A PROCESS FOR THE PURIFICATION OF (R)-2-AMINO-3-PHENYLPROPYL CARBAMATE

Abstract

The present invention relates to a process for the purification of (R)-2-amino-3-phenylpropyl carbamate in perspective of the subsequent conversion in the corresponding HCl salt (SOLRIAMFETOL). The invention further relates to the process for preparing a batch of purified solriamfetol, as well as to the purified (R)-2-amino-3-phenylpropyl carbamate or its hydrochloride salt.

Claims

1. A process for the purification of crude (R) 2-amino-3-phenylpropyl carbamate comprising the steps of: a) adding an aliphatic or aromatic monocarboxylic acid to a solution of (R) 2-amino-3-phenylpropyl carbamate so as to obtain the corresponding organic salt; b) isolating the organic salt by precipitation.

2. The process according to claim 1, wherein the aliphatic or aromatic monocarboxylic acid is selected from butyric acid, propionic acid, trilfluoroacetic acid, formic acid, acetic acid, lauric acid, benzoic acid, C1-C4 mono and dialkyl benzoic acid, alkoxybenzoic acid, phenylacetic acid, biphenyl-4-carboxylic acid, hydroxybenzoic acid, nitro benzoic acid and halo-benzoic acid; preferably benzoic acid, C1-C4 mono and dialkyl benzoic acid, alkoxybenzoic acid, phenylacetic acid, biphenyl-4-carboxylic acid, hydroxybenzoic acid, nitro benzoic acid and halo-benzoic acid.

3. The process according to claim 1, characterized in that step a) is performed in a polar solvent or in a mixture of polar solvents, preferably selected from DCM, methanol, ethanol, isopropanol, THF, Methyl-THF, ethyl acetate or isopropyl acetate.

4. The process according to claim 1, characterized in that step a) is carried out at a temperature from 5 to 80 ° C. and step b) is carried out at a temperature comprised from 80 to 0 ° C.

5. The process according to claim 1, wherein the molar ratio between (R) 2-amino-3-phenylpropyl carbamate and the aliphatic or aromatic monocarboxylic acid is from 1:0.9 to 1:1.5.

6. The process according to claim 1, characterized in that it further comprises a step c) of converting the organic salt into the corresponding hydrochloride salt.

7. The process according to claim 1, characterized in that it further comprises drying the organic salt or the hydrochloride salt at a temperature from 20 to 50 ° C.

8. A process for manufacturing (R) 2-amino-3-phenylpropyl carbamate or its hydrochloride salt, which comprises a process for the purification of crude (R) 2-amino-3-phenylpropyl carbamate according to claim 1.

9. A process for preparing a batch of purified solriamfetol, which comprises: A) analyzing a batch of solriamfetol for the presence of one or more of: phenylalaninol (Impurity 1); (2R)-2-amino-3-phenylpropyl (aminocarbamoyl) carbamate (Impurity 3); N-1-hydroxymethyl-2-phenyl-ethyl-N′-aminocarbamoyl urea (Impurity 5); B) if the batch does not meet pre-set specification for the amount of one or more of Impurity 1, 3 or 5, further purifying the solriamfetol.

10. The process according to claim 9, wherein the pre-set specification for each of the one or more Impurity 1, 3 or 5 is equivalent to or not more than 0.15% by weight.

11. The process according to claim 9 or 10, wherein the pre-set specification includes that the purity of solriamfetol is equivalent to or greater than 98% by area %.

12. The process according to claim 11, wherein the further pre-set specification includes that the amount of any single unidentified impurity is equivalent to or not more than 0.10% by weight.

13. The process according to claim 9, wherein step A) is carried out by HPLC.

14. The process according to claim 9, wherein the further purification in step B) includes: carrying out the displacement to the (R) 2-amino-3-phenylpropyl carbamate base ; repeating the purification process according to any one of claims 1 to 7, till matching the pre-set specification.

15. Purified (R)-2-amino-3-phenylpropyl carbamate or its hydrochloride salt having a purity equal to or greater than 98% by area %, wherein the (R)-2-amino-3-phenylpropyl carbamate or its hydrochloride salt does not contain any of the following impurities at a concentration greater than about 0.15% by weight: phenylalaninol (Impurity 1); (2R)-2-amino-3-phenylpropyl (aminocarbamoyl) carbamate (Impurity 3); N-1-hydroxymethyl-2-phenyl-ethyl-N′-aminocarbamoyl urea (Impurity 5).

16. The purified (R)-2-amino-3-phenylpropyl carbamate or its hydrochloride salt according to claim 15, characterized by not containing any single unidentified impurity at a concentration greater than about 0.10% by weight.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0058] An object of the present invention is a process for the purification of crude (R) 2-amino-3-phenylpropyl carbamate comprising the steps of: [0059] a) adding an aliphatic or aromatic monocarboxylic acid to a solution of (R) 2-amino-3-phenylpropyl carbamate so as to obtain the corresponding organic salt; [0060] b) isolating the organic salt by precipitation.

[0061] Preferably, the aliphatic or aromatic monocarboxylic acid is selected from butyric acid, propionic acid, trilfluoroacetic acid, formic acid, acetic acid, lauric acid, benzoic acid, C.sub.1-C.sub.4 mono and dialkyl benzoic acid, alkoxybenzoic acid, phenylacetic acid, biphenyl-4-carboxylic acid, hydroxybenzoic acid, nitro benzoic acid and halo-benzoic acid. More preferably benzoic acid, C.sub.1-C.sub.4 mono and dialkyl benzoic acid, alkoxybenzoic acid, phenylacetic acid, biphenyl-4-carboxylic acid, hydroxybenzoic acid, nitro benzoic acid and halo-benzoic acid.

[0062] In a preferred embodiment of the process, step a) is performed in a polar solvent or in a mixture of polar solvents, preferably selected from DCM, methanol, ethanol, isopropanol, THF, Methyl-THF, ethyl acetate or isopropyl acetate.

[0063] Preferably, step a) is carried out at a temperature from 5 to 80 ° C. and step b) is carried out at a temperature comprised from 80 to 0° C.

[0064] In another preferred embodiment, the molar ratio between (R) 2-amino-3-phenylpropyl carbamate and the aliphatic or aromatic monocarboxylic acid is from 1:0.9 to 1:1.5.

[0065] Preferably, the process according to the invention is characterized in that it further comprises a step c) of converting the organic salt into the corresponding hydrochloride salt.

[0066] Preferably, the process according to the invention is characterized in that it further comprises drying the organic salt or the hydrochloride salt at a temperature from 20 to 50° C.

[0067] A further object of the present invention is a process for manufacturing (R) 2-amino-3-phenylpropyl carbamate or its hydrochloride salt, which comprises a process for the purification of crude (R) 2-amino-3-phenylpropyl carbamate according to the invention.

[0068] Another object of the present invention is a process for preparing a batch of purified solriamfetol, which comprises: [0069] A) analyzing a batch of solriamfetol for the presence of one or more of: [0070] phenylalaninol (Impurity 1); [0071] (2R)-2-amino-3-phenylpropyl (aminocarbamoyl) carbamate (Impurity 3); [0072] N-1-hydroxymethyl-2-phenyl-ethyl-N′-aminocarbamoyl urea (Impurity 5); [0073] B) if the batch does not meet pre-set specification further purifying the solriamfetol.

[0074] Preferably, the pre-set specification for each of the one or more Impurity 1, 3 or 5 is equivalent to or not more than 0.15% by weight.

[0075] Preferably, the pre-set specification includes that the purity of solriamfetol is equivalent to or greater than 98% by area %.

[0076] The further pre-set specification includes that the amount of any single unidentified impurity is equivalent to or not more than 0.10% by weight.

[0077] In a preferred embodiment of the process for preparing a batch of purified solriamfetol, step A) is carried out by HPLC.

[0078] In another preferred embodiment, the further purification in step B) includes: [0079] carrying out the displacement to the (R) 2-amino-3-phenylpropyl carbamate base; [0080] repeating the purification process according to the invention, till matching the pre-set specification.

[0081] The pre-set specification is as defined above.

[0082] A further object of the present invention is purified (R)-2-amino-3-phenylpropyl carbamate or its hydrochloride salt having a purity equal to or greater than 98% by area %, wherein the (R)-2-amino-3-phenylpropyl carbamate or its hydrochloride salt does not contain any of the following impurities at a concentration greater than about 0.15% by weight: [0083] phenylalaninol (Impurity 1); [0084] (2R)-2-amino-3-phenylpropyl (aminocarbamoyl) carbamate (Impurity 3); [0085] N-1-hydroxymethyl-2-phenyl-ethyl-N′-aminocarbamoyl urea (Impurity 5). Preferably, the purified (R)-2-amino-3-phenylpropyl carbamate or its hydrochloride salt is characterized by not containing any single unidentified impurity at a concentration greater than about 0.10% by weight.

Experimental part

Example 1: Synthesis of (R)-2-amino-3-phenylpropyl carbamate

[0086] To a solution of D-Phenylalaninol (100.0 g; 0.66 mol) in dichloromethane (2000 mL) is added sodium cyanate (59.1 g; 0.92 mol). The mixture is cooled at 0° C. and methanesulfonic acid (222.5 g; 2.31 mol) is added dropwise maintaining the temperature below 5° C. The reaction mixture is stirred for about 24 h at about 5° C. A solution of sodium hydroxide 10% in water is added maintaining the temperature below 5° C., to the mixture till the pH is stable between 10-12. The organic layer is separated and the water phase is extracted twice with 500 mL of dichloromethane. The organic phases are combined together and washed twice with 500 ml and 100 ml of water.

[0087] The final organic phase is distilled under vacuum until residual weight of 2578 g and finally contains of crude (R)-2-amino-3-phenylpropyl carbamate base (116.5 g; 0.60 mol).

Example 2: Synthesis of (R)-2-amino-3-phenylpropyl carbamate hydrochloride salt

[0088] ##STR00009##

[0089] A solution (77 g) of 2-amino-3-phenylpropyl carbamate in DCM (1 eq, 17.8 mmo1) obtained in example 1, is added with 30 ml of DCM and heated to 35±2° C. Maintaining the T at 35±2° C., slowly flow anyhydrous HCl till the pH of the mixture decreases to about 1. The mixture is then cooled to 0° C. in about 3 h and stirred at 0° C. for another 2 h. It is then filtered, and the cake obtained is dried under vacuum at 40-45° C. to afford (R)-2-amino-3-phenylpropyl carbamate hydrochloride salt (16.0 mol; Y:89.9%). The resulting solid is subjected to HPLC analysis for purity, indicating a content area % of phenylalaninol Impurity 1 (5.31%), bis-adduct Impurity 3 (2.66%) and bis-adduct urea Impurity 5 (4.60%).

[0090] .sup.1HNMR (δ ppm): 8.48 (s, 3H), 7.37-7.24 (m, 5H), 6.60 (s, 2H), 4.04-3.99 (dd, 1H), 3.91-3.85 (dd, 1H), 3.59-3.51 (dd, 1H), 3.12-3.06 (dd, 1H), 2.89-2.82 (dd, 1H) .sup.13CNMR: 156.55, 136.50, 129.75-127.41, 62.48, 51.65, 35.38

Example 3: General salification procedure of CRUDE (R)-2-amino-3-phenylpropyl carbamate with an organic acid

[0091] A solution in DCM (77 g) containing 2-amino-3-phenylpropyl carbamate crude, obtained in Example 1, (1 eq, 17.8mmo1) is heated to 35±2° C. A mixture of the tested acid (1.1 eq, 19.8 mmol) in DCM (7.78 vol/g, 30 mL) is added in about 1 h, maintaining the T at 35±2° C. The mixture is then cooled to 0° C. in about 3 h and stirred at 0° C. for another 2 h. The suspension obtained is filtered and the cake obtained is washed and dried under vacuum at 40-45° C. to afford the corresponding salt.

[0092] The HPLC setup consist of Column USP L11 4.6×150 mm, 3.5 μm particle size; Column temperature 30° C.; Flow rate 1.0ml/min; Detection UV 210 nm; Run time 25 min; injection Volume 7.0 μL; Mobile phase A: water, pH 2; Mobile phase B acetonitrile with 0.1% strong inorganic acid; gradient

TABLE-US-00001 Flow Time A B (mL/min) (min) (%) (%) 1.0 0.00 90.0 10.0 1.0 15.00 75.0 25.0 1.0 25.00 10.0 90.0

Example 4: Synthesis of (R)-2-amino-3-phenylpropyl Carbamate Salts With Aliphatic and Aromatic Monocarboxylic Acids According to the Process of the Invention

Example 4A1: Synthesis of 2-amino-3-phenylpropyl carbamate benzoate salt

[0093] ##STR00010##

[0094] A solution of 2-amino-3-phenylpropyl carbamate in DCM (1 eq, 17.8mmol), obtained in Example 1, is heated to 35±2° C. A mixture of benzoic acid (1.1 eq, 19.8 mmol) in DCM (7.78v, 30 mL) is added in about 1 h, maintaining the T at 35±2° C. The mixture is then cooled to 0° C. in about 3 h and stirred at 0° C. for another 2 h. It is then filtered and the cake obtained is dried under vacuum at 40-45° C. to afford benzoate salt (15.5 mmol, Y:87.1%). The resulting solid is subjected to HPLC analysis resulting 99.5% pure (area %).

[0095] .sup.1HNMR (DMSO-d6) (δ ppm): 7.97-7.93 (m, 2H), 7.51-7.37 (m, 3H), 7.33-7.19 (m, 5H), 7.06 (brs, 3H), 6.59 (brs, 2H), 3.92-3.87 (dd, 1H), 3.83-3.77 (dd, 1H), 3.39-3.31 (m, 1H), 2.79 (d, 2H)

[0096] .sup.13CNMR: 169.23, 157, 138.20, 135.77, 131.37, 129.71-128.36, 126.86, 65.57, 51.72, 38.10

Example 4A2: Synthesis of 2-amino-3-phenylpropyl carbamate benzoate salt

[0097] A solution of 2-amino-3-phenylpropyl carbamate in DCM (1 eq; 89.07 mmoll), obtained as in example 1, is analyzed by HPLC resulting with a content area % of 0.76% of Impurity 1, 0.96% of Impurity 3 and 0.75% of Impurity 5. The solution is concentrated to residue and then added with 480 ml of THF. The solution is heated at 50° C. and added with a solution of benzoic acid (1.05 eq; 94.2 mmol) in 30 ml of THF. The mixture is cooled at 0-5° C. for 3 h and maintained at 0-5° C. for at least 2 h. The suspension is filtered, washed with THF and the cake obtained is dried under vacuum at 45° C. to afford (R)-2-amino-3-phenylpropyl carbamate benzoate salt (22 mmol; Y: 81.0%). The resulting solid is analysed by HPLC: Impurities 1-3 and 5 are absent.

Example 4A3: Synthesis of 2-amino-3-phenylpropyl carbamate benzoate salt

[0098] A solution of 2-amino-3-phenylpropyl carbamate in DCM (1 eq; 23.4 mmoll), obtained as in example 1, is analyzed by HPLC resulting with a content area % of 7.86% Impurity 1, 0.20% Impurity 3. The solution is concentrated to residue and then added with 23 ml of isopropanol. A solution of benzoic acid (1.1 eq; 25.74 mmol) in 8 ml of isopropanol is added to the mixture and then heated at 60-65° C. to obtain a clear solution. The mixture is cooled at 40° C., added with 50 ml of isopropanol and cooled at 25° C. The suspension was filtered, washed and dried to afford (R)-2-amino-3-phenylpropyl carbamate benzoate salt (14.4 mmol Y: 61.7%). The solid was analysed by HPLC by area % resulting with: 0.20% Impurity 1 and Impurity 3 absent.

Example 4B: Synthesis of 2-amino-3-phenylpropyl carbamate trifluoroacetate salt

[0099] ##STR00011##

[0100] Following the general procedure, trifluoroacetate salt (15.8 mmol, Y:88.7%) is obtained. The resulting solid is subjected to HPLC analysis.

[0101] .sup.1HNMR(DMSO-d6) (δ ppm): 8.22 (s, 3H), 7.38-7.26 (m, 5H), 6.63 (s, 2H), 4.04-3.99 (dd, 1H), 3.88-3.82 (dd, 1H), 3.64-3.56 (m, 1H), 3.00-2.94 (dd, 1H), 2.88-2.80 (dd, 1H)

[0102] .sup.13CNMR: 159.02-158.60, 156.54, 136.31, 129.72, 129.14, 127.45, 119.66, 115.69, 62.59, 51.57, 35.51

Example 4C: Synthesis of 2-amino-3-phenylpropyl carbamate formate salt

[0103] ##STR00012##

[0104] Following the general procedure, formate salt (15.9 mmol, Y:89.3%) is obtained. The resulting solid is subjected to HPLC analysis.

[0105] .sup.1HNMR (DMSO-d6) (5 ppm): 8.37 (s, 1H), 7.35-7.21 (m, 8H), 6.57 (brs, 2H), 3.91-3.86 (dd, 1H), 3.81-3.75 (dd, 1H), 3.37-3.27 (m, 1H), 2.77 (d, 2H) .sup.13CNMR: 165.6, 156.9, 137.97, 129.7, 128.9, 126.94, 65.36, 51.69, 37.91

Example 4D: Synthesis of 2-amino-3-phenylpropyl carbamate acetate salt

[0106] ##STR00013##

[0107] Following the general procedure, acetate salt (15.5 mmol, Y:87,1%) is obtained. The resulting solid is subjected to HPLC analysis.

[0108] .sup.1HNMR (DMSO-d6) (δ ppm): 7.32-7.18 (m, 5H), 6.50 (brs, 2H), 5.50 (s, 3H), 3.82-3.69 (ddd, 2H), 3.17-3.09 (m, 1H), 2.75-2.69 (dd, 1H), 2.60-2.52 (dd, 1H), 1.88 (s, 3H)

[0109] .sup.13CNMR: 172.89, 157.19, 139.18, 129.68, 128.72, 126.56, 67.69, 51.98, 22.11

Example 4E: Synthesis of 2-amino-3-phenylpropyl carbamate salicylate salt

[0110] ##STR00014##

[0111] Following the general procedure, salicylate salt (12.7 mmol, Y:71.3%) is obtained. The resulting solid is subjected to HPLC analysis.

[0112] .sup.1HNMR(DMSO-d6) (δ ppm): 8.39 (brs, 1H), 7.74-7.70 (dd, 1H), 7.37-7.16 (m, 6H), 6.69-6.64 (m, 4H), 4.06-4.00 (dd, 1H), 3.91-3.85 (dd, 1H), 3.67-3.59 (m, 1H), 3.05-2.99 (dd, 1H), 2.90-2.83 (dd, 1H)

[0113] .sup.13CNMR: 172.63, 162.84, 156.60, 136.55, 132.26-127.39, 120.32, 116.93, 116.34, 62.82, 51.55, 35.70

Example 4F: Synthesis of 2-amino-3-phenylpropyl carbamate 4-nitro-benzoate salt

[0114] Following the general procedure, except for the addition of nitrobenzoic acid as suspension and not as a solution, nitro benzoate salt (17.7 mmol, Y:99,4%) is obtained. The resulting solid is subjected to HPLC analysis.

[0115] .sup.1HNMR (DMSO-d6) (δ ppm): 8.82-7.65 (brs+d+d, 7H), 7.33-7.25 (m, 5H), 7.06 (brs, 3H), 6.69 (brs, 2H), 4.01-3.96 (dd, 1H), 3.83-3.84(dd, 1H), 3.60-3.52 (m, 1H), 3.04-2.98 (dd, 1H), 2.88-2.81 (dd, 1H)

[0116] .sup.13CNMR: 167.89, 156.75, 148.77, 144.63, 137.10 130.59, 129.73, 129.03, 127.20, 123.39, 63.51, 51.50, 36.27

Example 4G: Synthesis of 2-amino-3-phenylpropyl carbamate propionate salt

[0117] Following the general procedure, propionate salt (15.7 mmol, Y:88,0%) is obtained.

[0118] The resulting solid is subjected to HPLC analysis.

[0119] .sup.1HNMR (DMSO-d6) (δ ppm): 7.37-7.16 (m, 5H), 6.53 (brs, 2H), 5.59 (brs, 3H), 3.82-3.69 (ddd, 2H), 3.17-3.09 (m, 1H), 2.75-2.69 (dd, 1H), 2.61-2.54 (dd, 1H), 220-2.13 (q, 2H), 1.00-0.95 (t, 3H)

[0120] .sup.13CNMR: 176.22, 157.20, 139.18, 129.68, 128.72, 126.56, 67.65, 51.96, 28.08, 9.92

Example 4H: Synthesis of 2-amino-3-phenylpropyl carbamate 4-methoxy benzoate salt

[0121] Following the general procedure, propionate salt (Y:62,5%%) is obtained. The resulting solid is subjected to HPLC analysis.

[0122] .sup.1HNMR (DMSO-d6) (δ ppm): 7.90-7.88 (d, 2H), 7.33-7.18 (m, 5H), 7.02-6.99 (d, 2H), 6.50 (brs,2H), 3.80 (s, 3H), 3.78-3.68 (m, 2H), 3.16-3.08 (m, 1H), 2.65-2.69 (m, 1H), 2.59-2.56 (m, 1H) [0123] .sup.13CNMR: 167.78, 162.94, 157.20, 139.24, 131.70, 129.69, 128.72, 126.55, 124.70, 121.68, 114.09, 67.77, 55.85, 52.00

Example 41: Synthesis of 2-amino-3-phenylpropyl carbamate 2,4-dimethyl benzoate salt

[0124] Following the general procedure, 2,4-dimethyl benzoate salt (Y:66,1%) is obtained. The resulting solid is subjected to HPLC analysis.

[0125] .sup.1HNMR (DMSO-d6) (δ ppm): 7.22.-7.20 (d, 1H), 7.33-7.19 (m, 5H), 7.08-7.05 (m, 2H), 6.50 (brs, 2H), 3.82-3.69 (m, 2H), 3.16-3.08 (m, 1H), 2.76-2.69 (m, 1H), 2.60-2.57 (m, 1H), 2.49 (s, 3H), 2.30 (s, 3H).

[0126] .sup.13CNMR: 169.45, 157.20, 141.50, 139.28, 139.23, 132.47, 130.79, 129.68, 129.25, 128.72, 126.74, 126.55, 67.65, 55.38, 52.00, 21.76, 21.31.

Example 4L: Synthesis of 2-amino-3-phenylpropyl carbamate 4-Fluoro benzoate salt

[0127] Following the general procedure, 4-Fluoro benzoate salt (Y:73,0%) is obtained. The resulting solid is subjected to HPLC analysis.

[0128] .sup.1HNMR (DMSO-d6) (δ ppm): 8.02-7.95 (m, 2H), 7.33-7.20 (m, 7H), 6.52 (brs, 2H), 3.85-3.71 (m, 2H), 3.24-3.16 (m, 1H), 2.78-2.71 (m, 1H), 2.66-2.59 (m, 1H).

[0129] .sup.13CNMR: 157.09, 138.71, 132.35, 132.23, 129.70, 128.80, 126.72, 115.69, 115.41, 66.74, 60.26, 51.08.

Example 4M: Synthesis of 2-amino-3-phenylpropyl carbamate 4-chloro benzoate salt

[0130] Following the general procedure, 4-chloro benzoate salt (Y:77,5%) is obtained. The resulting solid is subjected to HPLC analysis.

[0131] .sup.1 HNMR (DMSO-d6) (5 ppm): 7.94-7.91 (d, 2H), 7.53-7.50 (d, 2H), 7.34-7.20 (m, 5H), 6.53 (brs, 2H), 3.87-3.72 (m, 2H), 3.28-3.20 (m, 1H), 2.79-2.62 (m, 2H). .sup.13CNMR: 167.22, 156.96, 138.10, 136.62, 133.75, 131.48, 129.71, 128.89, 128.61, 126.91, 65.57, 51.74, 38.08. Example 4N: Synthesis of 2-amino-3-phenylpropyl carbamate 4-methyl benzoate salt Following the general procedure, 4-methyl benzoate salt (Y:78,9%) is obtained. The resulting solid is subjected to HPLC analysis.

[0132] .sup.1HNMR (DMSO-d6) (5 ppm): 7.84-7.82 (d, 2H), 7.33-7.19 (m, 7H), 6.52 (brs, 2H), 3.84-3.71 (m, 2H), 3.22-3.14 (m, 1H), 2.77-2.71 (m, 1H), 2.65-2.58 (m, 1H), 2.36 (s, 3H). .sup.13CNMR: 168.37, 157.15, 142.35, 138.95, 130.36, 129.73, 129.69, 129.28, 128.77, 126.64, 67.17, 55.37, 51.92, 21.54. Example 40: Synthesis of 2-amino-3-phenylpropyl carbamate biphenyl-4-carboxylate salt Following the general procedure, biphenyl-4-carboxylate salt (Y:82,0%) is obtained. The resulting solid is subjected to HPLC analysis

[0133] .sup.1 HNMR (DMSO-d6) (δ ppm): 8.02 (d, 2H), 7.78-7.72 (m, 4H), 7.50 (t, 2H), 7.44-7.39 (m, 1H), 7.33-7.19 (m, 5H), 6.51 (bd, 2H), 3.84-3.70 (m, 2H), 3.19-3.13 (m, 1H), 2.77-2.71 (m, 1H), 2.64-2.56 (m, 1H).

[0134] .sup.13CNMR: 168.33, 157.06, 143.70, 139.84, 138.53, 157.06, 143.70, 139.84, 138.53, 130.33, 129.70, 129.50, 128.83, 128.50, 127.36, 126.94, 126.78, 66.37, 51.84, 38.78.

Example 4P: Synthesis of 2-amino-3-phenylpropyl carbamate phenylacetate salt

[0135] Following the general procedure, phenylacetate salt (Y:55,4%) is obtained. The resulting solid is subjected to HPLC analysis.

[0136] .sup.1HNMR (DMSO-d6) (δ ppm): 7.32-7.21 (m, 10H), 6.50 (br, 2H), 3.82-3.69 (m, 2H), 3.5 (s, 2H), 3.18-3.09 (m, 1H), 2.75-2.69 (m, 1H), 2.61-2.57 (m, 1H).

[0137] .sup.13CNMR: 173.42, 157.18, 139.13, 136.27, 129.80, 129.69, 128.74, 128.58, 126.76, 126.58, 67.58, 51.97, 42.02.

Example 4Q: Synthesis of 2-amino-3-phenylpropyl carbamate laurate salt

[0138] Following the general procedure, laurate salt (Y:49,2%) is obtained. The resulting solid is subjected to HPLC analysis

[0139] .sup.1HNMR (DMSO-d6) (δ ppm): 7.32-7.18 (m, 5H), 6.48 (br, 2H), 3.80-3.67 (m, 2H), 3.13-3.04 (m, 1H), 2.25-2.48 (m, 2H), 2.17 (t, 2H), 1.50-1.46 (m, 2H), 1.25 (s, 16H), 0.86 (t, 3H).

[0140] .sup.13CNMR: 175.09, 157.25, 139.48, 129.68, 128.68, 126.47, 68.24, 52.06, 34.37, 31.76, 29.47, 29.39, 29.23, 29.17, 29.06, 25.06, 22.56, 14.42.

Example 4R: Synthesis of 2-amino-3-phenylpropyl 2-methyl benzoate salt

[0141] Following the general procedure, 2-methyl benzoate salt (Y:84,1%) is obtained. The resulting solid is subjected to HPLC analysis.

[0142] .sup.1HNMR (DMSO-d6) (δ ppm):7.72-7.70 (m, 1H), 7.34-7.17 (m, 8H), 6.55 (br, 2H), 3.88-3.74 (m, 2H), 3.32-3.23 (m, 1H), 2.76-2.74 (m, 2H), 2.50 (s, 3H).

[0143] .sup.13CNMR: 170.77, 157.05, 138.53, 138.02, 135.19, 131.35, 130.38, 129.91, 129.70, 128.82, 126.76, 125.84, 66.29, 51.79, 38.71, 21.57.

Example 5: Synthesis of (R)-2-amino-3-phenylpropyl Carbamate Salts With Other Organic Acids Used as Reference Compounds

Example 5A: Synthesis of 2-amino-3-phenylpropyl carbamate PTSA salt

[0144] ##STR00015##

[0145] Following the general procedure, PTSA salt (16.9 mmol, Y:95.0%) is obtained. The resulting solid is subjected to HPLC analysis.

[0146] .sup.1HNMR (DMSO-d6) (δ ppm): 8.06 (s, 3H), 7.525 (d, 2H), 7.38-7.26 (m, 5H), 7.14 (d, 2H), 6.64 (s, 2H), 4.04-3.99 (dd, 1H), 3.88-3.82 (dd, 1H), 3.62-3.57 (m, 1H), 2.99-2.93 (dd, 1H), 2.87-2.80 (dd, 1H), 2.30 (s, 3H).

[0147] .sup.13CNMR: 156.54, 145.79, 138.38, 136.26, 129-74-125.97, 62.58, 51.63, 35.48, 21.26

Example 5B: Synthesis of 2-amino-3-phenylpropyl carbamate tartrate salt

[0148] ##STR00016##

[0149] Following the general procedure tartrate salt (15.71 mmol, Y:88.2%) is obtained. The resulting solid is subjected to HPLC analysis.

[0150] .sup.1HNMR (DMSO-d6) (δ ppm): 7.88 (brs, 6H), 7.37-7.22 (m, 5H), 6.62 (s, 2H), 4.04 (s, 2H), 4.01-3.95 (dd, 1H), 3.87-3.81 (dd, 1H), 3.59-3.51 (m, 1H), 3.00-2.94 (dd, 1H), 2.86-2.79 (dd, 1H)

[0151] .sup.13CNMR: 174.75, 156.65, 136.76, 129.75-127.31, 72.33, 63.08, 51.52, 35.89 Example 5C: Synthesis of 2-amino-3-phenylpropyl carbamate oxalate salt

##STR00017##

[0152] Following the general procedure oxalate salt (17,8 mmol, Y:100%) is obtained. The resulting solid is subjected to HPLC analysis.

[0153] .sup.1HNMR (DMSO-d6) (δ ppm): 8.12 (brs, 5H), 7.37-7.25 (m, 5H), 6.62 (s, 2H), 4.03-3.97 (dd, 1H), 3.88-3.82 (dd, 1H), 3.62-3.54 (m, 1H), 3.02-2.96 (dd, 1H), 2.87-2.80 (dd, 1H),

[0154] .sup.13CNMR: 163.92, 156.56, 136.43, 129.72-127.42, 62.60, 51.54, 35.50

Example 6: Synthesis of 2-amino-3-phenylpropyl carbamate hydrochloride salt Procedure a)

[0155] A suspension of 2-amino-3-phenylpropyl carbamate benzoate salt (12 g ; 37.9 mol) in a mixture of Ethanol (24 ml) and Isopropanol (36 ml) is heated at 65° C. till complete dissolution. A solution of HCl in isopropanol (1.5 eq; 20,7 g) is dropped into the solution obtaining the precipitation of a solid. The suspension is maintained at 65° C. for 1 h and then cooled at 0° C. in 3 h. The solid is filtered under vacuum, washed twice with isopropanol (24 ml×2) and dried under vacuum at 45° C. 2-amino-3-phenylpropyl carbamate hydrochloride salt (7.43 g; 32.2 mmol) is obtained. Residual content of benzoic acid by HPLC is less than 0.15%.

Procedure b)

[0156] 2-amino-3-phenylpropyl carbamate benzoate salt (10 g; 31.6 mmol) is suspended in isopropyl acetate (100 ml). A solution of HCl in isopropyl acetate (2 eq; 24 ml) is dropped and the suspension is stirred for 4 h. The solid is filtered and washed with isopropyl acetate (20 ml). The wet cake is suspended in isopropyl acetate (70 ml) and stirred for 1 h. The solid is filtered and washed twice with isopropyl acetate (2×20 ml). After drying at 45° C., 2-amino-3-phenylpropyl carbamate hydrochloride salt 6.92 g; 30.0 mmol) is obtained. Residual content of benzoic acid by HPLC is less than 0,15%.

Example 7: Synthesis of 2-amino-3-phenylpropyl carbamate hydrochloride salt

[0157] The same procedure of Example 6 may be carried out by using the other organic salts of Example 4, as starting material, instead of benzoate salt.

Example 8: Displacement of the hydrochloride salt to the (R) 2-amino-3-phenylpropyl carbamate base

[0158] 10 g of 2-amino-3-phenylpropyl carbamate hydrochloride (1 eq ; 43 mmol) is dissolved in 30 ml of water and added with 60 ml of DCM. NaOH 10% is added to the mixture till pH 11 and the phases separated. The water phase is extracted twice with 35 ml each of DCM. The organic phases are combined and washed with 5 ml of water. 2-amino-3-phenylpropyl carbamate base (0.95 eq: 41 mmol) in DCM solution is obtained, ready to be converted in the corresponding organic salt according to general procedure described in example 3.

Example 9

[0159] Different organic acid have been tested, selecting among aliphatic and aromatic monocarboxylic acids according to the invention, sulphonic and dicarboxylic acids (as reference compounds) and finally on the basis of different pKa.

LIST OF ACID TESTED

[0160] 1. Benzoic acid

[0161] 2. Trilfluoroacetic acid

[0162] 3. Formic acid

[0163] 4. Acetic acid

[0164] 5. Propionic acid

[0165] 6. 4-Nitro-benzoic acid

[0166] 7. 4-methoxy benzoic acid

[0167] 8. 2.4 dimethyl benzoic acid

[0168] 9. 4-methyl benzoic acid

[0169] 10. 4-fluoro benzoic acid

[0170] 11. 4-chloro benzoic acid

[0171] 12. Biphenyl-4-carboxylic acid

[0172] 13. Phenylacetic acid

[0173] 14. lauric acid

[0174] 15. 2-methyl benzoic acid

[0175] 16. p-Toluenesulfonic acid (PTSA)-Reference

[0176] 17. Salicylic acid

[0177] 18. L-Tartaric acid-Reference

[0178] 19. Oxalic acid-Reference

[0179] 20. Hydrochloride acid-Reference

[0180] The test was performed starting from a dichloromethane solution of crude (R)-2-amino-3-phenylpropyl carbamate base, obtained from the procedure reported as

Example 1

[0181] The solution was divided in equivalent portions. A solution in dichloromethane containing 1.1 eq of each acid tested was added in 1 hour to one portion of the API base solution, maintaining the temperature at 35-40° C. in order to allow the largest dissolution of the forming salt and to maximize the potential purification effect. The mixture was cooled in 3 h at 0° C. and maintained for 2 h at 0° C. Crystallization occurred over the time. The suspension was filtered and the solid dried under vacuum at 40-45° C. The obtained salts were analyzed by HPLC and the content of each impurity determined by area % normalized with respect to the area % of the API, in order to exclude the contribute in the HPLC trace of each single acid. Since the stability of the starting dichloromethane solution of (R)-2-amino-3-phenylpropyl carbamate base was rather poor, the composition of such solution was periodically controlled by HPLC in order to have a precise knowledge of the composition of the starting solution, before the salification and be more accurate in the evaluation of the purging factor related to each acid tested. The data, collected in two experimental sessions are summarized in Table 1 and 2.

TABLE-US-00002 TABLE 1 HPLC area % normalized respect the API BIS- BIS- ADDUCT compound Phenylalaninol ADDUCT UREA free base control 1 5.57% 4.15% 2.74% benzoate 0.21% 0.27% 0.00% trifluoroacetate 0.73% 0.81% 0.24% formate 1.94% 1.45% 0.78% acetate 1.71% 0.45% 0.39% free base control 2 5.46% 3.55% 3.76% p-toluensulphonate 4.84% 3.09% 3.18% salycilate 1.58% 0.85% 0.96% free base control 3 5.49% 3.29% 4.19% tartrate 5.34% 2.91% 4.10% oxalate 5.14% 3.30% 2.39% Free base control 4 5.53% 2.72% 5.19% Hydrochloride 5.31% 2.66% 4.60% Free base control 5 4.75% 2.96% 2.82% propionate 2.44% 1.44% 2.44% nitrobenzoate 1.29% 1.31% 0.85%

TABLE-US-00003 TABLE 2 HPLC area % normalized respect the API BIS- BIS- ADDUCT compound Phenylalaninol ADDUCT UREA free base control 1 2.71% 2.71% 2.99% 4-methoxy benzoate 0.68% 0.49% 1.13% 2,4-dimethyl benzoate 0.33% 0.23% 0.52% 4-fluoro benzoate 0.36% 0.80% 0.58% 4-chloro benzoate 0.28% 0.18% 0.49% 4-methyl benzoate 0.35% 0.20% 0.63% Biphenyl-4-carboxylate 0.57% 1.05% 0.39% laurate 0.38% 0.29% 0.67% Phenylacetate 0.58% 0.29% 0.98% Free base control 2 2.74% 1.20% 5.27% 2-methyl benzoate 0.42% 0.21% 0.60% benzoate 0.26% 0.08% 0.49%

[0182] For each impurity the purging factor was calculated and expressed as percentage ratio between the delta of content in the starting base and the content in the obtained salt, with respect to the starting amount. The data derived are summarized in Table 3:

TABLE-US-00004 TABLE 3 % purging factor BIS- BIS- ADDUCT compound Phenylalaninol ADDUCT UREA Benzoate (invention) 96.22% 93.49% 100.00% salycilate (invention) 71.02% 76.11% 74.32% Trifluoroacetate (invention) 86.84% 80.38% 91.10% Formate (invention) 65.20% 65.11% 71.53% Acetate (invention) 69.23% 89.13% 85.80% Propionate (invention) 48.63% 51.35% 13.48% Nitrobenzoate (invention) 72.84% 55.74% 69.86% 4-methoxy benzoate (invention) 74.91% 81.92% 62.21% 2,4-dimethyl benzoate 87.82% 91.51% 82.61% (invention) 4-fluoro benzoate (invention) 86.72% 70.48% 80.60% 4-chloro benzoate (invention) 89.67% 93.36% 83.61% 4-methyl benzoate (invention) 87.08% 92.62% 78.93% Biphenyl-4-carboxylate 78.97% 61.25% 86.96% (invention) laurate (invention) 85.98% 89.30% 77.59% Phenylacetate (invention) 78.60% 89.30% 67.22% 2-methyl benzoate (invention) 84.67% 82.50% 88.61% p-toluensulphonate (reference) 11.41% 12.99% 15.34% Tartrate (reference) 2.80% 11.49% 2.16% Oxalate (reference) 6.47% −0.24% 43.00% Hydrochloride (reference) 3.86% 2.26% 11.22%

[0183] As higher is the purging factor as more efficient is the salification method to remove the impurity.

[0184] As previously anticipated, the data showed that the salification with HCl does not allow any useful purging of the impurities.

[0185] Table 3 also shows that the salification with sulphonic and dicarboxylic acids does not allow any useful purging of the impurities.

[0186] On the contrary, the salification with aliphatic and aromatic mono carboxylic acids, according to the invention, surprisingly leads to the reduction of more than 48% of at least two impurities and that it is even more significant and unexpected if compared with low purging effect demonstrated by all the other organic acids tested. Preferably, the salification with benzoic acid surprisingly leads to the reduction of more than 93% of each impurity.

[0187] The inventors have found that also the derivatives of benzoic acid lead to an effective reduction of each impurity.

[0188] In addition, it is important to highlight that the purging effect is achieved with a good recovery of the material, being the yield of the purification close to 85%. This quantitative results makes the process extremely valuable in perspective of an industrial scale application.

[0189] For the same perspective the usage, in particular, of benzoic acid has in addition other two important advantages. Firstly, from toxicological point of view this is a reagent extremely safe, largely employed as preservative for food, and that guarantees the health and the safety of the worker employed in the manufacturing of the API, as well as of the patients which will use the final drug.

[0190] As well, aliphatic acids such as formic and acetic acid are widespread diffused and employed in the synthesis of active pharmaceutical ingredient as reagent or in most cases as solvent. According to Q3Cguideline of ICH (https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-14.pdf) they are classified in class 3 for the organic volatile impurities admitted for pharmaceuticals, therefore they are considered low toxic and of with low risk to human health.

[0191] Secondarily, but not for importance, concerning the economical impact of the overall process, the conversion of the salts object of this invention to the final HCl API is simple, fast and potentially extremely efficient.

[0192] As a matter of fact organic acids, both aromatic and aliphatic, have pKa definitively lower than HCl and are generally high soluble in the commonest organic solvents. Both these features make possible the direct displacement of these salts by HCl, without the need to pass through the corresponding base. HCl can be added to a suspension or solution of the organic salt. The displacement spontaneously occurs, salifying the API as hydrochloride and generating free organic acid. Performing this operation in the right solvent where the hydrochloride salt is low soluble and organic acid is soluble the recovery of the API can be practically quantitative and no traces of residual organic acid remains in the isolated product.