INTRODUCTION

Aspects of the present application relate to the processes for preparing dexpramipexole, its pharmaceutically acceptable salts, and its hydrates. More particularly the aspect of the present application relate to the processes for preparing dexpramipexole dihydrochloride monohydrate.

The drug compound having the adopted name "dexpramipexole", is the R(+) enantiomer of pramipexole and is under development by Knopp Neurosciences and Biogen Idee as a potential neuroprotective therapy for amyotrophic lateral sclerosis (ALS), a universally fatal neurodegenerative disease. (KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2, 6-benzothiazole-diamine dihydrochloride monohydrate] for the Treatment of Amyotrophic Lateral Sclerosis. Valentin K. Gribkoff and Michael E. Bozik. CNS Neuroscience & Therapeutics 14 (2008) 215-226.) A chemical name for dexpramipexole is (R)-N6-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine. Dexpramipexole dihydrochloride monohydrate can be represented by structural formula (I).

The synthesis of pramipexole and other tetrahydrobenzothiazoles was first described in the European patent 186087 and its counterpart, U.S. patent No. 4,886,812. An additional synthetic route has been described in J. Med. Chem., 1987, 30, 494-498. The prior art processes suffer drawbacks like low yield and formation of undesired impurities and thereby making the synthetic approach commercially less effective. Furthermore, the prior art is silent about the water content of the final product and no teachings have been provided to make the monohydrate of dexpramipexole dihydrochloride in high yield and high purity.

Hence, there is a need to provide simple, economical, cost effective, scalable, and robust processes for the preparation of dexpramipexole, its pharmaceutically acceptable salts, and its hydrates, in high yield and high purity.

SUMMARY

In one aspect, the present application provides a process for preparing dexpramipexole comprising:

(a) reacting (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with propionic anhydride in suitable organic solvent and in the presence of a suitable base to obtain (R)-N-(2-amino-4,5,6,7-tetrahydrobenzothiazol-6-yl)propionamide;

(b) converting the product of step (a) into (R)-N-(2-amino-4,5,6,7-tetrahydrobenzothiazol-6-yl)propionamide hydrochloride using a source of hydrogen chloride in an organic solvent;

(c) reducing the product of step (b) to provide dexpramipexole using a suitable reducing agent in a suitable organic solvent; and

(d) optionally converting dexpramipexole into its pharmaceutical^ acceptable salts, hydrates, or hydrates of salts thereof.

In another aspect, the present application provides a process for preparing dexpramipexole comprising:

(a) reacting (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with propionaldehyde in the presence of a suitable organic solvent to obtain the respective enamine in situ;

(b) reducing the enamine formed in situ in step (a), with a suitable reducing agent to provide dexpramipexole free base; and

(c) optionally converting dexpramipexole into its pharmaceutically acceptable salts, hydrates, or hydrates of salts thereof.

In yet another aspect, the present application provides dexpramipexole dihydrochloride monohydrate.

In yet another aspect, the present application provides a process comprising:

(a) dissolving dexpramipexole dihydrochloride in water; and

(b) adding a suitable organic solvent or mixture of suitable solvents to the solution of step (a) to precipitate dexpramipexole dihydrochloride monohydrate.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of dexpramipexole dihydrochloride monohydrate prepared according to Example 4.

Fig. 2 is an illustration of a powder X-ray diffraction (PXRD) pattern of dexpramipexole dihydrochloride monohydrate prepared according to Example 8.

DETAILED DESCRIPTION

In one aspect, the present application provides a process for preparing dexpramipexole comprising:

(a) reacting (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with propionic anhydride in suitable organic solvent and in the presence of a suitable base to obtain (R)-N-(2-amino-4,5,6,7-tetrahydrobenzothiazol-6-yl)propionamide;

(b) converting the product of step (a) into (R)-N-(2-amino-4,5,6,7-tetrahydrobenzothiazol-6-yl)propionamide hydrochloride using a source of hydrogen chloride in an organic solvent;

(c) reducing the product of step (b) to provide dexpramipexole using a suitable reducing agent in a suitable organic solvent; and

(d) optionally converting dexpramipexole into its pharmaceutical^ acceptable salts, hydrates, or hydrates of salts thereof.

In embodiments of step (a), (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole which is used as the starting material for the preparation of dexpramipexole can be prepared by any method known in the art and optionally, can be purified by any method known in the art to improve its chemical and chiral purities. In embodiments of step (a), the reaction may be carried out in a suitable organic solvent. Suitable organic solvent used in step (a) include, but are not limited to: ethers, such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl-tetrahydrofuran, cyclopropylmethyl ether, dioxane, or dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or diethyl ketone; alcohols, such as methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol or Ci-C6 alcohols; nitriles, such as acetonitrile or propionitrile; amides, such as formamide, N,N-dimethylformamide or N,N-dimethylacetamide; sulfoxides, such as dimethylsulfoxide; or mixtures of two or more thereof.

In embodiments of step (a), bases that are useful in the reaction include, but are not limited to; organic bases such as, for example, diisopropylamine, dimethylamine, ethylenediamine, N,N-diisopropylmethylamine, N- ethyldiisopropylamine, triethylamine, aniline, pyridine, piperidine or the like or inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, oxides, carboxylates, or alkoxides, e.g., potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, potassium acetate, potassium methoxide, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium acetate, sodium methoxide, lithium carbonate, lithium hydrogen carbonate, lithium hydroxide, lithium acetate, lithium methoxide, barium hydroxide, calcium oxide, or the like.

In embodiments of step (b), source of hydrogen chloride can be hydrochloric acid, such as concentrated hydrochloric acid, aqueous diluted hydrochloric acid, hydrogen chloride gas or an organic solvent hydrochloride, such as for example methanol hydrochloride, ethanol hydrochloride, isopropyl alcohol hydrochloride, ethylacetate hydrochloride or dioxane hydrochloride.

In embodiments of step (b), conversion of (R)-N-(2-amino-4,5,6,7-tetrahydrobenzothiazol-6-yl)propionamide into its hydrochloride salt, evades the formation of undesired dimer impurities.

In embodiments of step (c), the reaction can be carried out in presence of a suitable reducing agent. Suitable reducing agent used in step (c) include, but are not limited to; one or more of; borane; borane tetrahydrofuran; boron trifluoride etherate and sodium borohydride; sodium borohydride and iodine;

sodium borohydride and sulfuric acid or any other organic acid like boric acid, methane sulfonic acid, or para toluene sulfonic acid; sodium borohydride and cerium chloride; sodium cyanoborohydride; sodium triacetoxyborohydride; or mixtures thereof.

In embodiments of step (c), the reaction is carried out in a suitable organic solvent. Suitable organic solvent used in step (c) include, but are not limited to: ethers, such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopropylmethyl ether, dioxane, or dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or diethyl ketone; alcohols, such as methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol or C1-C6 alcohols; nitriles, such as acetonitrile or propionitrile; amides, such as formamide, N,N-dimethylformamide or N,N-dimethylacetamide; sulfoxides, such as dimethylsulfoxide; or mixtures of two or more thereof.

In embodiments of step (d), dexpramipexole is optionally converted in to dexpramipexole dihydrochloride monohydrate.

In another aspect, the present application provides a process for preparing dexpramipexole comprising:

(a) reacting (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with propionaldehyde in the presence of a suitable organic solvent to obtain the respective enamine in situ;

(b) reducing the enamine formed in situ in step (a), with a suitable reducing agent to provide dexpramipexole free base; and

(c) optionally converting dexpramipexole into its pharmaceutically acceptable salts, hydrates, or hydrates of salts thereof.

In embodiments of step (a), the reaction is carried out in the presence of suitable organic solvent. Suitable organic solvent used in step (a) include, but are not limited to: ethers, such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopropylmethyl ether, dioxane, or dimethoxyethane; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or diethyl ketone; alcohols, such as methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2,2,2-trifluoro ethanol or C1-C6 alcohols; nitriles, such as acetonitrile or propionitrile; amides, such as formamide, N,N-dimethylformamide or N,N-dimethylacetamide; sulfoxides, such as dimethylsulfoxide; or mixtures of two or more thereof. In embodiments of step (a), the enamine formed in situ is (R)-N6-propylidene-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine.

In embodiments of step (b), the reaction is carried out in presence of a suitable reducing agent. Suitable reducing agent used in step (b) include, but are not limited to; one or more of; borane, borane tetrahydrofuran, boron trifluoride etherate, sodium borohydride, sodium borohydride and sulfuric acid or other organic acid like boric acid, methane sulfonic acid or para toluene sulfonic acid monohydrate, benzoic acid;, sodium cyanoborohydride or sodium triacetoxyborohydride or mixtures thereof.

In embodiments of step (c), dexpramipexole is optionally converted in to dexpramipexole dihydrochloride monohydrate.

In yet another aspect, the present application provides a process for preparing dexpramipexole dihydrochloride monohydrate comprising:

(a) dissolving dexpramipexole in a suitable organic solvent;

(b) adding hydrochloric acid to the solution of step (a) to provide dexpramipexole dihydrochloride;

(c) optionally drying the product of step (b);

(d) dissolving the product of step (b) or (c) in water, suitable organic solvent or mixture thereof; and

(e) adding a suitable organic solvent to the solution of step (d) to precipitate dexpramipexole dihydrochloride monohydrate.

In embodiments of step (a), suitable organic solvent for dissolving dexpramipexole include, but are not limited to; alcohols such as 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, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, or C1-C6 alcohols or mixtures of two or more thereof.

In embodiments of step (b), hydrochloric acid used may be gaseous, aqueous, concentrated, or dissolved in a solvent. Preferably, hydrochloric acid dissolved in alcohol is used as the acid source for step (b) and the alcohol used for dissolving hydrochloric acid include but are not limited to; methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, phenol, glycerol, or CrC6 alcohols.

In embodiments of step (c), dexpramipexole dihydrochloride is optionally dried at a suitable temperature from about 40° C to about 70° C.

In embodiments of step (d), suitable organic solvent for dissolving dexpramipexole include, but are not limited to; alcohols, such as 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, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, or C1-C6 alcohols.

In embodiments of step (e), suitable organic solvent for precipitating dexpramipexole dihydrochloride monohydrate include, but are not limited to; esters, such as methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, or butyl acetate; ethers; aliphatic hydrocarbons; aromatic hydrocarbons; any suitable organic solvent; or mixtures of two or more thereof.

In yet another aspect, the present application provides dexpramipexole dihydrochloride monohydrate.

In an embodiment, the dexpramipexole dihydrochloride monohydrate has a powder X-ray diffraction pattern substantially in accordance with Fig. 1.

In an embodiment, the dexpramipexole dihydrochloride monohydrate has a powder X-ray diffraction pattern substantially in accordance with Fig. 2. In yet another aspect, the present application provides a process comprising:

(a) dissolving dexpramipexole dihydrochloride in water; and

(b) adding a suitable organic solvent or mixture of suitable solvents to the
solution of step (a) to precipitate dexpramipexole dihydrochloride
monohydrate.

In embodiments of step (a), suitable organic solvent for precipitating dexpramipexole dihydrochloride monohydrate include, but are not limited to; esters, such as methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, or butyl acetate; ethers; aliphatic hydrocarbons; aromatic hydrocarbons; any suitable organic solvent; or mixtures of two or more thereof.

In embodiments of the present application, suitable techniques that may be used for the removal of solvent include, but are not limited to, rotational evaporation using a device, such as, for example, a Buchi® Rotavapor®, spray drying, agitated thin film drying, freeze drying (lyophilization), or the like, optionally under reduced pressure.

In embodiments of the present application, the isolated dexpramixole or dexpramipexole dihydrochloride monohydrate, may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids.

In embodiments of the present application, the isolated dexpramixole or dexpramipexole dihydrochloride monohydrate, may optionally be further purified by precipitation, slurrying in a suitable solvent, or any other suitable techniques. Precipitation may be achieved by crystallization, such as by cooling a solution, concentrating a solution, or by combining an anti-solvent with a solution of the product, or any other suitable methods.

Suitable solvents that may be used for the purification of dexpramipexole or dexpramipexole dihydrochloride monohydrate include, but are not limited to: water, alcohol solvents, ketone solvents, or any mixtures thereof, to provide dexpramipexole of dexpramipexole dihydrochloride monohydrate having a purity by HPLC which is essentially pure, substantially pure, or even pure. Suitable anti-solvents include, but are not limited to, ester solvents; or any other suitable anti-solvents.

The recovered solid may be optionally further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under a reduced pressure at temperatures of less than about 150°C, or less than about 120°C, or less than about 100°C, or less than about 80°C, or less than about 65°C, or any other suitable temperature as long as the dexpramipexole dihydrochloride monohydrate is not degraded in quality. The drying may be carried out for any desired time until the required purity is achieved. For example, it may vary from about 1 to about 10 hours or longer.

The dried product may be optionally milled to get the required particle size. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation sifting; milling using mills, such as, for example, ball, roller or hammer mills, or jet mills, including, for example, air jet mills; or any other conventional technique. The desired particle size may also be achieved directly from the reaction mixture by selecting equipment that is able to provide dexpramipexole dihydrochloride monohydrate with the desired particle size.

In embodiments of the present application, the phrase "dexpramipexole or pharmaceutically acceptable salts, hydrates, or hydrates of salts thereof, more particularly refers to dexpramipexole dihydrochloride monohydrate. In embodiments of the present application, the chiral purity of dexpramipexole dihydrochloride monohydrate obtained may be at least greater than about 97%, or at least about 99% or at least about 99.9% chirally pure. In embodiments of the present application, chemical purity of dexpramipexole dihydrochloride monohydrate obtained may be at least greater than about 97%, or at least about 99% or at least about 99.9% pure.

In a further aspect, the present application provides dexpramipexole dihydrochloride monohydrate having water content of about 4.5% w/w to about 7.0% w/w, as determined by Karl Fischer method.

The aspects of the present application, overcomes the difficulties of the prior art and hence produces a simple, economical, cost effective, scalable and robust processes for the preparation of dexpramipexole and pharmaceutically salts, hydrates thereof.

DEFINITIONS

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

The phrase "pharmaceutically acceptable salt(s)", as used herein, means those salts of compounds of the invention that are safe and effective in human beings and that possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the invention. Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, dihydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate or pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, or diethanolamine salts.

Hydrates are inorganic salts "containing water molecules combined in a definite ratio as an integral part of the crystal", such as for example monohydrate, dihydrate, trihydrate etc.

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, 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, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, or the like.

An "aliphatic hydrocarbon" is a liquid hydrocarbon compound, which may be linear, branched, or cyclic and may be saturated or have as many as two double bonds. A liquid hydrocarbon compound that contains a six-carbon group having three double bonds in a ring is called "aromatic." Examples of "C5-C8 aliphatic or aromatic hydrocarbons" include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, 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.

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

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

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

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

A "nitrile" is an organic compound containing a cyano -(C=N) bonded to another carbon atom. "C2-C6 nitriles" include, but are not limited to, acetonitrile, propionitrile, butanenitrile, or the like.

An "anti-solvent" is a solvent in which the product is insoluble or less soluble or sparingly soluble.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at 25° C and normal pressure unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements that are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise. As used herein, "consisting essentially of means that the invention may include ingredients in addition to those recited in the claim, but only if the additional ingredients do not materially alter the basic and novel characteristics of the claimed invention. The terms "about," "generally," "substantially,", and the like are to be construed as modifying a term or value such that it is not an absolute, but does not read on the prior art. 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 very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.

The term "optional" or "optionally" is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.

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. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES

Example 1: Preparation of (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole. 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole (20 g) and water (200 ml_) are charged into a round bottom flask and stirred. D(-) Tartaric acid (19.5 g) is added to the reaction mixture at 25-30° C under stirring, further heated to 80-85° C, and maintained for 105 minutes. The reaction mixture is cooled to 30-35° C, the separated solid is collected by filtration, and washed with water (40 mL). The wet compound and water (200 mL) are charged into a round bottom flask, heated to BO SS0 C, and maintained for 95 minutes. The reaction mixture is cooled to 25-30° C and the separated solid is collected by filtration and washed with water (40 mL). The wet compound and water (200 mL) are charged into a round bottom flask, heated to 80-85 ° C, and maintained for 90 minutes. The reaction mixture is cooled to 25-30° C and the separated solid is collected by filtration and washed with water (40 mL). The wet compound and water (60 mL) are charged into a round bottom flask and stirred. Sodium hydroxide (7.1 g) in water (7.1 mL) is added slowly to the reaction mixture at 25-30° C and maintained for 65 minutes. The reaction mixture is cooled to 0-5° C and maintained for 90 minutes. The separated solid is collected by filtration and washed with chilled water (20 mL). The wet compound is dried in oven under reduced pressure for 8 hours at 65° C. Yield: 7.5 g; Purity by HPLC: 99.93%; Chiral purity by HPLC: 99.79%.

Example 2: Preparation of (R)-N-(2-amino-4,5,6,7-tetrahydrobenzothiazol-6-yl)propionamide hydrochloride.

(R)-2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole (20 g) and tetrahydrofuran (200 mL) are charged into a round bottom flask and stirred. Triethylamine (13.2 g) is added to the reaction mixture and cooled to -10 to 0° C. Propionic anhydride (16.2 g) and tetrahydrofuran (20 mL) are added slowly to the reaction mixture and maintained for 40 minutes at -10 to 0° C. The temperature is raised to 25-35° C and 50% potassium carbonate solution (200 mL) is added slowly to the reaction mixture. The layers are separated, the aqueous layer is extracted with tetrahydrofuran (80 mL), and the combined organic layers are dried over sodium sulfate (40 g). The resultant organic layer is evaporated under reduced pressure at below 45°C and the obtained crude is co-distilled twice with isopropyl alcohol (30 mL and 15 mL). Isopropyl alcohol HCI (30 mL) is added to the crude at 26°C, stirred for 30 minutes, and is evaporated under reduced pressure at 45° C. To the obtained crude, toluene (100 mL) is added at 26° C and stirred for 30 minutes. The compound is collected by filtration and washed with toluene (20 mL). The wet compound is dried in oven for 1 hour at 45° C. Yield: 24 g; Purity by HPLC: 97.36%; Chiral purity by HPLC: 98.47%.

Example 3: Preparation of (R)-N6-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (dexpramipexole),
Tetrahydrofuran (30 mL) and sodium borohydride (5.9 g) are charged into a round bottom flask, stirred and cooled to -10 to 0° C. (R)-N-(2-Amino-4,5,6,7-tetra hydrobenzothiazol-6-yl)propionamide hydrochloride (5 g) is added to the reaction mixture followed by slow addition of boron trifluoride etherate (19.5 mL) at -10 to 0° C. The reaction mixture is heated to 48-50° C, maintained for 85 minutes, and then cooled to 0-5° C. Chilled water (50 mL) is added slowly and the reaction mixture is maintained for 30 minutes at 0-5° C. Concentrated HCI (65 mL) is added slowly to the reaction mixture at 0-10° C and maintained for 1 hour. The solvent is evaporated under reduced pressure at below 40° C. To the obtained crude compound, water (300 mL) is added at 25-30° C and the pH is adjusted with 25% sodium hydroxide solution (70 mL) at 0-10° C and. Ethyl acetate (100 mL) is added to the reaction mixture under stirring at 0-10° C and the temperature is raised to 25-30° C. The layers formed are separated and the aqueous layer is extracted with ethyl acetate (100 mL). The combined organic layers are dried over sodium sulfate (5 g) and evaporated under reduced pressure and below 45° C. To the crude compound, ethyl acetate (15 mL) is added at 25-30° C and stirred for 1 hour. The compound obtained is collected by filtration, washed with ethyl acetate (5 mL), and the wet compound is dried in an oven for 2 hours at 60° C. Yield: 2.4 g; Purity by HPLC: 98.63%; Chiral purity by HPLC: 98.42%.

Example 4: Preparation of (R)-N6-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (dexpramipexole) dihydrochloride monohydrate.

(R)-N6-Propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (20 g) and ethanol (160 mL) are charged into a round bottom flask and stirred for 35 minutes at 25-30° C. The clear solution obtained is filtered and washed with ethanol (20 mL). The filtrate is again charged into a round bottom flask. To the filtrate, isopropyl alcohol HCI (63 mL) is added slowly at 25-30° C and maintained for 3 hours. The reaction mixture is cooled to 0-5° C and maintained for 80 minutes. The obtained solid is collected by filtration, washed with chilled ethanol (20 mL) and the wet compound is dried in oven for 4 hours at 45° C. The dry compound (20 g) and water (20 mL) are charged into a round bottom flask and stirred for 15 minutes to obtain a clear solution. The reaction mixture is cooled to 0-5° C and ethanol (140 mL) is added slowly, followed by ethyl acetate (400 mL), slowly at 0-5° C. The obtained solid is collected by filtration, washed with ethyl acetate (20 mL) and the wet compound is dried in oven for 220 minutes at 50° C.

Yield: 20 g; Purity by HPLC: 99.67%; Chiral purity by HPLC: 99.21%; Water content by KF: 6.25%; PXRD pattern of the title compound obtained in the above example is in accordance with Figure 1.

Example 5: Preparation of (R)-N6-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (dexpramipexole).
(R)-2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole (30 g) and methanol (660 mL) are charged into an automated reactor and stirred to obtain a clear solution. The reaction mixture is cooled to -15 to -20° C and propionaldehyde (20.6 g) is added, followed by sodium borohydride in lots (4 g). The reaction mixture is maintained for 20 minutes at -15 to -20° C, water (600 mL) is added at 0 to 5° C, followed by HCI, and stirred for 15 minutes. The resultant reaction mass is evaporated under reduced pressure below 48° C. To the crude compound obtained after evaporation, water (600 mL) is added to obtain a clear solution. The pH of the solution is adjusted by adding caustic lye (13.5 mL) at 0-5° C. Ethyl acetate (600 mL) is added to the reaction mixture at 25-30° C and the layers formed are separated. Aqueous layer is extracted with ethyl acetate (600 mL). The combined organic layers are dried over sodium sulfate (30 g) and evaporated under reduced pressure below 45° C. To the obtained crude compound, toluene (90 mL) is added at 25-30° C and maintained for 100 minutes. The obtained solid is collected by filtration, washed with toluene (30 mL), and dried in oven for 8 hours at 55° C. Yield: 21.9 g; Purity by HPLC: 93.50%; Chiral purity by HPLC: 99.58%.

Example 6: Purification of (R)-N6-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (dexpramipexole).

(R)-N6-Propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (12 g) and ethyl acetate (120 ml_) are charged into a round bottom flask, heated to 74-78° C for 1 hour, again cooled to 25-30° C, and maintained for 2 hours. The obtained solid is collected by filtration, washed with ethyl acetate (12 ml_), and dried in an oven for 4.5 hours at 52° C.

Yield: 7 g; Purity by HPLC: 94.04%; Chiral purity by HPLC: 99.52%.

Example 7: Purification of (R)-N6-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (dexpramipexole).

(R)-N6-Propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (10 g) and methanol (5 g) are charged into a round bottom flask, followed by acetone (20 ml_) under stirring, and heated to 45-50° C for 15 minutes. The reaction mixture is then cooled to 0-5° C and maintained for 2 hours. The obtained solid is collected by filtration, washed with acetone (10 ml_), and dried in an oven for 3.5 hours at 52° C.

Yield: 2.7 g; Purity by HPLC: 97.97%; Chiral purity by HPLC: 99.45%.

Example 8: Preparation of (R)-N6-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (dexpramipexole) dihydrochloride monohydrate.

(R)-N6-Propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (5 g) and ethanol (40 mL) are charged into a round bottom flask and stirred to obtain a clear solution. To the reaction mixture, isopropyl alcohol HCI (21.6 mL) is added slowly at 25-30° C and the reaction mixture is cooled to 0-5° C and maintained for 90 minutes. The solid obtained is collected by filtration, washed with ethanol (5 mL), and dried in an oven for 8 hours. The dry compound (5.5 g) and water (5.5 mL) are charged into a round bottom flask and stirred to obtain a clear solution. The reaction mixture is cooled to 0-5° C and ethanol (38.5 mL) is added slowly, followed by ethyl acetate (110 mL). The solid obtained is collected by filtration, washed with ethyl acetate (5.5 mL), and dried in an oven for 220 minutes at 60° C.

Yield: 5.3 g; Purity by HPLC: 98.56%; Chiral purity by HPLC: 99.93%; Water content by KF: 6.13%; PXRD pattern of the title compound obtained in the above example is in accordance with Figure 2.

While particular embodiments 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.

WE CLAIM:

1. A process for the preparation of dexpramipexole or a pharmaceutically acceptable salt thereof or a hydrate thereof or a hydrates of salts thereof, comprising;

a) reacting (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with propionic anhydride in suitable organic solvent and in the presence of a suitable base to obtain (R)-N-(2-amino-4,5,6,7-tetrahydrobenzothiazol-6-yl)propionamide;

b) converting the product of step (a) into (R)-N-(2-amino-4,5,6,7-tetrahydrobenzothiazol-6-yl)propionamide hydrochloride using a source of hydrogen chloride in an organic solvent;

c) reducing the product of step (b) to provide dexpramipexole using a suitable reducing agent in a suitable organic solvent; and

d) optionally converting dexpramipexole into its pharmaceutically acceptable salts, hydrates, or hydrates of salts thereof.

2. A process for the preparation of dexpramipexole or a pharmaceutically acceptable salt thereof or a hydrate thereof or a hydrates of salts thereof, comprising;

a) reacting (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with propionaldehyde in the presence of a suitable organic solvent to obtain the respective enamine;

b) reducing the enamine formed in situ in step (a), with a suitable reducing agent to provide dexpramipexole free base; and

c) optionally converting dexpramipexole into its pharmaceutically acceptable salts, hydrates, or hydrates of salts thereof.

3. A process according to claim 1 or 2, further comprises the preparation of dexpramipexole dihydrochloride monohydrate comprising;

a) dissolving dexpramipexole in a water-miscible organic solvent;

b) adding hydrochloric acid to the solution of step (a) to provide dexpramipexole dihydrochloride;

c) optionally drying the product of step (b);

d) dissolving the product of step (b) or (c) in water, water-miscible organic solvent or mixture thereof; and

e) adding a suitable organic solvent to the solution of step (d) to precipitate dexpramipexole dihydrochloride monohydrate.

4. A process of claim 3, wherein the said water-miscible organic solvent is alcohol selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol or a mixture thereof.

5. A process for the preparation of dexpramipexole dihydrochloride monohydrate comprising;

a) dissolving dexpramipexole dihydrochloride in water; and

b) adding a suitable organic solvent or mixture of suitable solvents to the solution of step (a) to precipitate dexpramipexole dihydrochloride monohydrate.

6. A process according to any of the preceding claims, wherein the suitable organic solvent is selected from alcohols, amides, ethers, ketones, nitriles or mixture of two or more thereof.

7. A process according to any of the preceding claims, wherein the Dexpramipexole dihydrochloride monohydrate obtained is having the chiral purity of at least 99.9%.

8. Dexpramipexole dihydrochloride monohydrate having a powder X-ray diffraction pattern substantially in accordance with fig. 1.

9. Dexpramipexole dihydrochloride monohydrate having a powder X-ray diffraction pattern substantially in accordance with fig. 2.

10. A process according to any of the preceding claims, wherein the dexpramipexole dihydrochloride monohydrate obtained is having water content of about 4.5% w/w to about 7.0% w/w, as determined by Karl Fischer method.