PROCESSES FOR THE SYNTHESIS OF VALBENAZINE
The present application relates to processes for preparing (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), which is an inhibitor of vesicular monoamine transporter 2 (VMAT2) useful in the treatment of hyperkinetic movement disorders such as tardive dyskinesia (TD).
1 . A process for preparing a compound of Formula I:
comprising the steps of:
a) reacting a compound of Formula F1:
with a Step a)-base to afford a compound of Formula F2:
b) cyclizing the compound of Formula F2 with a compound of Formula F3:
in the presence of sodium iodide to afford a compound of Formula F4:
c) reducing the compound of Formula F4 with a reducing agent to afford a compound of Formula F5:
d) resolving the compound of Formula F5 with (S)-(+)-camphorsulfonic acid (CSA) to afford a compound of Formula F6-CSA:
e) reacting the compound of Formula F6-CSA with a Step e)-base to afford a compound of Formula F6:
f) coupling the compound of Formula F6 and a carboxylic acid of Formula F7:
with a coupling reagent to afford a compound of Formula F8:
g) deprotecting the compound of Formula F8 with hydrogen chloride to afford a compound of Formula F9-HCl:
h) reacting the compound of Formula F9-HCl with a Step h)-base to afford a compound of Formula F9 (free base):
and
i) reacting the compound of Formula F9 with p-toluenesulfonic acid to afford the compound of Formula I.
2 . The process according to claim 1 , wherein reacting the compound of Formula F1 with a Step a)-base is carried out in the presence of a Step a)-solvent.
3 . The process according to claim 1 , wherein reacting the compound of Formula F1 with a Step a)-base is carried out in the presence of a Step a)-solvent comprising methyl tert-butyl ether (MTBE).
4 . The process according to claim 1 , wherein reacting the compound of Formula F1 with a Step a)-base is carried out in the presence of methyl tert-butyl ether (MTBE).
5 . The process according to claim 1 , wherein reacting the compound of Formula F1 with a Step a)-base is carried out in the presence of water and methyl tert-butyl ether (MTBE).
6 . The process according to any one of claims 1 to 5 , wherein the Step a)-base is potassium hydroxide.
7 . The process according to any one of claims 1 to 5 , wherein the Step a)-base is aqueous potassium hydroxide.
8 . The process according to any one of claims 1 to 7 , wherein reacting the compound of Formula F1 with a Step a)-base is carried out at a pH of about 10 to about 12.
9 . The process according to any one of claims 1 to 7 , wherein reacting the compound of Formula F1 with a Step a)-base is carried out at a pH of about 11.
10 . The process according to any one of claims 1 to 9 , wherein the molar ratio of sodium iodide to the compound of Formula F3 is about 0.35:1 to 0.45:1.
11 . The process according to any one of claims 1 to 10 , wherein cyclizing the compound of Formula F2 with a compound of Formula F3 in the presence of sodium iodide in Step b) is carried out in a cyclizing-step solvent.
12 . The process according to any one of claims 1 to 10 , wherein cyclizing the compound of Formula F2 with a compound of Formula F3 in the presence of sodium iodide in Step b) is carried out in a cyclizing-step solvent comprising isopropanol (IPA) and water.
13 . The process according to any one of claims 1 to 10 , wherein cyclizing the compound of Formula F2 with a compound of Formula F3 in the presence of sodium iodide in Step b) is carried out in isopropanol (IPA) and water.
14 . The process according to any one of claims 1 to 13 , wherein reducing the compound of Formula F4 with a reducing agent in Step c) is carried out in a reducing-step solvent.
15 . The process according to any one of claims 1 to 13 , wherein reducing the compound of Formula F4 with a reducing agent in Step c) is carried out in a reducing-step solvent comprising methyl tert-butyl ether (MTBE) and methanol.
16 . The process according to any one of claims 1 to 13 , wherein reducing the compound of Formula F4 with a reducing agent in Step c) is carried out in methyl tert-butyl ether (MTBE), acetic acid, and methanol.
17 . The process according to any one of claims 1 to 16 , wherein the reducing agent in Step c) is sodium borohydride.
18 . The process according to any one of claims 1 to 17 , wherein resolving the compound of Formula F5 with (S)-(+)-camphorsulfonic acid (CSA) in Step d) is carried out in a resolving-step solvent.
19 . The process according to any one of claims 1 to 17 , wherein resolving the compound of Formula F5 with (S)-(+)-camphorsulfonic acid (CSA) in Step d) is carried out in a resolving-step solvent comprising ethanol and water.
20 . The process according to any one of claims 1 to 17 , wherein resolving the compound of Formula F5 with (S)-(+)-camphorsulfonic acid (CSA) in Step d) is carried out in ethanol and water.
21 . The process according to any one of claims 1 to 20 , wherein the Step e)-base is sodium hydroxide.
22 . The process according to any one of claims 1 to 20 , wherein the Step e)-base is aqueous sodium hydroxide.
23 . The process according to any one of claims 1 to 20 , wherein the Step e)-base is potassium hydroxide.
24 . The process according to any one of claims 1 to 20 , wherein the Step e)-base is aqueous potassium hydroxide.
25 . The process according to any one of claims 1 to 24 , wherein reacting the compound of Formula F6-CSA with a Step e)-base is carried out in the presence of a Step e)-solvent.
26 . The process according to any one of claims 1 to 24 , wherein reacting the compound of Formula F6-CSA with a Step e)-base is carried out in the presence of a Step e)-solvent comprising dichloromethane.
27 . The process according to any one of claims 1 to 24 , wherein reacting the compound of Formula F6-CSA with a Step e)-base is carried out in the presence of dichloromethane.
28 . The process according to any one of claims 1 to 24 , wherein reacting the compound of Formula F6-CSA with a Step e)-base is carried out in the presence of dichloromethane and water.
29 . The process according to any one of claims 1 to 24 , wherein reacting the compound of Formula F6-CSA with a Step e)-base is carried out in the presence of a Step e)-solvent comprising 2-methyltetrahydrofuran (MeTHF).
30 . The process according to any one of claims 1 to 24 , wherein reacting the compound of Formula F6-CSA with a Step e)-base is carried out in the presence of 2-methyltetrahydrofuran (MeTHF).
31 . The process according to any one of claims 1 to 24 , wherein reacting the compound of Formula F6-CSA with a Step e)-base is carried out in the presence of 2-methyltetrahydrofuran (MeTHF) and water.
32 . The process according to any one of claims 1 to 31 , wherein coupling the compound of Formula F6 and a carboxylic acid of Formula F7 with a coupling reagent in Step f) is carried out in the presence of a coupling-step base.
33 . The process according to any one of claims 1 to 31 , wherein coupling the compound of Formula F6 and a carboxylic acid of Formula F7 with a coupling reagent in Step f) is carried out in the presence of a coupling-step base comprising 4-dimethylaminopyridine (DMAP).
34 . The process according to any one of claims 1 to 31 , wherein coupling the compound of Formula F6 and a carboxylic acid of Formula F7 with a coupling reagent in Step f) is carried out in the presence of 4-dimethylaminopyridine (DMAP).
35 . The process according to any one of claims 1 to 34 , wherein coupling the compound of Formula F6 and a carboxylic acid of Formula F7 with a coupling reagent in Step f) is carried out in the presence of a coupling-step solvent.
36 . The process according to any one of claims 1 to 34 , wherein coupling the compound of Formula F6 and a carboxylic acid of Formula F7 with a coupling reagent in Step f) is carried out in the presence of a coupling-step solvent comprising dichloromethane.
37 . The process according to any one of claims 1 to 34 , wherein coupling the compound of Formula F6 and a carboxylic acid of Formula F7 with a coupling reagent in Step f) is carried out in the presence of dichloromethane.
38 . The process according to any one of claims 1 to 34 , wherein coupling the compound of Formula F6 and a carboxylic acid of Formula F7 with a coupling reagent in Step f) is carried out in the presence of a coupling-step solvent comprising 2-methyltetrahydrofuran (MeTHF).
39 . The process according to any one of claims 1 to 34 , wherein coupling the compound of Formula F6 and a carboxylic acid of Formula F7 with a coupling reagent in Step f) is carried out in the presence of 2-methyltetrahydrofuran (MeTHF).
40 . The process according to any one of claims 1 to 39 , wherein the coupling reagent is N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC. HCl).
41 . The process according to any one of claims 1 to 39 , wherein the coupling reagent is N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDCI).
42 . The process according to any one of claims 1 to 41 , wherein the hydrogen chloride in Step g) is a hydrogen chloride dioxane mixture.
43 . The process according to any one of claims 1 to 41 , wherein the hydrogen chloride in Step g) is a hydrogen chloride isopropanol (IPA) mixture.
44 . The process according to any one of claims 1 to 41 , wherein the hydrogen chloride in Step g) is substantially anhydrous.
45 . The process according to any one of claims 1 to 44 , wherein deprotecting the compound of Formula F8 with hydrogen chloride in Step g) is carried out in a deprotecting-step solvent.
46 . The process according to any one of claims 1 to 44, wherein deprotecting the compound of Formula F8 with hydrogen chloride in Step g) is carried out in a deprotecting-step solvent comprising dichloromethane.
47 . The process according to any one of claims 1 to 44 , wherein deprotecting the compound of Formula F8 with hydrogen chloride in Step g) is carried out in dichloromethane.
48 . The process according to any one of claims 1 to 44 , wherein deprotecting the compound of Formula F8 with hydrogen chloride in Step g) is carried out in a deprotecting-step solvent comprising 2-methyltetrahydrofuran (MeTHF).
49 . The process according to any one of claims 1 to 44 , wherein deprotecting the compound of Formula F8 with hydrogen chloride in Step g) is carried out in a deprotecting-step solvent comprising 2-methyltetrahydrofuran (MeTHF) and ethyl acetate (EtOAc).
50 . The process according to any one of claims 1 to 44 , wherein deprotecting the compound of Formula F8 with hydrogen chloride in Step g) is carried out in 2-methyltetrahydrofuran (MeTHF).
51 . The process according to any one of claims 1 to 44 , wherein deprotecting the compound of Formula F8 with hydrogen chloride in Step g) is carried out in 2-methyltetrahydrofuran (MeTHF) and ethyl acetate (EtOAc).
52 . The process according to any one of claims 1 to 51 , wherein after Step g) and before Step h) the process further comprises the steps of:
1) reacting the compound of Formula F9-HCl with aqueous sodium bicarbonate in the presence of a solvent comprising dichloromethane to afford a compound of Formula F9 (free base); and
2) reacting the compound of Formula F9 (free base) in a solvent comprising acetonitrile with a hydrogen chloride isopropanol mixture to afford the compound of Formula F9-HCl.
53 . The process according to any one of claims 1 to 52 , wherein the Step h)-base is sodium bicarbonate.
54 . The process according to any one of claims 1 to 52 , wherein the Step h)-base is aqueous sodium bicarbonate.
55 . The process according to any one of claims 1 to 54, wherein reacting the compound of Formula F9-HCl with a Step h)-base is carried out in the presence of a Step h)-solvent.
56 . The process according to any one of claims 1 to 54 , wherein reacting the compound of Formula F9-HCl with a Step h)-base is carried out in the presence of a Step h)-solvent comprising dichloromethane.
57 . The process according to any one of claims 1 to 54 , wherein reacting the compound of Formula F9-HCl with a Step h)-base is carried out in the presence of dichloromethane.
58 . The process according to any one of claims 1 to 54 , wherein reacting the compound of Formula F9-HCl with a Step h)-base is carried out in the presence of dichloromethane and water.
59 . The process according to any one of claims 1 to 54 , wherein reacting the compound of Formula F9-HCl with a Step h)-base is carried out in the presence of a Step h)-solvent comprising 2-methyltetrahydrofuran (MeTHF).
60 . The process according to any one of claims 1 to 54 , wherein reacting the compound of Formula F9-HCl with a Step h)-base is carried out in the presence of a Step h)-solvent comprising ethyl acetate (EtOAc).
61 . The process according to any one of claims 1 to 54 , wherein reacting the compound of Formula F9-HCl with a Step h)-base is carried out in the presence of a Step h)-solvent comprising 2-methyltetrahydrofuran (MeTHF) and ethyl acetate (EtOAc).
62 . The process according to any one of claims 1 to 54 , wherein reacting the compound of Formula F9-HCl with a Step h)-base is carried out in 2-methyltetrahydrofuran (MeTHF) and ethyl acetate (EtOAc).
63 . The process according to any one of claims 1 to 62 , wherein reacting the compound of Formula F9 with p-toluenesulfonic acid in Step i) is carried out in a solvent comprising acetonitrile.
64 . The process according to any one of claims 1 to 62 , wherein reacting the compound of Formula F9 with p-toluenesulfonic acid in Step i) is carried out in acetonitrile.
65 . A process for preparing a compound of Formula I:
comprising the steps of:
a) reacting a compound of Formula F1:
with aqueous potassium hydroxide in the presence of methyl tert-butyl ether (MTBE) to afford a compound of Formula F2:
b) cyclizing the compound of Formula F2 with a compound of Formula F3:
in the presence of sodium iodide, isopropanol (IPA), and water to afford a compound of Formula F4:
c) reducing the compound of Formula F4 with sodium borohydride in the presence of methyl tert-butyl ether (MTBE), acetic acid, and methanol to afford a compound of Formula F5:
d) resolving the compound of Formula F5 with (S)-(+)-camphorsulfonic acid (CSA) in ethanol and water to afford a compound of Formula F6-CSA:
e) reacting the compound of Formula F6-CSA with aqueous sodium hydroxide in dichloromethane to afford a compound of Formula F6:
f) coupling the compound of Formula F6 and a carboxylic acid of Formula F7:
with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC·HCl) in the presence of 4-dimethylaminopyridine (DMAP) and dichloromethane to afford a compound of Formula F8:
g) deprotecting the compound of Formula F8 with a mixture of hydrogen chloride and dioxane in the presence of dichloromethane to afford a compound of Formula F9-HCl:
h) reacting the compound of Formula F9-HCl with aqueous sodium bicarbonate in the presence of dichloromethane to afford a compound of Formula F9 (free base):
and
i) reacting the compound of Formula F9 with p-toluenesulfonic acid in the presence of acetonitrile to afford the compound of Formula I.
66 . The process according to claim 65 , wherein after Step g) and before Step h) the process further comprises the steps of:
1) reacting the compound of Formula F9-HCl with aqueous sodium bicarbonate in the presence of a solvent comprising dichloromethane to afford a compound of Formula F9 (free base):
and
2) reacting the compound of Formula F9 (free base) in a solvent comprising acetonitrile with a hydrogen chloride isopropanol mixture to afford the compound of Formula F9-HCl.
67 . A process for preparing a compound of Formula I:
comprising the steps of:
a) reacting a compound of Formula F1:
with aqueous potassium hydroxide in the presence of methyl tert-butyl ether (MTBE) to afford a compound of Formula F2:
b) cyclizing the compound of Formula F2 with a compound of Formula F3:
in the presence of sodium iodide, isopropanol (IPA), and water to afford a compound of Formula F4:
c) reducing the compound of Formula F4 with sodium borohydride in the presence of methyl tert-butyl ether (MTBE), acetic acid, and methanol to afford a compound of Formula F5:
d) resolving the compound of Formula F5 with (S)-(+)-camphorsulfonic acid (CSA) in ethanol and water to afford a compound of Formula F6-CSA:
e) reacting the compound of Formula F6-CSA with aqueous sodium hydroxide in dichloromethane to afford a compound of Formula F6:
f) coupling the compound of Formula F6 and a carboxylic acid of Formula F7:
with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC·HCl) in the presence of 4-dimethylaminopyridine (DMAP) and dichloromethane to afford a compound of Formula F8:
g) deprotecting the compound of Formula F8 with a mixture of hydrogen chloride and dioxane in the presence of dichloromethane to afford a compound of Formula F9-HCl:
reacting the compound of Formula F9-HCl with aqueous sodium bicarbonate in the presence of a solvent comprising dichloromethane to afford a compound of Formula F9 (free base):
reacting the compound of Formula F9 (free base) in a solvent comprising acetonitrile with a hydrogen chloride isopropanol mixture to afford the compound of Formula F9-HCl;
h) reacting the compound of Formula F9-HCl with aqueous sodium bicarbonate in the presence of dichloromethane to afford a compound of Formula F9 (free base); and
i) reacting the compound of Formula F9 with p-toluenesulfonic acid in the presence of acetonitrile to afford the compound of Formula I.
68 . A process for preparing a compound of Formula I:
comprising the steps of:
a) reacting a compound of Formula F1:
with aqueous potassium hydroxide in the presence of methyl tert-butyl ether (MTBE) to afford a compound of Formula F2:
b) cyclizing the compound of Formula F2 with a compound of Formula F3:
in the presence of sodium iodide, isopropanol (IPA), and water to afford a compound of Formula F4:
c) reducing the compound of Formula F4 with sodium borohydride in the presence of methyl tert-butyl ether (MTBE), acetic acid, and methanol to afford a compound of Formula F1:
d) resolving the compound of Formula F5 with (S)-(+)-camphorsulfonic acid (CSA) in ethanol and water to afford a compound of Formula F6-CSA:
e) reacting the compound of Formula F6-CSA with aqueous potassium hydroxide in 2-methyltetrahydrofuran (MeTHF) to afford a compound of Formula F6:
f) coupling the compound of Formula F6 and a carboxylic acid of Formula F7:
with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDCI) in the presence of 4-dimethylaminopyridine (DMAP) and 2-methyltetrahydrofuran (MeTHF) to afford a compound of Formula F8:
g) deprotecting the compound of Formula F8 with a mixture of hydrogen chloride and isopropanol in the presence of 2-methyltetrahydrofuran (MeTHF) and ethyl acetate (EtOAc) to afford a compound of Formula F9-HCl:
h) reacting the compound of Formula F9-HCl with aqueous sodium bicarbonate in the presence of 2-methyltetrahydrofuran (MeTHF) and ethyl acetate (EtOAc) to afford a compound of Formula F9 (free base):
and i) reacting the compound of Formula F9 with p-toluenesulfonic acid in the presence of acetonitrile to afford the compound of Formula I.
69 . A process for preparing a compound of Formula I:
comprising the steps of:
a) reacting a compound of Formula F1:
with aqueous potassium hydroxide in the presence of methyl tert-butyl ether (MTBE) to afford a compound of Formula F2:
b) cyclizing the compound of Formula F2 with a compound of Formula F3:
in the presence of sodium iodide, isopropanol (IPA), and water to afford a compound of Formula F4:
c) reducing the compound of Formula F4 with sodium borohydride in the presence of methyl tert-butyl ether (MTBE), acetic acid, and methanol to afford a compound of Formula F5:
d) resolving the compound of Formula F5 with (S)-(+)-camphorsulfonic acid (CSA) in ethanol and water to afford a compound of Formula F6-CSA:
e) reacting the compound of Formula F6-CSA with aqueous sodium hydroxide in dichloromethane to afford a compound of Formula F6:
f) coupling the compound of Formula F6 and a carboxylic acid of Formula F7:
with N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC·HCl) in the presence of 4-dimethylaminopyridine (DMAP) and dichloromethane to afford a compound of Formula F8:
g) deprotecting the compound of Formula F8 with a mixture of hydrogen chloride and dioxane in the presence of dichloromethane to afford a compound of Formula F9-HCl:
and
h) reacting the compound of Formula F9-HCl with p-toluenesulfonic acid in a solvent comprising ethyl acetate (EtOAc) to afford the compound of Formula I.
70 . The process according to claim 68 or 69 , wherein after Step g) and before Step h) the process further comprises the steps of:
1) reacting the compound of Formula F9-HCl with aqueous sodium bicarbonate in the presence of a solvent comprising dichloromethane to afford a compound of Formula F9 (free base):
and
2) reacting the compound of Formula F9 (free base) in a solvent comprising acetonitrile with a hydrogen chloride isopropanol mixture to afford the compound of Formula F9-HCl.
71 . The process according to any one of claims 1 to 70 , wherein the compound of Formula I is crystalline.
72 . The process according to any one of claims 1 to 70 , wherein the compound of Formula I is crystalline form I.
73 . A process for preparing a pharmaceutical composition comprising: preparing a compound of Formula I according to any one of claims 1 to 72 , and formulating the compound of Formula I with a pharmaceutically acceptable carrier and/or diluent.
74 . The process for preparing a pharmaceutical composition of claim 73 , wherein the pharmaceutically acceptable carrier and/or diluent comprises silicified microcrystalline cellulose: isomalt: hydroxypropyl methylcellulose: partially pregelatinized maize starch:
and magnesium stearate.
75 . A process for preparing a unit dosage form comprising: preparing a compound of Formula I according to any one of claims 1 to 74 , and formulating the compound of Formula I with a pharmaceutically acceptable carrier and/or diluent.
76 . The process for preparing a unit dosage form of claim 75 , wherein the pharmaceutically acceptable carrier and/or diluent comprises silicified microcrystalline cellulose; isomalt:
hydroxypropyl methylcellulose: partially pregelatinized maize starch; and magnesium stearate.
77 . The process for preparing a unit dosage form of claim 75 or 76 , wherein the compound of Formula I in the unit dosage form is present in an amount ranging from about 20 mg to 160 mg as measured as the free base.
78 . The process for preparing a unit dosage form of claim 75 or 76 , wherein the compound of Formula I in the unit dosage form is present in an amount of 20 mg, 40 mg, 60 mg, 80 mg, or 100 mg as measured as the free base.
79 . The process for preparing a unit dosage form according to any one of claims 75 to 78 , wherein the unit dosage form is suitable for oral administration.
80 . The process for preparing a unit dosage form according to any one of claims 75 to 79 , wherein the unit dosage form is formulated for a once daily dosing.
81 . The process for preparing a unit dosage form according to any one of claims 75 to 80 , wherein the unit dosage form is in a capsule form.
82 . The process for preparing a unit dosage form of claim 81 , wherein the capsule is size 1 or smaller.
83 . The process for preparing a unit dosage form of claim 81 , wherein the capsule is size 1, 2, or 3.
84 . A pharmaceutical composition prepared by the process according to claim 73 or 74 .
85 . A unit dosage form prepared by the process according to any one of claims 75 to 83 .
86 . A method for inhibiting monoamine transporter isoform 2 (VMAT2) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to claim 84 or a unit dosage form according to claim 85 .
87 . A method of treating a neurological or psychiatric disease or disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to claim 84 or a unit dosage form according to claim 85 .
88 . A method of treating a hyperkinetic disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition according to claim 84 or a unit dosage form according to claim 85 .
89 . The use of a pharmaceutical composition according to claim 84 or a unit dosage form according to claim 85 for the manufacture of a medicament for inhibiting monoamine transporter isoform 2 (VMAT2) in a patient in need thereof.
90 . The use of a pharmaceutical composition according to claim 84 or a unit dosage form according to claim 85 for the manufacture of a medicament for treating a neurological or psychiatric disease or disorder in a patient in need thereof.
91 . The use of a pharmaceutical composition according to claim 84 or a unit dosage form according to claim 85 for the manufacture of a medicament for treating a hyperkinetic disorder in a patient in need thereof.