Non-distillative process for manufacturing high purity amphetamines
The invention provides a non-distillative process for manufacturing amphetamine and substituted amphetamines, comprising obtaining a highly pure phosphoramidate compound, converting the highly pure phosphoramidate compound to an amphetamine sulfate compound, concentrating the amphetamine sulfate compound in isopropanol, and then salting out the amphetamine compound directly to obtain an amphetamine salt, the amphetamine salt selected from amphetamine saccharate, amphetamine sulfate, amphetamine aspartate, alkyl-amphetamine saccharate, alkyl-amphetamine sulfate, alkyl-amphetamine aspartate, aryl-amphetamine saccharate, aryl-amphetamine sulfate, aryl-amphetamine aspartate, and mixtures thereof.
1 . A non-distillative process for manufacturing a substituted sulfate amphetamine, comprising: adding aqueous H 2 SO 4 to a (S or R,S) (dialkyl or diaryl) (1-phenylpropan-2-yl) phosphoramidate compound, warming to 80° C., cooling to 20° C., washing in isopropanol or toluene, combining organic layers, and collecting a solid by filtration, wherein the solid is (S,R, S,S, R,R or R,S) (dialkyl or diaryl)(1-phenylpropan-2-amine) sulfate.
2 . The process of claim 1 , wherein the substituted amphetamine sulfate is dexamphetamine sulfate and the (S or R,S) (dialkyl or diaryl) (1-phenylpropan-2-yl) phosphoramidate compound is (S or R,S) (diethyl) (1-phenylpropan-2-yl) phosphoramidate.
3 . The process of claim 1 , further comprising the steps of concentrating the substituted amphetamine sulfate in isopropanol, and then salting out the substituted amphetamine compound directly to obtain a substituted amphetamine salt, the substituted amphetamine salt selected from a substituted amphetamine saccharate, a substituted amphetamine sulfate, a substituted amphetamine aspartate, an alkyl-amphetamine saccharate, an alkyl-amphetamine sulfate, an alkyl-amphetamine aspartate, an aryl-amphetamine saccharate, an aryl-amphetamine sulfate, an aryl-amphetamine aspartate, and mixtures thereof.
4 . The process of claim 1 , wherein the substituted amphetamine sulfate is >99% pure.
5 . The process of claim 3 , wherein the substituted amphetamine salt is selected from dextroamphetamine saccharate, dextroamphetamine sulfate, or dextroamphetamine aspartate.
6 . The process of claim 1 , wherein the substituted amphetamine sulfate is optically active or a racemic mixture thereof.
7 . The process of claim 1 , wherein the substituted amphetamine sulfate is selected from the group consisting of a dextroamphetamine salt, a levoamphetamine salt, or a mixture thereof.
8 . The process of claim 1 , where the substituted amphetamine sulfate is formulated in a pharmaceutically acceptable composition.
9 . The process of claim 1 , further comprising the step of washing with methyl-tert-butyl-ether (MTBE) after washing with isopropanol or toluene but before combining organic layers.
10 . The process of claim 1 , wherein the phosphoramidate is diethyl-(1-phenylpropan-2-y) phosphoramidate and is optically active.
11 . The process of claim 1 , wherein the phosphoramidate is diethyl(S)-(1-phenylpropan-2-y) phosphoramidate, diethyl (R)-(1-phenylpropan-2-y) phosphoramidate or mixtures thereof.
12 . The process of claim 1 , wherein the substituted amphetamine is optically active, dextrorotatory, levorotatory, or racemic.
13 . The process of claim 1 , wherein the purity of the substituted amphetamine sulfate is not less than 98% on a weight basis.
14 . The process of claim 1 , wherein the substituted amphetamine sulfate comprises a regiospecific impurity β-methylphenethylamine present at a level of less than 0.1% on a weight basis.
15 . The process of claim 1 , further comprising wherein the substituted amphetamine sulfate is converted to lisdexamfetamine.
16 . A process, comprising:
(i) reacting (S or R,S) (dialkyl or diaryl)(1-phenylpropan-2-yl)phosphoramidate, with 3N HCl at 80° C. for 1.5 h, cooling to room temperature, adding toluene and agitating, and removing an organic layer;
(i reacting the organic layer with 50% NaOH to adjust pH to 13, agitating with methyl-tert-butyl-ether (MTBE), separating an aqueous layer from an organic layer, washing the organic layer with MTBE;
(iii) diluting the organic layer with isopropanol, warming to 45-50° C., and concentrating under vacuum to obtain (S or R,S) (dialkyl or diaryl)(1-phenylpropan-2-yl)amine dissolved in isopropanol;
(iv) adding H 2 SO 4 aq and isopropanol to the (S or R,S) (dialkyl or diaryl) (1-phenylpropan-2-yl)-amine dissolved in isopropanol while maintaining 45-50° C.;
(v) adding isopropanol, and warming to 80° C. for 1 h, cooling to 50° C. over 6 h, 20° C. over 5 h, and maintaining at 20° C. for 4 h;
(vi) adding isopropanol and cooling to 5° C., agitating for 6 h;
(vii) collecting a solid by filtration, washing with cold isopropanol/water;
wherein the solid is a (S or R,S) (dialkyl or diaryl) (1-phenylpropan-2-yl)-amine [H 2 SO 4 ] having a purity of >99.9%.
17 . The process of claim 16 , wherein the (S or R,S) (dialkyl or diaryl) (1-phenylpropan-2-yl)-amine is converted to a saccharic acid salt or a aspartic acid salt, the steps comprising:
(xi) making a slurry in water at RT of the (S or R,S) (dialkyl or diaryl) (1-phenylpropan-2-yl)-amine, adding 50% aq NaOH, stir 0.5 h, agitating 0.5 h w/MTBE, and obtaining an organic layer, diluting the organic layer with isopropanol, warming to 50° C., concentrating under vacuum, and cooling to RT;
(xii) making slurry from a saccharate or aspartate, cooling the slurry to 5° C. and treating with concentrated H 2 SO 4 aq., agitating for 0.25 h at 5° C., warming to RT, stirring for 1 h, diluting with isopropanol and agitating for 1 h, and filtering to obtain a saccharic acid filtrate or aspartic acid filtrate;
(xiii) adding saccharic acid filtrate or aspartic acid filtrate to the (S or R,S) (dialkyl or diaryl) (1-phenylpropan-2-yl)-amine to obtain a slurry, agitating for 1.5 h at RT, gradually warming and holding at 55° C., slowly adding water to yield clear solution, agitating the clear solution for 2 h, reducing the heat to 45° C. over 3 h, cooling to 5° C. over 5 h, holding for 7 h, and obtaining a white solid by filtration;
wherein the white solid is >99.9% chiral (dex) isomer of (S or R,S) (dialkyl or diaryl) (1-phenylpropan-2-yl)-amine or (S or R,S) (dialkyl or diaryl) (1-phenylpropan-2-yl)-amine.
18 . A process, comprising:
(i) reacting (S or R,S) (dialkyl or diaryl)(1-phenylpropan-2-yl)phosphoramidate, with H 2 SO 4 aq and warming to 80° C. for 1 h, cooling to 20° C.;
(ii) adding toluene, concentrating under vacuum, wash/repeat until water wt. is 0.11 weight %;
(iii) adding toluene, warming to 80° C., agitating 1 h, cooling to 50° C. over 2 h, cooling to RT, and holding at RT 4-24 h;
(iv) cooling to 5° C., and holding for 12 h;
(v) collecting a solid by filtration;
wherein the solid is a (S or R,S) (dialkyl or diaryl) (1-phenylpropan-2-yl)-amine [H 2 SO 4 ] having a purity of >99.92% AUC.
19 . The process of claim 18 , wherein the (S or R,S) (dialkyl or diaryl) (1-phenylpropan-2-yl)-amine is converted to a saccharic acid salt or a aspartic acid salt, the steps comprising:
(vi) making a slurry in water at RT of the (S or R,S) (dialkyl or diaryl) (1-phenylpropan-2-yl)-amine, adding 50% aq NaOH, stir 0.5 h, agitating 0.5 h w/MTBE, and obtaining an organic layer, diluting the organic layer with isopropanol, warming to 50° C., concentrating under vacuum, and cooling to RT;
(vii) making slurry from a saccharate or aspartate, cooling the slurry to 5° C. and treating with concentrated H 2 SO 4 aq., agitating for 0.25 h at 5° C., warming to RT, stirring for 1 h, diluting with isopropanol and agitating for 1 h, and filtering to obtain a saccharic acid filtrate or aspartic acid filtrate;
(viii) adding saccharic acid filtrate or aspartic acid filtrate to the (S or R,S) (dialkyl or diaryl) (1-phenylpropan-2-yl)-amine to obtain a slurry, agitating for 1.5 h at RT, gradually warming and holding at 55° C., slowly adding water to yield clear solution, agitating the clear solution for 2 h, reducing the heat to 45° C. over 3 h, cooling to 5° C. over 5 h, holding for 7 h, and obtaining a white solid by filtration;
wherein the white solid is >99.9% chiral (dex) isomer of (S or R,S) (dialkyl or diaryl) (1-phenylpropan-2-yl)-amine or (S or R,S) (dialkyl or diaryl) (1-phenylpropan-2-yl)-amine.