DESC:
Field of the Invention:
The present invention relates to a process for the preparation of dopamine and norepinephrine reuptake inhibitor (DNRI) compound Solriamfetol and pharmaceutically acceptable salts thereof, having the chemical name (R)-2-amino-3-phenylpropyl carbamate (APC) by using novel intermediates.

Background of the Invention:
Solriamfetol has been recently approved in USA and Europe. Solriamfetol is a phenylalanine analog that has been demonstrated to be useful in the treatment of a variety of disorders, including excessive daytime sleepiness, cataplexy, narcolepsy, fatigue, depression, bipolar disorder, fibromyalgia, and others.

Solriamfetol is a dopamine and norepinephrine reuptake inhibitor (DNRI) indicated to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea (OSA).

US 5,955,499 B2 discloses Solriamfetol (formula 1) and pharmaceutically acceptable salts thereof.

Formula 1
US 20050080268 A1 discloses process for preparation of solriamfetol and pharmaceutically acceptable salts thereof.

US 20190194126 A1 discloses solvates of Solriamfetol hydrochloride.

Summary of the Invention:
In one aspect, the present invention relates to a process for the preparation of solriamfetol and pharmaceutically acceptable salts thereof and intermediates thereof.

The process for preparation of Solriamfetol and pharmaceutically acceptable salts thereof according to present invention is described by reaction schemes-1 and 2:
Scheme-1 Process for preparation of Solriamfetol and pharmaceutically acceptable salts thereof:

Scheme-2 Process for preparation of Solriamfetol and pharmaceutically acceptable salts
thereof:

In another aspect, the present invention provides a novel intermediate compound-2 or pharmaceutically acceptable salts thereof and process for the preparation thereof.

In another aspect, the invention provides use of novel intermediate compound-2 or pharmaceutically acceptable salts thereof in the preparation of Solriamfetol or pharmaceutically acceptable salts thereof.

In another aspect, the present invention relates to a process for the preparation of pharmaceutically acceptable salts of solriamfetol without isolation of Solriamfetol free base.

Detail Description of the Invention:
There is always a need for alternative preparative routes, which for example, use reagents, solvents that are less expensive, and/or easier to handle, consume smaller amounts of reagents and solvents, provide a higher yield of product, involve fewer steps, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity.

Each PG independently is an amine protecting group. The term “amine protecting group” is well understood by the person skilled in synthetic organic chemistry as a moiety that can be selectively installed onto and removed from a suitable amine functional group. The field of protecting group methodology is advanced, and many amine protecting groups, and methods for using them, are well known in the art. The amine protecting group can be selected from tert-butyloxycarbonyl (BOC), Fluorenylmethyloxycarbonyl (F-MOC), N-benzyl, Trityl, substituted Carboxybenzyl (CBZ) group, etc.

The phrase "pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to: acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicylic acid, muconic acid, and the like or basic addition salts formed with the conjugate bases of any of the inorganic acids listed above, wherein the conjugate bases comprise a cationic component selected from among Na+, Mg2+, Ca2+, NHgR'''4-g+, in which R''' is a C1-3 alkyl and g is a number selected from among 0, 1, 2, 3, or 4. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.

According to one aspect, the present invention provides a process for the preparation of Solriamfetol comprising the steps of:

i) reducing D-phenylalanine or pharmaceutically acceptable salt thereof to obtain a D-phenylalaninol or pharmaceutically acceptable salt thereof;

ii) protecting D-phenylalaninol or pharmaceutically acceptable salt thereof to obtain amine protected D-phenylalaninol or pharmaceutically acceptable salt thereof

iii) converting amine protected D-phenylalaninol or pharmaceutically acceptable salt thereof to get amine protected Solriamfetol.

iv) deprotecting the amine protected solriamfetol to get solriamfetol.
v) converting solriamfetol to pharmaceutically acceptable salts of solriamfetol.

The reaction of Step-(i) can be performed in acidic conditions and in presence of reducing agent selected from but not limited to metal borohydrides like sodium borohydride, lithium borohydride.

The reaction of Step-(i) can optionally be performed in presence of metal catalyst such as palladium, platinum, nickel, iron with or without ligands and salts thereof.
The solvent for the reaction of step- (i) can be selected from one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water,1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

The reaction of step-(iii) is performed in presence of coupling agent like but not limited to 1,1'-carbonyldiimidazol. The reaction of step-(iii) can be performed in presence of base like but not limited to ammonia.

The solvent for the reaction of step- (iii) can be selected from one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, tetrahydrofuran, and acetonitrile or mixtures thereof.

Reaction of step-(iv) can be performed by maintaining the pH of the reaction to acidic by using reagents such as but not limited to hydrochloric acids.

In another aspect, the present invention provides a novel intermediate compound-2 or pharmaceutically acceptable salt thereof.

Compound-2
In another aspect, the invention provides a process for preparation of a novel intermediate of compound-2, comprising reaction of amine protected D-phenylalaninol with coupling reagent like but not limited to 1,1'-carbonyldiimidazol.

According to another aspect, the present invention provides a process for the preparation of Solriamfetol or pharmaceutically acceptable salts thereof comprising the steps of:

i) reacting the amine protected D-phenylalaninol with phenyl carbamate to get amine protected solriamfetol.

ii) deprotecting the protected solriamfetol to get solriamfetol.
iii) converting solriamfetol to pharmaceutically acceptable salts of solriamfetol.

The reaction of Step-(i) can be performed in presence of tin catalyst like but not limited to dibutyltin maleate.

The solvent for the reaction of step- (i) can be selected from one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water 1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

Reaction of step-(ii) can be performed by maintaining the pH of the reaction to acidic by using reagents such as but not limited to hydrochloric acids.

According to another aspect, the present invention provides a process for the preparation of pharmaceutically acceptable salts of solriamfetol without isolation of Solriamfetol free base comprising reacting amine protected solrimafetol with a solution of desired salt.

The solution of desired salt can be made using solvents selected from but not limited to one or more of alcohols like methanol; ethanol; isopropanol; esters like ethyl acetate, isopropyl acetate.

Solriamfetol generated from the processes described herein can be converted to pharmaceutically acceptable salts by any process from the literature.

A better understanding of the present invention may be obtained in light of following examples which are set forth to illustrate, but are not to be construed to limit, the present invention.

Examples:
Example 1
Preparation of D-phenylalaninol
D-phenylalanine (150 gm) and tetrahydrofuran (750ml) were added to the flask. Sodium borohydride (85.9gm) was added to the reaction mass. Solution of sulphuric acid in tetrahydrofuran was added to the reaction mass. Reaction mass was stirred till the completion of reaction. D-phenylalaninol was isolated and dried.

Example 2
Preparation of Amine Protected D-phenylalaninol
D-phenylalaninol (25gm) and dichloromethane (250ml) were added to flask. Solution of Boc-anhydride (43.3 gm) in dichloromethane (50ml) was added to the reaction mass. Reaction mass was stirred till the completion of reaction. Product was isolated and dried.

Example 3
Preparation of Boc-protected solriamfetol
1,1'-Carbonyldiimidazol (18.3gm) and toluene (125ml) were added to the flask. Slurry of N-Boc-D-phenylalaninol (25gm) in toluene (175ml) was added to the reaction mass. Reaction was stirred till the completion of reaction. Aq. Ammonia was added to the reaction and reaction mass was stirred. Boc-protected solriamfetol was isolated and dried.

Example 4
Preparation of Compound-2
1,1'-Carbonyldiimidazol (18.3gm) and toluene (125ml) were added to the flask. Slurry of N-Boc-D-phenylalaninol (25gm) in toluene (175ml) was added to the reaction mass. Reaction was stirred till the completion of reaction. Compound 2 was isolated and dried.

Example 5
Preparation of Boc-protected solriamfetol
N-Boc-D-phenyl-alaninol (10gm) and toluene(100 gm) were charged to flask. Phenyl carbamate (10.9gm) and dibutyltin maleate (0.38gm) were added to reaction mass. Reaction mass was heated to reflux and monitored till completion of reaction. Boc-protected solriamfetol was isolated and dried.

Example 6
Preparation of Solriamfetol
Boc protected solriamfetol (12gm) was added to water (50ml) in a flask. Hydrochloric acid was added to the reaction mass. Reaction mass was heated till the completion of reaction. After completion of reaction, solriamfetol was isolated and dried.

Example 7
Preparation of Solriamfetol Hydrochloride
Boc protected Solriamfetol; isopropyl alcohol were added to flask. Saturated solution of hydrochloric acid in Isopropyl alcohol was added to reaction mass. Reaction mass was stirred till the completion of reaction. After completion of reaction solrimafetol hydrochloride was isolated and dried.
,CLAIMS:
1. A process for preparation of solriamfetol or pharmaceutically acceptable salts thereof comprising:
i) reducing D-phenylalanine or pharmaceutically acceptable salt thereof in presence of reducing agent to obtain a D-phenylalaninol or pharmaceutically acceptable salt thereof;

ii) protecting D-phenylalaninol or pharmaceutically acceptable salt thereof to obtain amine protected D-phenylalaninol or pharmaceutically acceptable salt thereof

wherein PG is amine protecting group.
iii) converting amine protected D-phenylalaninol or pharmaceutically acceptable salt thereof to amine protected Solriamfetol in presence of coupling agent and base.

wherein PG is amine protecting group.
iv) deprotecting the amine protected solriamfetol to get solriamfetol.
v) converting solriamfetol to pharmaceutically acceptable salts of solriamfetol.

2. The process according to claim 1, wherein the step (i) is performed in presence of reducing agent selected from sodium borohydride and lithium borohydride.

3. The process according to claim 1, wherein the coupling agent used in step (iii) is 1,1'-carbonyldiimidazol and the base used in step (iii) is ammonia.

4. The process according to claim 1, wherein Solriamfetol hydrochloride is prepared by reacting Solriamfetol with alcoholic solution of hydrochloric acid.

5. A compound-2:

wherein PG is amine protecting group.

6. A process for preparation of a novel intermediate of compound-2, comprising reaction of amine protected D-phenylalaninol with 1,1'-carbonyldiimidazol.

7. A process for preparation of solriamfetol or pharmaceutically acceptable salts thereof comprising:
i) reacting the amine protected D-phenylalaninol with phenyl carbamate to get amine protected solriamfetol.

wherein PG is amine protecting group.
ii) deprotecting the protected solriamfetol to get solriamfetol.
iii) converting solriamfetol to pharmaceutically acceptable salts of solriamfetol.

8. The process according to claim 7 wherein, the step (i) is performed in presence of dibutylin maleate.

9. The process according to claim 1 and claim 7 wherein Solriamfetol hydrochloride is prepared by reacting amine protected Solriamfetol with alcoholic solution of hydrochloric acid.

10. A process for preparation of pharmaceutically acceptable salts of Solriamfetol without isolation of Solriamfetol free base comprising reaction of amine protected solrimafetol with a solution of desired salt.