Process to obtain solriamfetol hydrochloride

Abstract

The invention relates to a novel process for preparing solriamfetol hydrochloride (SLR HCl) in two steps characterized in that it is not needed to use H2 (g) and using in situ generated HCl (g).

Description

[0001] Process to obtain solriamfetol hydrochloride

[0002] The invention relates to a novel process for preparing solriamfetol hydrochloride in two steps characterized in that it is not needed to use H2(g) and using in situ generated HCI (g).

[0003] BACKGROUND ART

[0004] Solriamfetol, also known as (R)-2-amino-3-phenylpropyl carbamate (APC) 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. See, for example, US Patent Nos. 8,232,315; 8,440,715; 8,552,060; 8,623,913; 8,729,120; 8,741 ,950; 8,895,609; 8,927,602; 9,226,910; and 9,359,290; and U.S. Publication Nos. 2012 / 0004300 and 2015 / 0018414.

[0005] Solriamfetol is a derivative of the amino acid phenylalanine which acts as a nonamphetamine wake-promotor. The mechanism(s) by which solriamfetol exerts its wake-promoting effects in humans are presumed to be through its activity as a selective dopamine and norepinephrine reuptake inhibitor (DNRI). The compound was first approved in the U.S. to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. The product (Sunosi®) contains solriamfetol as hydrochloride salt.

[0006] WO 96 / 07637 A1 and WO 96 / 24577 A1 describe processes for the obtention of solriamfetol hydrochloride comprising the following steps: i) protecting D- phenylalaninol obtaining amine protected D-phenylalaninol, with Carboxybenzyl (Cbz) PG ii) converting amine protected D-phenylalaninol to amine protected solriamfetol in presence of coupling agent and base, in this case phosgene and ammonia, iii) deprotecting the amine protected solriamfetol to get solriamfetol by catalytic hydrogenation, iv) converting solriamfetol to the hydrochloride salt using anhydrous hydrogen chloride gas. The proposed process involves the use of phosgene as a reagent. Phosgene is a highly toxic gas or liquid that is classified as a pulmonary irritant. Additionally, the proposed amine protecting group requires the use of hydrogen gas with a catalyst for its deprotection. The primary hazard associated with the use of any form of hydrogen is inadvertently producing a flammable mixture, leading to a fire or detonation when exposed to air, oxygen, or sparks. Thus, applying a systematic approach of risk analysis is critical for small as well as large-scale laboratory hydrogenations. On the other hand, the health effects arising from exposure to catalysts depend on their form composition and the extent of exposure that may occur. The effects include skin irritation and sensitization, fibrogenicity and corrosion. Additionally, proposed conditions for the formation of the chloride salt involve the use of hydrogen chloride gas. Hydrogen chloride gas can irritate the lungs, causing a cough and shortness of breath. Breathing high levels of the gas or vapor can lead to a build-up of fluid in the lungs, which may cause death. Because hydrochloric acid is corrosive, it can cause eye damage, even blindness, if splashed in the eyes. Finally, the proposed process is silent about the conditions for the obtention of D-phenylalaninol.

[0007] WO 96 / 32375 A1 discloses general processes for the obtention of o-carbamoyl- phenylalaninol derivatives comprising the steps of: reacting N-t-butyloxycarbonyl- phenylalaninol with 1 ,1'-carbonyldiimidazole and then with ammonia, without purification in a solution, and followed by deprotecting the obtained derivative with aqueous hydrochloric acid solution in a solution to give O-carbamoyl-phenylalaninol. Proposed salt formation conditions involve the use of aqueous solutions of hydrogen chloride, that leads to a loss of yield because of high solubility of O-carbamoyl- phenylalaninol salts in water. On the other hand, the deprotection and the formation of the O-carbamoyl-phenylalaninol is carried out in two different stages. Again, the proposed process is silent about the conditions for the obtention of D-phenylalaninol.

[0008] WO 98 / 15526 A1 describes processes for the obtention of solriamfetol and its salts that involves the steps of protecting D-phenylalaninol obtaining the amine protected D-phenylalaninol, converting the amine protected D-phenylalaninol to amine protected solriamfetol in presence of coupling agent and base, deprotecting the amine protected solriamfetol to get solriamfetol free base, and converting solriamfetol to the hydrochloride salt using a HX acid capable of forming a pharmacologically useful salt with the basic nitrogen atom. The deprotection and the solriamfetol salt formation is carried out in two different stages. Again, the proposed process is silent about the conditions for the obtention of D-phenylalaninol. WO 2005 / 033064 A1 describes general processes for the obtention of O-carbamoyl amino alcohols, by reacting phenylalaninol with a cyanate and an excess of an acid in an organic solvent medium. In general terms, cyanates are toxic and corrosive agents. Inhalation, ingestion or contact (skin, eyes) with vapors, dusts or substance may cause severe injury, burns or death. Reaction with water or moist air may release toxic, corrosive or flammable gases.

[0009] WO 2018 / 048871 A1 discloses processes for preparing solriamfetol hydrochloride, that involve the step of crystallizing solriamfetol free base in isopropanol in the presence of hydrochloric acid 37%, at a temperature of around -15°C. According to this reference, prior art processes using HCI gas in a solution of the free base with isopropanol and water, produce unacceptable levels of the potential genotoxic impurity 2- chloropropane (2-CP). Hydrochloric acid 37% can be corrosive to the skin, eyes, nose, mucous membranes, and respiratory and gastrointestinal tracts. At the industrial level, the proposed process needs to reach and maintain low temperatures of around -15°C. Maintaining this low temperatures is complex and requires the use of specific industrial equipment. Additionally, because of the high solubility of solriamfetol hydrochloride in water, the use of aqueous solutions of hydrogen chloride leads to a loss of yield.

[0010] WO 2020 / 035769 A1 discloses processes for the preparation of solriamfetol and salts thereof, such as solriamfetol dibenzoyl-D-tartaric acid salt or solriamfetol di-p-toluyl- D-tartaric acid salt. Proposed preparation processes involve the use of solriamfetol cyanate. Drawbacks associated to the use of this kind of product have been previously discussed.

[0011] WO 2021 / 161232 A1 describes a process for preparation of solriamfetol or pharmaceutically acceptable salts thereof comprising the following steps: i) reducing D-phenylalanine or a pharmaceutically acceptable salt thereof in presence of a reducing agent to obtain D-phenylalaninol or a pharmaceutically acceptable salt thereof; ii) protecting D-phenylalaninol or a pharmaceutically acceptable salt thereof to obtain amine protected D-phenylalaninol or a pharmaceutically acceptable salt thereof, wherein PG is an amine protecting group, iii) converting amine protected D- phenylalaninol or a pharmaceutically acceptable salt thereof to amine protected solriamfetol in presence of a coupling agent and a base, wherein PG is an amine protecting group, iv) deprotecting the amine protected solriamfetol to get solriamfetol, v) converting solriamfetol to pharmaceutically acceptable salts of solriamfetol. The proposed amine protecting group can be selected from tert-butyloxy carbonyl (BoC), Fluorenylmethyloxycarbonyl (F-MOC), N-benzyl, Trityl, substituted Carboxybenzyl (Cbz) group, etc. The disclosed process does not involve the step of isolating solriamfetol free base. This process uses saturated solutions of HCI in organic solvent, such is the case of isopropyl alcohol. A saturated solution of HCI in isopropyl alcohol has a normality close to 6N that means a concentration close to 30%. This kind of solution is highly flammable, harmful if inhaled, may be corrosive to metals, causes severe skin burns and eye damage.

[0012] WO 2024 / 208791 A1 discloses a process for preparation of solriamfetol with specific carbamoylation reaction that avoids the formation of some specific impurities associated with this process. More specifically carbamoylation of (R)-2-amino-3- phenylpropan-1-ol or of nitrogen-protected (R)-2-amino-3-phenylpropan-1-ol thereof, provide solriamfetol having as main impurities the unreacted starting material (R)-2- amino-3-phenylpropan- 1-ol (Impurity A) and the (R)-(2-amino-3-phenylpropyl)- / V- carbamoylcarbamate (Impurity B), which derives from a second addition of the carbamoyl function to the previously formed (R)-2-amino-3-phenylpropyl carbamate skeleton.

[0013] Accordingly, it would be desirable to improve the process to obtain solriamfetol hydrochloride avoiding the drawbacks of the prior art.

[0014] SUMMARY OF THE INVENTION

[0015] A first aspect of the invention relates to a process to obtain solriamfetol hydrochloride (SLR HCI):

[0016] SLR HCI which comprises the following steps: i) the protection of the amine group of SLR-4 with a labile protecting group in acidic conditions (PG) and reduction of the carboxylic group to obtain SLR-2, characterized in that it is a one-step reaction and in that firstly is protected the amine group and secondly is reduced the carboxylic group. ; and ii) the reaction of SLR-2 obtained in step (i) with 1 ,1'-carbonyldiimidazole and then with ammonia to obtain the amino protected SLR-1 with the labile protecting group in acidic conditions (PG) and its conversion to SLR HCI, characterized in that it is a one- step reaction and in that HCI is in situ generated by the reaction of acetyl chloride and an alcohol.

[0017] SLR-1

[0018] In another embodiment the invention relates to the process as defined above, wherein the labile protecting group in acidic conditions (PG) of step (i) is selected from tert- butyloxycarbonyl (Boc), R-NH-tert-butyloxycarbonyl (R-NH-Boc), R-NH- benzyloxycarbonyl (R-NH-Cbz), R-NH-Trityl (R-NH-Tr) and R-N-Benzylideneamine; and preferably wherein the labile protecting group in acidic conditions (PG) of step (i) is tert-butyloxycarbonyl (Boc).

[0019] In another embodiment the invention relates to the process as defined above, wherein the alcohol of step (ii) is selected from the group of primary alcohols and short-chain alcohols; and preferably wherein the alcohol of step (II) is selected from methanol, ethanol, propanol, butanol, isopropanol and 2-butanol.

[0020] In another embodiment, the invention relates to the process as described above, which further comprises a purification process after step (i) to eliminate Impurity 1 , formed on step (i):

[0021] IMPURITY 1 wherein PG is the labile protecting group in acidic conditions defined above, which comprises the following steps: a) crystallizing the reaction crude in water; and b) recrystallizing the solid isolated in step (a) in a mixture of ethyl acetate and cyclohexane.

[0022] In another embodiment the invention relates to the process as described above, wherein Impurity 1 is tert-butyl N-[(2S)-1-hydroxy-3-phenylpropan-2-yl] carbamate, which has the following structure:

[0023] In another embodiment, the invention relates to the process as described above, which further comprises a purification step after step (i) to eliminate Impurity 8, formed during the reduction performed on step (i):

[0024]

[0025] IMPURITY 8 wherein PG is the labile protecting group in acidic conditions defined above, which comprises the following steps: a) crystallizing the reaction crude in water; and b) recrystallizing the solid isolated in step (a) in a mixture of ethyl acetate and cyclohexane.

[0026] In another embodiment the invention relates to the process as described above, wherein Impurity 8 is N-[(1 ,1-Dimethylethoxy)carbonyl]-D-phenylalanine (2R)-2-[[(1 ,1- dimethylethoxy)carbonyl]amino]-3-phenylpropyl ester, which has the following structure: Another aspect of the invention relates to a purification process of SLR-2 for reducing the presence of Impurity 1 in an amount of less than 0.15%,

[0027] SLR-2 IMPURITY 1 wherein PG in Impurity 1 is the labile protecting group in acidic conditions as defined for SLR-2, which comprises the following steps: a) crystallizing the reaction crude in water; and b) recrystallizing the solid isolated in step (a) in a mixture of ethyl acetate and cyclohexane.

[0028] In another embodiment the invention relates to the purification process of SLR-2 as described above, wherein the labile protecting group in acidic conditions (PG) is selected from terf-butyloxycarbonyl (Boc), R-NH-terf-butyloxycarbonyl (R-NH-Boc), R-NH-benzyloxycarbonyl (R-NH-Cbz), R-NH-Trityl (R-NH-Tr) and R-N- Benzylideneamine, and more preferably wherein the labile protecting group in acidic conditions (PG) is terf-butyloxycarbonyl (Boc).

[0029] In another embodiment the invention relates to the purification process of SLR-2 as described above, wherein step (a) is performed at a temperature between 0 °C and 5 °C.

[0030] In another embodiment the invention relates to the purification process of SLR-2 as described above, wherein step (a) is performed during a time between 1h and 3h, and preferably during a time of 2h.

[0031] In another embodiment the invention relates to the purification process of SLR-2 as described above, wherein the mixture of solvents of step (b) is in a proportion of 2 volumes of ethyl acetate and 20 volumes of cyclohexane with respect to the weight of crude SLR-2.

[0032] The above-described purification step of SLR-2 is an efficient process for reducing the presence of Impurity 1 in a quantity of below 0,15% without using chiral resolution agents

[0033] According to the first aspect of the invention, the synthesis of SLR HCI is performed using two one-step reactions wherein, in the first step (i) the transformation of SLR-4 in SLR-2 is performed protecting the amino group firstly and reducing the carboxylic group secondly. This is a difference between the previously disclosed processes to obtain SLR HCI, wherein the order of both transformations was to reduce firstly and to protect secondly. By doing this change in the order of both reactions the inventors have improved the obtention of SLR HCI because step (i) is a telescopic step (that is, one-step reaction) wherein it is not needed the use of H2gas as prior art does, since it is inflammable.

[0034] According to step (ii) of the process of the invention, the deprotection of SLR-1 and the in-situ formation of hydrogen chloride to obtain SLR HCI by one step reaction allows to perform the process without using HCI gas and saturated solutions. The in- situ generated HCI is obtained by reacting acetyl chloride and an alcohol. Preferred alcohols are selected from the group of primary alcohols and short-chain alcohols. In a most preferred embodiment, the alcohol is selected from methanol, ethanol, propanol, butanol, isopropanol and 2-butanol.

[0035] As used herein, the term "room temperature" in the context of the present invention refers to a temperature from 15 degrees centigrade to 30 degrees centigrade, preferably from 20 degrees centigrade to 25 degrees centigrade

[0036] Examples

[0037] Materials and methods

[0038] (1) RELATED SUBSTANCES / ASSAY (UHPLC)

[0039] Mobile phase A: Acetonitrile.

[0040] Mobile phase B: 0.085 % (v / v) of ortho-phosphoric acid in water at pH 2.2

[0041] Dilution solvent: Acetonitrile / water (30:70).

[0042] Column: Acquity BEH C18 1.7um, 2.1 x 50 mm.

[0043] Flow: 0.3 mL

[0044] Injection volume: 1 pL

[0045] Column temperature: 25 °C

[0046] Sampler temperature: 25 °C

[0047] Wavelength: 210 nm

[0048] Gradient:

[0049] Solutions for related substances:

[0050] Solriamfetol Standard solution: 0.0007 mg / mL of solriamfetol in dilution solvent (0.10 % relative to sample concentration).

[0051] Sample: 0.7 mg / mL of sample in dilution solvent.

[0052] Solutions for assay:

[0053] Solriamfetol Standard solution: 0.42 mg / mL of solriamfetol HCI in dilution solvent.

[0054] Sample: 0.42 mg / mL of sample in dilution solvent.

[0055] Specified impurities:

[0056] Expected retention time for SLR-2 = 5.7 minutes

[0057] IMPURITY 8

[0058] CAS 1042716-21-1

[0059] RRT = 1.72

[0060] (2) ENANTIOMERIC PURITY SLR-2 (HPLC)

[0061] Isocratic: premixed n-Heptane / Ethanol (95:5).

[0062] Dilution solvent: n-Heptane / Ethanol (95:5).

[0063] Column: Chiralpack IA 5 pm, 4.6 x 250 mm.

[0064] Flow: 1.0 mL / min

[0065] Injection volume: 10 pL

[0066] Column temperature: 25 °C

[0067] Sampler temperature: 25 °C

[0068] Wavelength: 220 nm

[0069] Run time: 25 min Solutions for enantiomeric

[0070] Standard solution 1.5 pg / mL of IMPURITY 1 in dilution solvent (0.15 % relative to sample concentration). sample in dilution solvent.

[0071] Expected retention time for SLR-2 = 10.7 minutes

[0072] IMPURITY 1

[0073] CAS 66605-57-0

[0074] RRT = 0.89

[0075] (3) ENANTIOMERIC PURITY SLR HCI (UHPLC)

[0076] Mobile phase A: Acetonitrile. 0.426 % (m / v) of perchloric acid in water at pH 1.5

[0077] Isocratic: premixed Aqueous phase / Acetonitrile (85:15).

[0078] Dilution solvent: Water.

[0079] Column Crownpack CR- (+) 5 pm, 3 x 150 mm.

[0080] Flow: 0.15 mL / min

[0081] Run time: 30 min

[0082] Solutions for enantiomeric

[0083] Standard solution 1.5 pg / mL of SLR HCI IMP2 in dilution solvent (0.15 % relative to sample concentration). of sample in dilution solvent.

[0084] Expected retention time for solriamfetol = 12.5 minutes

[0085] SLR HCI IMP2

[0086] [(2S)-2-amino-3-phenylpropyl] carbamate CAS 178429-63-5

[0087] RRT = 1.19

[0088] Reference Example 1 : Synthesis of D-phenylalaninol

[0089] In a first step, 5 g of D-phenylalanine, 2.75 g of sodium borohydride and 60 mL of tetrahydrofuran were introduced in a 250 mL vessel. The obtained suspension was stirred for 10 minutes at room temperature.

[0090] In a second vessel a dissolution of 7.8 g of iodine and 20 mL of tetra hydrofuran was prepared. This dissolution was added dropwise to the suspension prepared in the first step during 1 hour at room temperature. The obtained mixture was heated up to 60- 70°C and stirred for 5h. The reaction mixture was cooled down to 20-25°C and 10 mL of methanol were added dropwise and stirred at room temperature.

[0091] A solvent swap was carried out twice with 25 mL ethyl acetate. Two extractions were done with 25 mL of water. The pH was adjusted to 10 with NaOH 2N and two more extractions were done with 50 mL of ethyl acetate. The organic layers were joined, dried with anhydrous sodium sulphate and concentrated under vacuum to dryness. The obtained solid was analyzed by UHPLC. Yield: 23%, Purity: 97%

[0092] Reference Example 2: Synthesis of SLR-2 B

[0093] In a 2 L reactor 100 g of D-phenylalaninol, obtained according to Reference Example 1 , and 1 L of 2-methyltetrahydrofuran were added. The mixture was stirred until complete dissolution at room temperature. 92.2 mL of triethylamine were added dropwise and stirred at room temperature until complete dissolution (solution 1).

[0094] In the second reactor 173.2 g of BOC2O and 200 mL of THF were added. The mixture was stirred at room temperature until complete dissolution (solution 2).

[0095] Solution 2 was added dropwise to solution 1 at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to 2 residual volumes. A solvent swap was carried out twice with 400 ml of ethyl acetate. The obtained crude was heated up to 50 °C and 1.2 L of water were added dropwise during 2h. After 16h it was filtered and washed twice with 100 mL of water. The solid was dried under vacuum at 50 °C.

[0096] The obtained solid was analyzed by LIHPLC. Yield: 94%, Purity: 97% Example 1 : Telescopic synthesis of intermediate SLR-2

[0097] Example 1a

[0098] In a 2 L reactor 80 g of SLR-4 and 400 mL of NaOH 1.2M were charged. The mixture was stirred at room temperature until complete dissolution (solution 1).

[0099] In a second reactor, 133.18 g of BOC2O and 400 mL of THF were stirred at room temperature until complete dissolution (solution 2).

[0100] Solution 1 was heated to 40-50 °C and then the solution 2 was added dropwise maintaining the temperature.

[0101] After 2 hours, the reaction mixture was concentrated under vacuum. Then, 400 mL of ethyl acetate were added, and the pH was adjusted with HCI 4N to pH:3. The layers were separated, and the aqueous phase was extracted twice with 400 mL of ethyl acetate. The organic phases were rinsed with 400 mL of water. The organic phase was concentrated under vacuum. Two drags were done with 640 mL of ethyl acetate each. The obtained solution was concentrated.

[0102] 102.09 g of 1 ,1 -carbonyldiimidazole (GDI) were suspended in 1200 mL of THF. The concentrated solution obtained in the previous step was added dropwise to the GDI suspension for approximately 30 min. Once the addition was finished, it was stirred 1 h at 20-25 °C.

[0103] This reaction media was added dropwise to a separate suspension of 23.82 g of NaBH4, 80 mL of THF and 400 mL of water maintaining the T around 10°C. The obtained suspension was stirred at 0-5 °C for 1 hour.

[0104] Afterwards, 480 mL of acetone were added dropwise maintaining the internal temperature below 10 °C. The reaction media was stirred at 20-25 °C and for 2 hours. The reaction mixture was concentrated, and 800 mL of ethyl acetate were added. The pH was adjusted to 3 with HCI 4N. The layers were separated, and the organic phase was rinsed with 800 mL of water. The organic phase was analysed by LIHPLC. The content of Impurity 1 was 2.7% (LIHPLC (2) and the content of Impurity 8 was 4.9% (LIHPLC (1)).

[0105] Example 1b

[0106] Purification

[0107] The organic phase obtained in example 1a was submitted to a solvent swap with two drags of 800 mL of ethanol 96°. The organic phase was concentrated under vacuum.

[0108] The concentrated organic phase was dropwise added into 1440 mL of water.

[0109] The obtained suspension was stirred 2 hours at 0-5 °C.

[0110] The precipitated solid was filtered, and the cake was washed twice with 160 mL of water and then twice with 160 mL of cyclohexane. The solid was dried under vacuum at 50 °C until constant weight. Yield: 85%,

[0111] The obtained solid was analysed by UHPLC: Purity: 94.4% (UHPLC (1)), % Impurity 1 : 1.2% (UHPLC (2)), % Impurity 8: 4.3% (UHPLC (1)).

[0112] Example 1c

[0113] Purification by recrystallization

[0114] To a 2 L jacketed glass reactor with mechanical stirrer 103.44 g of SLR-2 obtained in example 1 b were charged with 206.88 mL of ethyl acetate and 206.88 mL of cyclohexane and the suspension was heated to 50 °C and then stirred for 1 hour.

[0115] Afterwards, 1861.92 mL of cyclohexane was added dropwise in 1 hour. Then, it was cooled until turbidity was observed (35 °C) and it was stirred for 1.5 hours at 35 °C. The suspension was cooled to around 10 °C and stirred for 2 more hours at this temperature.

[0116] The solid was filtered, and the cake was washed twice with 206.88 g of cyclohexane. The solid was dried under vacuum at 50 °C until constant weight. Yield: 85%, The solid was analysed by LIHPLC. Purity: 99.8% (LIHPLC (1)), % Impurity 1 : < 0.02% (UHPLC (2)), % Impurity 8: 0.12% (UHPLC (1)).

[0117] Example 2: Synthesis of SLR-1

[0118] 61.94 g of GDI were suspended in 480 mL of 2-Methyltetrahydrofuran at 20-25°C. Over this suspension, a solution of 80g of SLR-2 in 480 mL of 2-Methyltetrahydrofuran was added dropwise at 20-25°C. After stirring 1h at 20-25 °C 82.16 mL of NH3 25% were added dropwise. The reaction mixture was stirred 1 hour at 20-25 °C. Obtained solution was concentrated under vacuum and a solvent swap with 800 mL of Ethyl acetate was done. The reaction mixture was rinsed 3 times with 400 mL of Acetic acid 10% at 45 °C. Aqueous phases were brought together and extracted twice with 320 mL of Ethyl acetate. The organic phase was concentrated under vacuum. 1600 mL of cyclohexane were added dropwise over the concentrated solution. Again, the solution was concentrated under vacuum. Maintaining the reaction mixture at 50 °C, 160 mL of Ethyl acetate were added and subsequently 240 mL of methyl tert-butyl ether were added dropwise. The suspension was cooled to 7.5 °C and stirred for 2 hours.

[0119] The solid was filtered, and the cake was washed twice with a mixture of 128 mL of cyclohexane and 32 mL of methyl tert-butyl ether. The solid was dried under vacuum at 50°C until constant weight. Yield: 76%.

[0120] The obtained solid was analysed by UHPLC (1). Purity: 100%

[0121] Purification

[0122] This step depends on the IPC, if IPC is OK the solid is dried and if IPC is not OK, purification is carried out without drying the solid.

[0123] As SLR-1 is wet, all the parameters are based on the amount of SLR-2 used in the reaction step.

[0124] To a 2 Ljacketed glass reactor with mechanical stirrer 70.98 g of SLR-1 wet obtained previously were added with 400 mL of Ethyl acetate and 400 mL of Acetic acid 10%. The crude was heated to 45 °C, stirred and then the layers were separated. The organic phase was washed two more times with 400 mL of Acetic acid 10% at 45 °C. The aqueous phases were brought together and extracted with 320 mL of Ethyl acetate at 22.5 °C. The organic phases were brought together and heated to 50 °C and then, it was concentrated under vacuum to 5 residual volumes. After that, it was stirred at 50 °C for 30 minutes and 1600 mL of cyclohexane were added dropwise. It was concentrated under vacuum to 12 residual volumes. Maintaining the temperature at 50 °C, 160 mL of Ethyl acetate and 240 mL of methyl tert-butyl ether were added dropwise. The suspension was cooled to 7.5 °C and stirred for 2 hours.

[0125] The solid was filtered, and the cake was washed twice with a mixture of 128 mL of cyclohexane and 32 mL of methyl tert-butyl ether prepared previously and cooled in the reactor. The solid was dried under vacuum at 50 °C until constant weight. Yield: 75%.

[0126] The solid was analysed by UHPLC (1). Purity: 100%

[0127] Example 3: Synthesis of SLR HCI

[0128] In a reactor 35 g of SLR-1 with 175 mL of THF and 34.71 mL of EtOH absolute were stirred for 30 minutes. The reaction mixture was cooled to 0-5 °C and 42.27 mL of Acetyl chloride were added dropwise maintaining internal temperature between 0-5 °C. Finalized the addition, the reaction mixture was heated to 20-25 °C and stirred for 8 hours. 350 mL of acetone were added dropwise, and the obtained suspension was stirred at 20-25 °C for 2.5 hours.

[0129] The solid was filtered, and the cake was washed twice with 70 mL of acetone. The solid was dried under vacuum at 50 °C until constant weight. Yield: 93%.

[0130] The obtained solid was analysed by UHPLC (1) and (3). Purity: 100%.

[0131] Purification To a 500 mL jacketed glass reactor with mechanical stirrer were charged 25 g of SLR HCI, 25 mL of dimethyl sulfoxide and 225 mL of acetone. The suspension was stirred at 20-25 °C for 2.5 hours. The solid was filtered, and the cake was washed twice with 50 mL of acetone. The solid was dried under vacuum at 50 °C until constant weight. Yield: 97%.

[0132] The obtained solid was analysed by UHPLC (1) and (3). Purity: 100%

Claims

CLAIMS1. A process to obtain solriamfetol hydrochloride (SLR HCI):SLR HCI which comprises the following steps: i) the protection of the amine group of SLR-4 with a labile protecting group in acidic conditions (PG) and reduction of the carboxylic group to obtain SLR-2, characterized in that it is a one-step reaction and in that firstly is protected the amine group and secondly is reduced the carboxylic group.; and ii) the reaction of SLR-2 obtained in step (i) with 1 ,1'-carbonyldiimidazole and then with ammonia to obtain the amino protected SLR-1 with the labile protecting group in acidic conditions (PG) and its conversion to SLR HCI, characterized in that it is a one- step reaction and in that HCI is in situ generated by the reaction of acetyl chloride and an alcohol.

2. The process according to claim 1 , wherein the labile protecting group in acidic conditions (PG) of step (i) is selected from tert- butyl oxycarbony I (Boc), R-NH-terf- butyloxycarbonyl (R-NH-Boc), R-NH-benzyloxycarbonyl (R-NH-Cbz), R-NH-Trityl (R- NH-Tr) and R-N-Benzylideneamine.

3. The process according to claim 2, wherein the labile protecting group in acidic conditions (PG) of step (i) is terf-butyloxycarbonyl (Boc).

4. The process according to any of claims 1 to 3, wherein the alcohol of step (ii) is selected from the group of primary alcohols and short-chain alcohols.

5. The process according to claim 4, wherein the alcohol of step (ii) is selected from methanol, ethanol, propanol, butanol, isopropanol and 2-butanol.

6. The process according to any of claims 1 to 5, which further comprises a purification process after step (i) to eliminate Impurity 1 , formed on step (i):IMPURITY 1 wherein PG is the labile protecting group in acidic conditions as defined for SLR-2, which comprises the following steps: a) crystallizing the reaction crude in water; and b) recrystallizing the solid isolated in step (a) in a mixture of ethyl acetate and cyclohexane.

7. The process according to any of claims 1 to 6, which further comprises a purification step after step (i) to eliminate Impurity 8, formed during the reduction performed on step (i):wherein PG is the labile protecting group in acidic conditions as defined for SLR-2, which comprises the following steps: a) crystallizing the reaction crude in water; and b) recrystallizing the solid isolated in step (a) in a mixture of ethyl acetate and cyclohexane.

8. A purification process of SLR-2 for reducing the presence of Impurity 1 in an amount of less than 0.15%:SLR-2 IMPURITY 1 wherein PG in Impurity 1 is the labile protecting group in acidic conditions as defined for SLR-2, which comprises the following steps: a) crystallizing the reaction crude in water; and b) recrystallizing the solid isolated in step (a) in a mixture of ethyl acetate and cyclohexane.

9. The purification process according to any of claims 6 to 8, wherein the labile protecting group in acidic conditions (PG) is selected from terf-butyloxycarbonyl (Boc), R-NH-tert-butyloxycarbonyl (R-NH-Boc), R-NH-benzyloxycarbonyl (R-NH-Cbz), R- NH-Trityl (R-NH-Tr) and R-N-Benzylideneamine.

10. The purification process according to claim 9, wherein the labile protecting group in acidic conditions (PG) is tert-butyloxycarbonyl (Boc).

11. The purification process according to any of claims 6 to 10, wherein step (a) is performed at a temperature between 0 °C and 5 °C.

12. The purification process according to any of claims 6 to 11 , wherein step (a) is performed during a time between 1 h and 3h, and preferably during a time of 2h.

13. The purification process according to any of claims 6 to 12, wherein the mixture of solvents of step (b) is in a proportion of 2 volumes of ethyl acetate and 20 volumes of cyclohexane with respect to the weight of crude SLR-2.

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