DESC:FIELD OF THE INVENTION

The present invention relates to novel processes of Blarcamesine, its intermediate compounds, its pharmaceutically acceptable salts, and pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION

The drug compound, having the International Non-Proprietary Name Blarcamesine has a chemical name Tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine, and has the structure of Formula I:

Blarcamesine hydrochloride (Anavex2-73) is a Sigma-1 receptor agonist developed by Anavex Life Sciences and is undergoing clinical studies in Rett Syndrome, Alzheimer’s disease and Parkinson’s disease dementia.

PCT publication WO1997/30983A1 (“the ‘983 publication”) describes Blarcamesine, its enantiomers and its hydrochloride salt. Preparation of racemic Blarcamesine is exemplified as compound-7 and its melting point described as 87-90°C. The process exemplified in WO ‘983 is schematically represented below:

The process described in the WO ‘983 involves use of corrosive reaction conditions such as use of thionyl chloride; use of lithium aluminum hydride due to its pyrophoric nature, instability, toxicity, low shelf life and handling problems associated with its reactivity, for large-scale industrial production it’s not useful; further the WO ‘983 exemplified process involves use of benzene as solvent, benzene is classified as hazardous and carcinogen.
Therefore, with respect to the defects of the known process, developing a simple and direct, economic and environment-friendly synthesis technology with high quality, particularly seeking a process technology that is adaptable to the industrialized production, is of great realistic significance to the improvement of the drug's economic and social benefits.

SUMMARY OF THE INVENTION

The present invention generally relates to novel synthetic methods of Blarcamesine, its intermediate compounds, it’s pharmaceutically acceptable salts and pharmaceutical compositions thereof.

In accordance with one embodiment, the present invention provides a process for preparation of Blarcamesine or a pharmaceutically acceptable salt thereof, comprising:
(a) reacting a compound of formula VIII with dimethylamine to produce compound of formula VII,

(b) reacting the compound of formula VII with an aryl magnesium halide to produce a compound of formula II,

(c) cyclizing the compound of formula II to produce Blarcamesine, and

(d) optionally, converting the Blarcamesine into a pharmaceutically acceptable salt thereof.

In accordance with another embodiment, the present invention provides use of a compound of Formula VIII or a compound of Formula VII for the preparation of Blarcamesine or a pharmaceutically acceptable salt thereof.

In accordance with another embodiment, the present invention provides a process for purification of Blarcamesine, comprising:
(a) suspending or dissolving Blarcamesine in a suitable solvent at a suitable temperature;
(b) adding a suitable anti-solvent to the step a) reaction mass (or) adding step a) reaction mass to a suitable anti-solvent; and
(c) isolating the pure Blarcamesine;
wherein the suitable solvent is selected from the group comprising alcohols, halogenated hydrocarbons, ketones, esters, nitriles and mixtures thereof;
wherein the suitable anti-solvent is selected from the group comprising ethers, aliphatic hydrocarbons, cyclic hydrocarbons and water and mixtures thereof.

In accordance with another embodiment, the present invention provides a process for preparation of Blarcamesine or a pharmaceutically acceptable salt thereof, comprising:
(a) reacting a compound of formula VI with dimethylamine and formaldehyde to produce compound of formula V,

(b) protecting the compound of formula V to produce a compound of formula IV,

(c) reacting the compound of formula IV with phenyl magnesium halide to produce a compound of formula III,

(d) deprotecting the compound of formula III to produce a compound of formula II,

(e) cyclizing the compound of formula II to produce Blarcamesine, and

(f) optionally, converting the Blarcamesine into a pharmaceutically acceptable salt thereof.
Wherein, P is t-Butyldimethylsilyl, trimethylsilyl, t-Butyldiphenylsilyl, acetyl, pivalyl, methoxymethyl, tetrahydropyranyl, t-Butyl, allyl, benzyl or benzoyl.

In accordance with another embodiment, the present invention provides a process for preparation of an intermediate compound of Formula V, comprising:
(a) reacting a compound of formula VI with a compound of formula IX to produce compound of formula VI-A, and

(b) reacting a compound of formula VI-A with dimethylamine and formaldehyde to produce compound of formula V,

wherein, R is H, C1-4 alkyl or an aryl; M is a metal ion like Na, Li, K, Mg or Ca.

In accordance with another embodiment, the present invention provides a compound of Formula IV or a salt thereof.

Wherein, P is t-Butyldimethylsilyl, trimethylsilyl, t-Butyldiphenylsilyl, acetyl, pivalyl, methoxymethyl, tetrahydropyranyl, t-Butyl, allyl, benzyl or benzoyl.

In accordance with another embodiment, the present invention provides a compound of Formula III or a salt thereof.

Wherein, P is t-Butyldimethylsilyl, trimethylsilyl, t-Butyldiphenylsilyl, acetyl, pivalyl, methoxymethyl, tetrahydropyranyl, t-Butyl, allyl, benzyl or benzoyl.

In accordance with another embodiment, the present application provides pharmaceutical compositions comprising Blarcamesine or a pharmaceutically acceptable salt thereof prepared by the process of the present invention and one or more pharmaceutically acceptable polymer.

In accordance with another embodiment, the present application provides use of pharmaceutical compositions or formulations of any one of Blarcamesine salts prepared by the process of the present invention for the treatment of Neurodegenerative and Neurodevelopmental diseases such as Alzheimer’s disease, Parkinson’s disease dementia and/or Rett syndrome.

BRIEF DESCRIPTION OF DRAWINGS

Figure-1 is powder X-ray diffraction (PXRD) pattern of Blarcamesine free base prepared according to example 8.

Figure-2 is powder X-ray diffraction (PXRD) pattern of Blarcamesine HCl prepared according to example 9.

DETAILED DESCRITPION OF THE INVENTION

The present invention provides novel preparative methods of Blarcamesine, its intermediate compounds, it’s pharmaceutically acceptable salts and pharmaceutical compositions thereof.

In accordance with one embodiment, the present invention provides a process for preparation of Blarcamesine or a pharmaceutically acceptable salt thereof, comprising:
(a) reacting a compound of formula VIII with dimethylamine to produce compound of formula VII,

(b) reacting the compound of formula VII with phenyl magnesium halide to produce a compound of formula II,

(c) cyclizing the compound of formula II to produce Blarcamesine, and

(d) optionally, converting the Blarcamesine into a pharmaceutically acceptable salt thereof.

The step (a) involves reaction of compound of formula VIII with dimethylamine to produce compound of formula VII.

Compound of formula VIII and aqueous dimethylamine solution are mixed, and the reaction is carried out, preferably by stirring at a temperature of about 0°C to about 60°C; preferably at about 0°C to about 35°C. The stirring may be carried out for any suitable time, preferably for about 10 minutes to about 5 hours, preferably for about 1 hour to about 3 hours.

After completion of the reaction, the mixture is concentrated and the crude is added to a suitable solvent and may be extracted with water, and the organic layer may be concentrated to afford the compound of formula VII. The crude compound of formula VII may be purified or can be used directly for the next step.

The step (b) involves reaction of compound of formula VII with phenyl magnesium halide in presence of a suitable solvent.

The phenyl magnesium halide is selected from phenyl magnesium chloride, phenyl magnesium bromide or phenyl magnesium iodide; preferably, phenyl magnesium bromide or phenyl magnesium chloride. The solvent is selected from tetrahydrofuran, 2-Methyl tetrahydrofuran, dichloromethane or diethyl ether. Preferably, the solvent is tetrahydrofuran or 2-Methyl tetrahydrofuran. Further, phenyl magnesium halide can be prepared instantly by reacting Bromo/ Chloro benzene with magnesium in presence of an initiator Iodine.

The compound of formula VII, phenyl magnesium halide and the solvent are charged and may be stirred at -20°C to 35°C. The stirring may be carried out for any suitable time, preferably for about 30 minutes to about 20 hours, preferably for about 2 hours to about 12 hours.

After completion of the reaction the mass may be quenched with water and the organic layer may be concentrated to afford the compound of formula II or the reaction mass may be quenched with aq. Ammonium chloride and adjust the reaction mass pH to 6.5-7.8 with a suitable acid such as acetic acid and the organic layer may be concentrated to afford the compound of formula II. The crude compound of formula II may be purified or can be used directly for the next step.

The step (c) involves cyclization of the compound of formula II using a suitable dehydrating agent such as sulfuric acid or p-toluene sulfonic acid to afford Blarcamesine base.

The cyclization of the compound of formula II can be carried out in a suitable solvent such as Xylene, toluene and mixture thereof, or without using any solvent at a suitable temperature of about 0°C to about reflux temperature; preferably at 10°C to about reflux temperature.

After completion of the reaction the mass may be cooled to room temperature and washed with water. The organic layer may be concentrated to afford crude Blarcamesine base. The crude Blarcamesine base may be purified or can be used directly for salt formation.

In accordance with another embodiment, the present invention provides a process for purification of Blarcamesine, comprising:
(a) suspending or dissolving Blarcamesine in a suitable solvent at a suitable temperature,
(b) adding a suitable anti-solvent to the step a) reaction mass (or) adding step a) reaction mass to a suitable anti-solvent; and
(c) isolating the pure Blarcamesine;
wherein the suitable solvent is selected from the group comprising alcohols, halogenated hydrocarbons, ketones, esters, nitriles and mixtures thereof;
wherein the suitable anti-solvent is selected from the group comprising ethers, aliphatic hydrocarbons, cyclic hydrocarbons and water and mixtures thereof.

The suitable solvent used in aforementioned step a) is selected from the group comprising of but not limited to alcohols, halogenated hydrocarbons, ketones, esters, nitriles and mixtures thereof. The alcohols include, but are not limited to methanol, ethanol, butanol, isopropyl alcohol, tert-butanol and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, chloroform, chlorobenzene and the like; ketones include, but are not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone and the like; esters include, but are not limited to ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and the like; nitriles include, but are not limited to acetonitrile, propionitrile and the like and mixture thereof; preferably isopropyl alcohol.

The step a) of forgoing process involves, suspending or dissolving crude Blarcamesine in a suitable solvent at a temperature of about 0°C to about reflux temperature; preferably at about 45°C to about 65°C.

The suitable anti-solvent used in aforementioned step b) is selected from the group comprising of but not limited to ethers, aliphatic hydrocarbons, cyclic hydrocarbons and water and mixtures thereof. The ethers include, but are not limited to tetrahydrofuran, dimethyl ether, isopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and the like; aliphatic hydrocarbons include, but are not limited to hexane, heptane, octane and the like; cyclic hydrocarbons include, but are not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane and the like; and water and mixtures thereof; preferably water.

The step b) of the aforementioned process involves, adding a suitable anti-solvent to the step a) reaction mass (or) adding step a) reaction mass to a suitable anti-solvent at a temperature of about 0°C to about reflux temperature; preferably at about 45°C to about 65°C.

Then the resultant pure Blarcamesine can be isolated by conventional techniques such as precipitation by cooling the reaction mass, isolated by solvent precipitation, crystallization, concentrated by subjecting the solution to heating, decantation or filtration; preferably precipitation by cooling the reaction mass to below 35°C. The resultant product may optionally be further dried at a temperature of about 35°C to about 85°C for sufficient period.

The obtained Blarcamesine base may be converted into a pharmaceutically acceptable salt such as hydrochloride, hydrobromide, acetate, sulfate, formate, citrate, oxalate, malate, maleate, succinate, tartrate and the like.

In accordance with another embodiment, the present invention provides a process of conversion of Blarcamesine base into Blarcamesine hydrochloride salt; comprising:
(a) dissolving Blarcamesine in a mixture of ethyl acetate and Isopropyl alcohol at a suitable temperature;
(b) adding a source of hydrochloric acid to step a) solution, and
(c) isolating the Blarcamesine hydrochloride salt.
wherein the source of hydrochloric acid is selected from the group comprising hydrochloric acid, hydrochloric acid in Isopropyl alcohol, hydrochloric acid in methanol, hydrochloric acid in ethanol, hydrochloric acid in acetone, hydrochloric acid in methylene chloride, hydrochloric acid in tetrahydrofuran, hydrochloric acid in ethyl acetate and the like.

The step (a) process of Blarcamesine hydrochloride involves dissolving Blarcamesine in a mixture of ethyl acetate and Isopropyl alcohol at a suitable temperature; preferably at 0°C to about reflux temperature; more preferably at 25°C to about 35°C.

The step (b) process of Blarcamesine hydrochloride involves adding a source of hydrochloric acid to step a) solution. wherein the source of hydrochloric acid is selected from the group comprising hydrochloric acid, hydrochloric acid in Isopropyl alcohol, hydrochloric acid in methanol, hydrochloric acid in ethanol, hydrochloric acid in acetone, hydrochloric acid in methylene chloride, hydrochloric acid in tetrahydrofuran, hydrochloric acid in ethyl acetate and the like; preferable hydrochloric acid in Isopropyl alcohol, hydrochloric acid in methanol, aqueous hydrochloric acid.

Then the resultant Blarcamesine hydrochloric acid can be isolated by conventional techniques such as precipitation by cooling the reaction mass, isolated by solvent precipitation, crystallization, concentrated by subjecting the solution to heating, decantation or filtration; preferably by filtering the reaction mass. The resultant product may optionally be further dried at a temperature of about 35°C to about 85°C for sufficient period.

In accordance with another embodiment, the present invention provides a process for preparation of Blarcamesine or a pharmaceutically acceptable salt thereof, comprising:
(a) reacting a compound of formula VI with dimethylamine and formaldehyde to produce compound of formula V,

(b) protecting the compound of formula V to produce a compound of formula IV,

(c) reacting the compound of formula IV with phenyl magnesium halide to produce a compound of formula III,

(d) deprotecting the compound of formula III to produce a compound of formula II,

(e) cyclizing the compound of formula II to produce Blarcamesine, and

(f) optionally, converting the Blarcamesine into a pharmaceutically acceptable salt thereof.
Wherein, P is t-Butyldimethylsilyl, trimethylsilyl, t-Butyldiphenylsilyl, acetyl, pivalyl, methoxymethyl, tetrahydropyranyl, t-Butyl, allyl, benzyl or benzoyl.

The step (a) involves reaction of compound of formula VI with dimethylamine and formaldehyde to produce compound of formula V.

The reaction is carried out in presence of a suitable acid such as hydrochloric acid and a solvent such as methanol, ethanol, isopropanol, THF, acetic acid or a mixture thereof.

Compound of formula VI, paraformaldehyde, dimethylamine HCl and ethanol are mixed and concentrated HCl is added slowly.

The reaction is carried out, preferably by stirring at a temperature of about 25°C to about 120°C, or at about 55°C to about reflux temperature. The stirring may be carried out for any suitable time, preferably for about 30 minutes to about 30 hours, preferably for about 2 hours to about 20 hours.

After completion of the reaction, the mixture is concentrated, and the crude is added to water and extracted with a suitable solvent such as dichloromethane and concentrated to afford the compound of formula V.

The step (b) involves protection of the compound of formula V using suitable hydroxyl protecting group and base and a suitable solvent.

The suitable hydroxyl protecting group is selected from t-Butyldimethylsilyl, trimethylsilyl, t-Butyldiphenylsilyl, acetyl, pivalyl, methoxymethyl, tetrahydropyranyl, t-Butyl, allyl, benzyl or benzoyl. The base is selected from triethylamine, diisopropylethylamine, imidazole, pyridine DMAP and DBU. Preferably the base is DMAP, imidazole or triethylamine. The solvent is selected from dichloromethane, chlorobenzene, acetonitrile, THF, DMF, DMA, NMP, toluene, ethyl acetate and isopropyl acetate. Preferably, the solvent is dichloromethane.

The compound of formula V, a suitable hydroxyl protecting reagent, the base and the solvent are charged and the reaction is carried out, preferably by stirring at a temperature of about 5°C to about 70°C, or at about 15°C to about 35°C. The stirring may be carried out for any suitable time, preferably for about 30 minutes to about 10 hours, preferably for about 1 hour to about 3 hours.

After completion of the reaction the mass may be washed with water and the organic layer may be concentrated to afford the compound of formula IV. The crude compound of formula IV may be purified or can be used directly for the next step.

The step (c) involves reaction of compound of formula IV with phenyl magnesium halide in presence of a suitable solvent.

The phenyl magnesium halide is selected from phenyl magnesium chloride, phenyl magnesium bromide or phenyl magnesium iodide, preferably, the phenyl magnesium halide is phenyl magnesium bromide. The solvent is selected from tetrahydrofuran, dichloromethane or diethyl ether. Preferably, the solvent is tetrahydrofuran.
The compound of formula IV, phenyl magnesium halide and the solvent are charged, and the reaction is carried out, preferably by stirring at a temperature of about 0°C to about 60°C, or at about 5°C to about 35°C. The stirring may be carried out for any suitable time, preferably for about 30 minutes to about 20 hours, preferably for about 2 hours to about 12 hours.

After completion of the reaction the mass may be quenched with water and the organic layer may be concentrated to afford the compound of formula III. The crude compound of formula III may be purified or can be used directly for the next step.

The step (d) involves deprotection of compound of formula IV using a suitable acid and a suitable solvent. The acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, trifluoro acetic acid or p-Toluene sulfonic acid. Preferably, the acid is hydrochloric acid. More preferably, the acid is aqueous hydrochloric acid. The solvent is selected from tetrahydrofuran, dioxane, ethyl acetate, diethyl ether and the like. Preferably, the solvent tetrahydrofuran.

The compound of formula III, the acid and the solvent are charged and the reaction is carried out, preferably by stirring at a temperature of about 10°C to about 50°C, or at about 25°C to about 35°C. The stirring may be carried out for any suitable time, preferably for about 30 minutes to about 10 hours, preferably for about 1 hour to about 3 hours.

After completion of the reaction the mass may be diluted with ethyl acetate and filtered to afford the compound of formula II. The crude compound of formula II may be purified or can be used directly for the next step.

The step (e) involves cyclization of the compound of formula II using a suitable dehydrating agent such as p-toluene sulfonic acid to afford Blarcamesine base.

The compound of formula II, the dehydrating agent and a solvent are charged, and the reaction is carried out, preferably by stirring at a temperature of about 80°C to about 150°C, or at about 100°C to reflux temperature of the solvent. The water formed is removed continuously by using a Dean-Stark apparatus.

After completion of the reaction the mass may be cooled to room temperature and washed with water. The organic layer may be concentrated to afford crude Blarcamesine base. The crude Blarcamesine base may be purified or can be used directly for salt formation.
In accordance with another embodiment, the present invention provides a process for preparation of an intermediate compound of Formula V, comprising:
(a) reacting a compound of formula VI with a compound of formula IX to produce compound of formula VI-A,

(b) reacting a compound of formula VI-A with dimethylamine and formaldehyde to produce compound of formula V,

wherein, R is H, C1-4 alkyl or an aryl; M is a metal ion like Na, Li, K, Mg or Ca.

The step (a) involves reaction of compound of formula VI with a compound of formula IX to produce compound of formula VI-A.

In accordance with another embodiment, the compound of Formula IX is selected from the group comprising sodium acetate, potassium acetate, lithium acetate, magnesium acetate, calcium acetate, sodium propionate, potassium propionate, sodium benzoate and potassium benzoate. Preferably, the compound of Formula IX is sodium acetate.

The reaction is carried out in presence of a suitable catalyst such as potassium iodide, and a solvent such as acetic acid.

Compound of formula VI, Compound of formula IX, the catalyst and the solvent are mixed and the reaction is carried out, preferably by stirring at a temperature of about 25°C to about 120°C, or at about 55°C to about reflux temperature. The stirring may be carried out for any suitable time, preferably for about 30 minutes to about 30 hours, preferably for about 2 hours to about 20 hours.

After completion of the reaction, the mixture may be diluted with water and extracted with a suitable solvent such as dichloromethane and the organic layer is concentrated to afford the compound of formula VI-A.

The step (b) involves reaction of compound of formula VI-A with dimethylamine and formaldehyde to produce compound of formula V.

The reaction is carried out in presence of a suitable acid such as hydrochloric acid and a solvent such as methanol, ethanol, isopropanol, THF or a mixture thereof.

Compound of formula VI-A, paraformaldehyde, dimethylamine HCl and isopropanol are mixed and concentrated HCl is added slowly.

The reaction is carried out, preferably by stirring at a temperature of about 25°C to about 120°C, or at about 55°C to about reflux temperature. The stirring may be carried out for any suitable time, preferably for about 30 minutes to about 30 hours, preferably for about 2 hours to about 20 hours.

After completion of the reaction, the mixture is concentrated, and the crude is added to water and extracted with a suitable solvent such as dichloromethane and concentrated to afford the compound of formula V.

In another aspect, the present application provides pharmaceutical compositions comprising Blarcamesine or a pharmaceutically acceptable salt prepared by the process of the present invention, and one or more pharmaceutically acceptable polymer.

The Blarcamesine or a pharmaceutically acceptable salt prepared by the process of the present invention and their pharmaceutical compositions or formulations may be used as medicaments, particularly for the treatment of Neurodegenerative and Neurodevelopmental diseases such as Alzheimer’s diseases, Parkinson’s disease dementia and/or Rett syndrome.

DEFINITIONS

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

The terms “amorphous” and “amorphous form” are used herein to describe a substance, component, or product that is not substantially crystalline as determined by X-ray diffraction. In certain embodiments, an amorphous form of a substance may be substantially free of crystal forms. In other embodiments, an amorphous form of a substance may contain less than about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% of one or more crystal forms on a weight basis. In other embodiments, an amorphous form of a substance may comprise additional components or ingredients (for example, an additive, a polymer, or an excipient that may serve to further stabilize the amorphous form).

Unless otherwise specified, the term “solid dispersion” refers to a solid state which comprises at least two constituents, wherein one constituent is homogenously dispersed significantly evenly throughout the other constituent or constituents. It includes solid or glassy solutions, i.e., the dispersion of the constituents is in such a way that the composition is chemically and physically homogenous in nature.

The term “polymer” refers to a compound comprising repeating structural units (monomers) connected by covalent chemical bonds. Polymers may be further derivatized, crosslinked, grafted or end- capped. Non-limiting examples of polymers include copolymers, terpolymers, quaternary polymers, and homologues. The term “copolymer” refers to a polymer consisting essentially of two or more different types of repeating structural units (monomers).

The term “pharmaceutically acceptable excipient” includes, without limitation, any adjuvant, carrier, excipient, binder, filler, disintegrant, lubricant, glidant, sweetening agent, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example, "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.

All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.

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

EXAMPLES

Example 1: Preparation of 3-((dimethylamino)methyl)dihydrofuran-2(3H)-one (Compound of Formula VII)

3-Methylenedihydrofuran-2(3H)-one (compound of Formula VIII, 1.0 g, 10.19 mmole) and aq. Dimethyl amine solution (2 mL) were charged into a round bottom flask and the mixture was stirred for 1 hr at 25-35°C. The progress of reaction was monitored by TLC and after completion of reaction, the reaction was evaporated to dryness. The resulted residue was dissolved in dichloromethane (10 mL), washed with water (10 mL), organic layer was concentrated under vacuum at below 50°C to afford 0.98 g of compound of Formula VIII. 1H NMR (500 MHz, DMSO-d6) d 2.95-2.91- (m, 1H), 2.82-2.77 (m, 1H), 1.14-1.11 (m, 1H), 1.06-1.01 (m, 1H), 0.99-0.93 (m, 1H), 0.79 (s, 6H), 0.67-0.59 (m, 1H) ppm. Mass (m/z): 144.10 (M + H)+.

Example 2: Preparation of 3-((dimethylamino)methyl)dihydrofuran-2(3H)-one (Compound of Formula VII)

3-Methylenedihydrofuran-2(3H)-one (compound of Formula VIII, 200 g, 2.039 mol) and aq. Dimethyl amine solution (97 g) were charged into a round bottom flask and the mixture was stirred for 1 hr at 0-5?. The progress of reaction was monitored by TLC and after completion of reaction, extracted the reaction mass with methylene chloride (1000 mL), the organic layer was concentrated under vacuum at below 40°C to afford 265 g of compound of Formula VIII.

Example 3: Preparation of 2-((dimethylamino)methyl)-1,1-diphenylbutane-1,4-diol (Compound of Formula II)

Phenyl magnesium bromide (1.58 g, 8.73 mmole) was added to a mixture of compound of Formula VII (0.5 g, 3.49 mmole) and tetrahydrofuran (10 mL) at -25 to -20°C under nitrogen atmosphere and stirred for 1 hr at same temperature. Reaction mass temperature is then raised to 25-35°C and stirred for overnight at same temperature. The progress of reaction was monitored by TLC and after completion of reaction, the reaction was quenched with 10% aq. Ammonium chloride (10.0 mL) and the organic phase was separated; the aqueous layer was extracted with dichloromethane (2×10.0 mL). The organic layer was washed with brine solution (10.0 mL) and organic layer was concentrated under vacuum at below 50°C, the resulted crude was purified by column chromatography (Methanol: dichloromethane). The collected fractions were evaporated under vacuum at 50°C to afford 0.58 g of compound of Formula II.

Example 4: Preparation of 2-((dimethylamino)methyl)-1,1-diphenylbutane-1,4-diol (Compound of Formula II)

Grignard reagent preparation: Initiate the Grignard reagent with of Bromobenzene (1.09 g, 0.00698 mol) of Iodine (0.23 g, 0.908 mmol) and magnesium (6.7 g, 0.276 mol) in 2-methyl tetrahydrofuran (30 ml) medium at reflux, after the Grignard initiation add a solution of chlorobenzene (30.7 g, 0.272 mol) in 2-methyl tetrahydrofuran (20 ml) and maintain at reflux for 4-6 hours till to dissolve the all magnesium tunings.
Added a mixture of compound-VII (10 g, 0.0698 mol) in methylene chloride (15 vol.) to the above prepared Grignard reagent at below 30? under nitrogen atmosphere and stirred for 10 hr at 25-35?. The progress of reaction was monitored by TLC and after completion of reaction, the reaction was quenched with 20% aq. Ammonium chloride (150 ml) and adjust the reaction mass pH to 6.5-7.8 with acetic acid, then the organic phase was separated; the aqueous layer was extracted with dichloromethane (10 ml). combined the total organic layer and further adjust the pH below 2 with Conc. HCl, the isolated material filter and dry under vacuum at 50°C to afford 20.4 g of compound of Formula II.

Example 5: Preparation of Blarcamesine

A mixture of Compound of Formula II (4.0 g, 13.35 mmole) and sulfuric acid (0.659 g) in Water (10 mL) was refluxed for 6 hours. The progress of reaction was monitored by TLC and after completion of reaction, the reaction was cooled to 15-20°C and washed with 10% aq. sodium hydroxide solution (4.0 mL) and the organic phase was separated; the aqueous layer was extracted with toluene (10.0 mL). The combined organic layer was washed with water (2 x 20.0 mL) and organic layer was concentrated under vacuum at below 50°C to afford 0.7 g of Blarcamesine.

Example 6: Preparation of Blarcamesine

A mixture of Compound of Formula II (40.0 g, 119 mmol) and sulfuric acid (23.36 g, 238 mmol) in water (400 mL) was reflux for 5-6 hours. The progress of reaction was monitor by TLC and after completion of reaction, the reaction was cool to 25-35? and adjust the reaction mass to pH 8.5-10 with 30% aq. sodium hydroxide solution (90 mL) and filter the isolated material, dry the material under vacuum at below 50°C to afford 28.9 g of Blarcamesine. HPLC Purity: 98.7%

Example 7: Preparation of Blarcamesine

A mixture of Compound of Formula II (25.0 g, 83 mmol) and p-toluene sulfonic acid (28.8 g, 167 mmol) in toluene (250 mL) was reflux for 3-4 hours and collect the water by azeotrope. The progress of reaction was monitor by TLC and after completion of reaction, the reaction was cool to 25-35? and adjust the reaction mass to above 10 with 10% aq. sodium hydroxide solution (50 mL) and the organic phase was separated; the aqueous layer was extracted with toluene (60.0 mL). The combined organic layer was washed with water (2x75.0 mL) and organic layer was concentrated under vacuum at below 50°C Blarcamesine crude. Add water (200 ml) to residue and stir for 1-2 hours at 25-35?, then filter the precipitated solid followed by drying at below 50? under vacuum to afford 17 g of Blarcamesine.

Example 8: Purification of Blarcamesine

To a clear solution of Blarcamesine (15 g; HPLC Purity: 98.7%) in isopropyl alcohol (90 ml), water (90 ml) was added at 50-60?. The precipitated material was stirred at 50-60?, then cooled to 25-30? and stirred for 1 hour and filtered and isolated as white color solid (12 g). HPLC Purity: 99.7%; PXRD: Fig. 1.

Example 9: Preparation of Blarcamesine Hydrochloride

To a clear solution of Blarcamesine free base (85 g, 302 mmol) in Ethyl acetate (850 ml) and Isopropyl alcohol (85 ml) at 30-35? activated carbon was added followed by particle free. To this clear solution isopropyl alcohol. HCl (11.58 g, 317 mmol) was added and maintained for 1-2 hours at 25-30?, filter the precipitated compound and dried at 50? under vacuum to afford 82 g of a white color Blarcamesine HCl. HPLC Purity: 99.96%; PXRD: Fig. 2.

Example 10: Preparation of 4-Chlorobutyrophenone (Compound of Formula VI)

Aluminum chloride (89.0 g, 0.667 moles), Benzene (130 mL) and 4-Chloro butyryl chloride (90 g, 0.638 mole) were charged at 0-5°C portion wise into a round bottom flask, and stirred for 1 hr at same temperature. Reaction mass temperature was then raised to 0-5°C and stirred for 1 hr at same temperature. The progress of reaction was monitored by TLC and after completion of reaction, the reaction mas was quenched with ice and stirred rapidly until the solution was separated. The organic phase was separated and washed with a saturated aqueous solution of sodium chloride (242 mL) and organic layer was concentrated under vacuum at below 60°C to afford 104 g of compound of Formula VI. 1H NMR (500 MHz, DMSO-d6) d 7.98-7.93- (m, 2H), 7.64-7.62 (m, 1H), 7.53-7.50 (m, 2H), 3.72-3.69 (t, 2H), 3.18-3.15 (t, 2H), 2.10-2.05 (q, 2H) ppm. Mass (m/z): 183.06(M + H)+.

Example 11: Preparation of 2-((Dimethylamino)methyl)-4-hydroxy-1-phenylbutan-1-one (Compound of Formula V)

A mixture of compound VI (90 g, 0.49 mole), Para formaldehyde (19.24 g, 0.64 mole), Dimethyl amine hydrochloride (52.2 g, 1.73 mole) and ethanol (900.0 mL) were charged into a round bottom flask and the mixture was heated to reflux temperature. Slowly added conc. hydrogen chloride (9.0 mL) to the reaction mass at reflux temperature and stirred for 48 hr at same temperature. The progress of reaction was monitored by TLC and after completion of reaction, ethanol was evaporated in vacuo at below 60°C, then water (450 mL) and dichloromethane (720.0 mL) were added. The reaction mass was stirred and settled for 10 min. The organic phase was separated; the aqueous layer was washed with dichloromethane twice (2 x 270.0 mL). Adjust the pH of aqueous layer to 7.5 with Sodium bicarbonate and extracted with dichloromethane (3 x 270.0 mL). The organic layer was washed with a saturated aqueous solution of sodium chloride (180.0 mL) and concentrated under vacuum at below 50°C to afford 16.5 g of compound of Formula V. 1H NMR (500 MHz, DMSO-d6) d 8.00-7.98- (m, 2H), 7.64-7.61 (m, 1H), 7.54-7.51 (m, 2H), 4.70-4.60 (bs, 1H), 3.91-3.85 (m, 1H), 3.41-3.31 (m, 2H), 2.65-2.61 (m, 1H), 2.28-2.25 (m, 1H), 2.09 (s, 6H), 1.79-1.72 (m, 1H), 1.59-1.64 (m, 1H) ppm. Mass (m/z): 222.14 (M + H)+.

Example 12: Preparation of 4-((tert-butyldimethylsilyl)oxy)-2-((dimethylamino)methyl)-1-phenylbutan-1-one (Compound of Formula IV)

The compound of Formula V (1 g, 4.51 mmole), t-Butyl dimethyl silyl chloride (0.81 g, 5.42 mmole), Dimethyl aminopyridine (0.028 g, 0.23 mmole) and dichloromethane (10.0 mL) were charged into a round bottom flask. Triethylamine (0.553 g, 5.42 mmole) was added at 25-35°C and stirred for 2 hr at same temperature. The progress of reaction was monitored by TLC and after completion of reaction, mass was washed with water (2 x 10 mL). The aq. Layer was back extracted with dichloromethane (10.0 mL) and organic layer was concentrated under vacuum at below 50°C to afford 2.0 g of compound of Formula IV. The obtained residue was proceeded to next step without purification. 1H NMR (500 MHz, DMSO-d6) d 7.98-7.96- (m, 2H), 7.63-7.60 (m, 1H), 7.53-7.51 (m, 2H), 3.89-3.86 (m, 1H), 3.60-3.50 (m, 2H), 2.62-2.58 (m, 1H), 2.27-2.21 (m, 1H), 2.08 (s, 6H), 1.79-1.72 (m, 1H), 1.68-1.65 (m, 1H), 0.79 (s, 9H), 0.024(s, 6H) ppm. Mass (m/z): 336.25 (M + H)+.

Example 13: Preparation of 4-((tert-butyldimethylsilyl)oxy)-2-((dimethylamino)methyl)-1,1-diphenylbutan-1-ol (Compound of Formula III)

Phenyl magnesium bromide (2.431 g, 13.4 mmole) was added to a mixture of Compound of Formula IV (1.5 g, 4.51 mmole) and tetrahydrofuran (22.5 mL) at -40 to -45°C under nitrogen atmosphere and stirred for 1 hr at same temperature. Reaction mass temperature is then raised to 25-35°C and stirred for 12 hr at same temperature. The progress of reaction was monitored by TLC and after completion of reaction, the reaction was quenched with water (20.0 mL) and the organic phase was separated; the aqueous layer was extracted with ethyl acetate (20.0 mL). The organic layer was washed with water (20.0 mL) and organic layer was concentrated under vacuum at below 50°C to afford 2.5 g of Compound of Formula III. The obtained residue was proceeded to next step without purification. 1H NMR (500 MHz, DMSO-d6) d 7.51-7.49- (m, 4H), 7.23-7.28 (m, 4H), 7.16-7.11 (m, 2H), 6.64-6.63 (d, 1H), 3.64-3.59 (m, 1H), 3.51-3.46 (m, 1H), 2.83-2.80 (m, 1H), 2.37-2.33 (m, 1H), 2.10-2.08 (m, 7H), 1.67-1.64 (m, 1H), 1.39-1.33 (m, 1H), 0.85 (s, 9H), 0.045(s, 6H) ppm. Mass (m/z): 414.27 (M + H)+.

Example 14: Preparation of 2-((dimethylamino)methyl)-1,1-diphenylbutane-1,4-diol (Compound of Formula II)

The crude compound III was dissolved in tetrahydrofuran (30.0 mL) and treated with 2N hydrochloric acid (1.0 mL) at 25-35°C and stirred for 2 hr at 25-35°C. The progress of reaction was monitored by TLC and after completion of reaction, the reaction was quenched with ethyl acetate (30.0 mL) and stirred for 15 min at 25-35°C. The resulted solids were separated by filtration and the wet material was washed with ethyl acetate. Hydrochloric acid was added to a mixture of water (15.0 mL) and wet material till pH gets the 2.0 and the solution was washed with ethyl acetate. The aq. Layer pH adjusted to 7.0-7.5 by using aq. Sodium bicarbonate solution. The aqueous layer was extracted with ethyl acetate (20.0 mL) and the organic layer was concentrated under vacuum at below 50°C to afford 0.2 g of compound of Formula II. 1H NMR (500 MHz, DMSO-d6) d 7.56-7.54- (m, 4H), 7.27-7.23 (m, 4H), 7.13-7.16 (m, 2H), 6.30-6.20 (bs, 1H), 5.60-5.50 (bs, 1H), 3.46-3.42(m, 1H), 3.38-3.33 (m, 1H), 2.89-2.86 (m, 1H), 2.40-2.36 (m, 1H), 2.10 (s, 6H), 2.06-2.03 (m, 1H), 1.67-1.62 (m, 1H), 1.41-1.36 (m, 1H) ppm. Mass (m/z): 300.17 (M + H)+.

Example 15: Preparation of Blarcamesine

A mixture of Compound of Formula II (4.0 g, 13.35 mmole) and p-toluene sulphonic acid monohydrate (3.45 g, 20.03 mmole) in Toluene (50 mL) was refluxed for 4 hr with continuous removal of water via Dean-Stark trap. The progress of reaction was monitored by TLC and after completion of reaction, the reaction was cooled to 15-20°C and washed with 10% aq. sodium hydroxide solution (160.0 mL) and the organic phase was separated; the aqueous layer was extracted with toluene (30.0 mL). The combined organic layer was washed with water (2 x 50.0 mL) and organic layer was concentrated under vacuum at below 50°C to afford 2.5 g of Blarcamesine. 1H NMR (500 MHz, DMSO-d6) d 7.55-7.53- (m, 2H), 7.33-7.30 (m, 4H), 7.25-7.20 (m, 3H), 7.12-7.18 (m, 1H), 4.07-4.02 (m, 1H), 3.70-3.66 (m, 1H), 3.19-3.16 (m, 1H), 2.06-2.008 (m, 7H), 1.85-1.72 (m, 3H) ppm. Mass (m/z): 282.17 (M + H)+.

Example 16: Preparation of 4-oxo-4-phenylbutyl acetate (Compound of Formula VI-A)

4-chloro-1-phenylbutan-1-one (20.0 g), Sodium acetate (44.9 g) and Potassium iodide (1.99 g) in Acetic acid (60 mL) were charged into a round bottom flask and the mixture was refluxed for 10 hr. The progress of reaction was monitored by TLC and after completion of reaction, the reaction mass was cooled to 25-35°C and charged water (200 mL), extracted with dichloromethane (2x10 mL) then washed with saturated bicarbonate solution (100 mL) followed by brine solution (100 mL) and the organic phase was separated and concentrated under vacuum at below 40°C, the crude material was subjected to column purification to afford 14.6 g of compound of Formula VI-A. 1H NMR (600 MHz, DMSO-d6) d 7.97-7.53- (m, 5H), 4.07-4.05 (m, 2H), 3.12-3.109 (m, 2H), 1.98 (s, 3H), 1.94-1.92 (m, 2H) ppm. Mass (m/z): 207.10 (M + H)+.

Example 17: Preparation of 2-((Dimethylamino)methyl)-4-hydroxy-1-phenylbutan-1-one (Compound of Formula V)

A mixture of compound VI-A (1 g), Para formaldehyde (0.274 g), Dimethyl amine hydrochloride (0.745 g) and isopropanol (10.0 mL) were charged into a round bottom flask and the mixture was heated to reflux temperature. Slowly added conc. hydrogen chloride to the reaction mass at reflux temperature and stirred for 4 hours at same temperature. The progress of reaction was monitored by TLC and after completion of the reaction, isopropanol was evaporated in vacuo at below 60°C, then water (10 mL) and dichloromethane (10 mL) were added. The reaction mass was stirred and settled for 10 min. The organic phase was separated; the aqueous layer was washed with dichloromethane twice (2 x 10 mL). Adjust the pH of aqueous layer to 7.5 with Sodium bicarbonate and extracted with dichloromethane (3 x 270.0 mL). The organic layer was washed with a saturated aqueous solution of sodium chloride (10 mL) and concentrated under vacuum at below 50°C to afford 0.7 g of compound of Formula V. ,CLAIMS:We Claim:

1) A process for preparation of Blarcamesine or a pharmaceutically acceptable salt thereof, comprising:
(a) reacting a compound of formula VIII with dimethylamine to produce compound of formula VII,

(b) reacting the compound of formula VII with an aryl magnesium halide to produce a compound of formula II,

(c) cyclizing the compound of formula II to produce Blarcamesine, and

(d) optionally, converting the Blarcamesine into a pharmaceutically acceptable salt thereof.

2) The process as claimed in claim 1, wherein in the aryl magnesium halide is selected from the group comprising phenyl magnesium chloride, phenyl magnesium bromide or phenyl magnesium iodide.

3) The process as claimed in claim 1, wherein in the step c) cyclization is carried out in presence of a suitable dehydrating agent selected from the group comprising sulfuric acid or p-toluene sulfonic acid.

4) A process for purification of Blarcamesine, comprising:
(a) suspending or dissolving Blarcamesine in a suitable solvent at a suitable temperature;
(b) adding a suitable anti-solvent to the step a) reaction mass (or) adding step a) reaction mass to a suitable anti-solvent; and
(c) isolating the pure Blarcamesine;
wherein the suitable solvent is selected from the group comprising alcohols, halogenated hydrocarbons, ketones, esters, nitriles and mixtures thereof;
wherein the suitable anti-solvent is selected from the group comprising ethers, aliphatic hydrocarbons, cyclic hydrocarbons and water and mixtures thereof.

5) The process as claimed in claim 4, wherein in the suitable solvent is selected from the group comprising methanol, ethanol, butanol, isopropyl alcohol, tert-butanol, methylene chloride, chloroform, chlorobenzene, acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, acetonitrile, propionitrile and mixture thereof; wherein in the anti-solvent is selected from the group comprising tetrahydrofuran, dimethyl ether, isopropyl ether, methyl tertiary butyl ether, 1,4-dioxane, hexane, heptane, octane, cyclopropane, cyclobutane, cyclopentane, cyclohexane, methyl cyclohexane, cycloheptane, cyclooctane, water and mixtures thereof.

6) A process for preparation of Blarcamesine or a pharmaceutically acceptable salt thereof, comprising:
(a) reacting a compound of formula VI with dimethylamine and formaldehyde to produce compound of formula V,
,
(b) protecting the compound of formula V to produce a compound of formula IV,
,
(c) reacting the compound of formula IV with aryl magnesium halide to produce a compound of formula III,
,
(d) deprotecting the compound of formula III to produce a compound of formula II,
,
(e) cyclizing the compound of formula II to produce Blarcamesine, and

(f) optionally, converting the Blarcamesine into a pharmaceutically acceptable salt thereof; Wherein, P is t-Butyldimethylsilyl, trimethylsilyl, t-Butyldiphenylsilyl, acetyl, pivalyl, methoxymethyl, tetrahydropyranyl, t-Butyl, allyl, benzyl or benzoyl.

7) The process as claimed in claim 6, wherein in the aryl magnesium halide is selected from the group comprising phenyl magnesium chloride, phenyl magnesium bromide or phenyl magnesium iodide; wherein in the step c) cyclization is carried out in presence of a suitable dehydrating agent selected from the group comprising sulfuric acid or p-toluene sulfonic acid.

8) A process for preparation of an intermediate compound of Formula V, comprising:
(a) reacting a compound of formula VI with a compound of formula IX to produce compound of formula VI-A, and

(b) reacting a compound of formula VI-A with dimethylamine and formaldehyde to produce compound of formula V,
,
wherein, R is H, C1-4 alkyl or an aryl; M is a metal ion like Na, Li, K, Mg or Ca.

9) The process as claimed in claim 8, wherein in the formula IX is sodium acetate; wherein the step a) is carried out in presence of potassium iodide and acetic acid.

10) A composition comprising Blarcamesine or a pharmaceutically acceptable salt thereof as prepared according to claim 1-9 and at least one pharmaceutically acceptable excipient.