DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR THE PREPARATION OF SOLRIAMFETOL AND SALT THEREOF”

Glenmark Pharmaceuticals Limited; Glenmark Life Sciences Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification particularly describes the nature of the invention and the manner in which to be performed.
PRIORITY
This application claims the benefit to Indian Provisional Application No. 201821030526, filed on 14 August, 2018, the contents of which are incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates to solriamfetol or salt thereof and its process for preparation.
BACKGROUND OF THE INVENTION
Solriamfetol hydrochloride, chemically known as (R)-2-amino-3-phenylpropylcarbamate hydrochloride, is represented by compound of formula Ia.

Formula Ia
Solriamfetol, a dopamine and norepinephrine reuptake inhibitor (DNRI), is marketed in the United States under the trade name SUNOSI® as tablets in the dosage strength of 75mg and 150mg.
Solriamfetol hydrochloride can be used to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea (OSA).
United States Patent No.5,955,499 discloses a process for the preparation of solriamfetol hydrochloride
There is a need for an improved process for the preparation of solriamfetol, which avoids the formation of isomeric and other process-related impurities, while affording the desired solriamfetol hydrochloride product with good yield and high purity.
The present invention provides a process for solriamfetol HCl in a high chemical and chiral purity by using novel acid addition salts of solriamfetol without using chromatographic techniques.

SUMMARY OF THE INVENTION
The present invention provides, a process for the preparation of R- solriamfetol HCl of formula Ia,

Formula Ia
the process comprising: (a) reacting solriamfetol of formula I,

Formula I
with an acid to form solriamfetol acid addition salt of formula II;

Formula II
(b) optionally purifying the solriamfetol acid addition salt of formula II;
(c) converting the solriamfetol acid addition salt of formula II to solriamfetol HCl of formula Ia; and
(d) optionally purifying the solriamfetol hydrochloride of formula Ia.
The present invention provides solriamfetol dibenzoyl-D-tartaric acid salt of formula IIa characterized by 1H NMR having peaks at 2.65-2.71, 2.88, 3.39, 3.72-3.86, 5.69, 6.61, 7.16-7.25, 7.44-7.48, 7.60-8.00 (400 MHz, DMSO d6).
The present invention provides, a process for solriamfetol dibenzoyl-D-tartaric acid salt of formula IIa, comprising reacting solriamfetol of formula I with dibenzoyl-D-tartaric acid.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic XRPD of solriamfetol di-p-toluoyl-D-tartaric acid as obtained in Example 8. Figure 2 is a DSC thermogram of solriamfetol di-p-toluoyl-D-tartaric acid as obtained in Example 8. Figure 3 is a characteristic XRPD of solriamfetol dibenzoyl-D-tartaric acid as obtained in Example 17. Figure 4 is a DSC thermogram of solriamfetol dibenzoyl-D-tartaric acid as obtained in Example 17. Figure 5 is a characteristic XRPD of solriamfetol hydrochloride as obtained in Example 20. Figure 6 is a DSC thermogram of solriamfetol hydrochloride as obtained in Example 20. Figure 7 is a TGA thermogram of solriamfetol hydrochloride as obtained in Example 20.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of R-solriamfetol HCl of formula Ia,

Formula Ia
the process comprising: (a) reacting solriamfetol of formula I,

Formula I
with an acid to form solriamfetol acid addition salt of formula II;

Formula II
(b) optionally purifying the solriamfetol acid addition salt of formula II;
(c) converting the solriamfetol acid addition salt of formula II to solriamfetol HCl of formula Ia; and
(d) optionally purifying the solriamfetol hydrochloride of formula Ia.
In one embodiment, the present invention provides R-solriamfetol HCl of formula Ia having chemical purity of at least 98% as determined by HPLC.
The acid used in step (a) may be selected from the group consisting of an organic acid and an optically active acid.
The organic acid may be selected from the group consisting of formic acid, acetic acid, citric acid, tartaric acid, bitartaric acid, benzoic acid, lactic acid, oxalic acid, malic acid, fumaric acid, succinic acid, gluconic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid.
The optically active acid may be selected from the group consisting of (+)-dibenzoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, (-)-di-p-toluoyl-L-tartaric acid, S-(+) mandelic acid, R-(-) mandelic acid, L-(+) tartaric acid, D-(-) tartaric acid, L-malic acid, D-malic acid, D-maleic acid, (lR)-(-)-camphor sulfonic acid, (lS)-(+)-camphor sulfonic acid, L(-)-pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid.
In one embodiment, the optically active acid is dibenzoyl-D-tartaric acid or di-p-toluoyl-D-tartaric acid.
In one embodiment, in step (a) the reaction is carried out in presence of a solvent which includes but is not limited to hydrocarbons such as methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride, toluene, xylene, heptane, hexane, cyclohexane and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate and the like; alcohols such as methanol, ethanol, isopropanol, n-propanol, butanol and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; water and or mixtures thereof.
In step (b) the acid addition salt of compound of formula II is purified by a solvent selected from but not limited to alcohols such as methanol, ethanol, isopropanol, n-propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate and the like; water and or mixtures thereof.
In one embodiment, solriamfetol acid addition salt of formula II obtained in step (b) is filtered and dried.
In one embodiment, solriamfetol acid addition salt of formula II is isolated by filtration, centrifugation or by a method known in the art.
In one embodiment, drying may be performed under vacuum at a temperature of about 50-70°C, preferably at a temperature of 50-60°C.
In step (c) solriamfetol acid addition salt of formula II is treated with HCl in an organic solvent to form solriamfetol HCl of formula Ia.
The organic solvent used in step (c) includes, but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, butyl acetate, tert-butyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, isopropanol, n-propanol, butanol and the like; mixtures thereof.
In one embodiment, in step (c) solriamfetol acid addition salt of formula II is treated with HCl source in an organic solvent to directly obtain solriamfetol HCl.
In one embodiment, in step (c) solriamfetol acid addition salt of formula II is treated with HCl source in an organic solvent to directly obtain solriamfetol HCl of formula Ia, without isolating solriamfetol free base.
In one embodiment, in step (c) solriamfetol acid addition salt of formula II is treated with HCl in non-aqueous medium.
The addition of hydrochloric acid may be by purging dry HCl gas or by addition of of hydrochloric acid dissolved in an organic solvent.
In one embodiment, solriamfetol HCl obtained in step (c) is filtered and dried.
In step (d) R-solriamfetol HCl of formula Ia may be purified from a suitable solvent selected from alcohols such as methanol, ethanol, propanol, isopropanol and the like; esters such as ethyl acetate, isopropyl acetate and the like; ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran and the like or mixtures thereof.
In one embodiment, solriamfetol HCl is isolated by filtration, centrifugation or by a method known in the art.
In one embodiment, drying may be performed under vacuum at a temperature of about 50-70°C, preferably at a temperature of 50-60°C.
In one embodiment, the present invention provides a process for the preparation of R- solriamfetol HCl of formula Ia, the process comprising: (a) reacting solriamfetol of formula I, with an optically active acid to form solriamfetol acid addition salt of formula II; (b) optionally purifying the solriamfetol acid addition salt of formula II;
(c) converting the solriamfetol acid addition salt of formula II to solriamfetol HCl of formula Ia.
In step (a) an optically active acid is selected from the group consisting of (+)-dibenzoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, (-)-di-p-toluoyl-L-tartaric acid.
In step (c) solriamfetol acid addition salt of formula II is treated with HCl source in an organic solvent to form solriamfetol HCl of formula Ia.
The hydrochloride source is selected from but not limited to hydrochloride gas, concentrated hydrochloric acid, ethyl acetate-hydrochloride, ethanol-hydrochloride, isopropanol-hydrochloride and the like.
The organic solvent used is as described supra.
In one embodiment, the present invention provides a process for the preparation of R- solriamfetol HCl of formula Ia, the process comprising:
(a) reacting solriamfetol of formula I, with (+)-dibenzoyl-D-tartaric acid to form solriamfetol dibenzoyl-D-tartaric acid of formula IIa;

Formula IIa
(b) optionally purifying the solriamfetol dibenzoyl-D-tartaric acid of formula IIa;
(c) converting the solriamfetol dibenzoyl-D-tartaric acid of formula IIa to solriamfetol HCl of formula Ia; and
(d) optionally purifying the solriamfetol hydrochloride of formula Ia.
In step (b) solriamfetol dibenzoyl-D-tartaric acid of formula IIa is purified from methanol, ethanol, isopropanol or aqueous mixture thereof.
In step (c) solriamfetol dibenzoyl-D-tartaric acid of formula IIa is treated with HCl source in an organic solvent to form solriamfetol HCl of formula Ia.
The hydrochloride source used is as described supra. The organic solvent used is as described supra.
In step (d) solriamfetol HCl of formula Ia is purified or recrystallized from a suitable solvent as described supra.
In one embodiment, the present invention provides R-solriamfetol HCl of formula Ia having chemical purity of at least 99% as determined by HPLC.
In one embodiment, the present invention provides R-solriamfetol HCl of formula Ia having chemical purity greater than 99.5% as determined by HPLC.
In one embodiment, the present invention provides R-solriamfetol HCl of formula Ia having chemical purity greater than 99.8% as determined by HPLC.
In one embodiment, the present invention provides R-solriamfetol HCl of formula Ia having chemical purity in the range of 99% to 99.98% as determined by HPLC.
In one embodiment, the present invention provides R-solriamfetol HCl of formula Ia having chiral purity greater than 99% as determined by HPLC.
In one embodiment, the present invention provides R-solriamfetol HCl of formula Ia having chiral purity greater than 99.5% as determined by HPLC.
In one embodiment, the present invention provides R-solriamfetol HCl of formula Ia having chiral purity greater than 99.8% as determined by HPLC.
In one embodiment, the present invention provides R-solriamfetol HCl with a chemical purity of at least 99% and a chiral purity of at least 99% as determined by HPLC.
In one embodiment, the present invention provides R-solriamfetol HCl of formula Ia free of other isomer i.e. S-solriamfetol.
In one embodiment, the present invention provides R-solriamfetol HCl of formula Ia having chiral purity of 100% as determined by HPLC.
In one embodiment, the present invention provides solriamfetol hydrochloride, where is one or more of impurity A, impurity B, impurity C, impurity D, impurity E, impurity F, impurity G, impurity H or impurity I are present less than 0.15% w/w relative to the amount of R-solriamfetol as determined by HPLC.

Impurity A
Impurity B
Impurity C

Impurity D
Impurity E Impurity F
Impurity G

Impurity H
Impurity I

In one embodiment, the present invention provides solriamfetol hydrochloride of formula Ia, wherein impurity B, impurity F or impurity G are present less than 0.15% w/w relative to the amount of R-solriamfetol as determined by HPLC.
HPLC Methodology
Reagents and Solvents: Water (Milli Q or equivalent); Acetonitrile (Gradient Grade, Rankem) Perchloric acid 70% (AR grade, Rankem)
Chromatographic Conditions:
Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software.
Column: Inertsil ODS HL, 250 x 4.6mm, 5µ; Column temperature: 40°C
Mobile Phase: Mobile Phase A = Buffer (100%)
Buffer: 0.1% Perchloric acid in water
Mobile Phase B = Acetonitrile: Buffer (90: 10, v/v)
Diluent: Water: Acetonitrile (80: 20, v/v)
Flow Rate: 1.0 mL/min; Detection: UV 210nm; Injection Volume: 20µL
The retention time of main peak of solriamfetol hydrochloride is about 14.0 minutes under these conditions.
In one embodiment, the present invention provides solriamfetol dibenzoyl-D-tartaric acid salt of formula IIa,

Formula IIa
In one embodiment, the present invention provides solriamfetol dibenzoyl-D-tartaric acid salt IIa characterized by 1H NMR having peaks at 2.65-2.71, 2.88,3.39, 3.72-3.86, 5.69, 6.61,7.16-7.25, 7.44-7.48,7.60-8.00 (400MHz,DMSO d6).
In one embodiment, the present invention provides a crystalline solriamfetol dibenzoyl-D-tartaric acid salt of formula IIa characterized by an X-ray powder diffraction spectrum having peak reflections at about 6.68, 15.53, 16.22, 18.73 and 20.12 ±0.2 degrees 2 theta which is substantially in accordance with Figure 3.
In one embodiment, the present invention provides a crystalline solriamfetol dibenzoyl-D-tartaric acid salt of formula IIa characterized by DSC thermogram having endothermic peak at about 177.600C and 181.410C ±2°C which is substantially in accordance with Figure 4.
In one embodiment, present invention provides crystalline solriamfetol dibenzoyl-D-tartaric acid salt of formula IIa characterized by TGA thermogram, showing weight loss of about less than 0.5 weight% up to 100ºC determined over the temperature range of 0°C to 350°C and heating rate 10°C/min.
In one embodiment, the present invention provides, a process for solriamfetol dibenzoyl-D-tartaric acid salt of formula IIa, comprising reacting solriamfetol of formula I with dibenzoyl-D-tartaric acid.
In one embodiment, the present invention provides a process for dibenzoyl-L-tartaric acid salt of solriamfetol of formula IIb, comprising reacting solriamfetol of formula I with dibenzoyl-L-tartaric acid.
In one embodiment, the purification or recrystallization of dibenzoyl-D-tartaric acid or dibenzoyl-L-tartaric salt of solriamfetol, a compound of formula IIa or IIb may be carried out in a suitable solvent selected from alcohols such as methanol, ethanol, propanol, isopropanol and the like; esters such as ethyl acetate, isopropyl acetate and the like; ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran and the like; water or mixtures thereof.
In one embodiment, the present invention provides crystalline solriamfetol dibenzoyl-D-tartaric acid salt of formula IIa.
In one embodiment, the present invention provides crystalline solriamfetol dibenzoyl-D-tartaric acid salt of formula IIa having chemical purity of at least 98% as determined by HPLC.
In one embodiment, the present invention provides crystalline solriamfetol dibenzoyl-D-tartaric acid salt of formula IIa having chiral purity greater than 99% as determined by HPLC.
In one embodiment, the present invention provides solriamfetol di-p-toluoyl-D-tartaric acid salt of formula IIc,

Formula IIc
In one embodiment, the present invention provides solriamfetol di-p-toluoyl-D-tartaric acid salt of formula IIc characterized by 1H NMR having peaks at 2.34, 2.70-2.76, 2.88-2.93, 3.48-3.51, 3.72-3.86, 5.60, 6.61, 7.16-7.31, 7.84-7.86 (400 MHz, DMSO d6).
In one embodiment, the present invention provides a crystalline solriamfetol di-p-toluoyl-D-tartaric acid salt of formula IIc characterized by an X-ray powder diffraction spectrum having peak reflections at about 6.33, 16.32, 18.55, 19.65 and 21.85 ±0.2 degrees 2 theta which is substantially in accordance with Figure 1.
In one embodiment, the present invention provides a crystalline solriamfetol di-p-toluoyl-D-tartaric acid salt of formula IIc characterized by DSC thermogram having endothermic peak at about 184.570C and 190.370C ±2°C which is substantially in accordance with Figure 2.
In one embodiment, present invention provides crystalline solriamfetol di-p-toluoyl-D-tartaric acid salt, a compound of formula IIc characterized by TGA thermogram, showing weight loss of about less than 1.0 weight% up to 100ºC determined over the temperature range of 0°C to 350°C and heating rate 10°C/min.
In one embodiment, the present invention provides a process for di-p-toluoyl-D-tartaric acid salt of solriamfetol, a compound of formula IIc, comprising reacting solriamfetol of formula I with di-p- toluoyl-D-tartaric acid.
In one embodiment, the present invention provides a process for di-p-toluoyl-L-tartaric acid salt of solriamfetol of formula IId, comprising reacting solriamfetol, a compound of formula I with di-p- toluoyl-L-tartaric acid.
In one embodiment, the purification or recrystallization of D or L di-p-toluoyl-tartaric acid salt of solriamfetol, a compound of formula IIc or IId may be carried out in a suitable solvent as described supra.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 6.58, 12.27, 13.18, 19.81, 24.66, 30.98 ±0.2 degrees 2 theta which is substantially in accordance with Figure 5.
In one embodiment, the present invention provides a crystalline solriamfetol hydrochloride characterized by DSC thermogram having endothermic peak at about 183.91±2°C and185.27±2°C which is substantially in accordance with Figure 6.
In one embodiment, present invention provides crystalline solriamfetol hydrochloride characterized by TGA thermogram, showing weight loss of about less than 0.1weight% up to 100ºC determined over the temperature range of 0°C to 350°C and heating rate 10°C/min which is substantially in accordance with Figure 7.
In one embodiment, present invention provides crystalline solriamfetol hydrochloride showing water content less than 0.5% by KF.
In one embodiment, the present invention provides solriamfetol hydrochloride, having D10 particle size of less than about 50 microns, preferably less than about 20 microns, more preferably less than about 10 microns.
In one embodiment, the present invention provides solriamfetol hydrochloride, having D50 particle size of less than about 150 microns, preferably less than about 130 microns, more preferably less than about 115 microns.
In one embodiment, the present invention provides solriamfetol hydrochloride, having D90 particle size of less than about 300 microns, preferably less than about 250 microns, more preferably less than about 225 microns.
The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state solriamfetol or hydrochloride or solvate thereof into any of the foregoing desired particle size range.
In one embodiment, the present invention provides a process for the preparation of D-phenyl alanine methyl ester HCl, a compound of formula IV,

Formula IV
the process comprising reacting D-phenyl alanine with thionyl chloride in presence of solvent or mixture of solvents to form compound of formula IV.
In one embodiment, the compound of formula IV may be purified or crystallized from solvent or mixture of solvents.
In one embodiment, the present invention provides a process for the preparation of
(2R)-2-amino-3-phenylpropan-1-ol, a compound of formula III,

Formula III
the process comprising reacting compound of formula IV with reducing agent in the presence of a base and suitable organic solvent or mixture of organic solvents.
In one embodiment, the compound of formula III may be purified or crystallized from solvent or mixture of solvents.
In one embodiment, the present invention provides a process for the preparation of
Solriamfetol, a compound of formula I, comprising reacting compound of formula III with an alkali cyanate or alkaline earth cyanate and an acid in presence an organic solvents.
The present invention provides solriamfetol hydrochloride, obtained by the above processes, as characterized and analyzed by following techniques:
A. X-ray powder diffraction profiles were obtained using an X-ray Diffractometer (Philips X’Pert Pro, PANalytical). The measurements were carried out with a Pre FIX module programmable divergence slit and anti-scatter Slit (Offset 0.00°) ; target, Cu; filter, Ni; detector, X’Celerator; Scanning Mode; Active length (2Theta) = 2.122°; generator 45KV; tube current 40mAmp. The samples were scanned in the full 2? range of 2-50° with a “time-per-step” optimized to 50 sec.
B. DSC (TA 250): Temperature range is “30°C to 350°C” and heating rate is 10°C/minute.
C. Thermo Gravimetric Analyzer: TGA Q500 V6.5. Thermogram was recorded at 30-350°C at the rate of 10°C/min.
D. Karl Fischer: The water content was calculated by the following formula:
water content (%) = Burette reading × KF Factor × 100
Weight of sample in mg
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES
Example 1: Preparation of (2R)-2-amino-3-phenylpropan-1-ol
To a stirred solution of D-phenylalanine methyl ester hydrochloride (100gm) in methylene dichloride (500ml) and water (300ml), sodium carbonate (50gm) added in one lot at about 25-30°C. The reaction mixture was stirred for about 30 minutes and organic layer was separated and collected in clean and dry container. The aqueous layer was extracted with methylene dichloride. The combined organic layer was washed with water and dried over Na2SO4. The organic layer was evaporated under vacuum to give D-phenylalanine methyl ester as an oil (79gm) which was taken in methanol and reaction mixture was cooled to 0-5 0C. Sodium borohydride (35.304gm) was added to reaction mixture lot wise by maintaining temperature between 0-10°C in about 1 hour. The ice-bath was removed and reaction mixture was stirred until D-phenylalanine methyl ester was no longer detected by TLC. After completion of reaction, solvent was evaporated and thick solid was dissolved in water. The aqueous layer was extracted three times with methylene dichloride. The product containing methylene dichloride was concentrated and n-heptane (600ml) was added. The slurry was stirred for about 2 hour and the precipitated solid was collected by filtration. The solid was dried under vacuum to form titled compound as a white solid. Yield: 57gm, 81%.
EXAMPLE 2: Preparation of crystalline (2R)-2-amino-3-phenylpropyl carbamate (Solriamfetol)
In a dry round bottom flask dichloromethane (224mL) was charged followed by addition of (2R)-2-amino-3-phenylpropan-1-ol (28g) and sodium cyanate (23.59g). The reaction mixture was cooled to about 0-5°C and methane sulfonic acid (62.28g) was slowly added to the reaction mass. After completion of the addition of methane sulfonic acid, temperature of the reaction mass was raised to about 20-30°C and stirred for about 3 hours. After completion of the reaction, the reaction mass cooled to about 0-5°C and 20% aq. sodium hydroxide solution was added at temperature below 5°C. The aqueous and organic layers were separated and the aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water and brine and dried over sodium sulfate overnight followed by filtration. The filtrate was concentrated under vacuum to obtain 29.5g solriamfetol as an oil. The obtained oil was taken in n-heptane (300ml) and stirred for about 5 hours at 0-10°C. The precipitated solid was filtered and dried under vacuum at about 20-30°C to form 27gm of titled compound.
EXAMPLE 3: Preparation of crystalline solriamfetol hydrochloride
Solriramfetol (1gm) was dissolved in dichloromethane (5ml) in round bottom flask. The reaction mass cooled to about 0-5°C and ethyl acetate hydrochloride (3ml) was added at about 0-5°C. The reaction mixture was stirred for about 1hour, a white precipitated formed. The obtained precipitate was filtered and dried in vacuum at about 50°C to form 1gm of titled compound.
Example 4: Preparation of Solriamfetol
A solution of methane sulfonic acid (88.98gm) in dichloromethane (80ml) was charged slowly to a solution of D-phenylalaninol (40gm) and sodium cyanate (33.7gm) in 320ml dichloromethane at about 0-5°C and the reaction mass was stirred for about 3 hours. The progress of reaction was monitored by TLC till completion of the reaction. After completion of reaction, water was added and pH of the reaction mixture was adjusted in between 10 to 12 using 20% sodium hydroxide solution. The mixture was transfer to separator and organic layer separated. Aqueous layer was extracted with dichloromethane. Combined organic layer was washed with brine solution and dried over sodium sulphate. Organic layer was concentrated in vacuum to get an oil which was stirred in 300ml n-heptane at 0-5 °C for about 15 minutes then temperature was raised to 20-30°C and stirred for about 2 hour. The precipitated solid was filtered and dried under vacuum at about 35-40 °C for about 12 hours to form titled compound as a solid. Yield: 43gm, 71%; HPLC chemical purity: 92%.
Example 5: Preparation of solriamfetol dibenzoyl-D-tartaric acid
A solution of solriamfetol dibenzoyl-D-tartaric acid (11.12gm) in dichloromethane (50ml) was added to a stirred solution of solriamfetol free base (6.2gm) from example 4 in dichloromethane in about 20 minutes. The thick slurry of reaction mass was stirred for about two hour at 25-30°C. The precipitated solid was filtered and dried under vacuum at about 50-60°C for12 hours to form 16.5gm of titled compound as a white solid. Yield: 92%; HPLC chemical purity: 87.6%;
Example 6: Purification of solriamfetol dibenzoyl-D-tartaric acid
A suspension of solriamfetol dibenzoyl-D-tartaric acid salt (5gm) in 25ml isopropyl alcohol containing 10% water was heated to reflux to get a clear solution and stirred for about 30 minutes the reaction mass was cooled gradually to room temperature and stirred for about 2 hour. The solid was filtered and dried under vacuum at 50-60°C to form 2.2gm of titled compound. HPLC chemical purity: 99.16%. 1H NMR, 400MHZ, DMSO, ppm: 2.65-2.71 (t, 1H), 2.88(m, 1H), 3.39(q, 1H), 3.72-3.86(m, 4H), 5.69 (s, 1H), 6.61(br s, 2H), 7.16-7.25(m, 5H), 7.44-7.48(m, 5H), 7.60-8.00(m, 5H).
Example 7: Preparation of Solriamfetol HCl
5ml ethyl acetate hydrochloride (10-12%) was added slowly to a suspension of 1gm solriamfetol dibenzoyl-D-tartaric acid salt obtained from example 6 in 5ml ethyl acetate and the reaction mixture was stirred for about 2 hours at room temperature. The precipitated solid was filtered and dried under vacuum at about 50-60 °C for about 12 hours to form 1gm of titled compound. HPLC chemical purity: 99.47%; HPLC chiral purity greater than 99%.
Example 8: Preparation of solriamfetol di-p-toluoyl-D-tartaric acid
To a stirred solution of solriamfetol free base (5gm) from example 4, in 30ml ethyl acetate was added di-p-toluoyl-d-tartaric acid salt (9.93gm) solution in 30ml ethyl acetate in about 20 minutes. The thick slurry of reaction mass was stirred for two hour at 25-30 °C. The precipitated solid was filtered and dried under vacuum for overnight to afford 5.7gm of titled compound as a white solid. HPLC chemical purity: 96.37%; 1H NMR, 400MHZ, DMSO, ppm: 2.34(m, 1H), 2.70-2.76 (m, 1H), 2.88-2.93(m, 1H), 3.48-3.51(q, 1H), 3.72-3.86(m, 4H), 5.60 (s, 1H), 6.61(br s, 2H), 7.16-7.31(m, 8H), 7.84-7.86(m, 5H). XRD peaks are listed in Table1.
Table 1
Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%]
6.33 100.00 22.78 7.84 33.66 2.07
9.65 1.94 23.95 18.78 34.16 1.70
11.13 9.33 24.23 20.10 35.79 3.47
11.93 5.25 24.81 7.38 36.28 2.32
12.36 10.72 25.31 20.64 37.57 2.18
12.66 4.50 26.44 18.69 38.61 1.64
13.52 16.60 26.87 13.18 39.87 0.65
15.26 13.64 28.30 3.78 41.13 0.81
15.59 18.95 28.61 1.88 42.84 1.18
16.32 35.53 29.00 4.51 43.88 2.24
18.23 18.26 30.15 6.34 44.44 2.06
18.55 32.79 30.35 6.26 46.79 1.95
19.65 36.18 31.44 3.79
21.85 42.75 32.39 2.39
DSC analysis of solriamfetol di-p-toluoyl-D-tartaric shows endothermic peaks at about 184.570C and 190.370C.
TGA analysis of solriamfetol di-p-toluoyl-D-tartaric shows a weight loss of less than 1.0 weight% up to 1000C determined over the temperature range of 00C to 3500C and heating rate 10 0C/min.
Example 9: Preparation of Solriamfetol HCl
5ml ethyl acetate HCl solution (10-12%) was added slowly to a suspension of 2gm solriamfetol di-p-toluoyl-D-tartaric acid salt obtained from example 8, in 20ml ethyl acetate. After the complete addition mixture was stirred for about 2 hours and solid was collected by filtration. The product was washed with ethyl acetate and dried under vacuum at about 50-60 °C for about 12 hours to form 1gm of titled compound. HPLC chemical purity: 99.52%; HPLC chiral purity greater than 99%.
Example 10: Preparation of Solriamfetol oxalate
To a stirred solution of solriamfetol free base (8gm) from example 4, in 30ml ethyl acetate was added oxalic acid (5.18gm) solution in 30ml ethanol in about 20 minutes. The thick slurry of reaction mass was stirred for about two hour at 25-30 °C. The precipitated solid was filtered and dried under vacuum for overnight to afford 8.5gm of titled compound as a white solid. 1H NMR, 400MHZ, DMSO, ppm: 2.80-2.86 (m, 1H), 2.98-3.03(m, 1H), 3.57-3.58(q, 1H), 3.82-4.00(m, 4H), 6.64(br s, 2H), 7.26-7.36(m, 5H), 8.89(br s, 4H). HPLC chemical purity: 97.97%.
Example 11: Preparation of Solriamfetol HCl
5ml ethyl acetate HCl solution (10-12%) was added slowly to a suspension of 2gm solriamfetol oxalate obtained from example 10, in 50ml acetone. After the complete addition mixture was stirred for about 2 hours and solid was collected by filtration. The product was washed with acetone and dried under vacuum at about 50-60°C for about 12 hours to form 1.2gm of titled compound. HPLC chemical purity: 98.77%.
Example 12: Preparation of Solriamfetol tartrate
To a stirred solution of solriamfetol free base (5gm) from example 4, in 50ml ethyl acetate was added tartaric acid (3.85gm) solution in 50ml ethyl acetate in about 20 minutes. The thick slurry of reaction mass was stirred for about two hour at 25-30 °C. The precipitated solid was filtered and dried under vacuum for overnight to afford 7gm of titled compound as a white solid. HPLC chemical purity: 93.27 %.
Example 13: Preparation of Solriamfetol HCl
5ml ethyl acetate HCl solution (10-12%) was added slowly to a suspension of 2gm solriamfetol tartrate obtained from example 12, in 50ml acetone. After the complete addition mixture was stirred for about 2 hours and solid was collected by filtration. The product was washed with acetone and dried under vacuum at about 50-60 °C for about 12 hours to form 1.1gm of titled compound. HPLC chemical purity: 98.81%.
Example 14: Preparation of Solriamfetol citrate
To a stirred solution of solriamfetol free base (5gm) from example 4 in acetone (30ml) was added citric acid (4.98gm) solution in 30ml acetone in about 20 minutes. The thick slurry of reaction mass was stirred for about two hour at about 25-30 °C. The precipitated solid was filtered and dried under vacuum for overnight to afford 9.5 gm of titled compound as a white solid. HPLC chemical purity: 98.88%.
Example 15: Preparation of (2R)-2-amino-3-phenylpropan-1-ol
To a stirred solution of D-phenylalanine methyl ester hydrochloride (100gm) in methylene dichloride (400ml) and aqueous sodium carbonate solution was added in one lot. The reaction mixture was stirred for about 15 minutes and organic layer was separated and collected in clean and dry container. The aqueous layer was extracted with methylene dichloride (MDC). The combined organic layer was passed over Na2SO4 and transferred to clean and dry round bottom flask. Sodium borohydride (35.304gm) was added to organic layer in one lot and methanol (200ml) was added to the reaction mass between 20-30°C. Reaction mixture was refluxed until D-phenylalanine methyl ester was no longer detected by HPLC. After completion of reaction, sodium chloride (10%) was added to reaction mass and stirred for about 30 minutes. Organic layer was separated and aqueous layer was extracted with MDC and product containing MDC layer was passed over Na2SO4. The organic layer was evaporated under reduced pressure to obtain solid. The solid was recrystallized from ethyl acetate and the precipitated solid was collected by filtration and dried under vacuum to form titled compound as a white solid. Yield: 50gm, 71%; HPLC chemical purity: 99.89%.
Example 16: Preparation of solriamfetol dibenzoyl-D-tartaric acid
Methane sulfonic acid (222.40gm) was charged slowly to a solution of (R)-2-amino-3-pheylpropan-1-ol (100gm) and sodium cyanate (120.36gm) in MDC (2000ml) at about 0 0C to about 10 0C. The progress of reaction was monitored by HPLC till completion of the reaction. After completion of reaction, sodium hydroxide (10%) solution was added to the reaction mass. The reaction mass was filtered through hyflow bed, organic layer was separated and aqueous layer was extracted with MDC. Combined organic layer was washed with brine solution and dibenzoyl-D-tartaric acid (118.46gm) was added in above organic layer. The reaction mass was stirred for about 3 hours. The precipitated solid was filtered, dried under vacuum at about 50-60 0C for about 12 hours form titled compound. Yield: 220gm; HPLC chemical purity: 96%.
Example 17: Purification of solriamfetol dibenzoyl-D-tartaric acid
Solriamfetol dibenzoyl-D-tartaric acid (200gm) was refluxed in 5% aqueous methanol solution (1000ml) and the suspension was stirred for about 30 minutes at reflux temperature and cooled to room temperature gradually. The thick slurry of reaction mass was stirred for about one hour at about 10-15 0C and precipitated solid was filtered and suck dried for about 30 minutes. The wet material further purified using 5% aqueous methanol to form titled compound. HPLC chemical purity: 99.63%. XRD peaks are listed in Table 2
Table 2:
Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%]
6.68 100.00 20.12 36.07 31.90 0.40
7.18 2.29 20.98 0.67 32.57 0.99
9.80 1.34 22.07 4.52 33.83 0.81
11.36 7.96 22.50 11.25 34.82 1.54
11.87 7.63 22.80 5.66 36.56 1.58
12.33 3.48 23.81 4.24 37.43 1.68
13.33 5.26 24.07 5.64 38.62 0.73
13.60 5.01 24.93 11.28 39.85 0.83
14.25 1.41 25.20 10.33 40.64 1.12
15.53 15.38 25.75 11.02 41.52 0.80
16.21 15.55 26.31 3.33 42.57 0.90
16.43 6.54 27.34 16.20 43.36 1.21
17.06 2.27 27.91 7.13 44.41 1.20
18.08 9.21 28.57 2.22 45.19 0.96
18.42 7.58 29.82 1.50 45.95 0.91
18.73 16.90 30.91 3.38 48.61 1.10

DSC analysis of solriamfetol dibenzoyl-D-tartaric acid shows endothermic peaks at about 177.600C and 181.410C.
TGA analysis of solriamfetol dibenzoyl-D-tartaric acid shows a weight loss of less than 0.5 weight% up to 1000C determined over the temperature range of 00C to 3500C and heating rate 10 0C/min
Example 18: Purification of solriamfetol dibenzoyl-D-tartaric acid
Solriamfetol dibenzoyl-D-tartaric acid (200gm) was refluxed in 5% aqueous ethanol solution (1000ml) and suspension was stirred for about 30 minutes at reflux temperature and cooled to room temperature gradually. The thick slurry of reaction mass was stirred for about one hour at about 10-15°C and precipitated solid was filtered and suck dried for about 30 minutes. The wet material further purified using 5% aqueous ethanol to form titled compound. HPLC chemical purity: 98.35%.
Example 19: Preparation of Solriamfetol hydrochloride
Solriamfetol dibenzoyl-D-tartaric acid obtained from example 17 was charged in ethyl acetate (800ml) and water (400ml). The reaction mass was cooled below 20 0C and aqueous sodium hydroxide solution was added slowly to get clear solution. The mixture was transfer to separator and organic layer was separated. Aqueous layer was extracted with ethyl acetate (2 time). Combined organic layer was washed with purified water and filtered through hyflow bed and concentrated under vacuum to get an oil (80gm). Obtained oily mass was dissolved in isopropanol (240ml) and IPA-HCl (117ml) was added slowly below 10 0C. The precipitated solid was stirred for 2 about hour, filtered, dried under vacuum at about 50-60 °C for about 12 hours to form titled compound as white solid. Yield: 90gm; HPLC chemical purity: 99.96%; chiral purity: 100%.
Example 20: Purification of Solriamfetol hydrochloride
Solriamfetol Hydrochloride (100gm) was dissolved in methanol (500ml) and stirred for about 30 minutes to get clear solution, filtered through suitable filter to remove foreign particle and distilled under vacuum. The obtained solid was slurried in ethyl acetate (500ml), filtered and dried under vacuum at about 65-70 0C for about 12 hours to form titled compound. Melting point: 177-179 0C; Yield: 95gm white solid; HPLC chemical purity: 99.96%; chiral purity 100%.
XRD peaks are listed in Table 3
Table 3:
Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%] Pos. [°2Th.] Rel. Int. [%]
6.58 17.5 26.21 14.57 35.39 3.16
12.27 16.27 26.91 2.41 35.71 4.15
13.17 16.85 27.17 7.69 35.95 3.07
15.33 8.02 28.58 6.70 36.19 10.38
15.54 7.57 29.20 10.39 37.61 0.69
16.04 14.91 29.28 9.24 39.05 1.83
17.32 3.89 30.01 1.92 39.70 2.82
19.19 6.82 30.55 1.36 40.10 0.83
19.64 13.03 30.98 38.81 40.99 1.71
19.81 25.41 31.37 3.98 41.62 1.42
20.24 16.96 32.11 2.54 42.21 1.02
21.20 5.58 32.41 6.70 42.46 2.81
21.29 6.79 32.78 1.36 43.09 1.45
22.26 5.63 33.35 2.02 44.18 0.71
22.84 8.83 34.03 4.08 44.86 1.16
23.72 24.52 34.45 2.16 45.40 1.92
24.66 100.00 35.07 2.30

DSC analysis of solriamfetol hydrochloride shows endothermic peaks at about 183.910C and 185.270C.
TGA analysis of solriamfetol hydrochloride shows a weight loss of less than 0.1 weight% up to 1000C determined over the temperature range of 00C to 3500C and heating rate 10 0C/min.
Particle size: d(10) 5.109; d(50) 101.52; d(90) 213.34
Comparative Example 1: Preparation of Solriamfetol hydrochloride
10% ethyl acetate hydrochloride (20ml) was added slowly to a solution of solriamfetol free base (10gm) from example 4 in 50ml ethyl acetate and stirred for about 2 hours at about 25-30 °C. The precipitated solid was filtered and was washed with ethyl acetate. The solid was dried under vacuum at about 50-60 °C for about 12 hours to afford titled compound as white solid. Yield: 11gm, 73%; HPLC chemical purity: 95.11%.
Comparative Example 2: Purification of Solriamfetol hydrochloride
A suspension of solriamfetol hydrochloride (2gm) in 20ml of ethyl acetate was heated to reflux and stirred for about 30 minutes the reaction mass was cooled gradually to room temperature and further stirred for about 2 hours. The solid was filtered and dried under vacuum at about 50-60 °C to yield 1.5gm of titled compound. HPLC chemical purity: 97%; 1H NMR, 400MHZ, DMSO, ppm: 2.50-2.51 (t, 1H), 2.84(m, 1H), 3.09(q, 1H), 3.84-4.01(m, 4H), 6.62 (s, 2H), 7.24-7.35(m, 5H), 8.40 (br s, 3H).
The above process was repeated using below listed solvents instead of ethyl acetate.
Purification solvent HPLC Chemical Purity
Acetonitrile 87.09%
Methyl tertiary butyl ether 93.88%
Ethanol 94.12
Acetic acid 97.59%

,CLAIMS:We Claim:
1. A process for the preparation of R- solriamfetol HCl of formula Ia,

Formula Ia
the process comprising: (a) reacting solriamfetol of formula I,

Formula I
with an acid to form solriamfetol acid addition salt of formula II;

Formula II
(b) optionally purifying the solriamfetol acid addition salt of formula II;
(c) converting the solriamfetol acid addition salt of formula II to solriamfetol HCl of formula Ia; and (d) optionally purifying the solriamfetol HCl of formula Ia.
2. The process as claimed in claim 1, wherein chemical purity of R-solriamfetol HCl of formula Ia is at least 98% as determined by HPLC.
3. The process as claimed in claim 1, wherein an acid is selected from the group consisting of an organic acid and an optically active acid.
4. The process as claimed in claim 3, wherein an organic acid is selected from the
group consisting of formic acid, acetic acid, citric acid, tartaric acid, benzoic acid, lactic acid, oxalic acid, malic acid, fumaric acid, succinic acid, gluconic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid.
5. The process as claimed in claim 3, wherein an optically active acid is selected from the group consisting of (+)-dibenzoyl-D-tartaric acid, (-)-dibenzoyl-L-tartaric acid, (+)-di-p-toluoyl-D-tartaric acid, (-)-d-p-toluoyl-L-tartaric acid, S-(+) mandelic acid, R-(-) mandelic acid, L-(+) tartaric acid, D-(-) tartaric acid, L-malic acid, D-malic acid, D-maleic acid, (lR)-(-)-camphor sulfonic acid, (lS)-(+)-camphor sulfonic acid, L(-)-pyroglutamic acid, L(+)-pyroglutamic acid, (-)-lactic acid.
6. The process as claimed in claim 1, wherein in the step (c) solriamfetol acid addition salt of formula II is treated with HCl source in an organic solvent to form Formula Ia.
7. The process as claimed in claim 6, wherein an organic solvent is selected from the group consisting of ester, ether, ketone and alcohol.
8. The process as claimed in claim 1, wherein solriamfetol acid addition salt of formula II is solriamfetol dibenzoyl-D-tartaric acid salt of formula IIa,

Formula IIa
9. Solriamfetol dibenzoyl-D-tartaric acid salt of formula IIa characterized by 1H NMR having peaks at 2.65-2.71, 2.88, 3.39, 3.72-3.86, 5.69, 6.61, 7.16-7.25, 7.44-7.48, 7.60-8.00 (400 MHz, DMSO d6).
10. A process for solriamfetol dibenzoyl-D-tartaric acid salt of formula IIa, comprising reacting solriamfetol of formula I with dibenzoyl-D-tartaric acid.