AN IMPROVED PROCESS FOR THE PREPARATION OF ELIGLUSTAT AND ITS INTERMEDIATE

Abstract

The present invention relates to an improved process for the preparation of N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide (A), which is known as ELIGLUSTAT and its pharmaceutically acceptable salts, comprising the formation of novel intermediate metal complex (III), which on hydrolysis in presence of acid provides amine compound (IV) (as described herein), which is treated with pyrrolidine and subsequently reduced to convert into Eliglustat (A).

Claims

1. (canceled)

2. A process for preparing N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide (A) (Eliglustat) or a salt thereof, having a purity greater than 99.5% ee, represented by the following formula, ##STR00029## comprising the steps of: (i) reacting the aldehyde compound (II) represented by the following formula, ##STR00030## with nickel complex compound (Ia) represented by the following formula, ##STR00031## in the presence of a base to obtain compound (IIIa): ##STR00032## (ii) hydrolysis of the compound (IIIa) obtained from step (i) in presence of acid to obtain amine compound (IV) represented by the following formula, ##STR00033## (iii) treating the amine compound (IV) of stage (ii) with a protecting group to obtain amine protected compound (V) represented by the following formula, ##STR00034## wherein P represents a protecting group. (iv) treating the amine protected compound (V) of stage (iii) with pyrrolidine to obtain compound (VI) represented by the following formula, ##STR00035## (v) reducing the compound (VI) of stage (iv) in the presence of a reducing agent to obtain compound (VII) represented by the following formula, ##STR00036## (vi) deprotecting the compound (VII) of stage (v) and treating with octanoic acid to obtain Eliglustat compound (A) or its salts, wherein Eliglustat (A) is obtained with a purity greater than 99.5% ee.

3. The process according to claim 2, further comprising; (1) in step (i) adding the compound (Ia) in a solvent; (2) adding metal alkoxide selected from sodium methoxide, sodium ethoxide, sodium isopropoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide, or a mixture thereof; and the aldehyde compound (II) to the reaction mixture of step (i); (3) optionally isolating the compound (IIIa) obtained from step (i); (4) adding an acid to the stirring solution containing compound (IIIa); (5) optionally isolating the compound (IV) obtained from step (ii); (6) adding an amine protecting agent to the solution containing the compound (IV); (7) dissolving the compound (V) obtained from step (iii) in solvent followed by the addition of pyrrolidine and a coupling agent to form compound (VI); (8) dissolving the compound (VI) obtained from step (iv) in solvent followed by the addition of reducing agent; (9) treating the compound (VII) obtained from step (iv) with an acid to form acid addition salt as compound (VIII); (10) treating the compound (VIII) with octanoic acid and isolating the desired product.

4. The process according to claim 3, wherein the acid used in the step (4) is selected from hydrochloric acid, hydrobromic acid, hydrofluoric acid, nitric acid, sulfuric acid and phosphoric acid or a mixture thereof.

5. The process according to claim 3, wherein the protecting agent used in the step (6) is selected from tert-Butyloxycarbonyl (Boc), Fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz).

6. The process according to claim 3, wherein the coupling agent used in the step (7) is selected from O-(Benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate (TB TU), N,N′-Dicyclohexylcarbodiimide (DCC), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP).

7. The process according to claim 3, wherein the solvent used in step (1) is selected from alcohols such as methanol, ethanol, isopropanol and that used in step (7) and step (8) is an ether solvent selected from tetrahydrofuran (THF), cyclopentyl methyl ether, methyl tert-Butyl ether (MTBE), 2-methyltetrahydrofuran, diethyl ether, 1,4-dioxane.

8. The process according to claim 3, wherein the reducing agent used in step (8) is selected from diborane, borane-dimethyl sulphide (DMS), borane-tetrahydrofuran (THF) complex, sodium triacetoxyborohydride, sodium cyanoborohydride, NaBH.sub.4,BF.sub.3.etherate, LiBH.sub.4, diethyl methoxy borane+NaBH.sub.4, trialkyl boranes.

9. The process according to claim 3, wherein the acid in step (9) is selected from trifluoroacetic acid (TFA), hydrochloric acid, hydrobromic acid, hydrofluoric acid, nitric acid, sulfuric acid and phosphoric acid or a mixture thereof.

10. A novel intermediate metal complex (III); ##STR00037## wherein M is a metal selected from Cu.sup.2+, Ni.sup.2+, or Zn.sup.2+.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0032] Accordingly, the present invention relates to an improved process for the preparation of ((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide (A) [Eliglustat] or a salt thereof represented by the following formula,

##STR00008##

comprising the steps of,
(a) reacting the aldehyde compound (II) represented by the following formula,

##STR00009##

with metal complex compound (I) represented by the following formula,

##STR00010##

in the presence of a base to obtain compound (III):

##STR00011## [0033] wherein NI is a metal selected from Cu.sup.2+, Ni.sup.2+, or Zn.sup.2+
(b) hydrolysis of the compound (III) obtained from step (a) in presence of acid to obtain amine compound (IV) represented by the following formula,

##STR00012##

(c) treating the amine compound (IV) of stage (b) with a protecting group to obtain amine protected compound (V) represented by the following formula.

##STR00013##

wherein P represents a protecting group.
(d) treating the amine protected compound (V) of stage (c) with pyrmlidine to obt n compound (VI) represented by the following formula,

##STR00014##

(e) reducing the compound (VI) of stage (d) and converting to Eliglustat compound (A) or its salts.

[0034] In the context of the present invention, the term ‘hydrolysis’ used in reference to any step of the reaction corresponds to the decomposition of metal complex (III).

[0035] Accordingly, in the process of the present invention the intermediate metal complex compound (III) is optionally isolated during reaction, or in-situ converted to the compound (IV) and subsequently to compound (V).

[0036] In an embodiment the ‘base’ is selected from the group consisting of inorganic base such as alkali hydroxide, alkali hydride, alkali carbonate, metal alkoxide organic base such as alkyl amine, aryl amine, tertiary amine, or mixture thereof.

[0037] In an embodiment the ‘metal alkoxide’ is selected from the group consisting of sodium methoxide, sodium ethoxide, sodium isopropoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide, or mixtures thereof.

[0038] In an embodiment the ‘acid’ is selected from the group consisting of hydrochloric acid (HCl), hydrobromic acid, hydrofluoric acid, nitric acid, sulfuric acid and phosphoric acid, or mixtures thereof.

[0039] In accordance with the embodiments of the present invention, the ‘protecting group’ is an amine protecting group which refers to the group tert-Butyloxycarbonyl (Boc), Fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz) and the like.

[0040] Accordingly, the present invention relates to an improved process for the preparation of N-(1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3- (pyrrolidin-1-yl)propan-2-yl)octanamide (A) [Elighistat] or a salt thereof represented by the following formula,

##STR00015##

comprising the steps of, [0041] (i) reacting the aldehyde compound (II) represented by the following formula,

##STR00016## [0042] with nickel complex compound (Ia) represented by the following formula,

##STR00017## [0043] in the presence of a base to obtain compound (IIIc):

##STR00018## [0044] (ii) hydrolysis of the compound (IIIa) obtained from step (i) in presence of acid to obtain amine compound (IV) represented by the following formula,

##STR00019## [0045] (iii) treating the amine compound (IV) of stage (ii) with a protecting group to obtain amine protected compound (V) represented by the following formula,

##STR00020##

wherein P represents a protecting group. [0046] (iv) treating the amine protected compound (V) of stage (iii) with pyrrolidine to obtain compound (VI) represented by the following formula,

##STR00021## [0047] (v) reducing the compound (VI) of stage (iv) in the presence of a reducing agent to obtain compound (VII) represented by the following formula,

##STR00022## [0048] (vi) deproteeting the compound (VII) of stage (v) and treating with octanoic acid to obtain Eliglustat compound (A) or its salts.

[0049] In an embodiment the ‘reducing agent’ is selected from the group consisting of diborane, borane-dimethyl sulphide (DMS), borane-tetrahydrofuran (THF) complex, sodium triacetoxyborohydride, sodium cyanoborohydride, NaBH.sub.4,BF.sub.3. etherate, LiBH.sub.4, diethyl methoxy borane+NaH.sub.4, Trialkyl boranes and the like.

[0050] In a specific embodiment, the process for the preparation of N-((1R,2R)-1-(2,3-dihydrohenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrrolidin-1-yl)propan-2-yl)octanamide (A) [Eliglustat] or a salt thereof comprises the steps of; [0051] (1) adding the compound (Ia) in a solvent, [0052] (2) adding metal alkoxide and the aldehyde compound (II) to the reaction mixture of step (1), [0053] (3) optionally isolating the compound (IIIa) obtained from step (2), [0054] (4) adding an acid to the stirring solution containing compound (IIIa), [0055] (5) optionally isolating the compound (IV) obtained from step (4), [0056] (6) adding an amine protecting agent to the solution containing the compound (IV), [0057] (7) dissolving the compound (V) obtained from step (6) in solvent followed by the addition of pyrrolidine and a coupling agent to form compound (VI). [0058] (8) dissolving the compound (VI) obtained from step (7) in solvent followed by the addition of reducing agent, [0059] (9) treating the compound (VII) obtained from step (8) with an acid to form acid addition salt as compound (VIII), [0060] (10) treating the compound (VIII) with octanoic acid and isolating the desired product.

[0061] The process of the present invention as per the specific embodiment described above is illustrated in the following Scheme (1),

##STR00023## ##STR00024## [0062] wherein ‘M’ is a metal selected from Cu.sup.2+, Ni.sup.2+, or Zn.sup.2+ and ‘P’ represents a protecting group

[0063] The solvent used in the step (1) to step (10) of the above process (as depicted in the Scheme-1) is selected from a halogenated solvent such as dichloromethane, 4-bromotoluene, diiodomethane, carbon tetrachloride, chlorobenzene, ethylene chloride and chloroform; alcoholic solvent such as methanol, ethanol, isopropanol, t-amyl alcohol, t-butyl alcohol and hexanol; an ether solvent such as tetrahydrofuran (THF), cyclopentyl methyl ether, methyl tert-Butyl ether (MTBE), 2-methyltetrahydrofuran, diethyl ether and 1,4-dioxane; a ketone selected from methyl ethyl ketone, acetone, methyl isohutyl ketone (MIBK), ethyl methyl ketone; an ester selected from ethyl acetate, isopropyl acetate; an aprotic solvent such as acetonitrile, N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide, dimethyl sulfoxide (DMSO) and N-methylpyrrolidone (NMP) an aromatic solvent such as toluene, xylene and benzene; acetone; water or a mixture thereof.

[0064] The metal alkoxide used in the step (2) of the above process (as depicted in the Scheme (1)) is selected from the sodium methoxide, sodium ethoxide, sodium isopropoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide, or a mixture thereof.

[0065] The term ‘isolating’ referred to in the step (3), step (5) and step (10) of the above process (as depicted in the Scheme (1)) corresponds to the steps involving biphasic separation, separation of organic phase, filtration, evaporation of solvent, cooling, precipitation, washing and/or drying.

[0066] The acid used in the step (4) of the above process (as depicted in the Scheme (I)) is selected from hydrochloric acid, hydrobromic acid, hydrofluoric acid, nitric acid, sulfuric acid and phosphoric acid or a mixture thereof.

[0067] The protecting agent used in the step (6) of the above process (as depicted in the Scheme (1)) which corresponds to the group tert-Butyloxycarbonyl (Boc)), Fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz) and the like.

[0068] The coupling agent used in the step (7) of the above process (as depicted in the Scheme (1)) is selected from O-(Benzotriazol-1-yl)-N N N′N′-tetramethyluronium tetrafluoroborate (TBTU), N,N′-Dicyclohexylcarbodiimide (DCC), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 3-(dietboxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP).

[0069] The ‘acid addition salt’ formed in the step (9) of the above process (as depicted in the Scheme (1)) refers to the acid selected from trifluoroacetic acid (TFA), hydrochloric acid, hydrohronic acid, hydrofluoric acid, nitric acid, sulfuric acid and phosphoric acid or a mixture thereof.

[0070] The overall process of the present invention involving preparation of N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1- yl)propan-2-yl)octanamide (A) [Eliglustat] or a salt thereof via formation of intermediate compound (IIIa) is illustrated in the following Scheme (2):

##STR00025## ##STR00026##

[0071] The process illustrated in the above scheme (2) comprises reaction of the compound (Ia) with 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (II) in the presence of a metal alkoxide selected from sodium methoxide to obtain compound (IIIa) which is optionally isolated or in-situ hydrolysed by the treatment with an acid selected from hydrochloric acid to obtain the compound (IV), which is optionally isolated and was treated with di-tert-butyl dicarbonate reagent to form N-Boc compound (V). Further, the (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxypropanoic acid compound (V) was dissolved in THF and treated with pyrrolidine in the presence of TBTU to form compound (VI). The compound tert-butyl((1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-oxo-3-(pyrrolidin-1-yl)proparn-2-yl)carbamate compound (VII) was further reduced using Borane-dimethyl sulfide complex. The obtained compound was treated with trifluoroacetic acid to provide TFA acid addition salt as compound (VIIIa). Finally, the compound was treated with octanoic acid to provide Eliglustat (A) with more than 99% ee.

[0072] The inventors of the process of the instant invention observed that the elemental impurity content of the final product Eliglustat (A) obtained by this process is very low and does not require any specific purification technology to remove elemental impurities such Nickel (Ni).

[0073] Accordingly, it is also evident that the product Eliglustat (A) obtained by the process of the instant invention has a high enantiomeric excess (ee).

[0074] In an another embodiment, there is provided N-((1R ,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)octanamide (A) [Eliglustat] with more than 99% ee.

[0075] In an another embodiment, there is provided N-((1R,2R) -1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)octanamide (A) [Eliglustat] with more than 99.5% ee.

[0076] In an another embodiment, there is provided N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)octanamide (A) iElighistati with more than 99.99% ee.

[0077] In an embodiment, there k provided a novel intermediate metal complex (III);

##STR00027##

[0078] wherein M is a metal selected from Cu.sup.2+, Ni.sup.2+, or Zn.sup.2+

[0079] In an embodiment, there is provided a novel intermediate metal complex (IIIa);

##STR00028##

[0080] The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES

Example 1

Preparation of (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxypropanoic acid (V)

[0081] Charged 125 mL, of methanol in a flask followed by the addition of sodium methoxide (250 mmol) at temperature of about 25-30° C. and cooled to 0-10° C. temperature. To the reaction mixture was added 25 g of Nickel complex (Ia) and (25 g, 50 mmol) 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde compound (II). The reaction mixture was stirred for about 1 h and quenched using 25 mL of concentrated hydrochloric acid. The reaction mixture was evaporated under vaccuo and crude mixture was diluted with 2N hydrochloric acid (38 mL). The precipitated solid was filtered. The aqueous layer was extracted with dichloromethane (100 mL) and washed with ethyl acetate (2×100 mL). The filtrate was taken in a flask followed by the addition of ammonium pyrrolidine dithiocarbamate (PDTC, 14.0 g), and the solution was heated to 70-75° C. for about 1 h. The obtained solids were filtered, washed with isopropyl alcohol (50 mL), and the aqueous layer was evaporated to obtain (2S,3R)-2-amino-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxypropanoic acid (IV).

[0082] The crude material was diluted with 1,4 dioxane (100 and water (50 at a temperature of 25-30° C. To the reaction mixture was added triethylamine (24 mL) and added ditert-butyl dicarbonate (19.0 g), and the reaction mixture was stirred for about 16 h. The reaction mixture was evaporated under vacuum and the crude was diluted with ethyl acetate (70 mL). The mixture was acidified with citric acid (10%) and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2×35 mL) and the combined organic layer was evaporated under vacuum to provide the compound (V) (yield: 9.2 g, (54% from two stages); HPLC purity: 94.38%).

Example 2

Preparation of tert-butyl (1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-oxo-3-(pyrrolidin-1-yl)propan-2-yl)carbamate (VI)

[0083] Charged 112 mL of tetrahydrofuran in a flask followed by the addition of (2S,3R)-2-((tert-butoxycarbonyl)amino)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-hydroxypropanoic acid (V), pyrrolidine (1.87 g, 262 mmol), diisopropyl ethylamine (DIPEA) (8.4 g, 651 mmol) and TBTU (7.72 g, 240 mmol) at a temperature of 25-30° C. The reaction mixture was evaporated under vacuum and the crude was diluted with ethyl acetate (160 mL). The separated organic layer was washed with 10% citric acid. solution (2×40 mL) and 5% sodium bicarbonate (2×40 mL). The organic layer was evaporated to provide compound (VI) (yield: 4.5 g, 52%).

Example 3

Preparation of tert-butyl ((1R,2R)-1-(2,3-dihydrobnzo[b][4,1]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)carbamate (VII).

[0084] Charged 27 mL of tetrahydrofuran in a flask followed by the addition of tert-butyl ((1R,2S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-oxo-3- (pyrrolidin-1-yl)propan -2-yl) carbamate (VI) (1.5 g, 38 mmol) and Borane-dimethyl sulfide complex (8.1 mL, 106 mmol) at a temperature of about 0-5° C. The reaction mixture was further stirred for about 2 h at a temperature of about 45-50 ° C. The reaction mixture was quenched by the addition of methanol (82 mL) and the reaction mixture was evaporated under vacuum. The crude reaction mixture was diluted with ethyl acetate (82 mL) and washed with water (40 mL). The organic layer was evaporated to provide compound (VII) (yield: 0.9 g, 62.5%)

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 (VIIIa) and conversion into Eligiustat A).

[0085] Charged 12 mL of dichlorometbane in a flask followed by the addition of tert-butyl ((1R,2R)-1-(2,3-dihydrobenzo[b])-1-hydroxy-3-(pyrrolidin-1-yl)propan-2- yl)carbamate (VII) and trifluoroacetic acid (3 mL) at a temperature of about 10-15° C. The reaction mixture was stirred for 4 h at temperature of about 25-30° C. and evaporated under vacuum to provide (1R,2R)-2-amino-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-(pyrrolidin-1-yl)propan-1 -ol (VIIIa).

[0086] The compound (VIIIa) was dissolved in tetrahydrofuran (15 mL) followed by the addition of n-octanoic acid (0.13 g, 9 mmol), diisopropylethyhtmine (DIPEA) (2.0 mL, 15 mmol) and TBTU (1.22 g, 25 mmol). The reaction mixture was stirred for 16 h and the evaporated under vacuum. The crude was diluted with ethyl acetate (40 mL) and washed with 5% citric acid (2×20 mL), 5% sodium bicarbonate (2×20 mL). The organic layer was evaporated and crude compound was purified by preparative ITPLC to provide Eliglustat (A).