis of Eliglustat or pharmaceutically acceptable salts thereof comprising using a compound of Formula VI in the form of a crystalline solid as an intermediate.