INTRODUCTION

Aspects of the present application relate to an improved process for preparing dexpramipexole, its pharmaceutically acceptable salts, and its hydrates. More particularly the aspect of the present application relate to an improved process 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 0 186 087 and its counterpart, U.S. patent No. 4,886,812, wherein (S)-Pramipexole was prepared by reductive alkylation of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with propionyl aldehyde in the presence of a reducing agent. An additional synthetic route has been described in J. Med. Chem., 1987, 30, 494-498, which involves acylation of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with propionic anhydride followed by reduction of the 6-acylamino derivative using a reducing agent.

The preparative methods described in the prior art suffer drawbacks like low yield, formation of undesired impurities and therefore makes the large scale production inconvenient and commercially less efficient.

An alternate process has been described in the experimental details of EP0186087 for preparing the dialkyl derivatives of benzothiazol. An N-dialkylation reaction for preparing 2-amino-6-di-n-propylamino-4,5,6,7-tetrahydro-benzothiazole, was carried out by reacting 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole with n-propylbromide and methanol solvent in the presence of potassium carbonate as a base. This synthetic method is not convenient for high scale production, because of tedious separation is required, produces poor yield and forms undesired impurities.

A similar process has been described in WO 2008/113056 wherein, propyl tosylate was reacted with a heated solution comprising enantiomerically enriched 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole in an organic solvent to precipitate (R)-dexpramipexole tosylate in 56% yield. This synthetic procedure suffers drawbacks of poor yield and also tends to form unwanted impurities.

A process for purifying dexpramipexole dihydrochloride monohydrate has been described in example of WO 2011/109596 application. The yield of the final compound is only 82% and chiral purity is 99.97%.

Hence, there is a need to provide simple, improved, 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 an improved process for preparing dexpramipexole comprising:

(a) reacting (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with a propylating agent in a suitable organic solvent to provide a dexpramipexole salt;

(b) converting the dexpramipexole salt into its free base; and

(c) optionally converting the dexpramipexole free base into a pharmaceutically acceptable salts or hydrates thereof.

In another aspect, the present application provides a process for preparing 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.

In another aspect, the present application provides 100% chirally pure dexpramipexole dihydrochloride monohydrate.

BRIEF DESCRIPTION OF THE DRAWING

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

DETAILED DESCRIPTION

After carrying out a detailed research and analysis, inventors of this present application have surprisingly found that the N-alkylation of 2,6-diamino-4,5,6,7-tetrahydrobenzothiazole can be selectively carried out in appropriate conditions, that are contrary to the teachings of prior art. Aspects of the present application relate to a simple, improved and cost effective method of preparing dexpramipexole, its pharmaceutical^ acceptable salts, and its hydrates, in high yield and high purity, which is devoid of the drawbacks of prior art.

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

(a) reacting (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with a propylating agent in a suitable organic solvent to provide a dexpramipexole salt;

(b) converting dexpramipexole salt into its free base; and

(c) optionally converting dexpramipexole free base into a pharmaceutical^ acceptable salts or hydrates 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), propylation is carried out in the absence of an additional base. In embodiments of step (a), the propylating agent used for the reactions include but are not limited to; n-propyl halides such as n-propyl bromide, n-propyl chloride, n-propyl iodide, or n-propyl fluoride; n-propyl sulfonates, such as n-propyl tosylate, n-propyl methanesulfonate, n-propyl trifluoromethanesulfonate, n-propyl benzenesulfonate; or the like. In embodiments of step (a), propyl halide is used. In another embodiment of step (a), n-propyl bromide is used as a propylating agent.

In embodiments of step (a), the molar ratio of (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole and the propylating agent is in a ratio of from about 1:1 to about 1:5. 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: alcohols, such as methanol, ethanol, 1-propanol, or2-propanol (isopropyl alcohol); ethers such as dioxane, dihydrofuran, tetrahydrofuran, 2-methyl tetrahydrofuran, or cyclopropylmethyl ether; cyclic or acyclic tertiary amides, derived from short chain, Ci-C3 carboxylic acids such as N,N-dimethylformamide, N,N-diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, or N-methylpyrrolidone; sulfoxides, such as dimethylsulfoxide; water; or mixtures of two or more thereof. In embodiments of step (a), the reaction may be carried out in a single phase solvent system or a biphasic solvent system. In embodiments of step (a), the reaction may be carried out in N,N-diethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, or N-methylpyrrolidone.

In embodiments of step (a), the reaction is carried out at a suitable temperature ranging from about 0° C to about 60° C. In embodiments of step (a), the reaction is carried out at a suitable temperature ranging from about 0° C to about 50° C. In embodiments of step (a), the reaction is carried out at a temperature ranging from about 0 to about 40° C. In embodiments of step (a), the reaction is carried out at a temperature ranging from about 0 to about 35° C. In embodiments of step (a), the reaction is carried out at a suitable temperature ranging from about 15° C to about 40° C. In embodiments of step (a), the reaction is carried out at a suitable temperature ranging from about 25° C to about 30° C. In embodiments of step (a), the reaction is carried out at a suitable temperature ranging from about 35° C to about 60° C. In embodiments of step (a), the reaction is carried out at a suitable temperature ranging from about 45° C to about 50° C.

In the embodiments of step (a), the dexpramipexole salt formed is either a dexpramipexole halide or a dexpramipexole sulfonate, depending on the propylating agent used. In embodiments of step (b), the dexpramipexole salt is a dexpramipexole halide. In another embodiment, the dexpramipexole salt is dexpramipexole hydrobromide.

In embodiments of step (a), the obtained dexpramipexole salt may be optionally subjected for purification in a suitable solvent. Suitable solvent for purification of dexpramipexole include, but are not limited to 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; 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; water or mixtures of two or more thereof.

In embodiments of step (b), dexpramipexole salt is converted into a free base by treating with a suitable base to provide dexpramipexole free base. Suitable bases for the conversion of dexpramipexole salt into free base include, but are not limited to; one or more of inorganic bases, such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, oxides, for e.g., potassium carbonate, potassium hydrogen carbonate, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, lithium carbonate, lithium hydrogen carbonate, lithium hydroxide, barium hydroxide, calcium oxide, or the like.

In embodiments of step (b), dexpramipexole halide or sulfonate is converted into dexpramipexole free base. In embodiments of step (b), dexpramipexole halides are converted into dexpramipexole free base. In another embodiment of step (c), dexpramipexole hydrobromide is converted into dexpramipexole free base.
In embodiments of step (c), dexpramipexole free base is optionally converted into 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 either step (b) or step (c) in water, a suitable organic solvent, or mixtures 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. In one embodiment, 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 C1-C6 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 an embodiment, the dexpramipexole dihydrochloride monohydrate has a powder X-ray diffraction pattern substantially in accordance with Fig. 1.

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

(a) dissolving dexpramipexole dihydrochloride in water, water-miscible solvents or
mixture of two thereof; 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), dexpramipexole dihydrochloride is dissolved in water, water-miscible solvent include, but not limited to; alcohols such as methanol, ethanol, iso-propanol, n-propanol; ketones such as acetone; amides such as N,N-dimethyl formamide; nitriles such as acetonitrile; tetrahydrofuran; dimethylsulfoxide; dioxane; or a mixture of two or more thereof.

In embodiments of step (b), 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; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol; water; 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 dexpramipexole 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 dexpramipexole 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 yet another aspect, the present application provides 100% chirally pure dexpramipexole dihydrochloride monohydrate, as determined by High performance liquid chromatography (HPLC).

In one embodiment 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 100% 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 embodiments of this present application, water content of dexpramipexole dihydrochloride monohydrate obtained, is in the range of about 4.5% w/w to about 7.0% w/w, as determined by Karl Fischer method.

In another aspect, the present application provides a process comprising reacting (R)-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole with a propylating agent in a suitable organic solvent to provide a dexpramipexole salt.

In another aspect, the present application provides a process further comprising converting the dexpramipexole salt into its free base.

In another aspect, the present application provides a process comprising converting the dexpramipexole free base into a pharmaceutically acceptable salt, hydrate, or hydrate of a salt thereof.

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

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 compounds 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. "Ci-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 "Cs-Ce 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 "amide solvent" is an organic solvent containing a carbonyl group (C=0) or phosphorus atom bonded to a nitrogen atom. "Amide solvents" include, but are not limited to, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), formamide, acetamide, propanamide, 1,1,3,3-tetramethyl urea, N,N'-dimethylpropylene urea, hexamethyl phosphoramide (HMPA), or hexamethyl phosphorus triamide (HMPT).

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 "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 "halide" is a binary compound, of which one part is a halogen atom and the other part is an element or radical that is less electronegative (or more electropositive) than the halogen, to make a fluoride, chloride, bromide or iodide compound.

A "sulfonate" is a salt or ester of a sulfonic acid. Examples of sulfonates include but are not limited to methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, or the like.

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

A "water-miscible solvent" is a solvent that is miscible with water in all proportions, forming a homogeneous solution.

As used herein, the term "chiral purity" may indicate the measurement of the composition of isomers in a compound, which is determined by methods conventional in the art such as high performance liquid chromatography (HPLC) or spectroscopic methods. For example, 99% chirally pure dexpramipexole dihydrochloride monohydrate indicates that, the compound has a composition of 99% (R)-isomer and 1% (S)-isomer. So, 100% chirally pure dexpramipexole dihydrochloride monohydrate means, that the compound has a composition of 100% (R)-isomer and 0% (S)-isomer.

As used herein, the term "chemical purity" refers to the purity with regard to unwanted residual solvents, reaction byproducts, impurities, and unreacted starting materials.

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)-N6-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (dexpramipexole) hydrobromide.

(R)-2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole (5 g, 29.5 mmole) and N,N-dimethylacetamide (25 ml_) are charged into a round bottom flask and stirred, n-Propyl bromide (18.2 g) is added into the reaction mixture at 25-30° C and maintained for 72 hours at 25-30° C. The reaction mixture is cooled to 0-5° C and the solid that separates is collected by filtration, followed by washing with isopropyl alcohol (5 ml_). The wet compound is dried under reduced pressure for 4 hours at 60° C, to afford the title compound. Yield: 8.1 g; (94.6%) Purity by HPLC: 97.47%; Chiral purity by HPLC: 99.80%.

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

(R)-2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole (10 g, 59.1 mmole) and N,N-dimethylacetamide (80 ml_) are charged into a round bottom flask and stirred, n-Propyl bromide (14.5 g) is added slowly into the reaction mixture at 25-30° C and heated to 45-50 ° C. The reaction mixture is maintained for 17 hours at 45-50° C. The reaction mixture is cooled to 0-5° C and the solid separated is collected by filtration, followed by washing with isopropyl alcohol (10 ml_). The wet compound is dried under reduced pressure for 6 hours at 55° C, to afford the title compound. Yield: 15.6 g (91 %); Purity by HPLC: 98.25%; Chiral purity by HPLC: 99.90%.

Example 3: Purification of (R)-N6-propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine (dexpramipexole) hydrobromide.

(R)-N6-Propyl-4,5,6,7-tetrahydrobenzothiazole-2,6-diamine hydrobromide (15 g) and acetone/water (7:3 v/v) (90 ml_) are charged into a round bottom flask and stirred. The reaction mixture is heated to 55-60° C to obtain a clear solution and maintained for 40 minutes. The reaction mixture is cooled to 0-5° C and maintained for 2 hours. The solid obtained is collected by filtration, washed with acetone/water (7:3 v/v) (15 ml_) and dried in an oven for 4.5 hours at 60° C. Yield: 9.6 g; Purity by HPLC: 99.77%; Chiral purity by HPLC: 99.99%.

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 hydrobromide (9 g) and water (90 ml_) are charged into a round bottom flask and stirred to obtain a clear solution. The reaction mixture is cooled to 5-10° C and ethyl acetate (180 ml_) is added to it. pH of the reaction mixture is adjusted with 85% potassium hydroxide solution (9 ml_) and the temperature is raised to 25-30° C. Layers formed are separated and the aqueous layer is extracted with ethyl acetate (270 ml_). The combined organic layers are dried over sodium sulfate (9 g) and evaporated under reduced pressure at below 45° C to provide the crude compound. To the crude compound (6.5 g), ethanol (52 ml_) is added at 25-30° C and stirred to obtain a clear solution followed by filtration and washing with ethanol (6.5 ml_). Isopropyl alcohol HCI (35 ml_) is added slowly at 25-30° C and the reaction mixture is cooled to 0-5° C and maintained for 75 minutes. The solid separated is collected by filtration, washed with chilled ethanol (6.5 mL) and the wet compound is dried under reduced pressure for 75 minutes at 60° C. The dry compound (7.7 g) and water (7.7 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 (53.9 mL) is added slowly, followed by ethyl acetate (154 mL). The solid separated is collected by filtration, washed with ethyl acetate (7.7 mL) and dried in an oven under reduced pressure for 3.5 hours at 60° C to afford the title compound.

Yield: 7.7 g; Purity by HPLC: 99.83%; Chiral purity by HPLC: 100%; Water content by KF: 6.07%; PXRD pattern of the title compound obtained in the above example is in accordance with Figure 1.

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 a propylating agent in a suitable organic solvent to provide a dexpramipexole salt;

b) converting dexpramipexole salt into its free base; and

c) optionally converting dexpramipexole free base into a pharmaceutical^ acceptable salts, hydrates or hydrates of salts thereof.

2. A process according to step (a) of claim 1, wherein propylation is carried out in the absence of an additional base.

3. A process according to step (a) of claiml, wherein propylating agent is selected from n-propyl bromide, n-propyl chloride, n-propyl iodide, or n-propyl fluoride, n-propyl tosylate, n-propyl methanesulfonate, n-propyl trifluoromethanesulfonate, n-propyl benzenesulfonate; or the like.

4. A process according to step (a) of claiml, wherein the dexpramipexole salt formed is either a dexpramipexole halide or a dexpramipexole sulfonate, depending on the propylating agent used.

5. A process according to step (b) of claim 1, wherein the salt of dexpramipexole thus formed in step (a) is converted into a free base by treating with a suitable base.

6. A process according to any of the preceding claims, further comprises the preparation of dexpramipexole dihydrochbride 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.

7. A process according to claim 5, wherein the hydrochloric acid is gaseous,
aqueous, concentrated, or dissolved in a suitable solvent.

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

a) dissolving dexpramipexole dihydrochloride in water, water-miscible solvents or mixture of two thereof; and

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

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

10. A process according to any of the preceding claims, wherein the Dexpramipexole dihydrochloride monohydrate obtained is 100% chirally pure.