How to synthesize valbenazine

Abstract

The present application relates to a method 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), an inhibitor of vesicular monoamine transporter 2 (VMAT2) useful in the treatment of hyperkinetic disorders such as tardive dyskinesia (TD). Another aspect of the present application provides a method for preparing a pharmaceutical composition, comprising preparing a compound of formula I according to any of the methods described herein and formulating the compound of formula I with a pharma- ceutically acceptable carrier and / or diluent.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present application relates to a method 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), an inhibitor of vesicular monoamine transporter 2 (VMAT2) useful in the treatment of hyperkinetic disorders such as tardive dyskinesia (TD). [Background technology]

[0002] 2. Background of the Invention Hyperkinetic disorders are characterized by an excess of abnormal involuntary movements. These neurological disorders include tremor, dystonia, ballism, tics, akathisia, stereotypies, chorea, myoclonus, and athetosis. The pathophysiology of these movement disorders is poorly understood, but dysregulation of neurotransmitters in the basal ganglia is thought to play an important role (Kenney et al., Expert Review Neurotherapeutics, 2005, 6, 7-17). Continuous and high doses of typical neuroleptic or centrally acting dopamine receptor blocking antiemetics cause patients to develop a delayed syndrome. One subtype of the latter syndrome, tardive dyskinesia, is characterized by rapid, repetitive, stereotyped, involuntary movements of the face, limbs, or trunk (Muller, Expert Opin. Investig. Drugs, 2015, 24, 737-742).

[0003] Reversible inhibition of the vesicular monoamine transporter system 2 (VMAT2) by 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one, also known as tetrabenazine (TBZ), improves the treatment of various hyperkinetic disorders. However, drawbacks of such treatment are variable response, the need for frequent ingestion due to the rapid metabolism of TBZ, and side effects. Side effects associated with TBZ include sedation, depression, akathisia, and parkinsonism.

[0004] Tetrabenazine contains two chiral centers and is a racemic mixture of two stereoisomers that is rapidly and extensively metabolized in vivo to its reduced form, 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, also known as dihydrotetrabenazine (DHTBZ). DHTBZ is believed to exist as four distinct isomers: (±) alpha-DHTBZ and (±) beta-DHTBZ. (2R,3R,11bR) or (+) alpha-DHTBZ is reported to be the absolute configuration of the active metabolite (Kilbourn et al., Chirality, 1997, 9, 59-62). Tetrabenazine has orphan drug status in the United States and is approved in certain European countries. Its use has also been considered for the treatment of chorea in patients with Huntington's disease, but tetrabenazine is rapidly metabolized and must be administered frequently throughout the day (Muller, Expert Opin. Investig. Drugs, 2015, 24, 737-742).

[0005] Ingrezza®, the first FDA approved treatment for patients suffering from tardive dyskinesia, contains valbenazine [(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], present as valbenazine ditosylate. Valbenazine is a potent and selective VMAT2 inhibitor and a prodrug of the (+)-α-isomer of dihydrotetrabenazine, which has been reported to be the most potent of the dihydrotetrabenazine isomers (binding affinity, K reported by Kilbourn et al., Chirality, 1997, 9, 59-62). i = 0.97 nM; and absolute configuration). Valbenazine ditosylate is referred to herein as the compound of formula I. Methods for synthesizing (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 are described, for example, in WO 2008 / 058261, WO 2017 / 112857, and WO 2021 / 050977, each of which is incorporated herein by reference in its entirety. Certain salts and crystalline forms of valbenazine are described in WO 2017 / 075340, and certain formulations of valbenazine are also described in WO 2019 / 060322, each of which is incorporated herein by reference in its entirety. The high demand and usefulness of Ingrezza® necessitates the development of new methods for its manufacture, particularly more environmentally friendly methods. This application addresses this need and others. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] International Publication No. 2008 / 058261 [Patent Document 2] International Publication No. 2017 / 112857 [Patent Document 3] International Publication No. 2021 / 050977 [Patent Document 4] International Publication No. 2017 / 075340 [Patent Document 5] International Publication No. 2019 / 060322 [Non-patent literature]

[0007] [Non-Patent Document 1] Kenney et al., Expert Review Neurotherapeutics, 2005, 6, 7-17 [Non-Patent Document 2] Muller, Expert Opin. Investig. Drugs, 2015, 24, 737-742 [Non-Patent Document 3] Kilbourn et al., Chirality, 1997, 9, 59-62 Summary of the Invention [Means for solving the problem]

[0008] Summary of the Invention The present invention relates, inter alia, to methods useful in the preparation of (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) (the compound of formula I), intermediates related thereto, and crystalline forms.

[0009] One aspect of the invention is, inter alia, a particular method of preparing a compound of formula I, comprising the steps of: [ka] a) reacting a compound of formula F1 with [ka] Step a) - reacting with a base to obtain a compound of formula F2; [ka] b) cyclizing a compound of formula F2 with a compound of formula F3 in the presence of sodium iodide, [ka] obtaining a compound of formula F4; [ka] c) reducing the compound of formula F4 with a reducing agent to obtain a compound of formula F5; [ka] d) resolving the compound of formula F5 using (S)-(+)-camphorsulfonic acid (CSA) to obtain a compound of formula F6-CSA; [ka] e) reacting the compound of formula F6-CSA with step e)-base to obtain a compound of formula F6; [ka] f) coupling a compound of formula F6 and a carboxylic acid of formula F7 using a coupling reagent, [ka] obtaining a compound of formula F8; [ka] g) deprotecting the compound of formula F8 using hydrogen chloride to obtain a compound of formula F9-HCl; [ka] h) reacting the compound of formula F9-HCl with step h)-base to obtain the compound of formula F9 (free base); [ka] i) reacting a compound of formula F9 with p-toluenesulfonic acid to obtain a compound of formula I; The present invention encompasses a method comprising the steps of:

[0010] Another aspect of the present application provides a method of preparing a pharmaceutical composition, the method comprising preparing a compound of formula I according to any of the methods described herein and formulating the compound of formula I with a pharma- ceutically acceptable carrier and / or diluent.

[0011] Another aspect of the application provides a method of preparing a unit dosage form, the method comprising the steps of preparing a compound of formula I according to any of the methods described herein and formulating the compound of formula I with a pharma- ceutically acceptable carrier and / or diluent.

[0012] In some embodiments, the compound of formula I is crystalline.In some embodiments, the compound of formula I is crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V, crystalline form VI, or amorphous solid as described in International Publication No. 2017 / 075340, which is incorporated herein by reference in its entirety.In some embodiments, the crystalline compound of formula I is form I.

[0013] Another aspect of the application provides a pharmaceutical composition prepared by any of the processes described herein.

[0014] Another aspect of the application provides a unit dosage form prepared by any of the processes described herein.

[0015] Another aspect of the present application provides a method of 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 or unit dosage form, wherein the pharmaceutical composition and unit dosage form can be prepared according to any of the methods described herein.

[0016] Another aspect of the application provides 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 or unit dosage form, wherein the pharmaceutical composition and unit dosage form can be prepared according to any of the methods described herein.

[0017] Another aspect of the application provides a method of treating hyperactivity disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or unit dosage form, wherein the pharmaceutical composition and unit dosage form can be prepared according to any of the methods described herein.

[0018] Another aspect of the present application provides the use of a pharmaceutical composition or unit dosage form for the manufacture of a medicament for inhibiting monoamine transporter isoform 2 (VMAT2) in a patient in need thereof, wherein the pharmaceutical composition and unit dosage form can be prepared according to any of the methods described herein.

[0019] Another aspect of the present application provides the use of a pharmaceutical composition or unit dosage form for the manufacture of a medicament for treating a neurological or psychiatric disease or disorder in a patient in need thereof, wherein the pharmaceutical composition and unit dosage form may be prepared according to any of the methods described herein.

[0020] Another aspect of the present application provides the use of a pharmaceutical composition or unit dosage form for the manufacture of a medicament for treating hyperactivity disorder in a patient in need thereof, wherein the pharmaceutical composition and unit dosage form can be prepared according to any of the methods described herein.

[0021] These and other aspects of the invention disclosed herein will be described in more detail as the patent disclosure proceeds. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 shows a general synthetic scheme for the preparation of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (S)-(+)-camphorsulfonate (compound of formula F6-CSA) from 3-((dimethylamino)methyl)-5-methylhexan-2-one oxalate (compound of formula F1).

[0023] [Diagram 2] FIG. 2 shows a general synthetic scheme 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) (compound of formula I) from (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (S)-(+)-camphorsulfonate (compound of formula F6-CSA), which may be prepared according to any of the methods described herein.

[0024] [Diagram 3]FIG. 3 shows a general synthetic scheme for the preparation of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (S)-(+)-camphorsulfonate (compound of formula F6-CSA) from 3-((dimethylamino)methyl)-5-methylhexan-2-one oxalate (compound of formula F1).

[0025] [Figure 4] FIG. 4 shows a general synthetic scheme 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) (compound of formula I) from (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (S)-(+)-camphorsulfonate (compound of formula F6-CSA), which may be prepared according to any of the methods described herein.

[0026] [Diagram 5] FIG. 5 shows a general synthetic scheme 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) (compound of formula I) from (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (S)-(+)-camphorsulfonate (compound of formula F6-CSA), which may be prepared according to any of the methods described herein.

[0027] [Figure 6]FIG. 6 shows a general synthetic scheme 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) (compound of formula I) from (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 dihydrochloride (compound of formula F9-HCl), which may be prepared according to any of the methods described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0028] Detailed Description of the Invention One aspect of the invention is, inter alia, a particular method of preparing a compound of formula I, comprising the steps of: [ka] a) reacting a compound of formula F1 with [ka] Step a) - reacting with a base to obtain a compound of formula F2; [ka] b) cyclizing a compound of formula F2 with a compound of formula F3 in the presence of sodium iodide; [ka] obtaining a compound of formula F4; [ka] c) reducing the compound of formula F4 with a reducing agent to obtain a compound of formula F5; [ka] d) resolving the compound of formula F5 using (S)-(+)-camphorsulfonic acid (CSA) to obtain a compound of formula F6-CSA; [ka] e) reacting the compound of formula F6-CSA with step e)-base to obtain a compound of formula F6; [ka] f) coupling a compound of formula F6 and a carboxylic acid of formula F7 using a coupling reagent, [ka] obtaining a compound of formula F8; [ka] g) deprotecting the compound of formula F8 using hydrogen chloride to obtain a compound of formula F9-HCl; [ka] h) reacting the compound of formula F9-HCl with step h)-base to obtain the compound of formula F9 (free base); [ka] i) reacting a compound of formula F9 with p-toluenesulfonic acid to obtain a compound of formula I; The present invention provides a method comprising:

[0029] Step a)—Method for preparing 3-((dimethylamino)methyl)-5-methylhexan-2-one (compound of formula F2)

[0030] In some embodiments, the compound of formula F2 is prepared by a method described herein comprising step a)-reacting a compound of formula F1 with a base to obtain a compound of formula F2. [ka]

[0031] In some embodiments, the reaction of the compound of formula F1 with step a)-base is carried out in the presence of a step a)-solvent. The step a)-solvent can be any suitable solvent. In some embodiments, the reaction of the compound of formula F1 with step a)-base is carried out in the presence of a step a)-solvent comprising methyl tert-butyl ether (MTBE). In some embodiments, the reaction of the compound of formula F1 with step a)-base is carried out in the presence of methyl tert-butyl ether (MTBE).

[0032] In some embodiments, the step a)-solvent is a mixture of solvents. In some embodiments, the reaction of the compound of formula F1 with step a)-base is carried out in the presence of a step a)-solvent comprising water and an organic solvent. In some embodiments, the mixture of solvents comprises water and an ether solvent. In some embodiments, the reaction of the compound of formula F1 with step a)-base is carried out in the presence of a step a)-solvent comprising water and methyl tert-butyl ether (MTBE).

[0033] In some embodiments, the volume ratio of water to MTBE prior to step a)-reacting with base is about 1:1 to about 4:1. In some embodiments, the volume ratio of water to MTBE prior to step a)-reacting with base is about 1.3:1 to about 3.5:1. In some embodiments, the volume ratio of water to MTBE prior to step a)-reacting with base is about 1.8:1 to about 3:1. In some embodiments, the volume ratio of water to MTBE prior to step a)-reacting with base is about 2.0:1 to about 2.8:1. In some embodiments, the volume ratio of water to MTBE prior to step a)-reacting with base is about 2.3:1 to about 2.5:1. In some embodiments, the volume ratio of water to MTBE prior to step a)-reacting with base is about 2.35:1 to about 2.45:1. In some embodiments, the volume ratio of water to MTBE is 2.4:1.

[0034] In some embodiments, the step a)-base comprises an inorganic base. In some embodiments, the step a)-base is a carbonate, bicarbonate, or hydroxide base. In other embodiments, the step a)-base is sodium carbonate. In some embodiments, the step a)-base is potassium hydroxide. In some embodiments, the step a)-base is an aqueous potassium hydroxide solution. In some embodiments, the step a)-base is an 8 wt% to 12 wt% potassium hydroxide solution. In some embodiments, the step a)-base is a 10 wt% potassium hydroxide solution.

[0035] In some embodiments, the reaction of the compound of formula F1 with step a)-base is carried out at a pH of about 10 to about 12. In some embodiments, the reaction of the compound of formula F1 with step a)-base is carried out at a pH of about 11.

[0036] In some embodiments, the compound of formula F2 is not isolated. Accordingly, in some embodiments, the reaction of the compound of formula F1 with step a)-base is carried out in the presence of a step a)-solvent, which is removed after completion of the reaction and replaced with a cyclization step solvent described in step b) (e.g., isopropanol (IPA)). In some embodiments, the reaction of the compound of formula F1 with step a)-base is carried out in the presence of a step a)-solvent, which is removed after completion of the reaction (i.e., the formation of the compound of formula F2) and replaced with a cyclization step solvent described in step b) (e.g., a mixture of isopropanol (IPA) and water).

[0037] Step b) - Method for preparing 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (compound of formula F4)

[0038] In some embodiments, the compound of formula F4 is prepared by a method described herein comprising the step of cyclizing a compound of formula F2 (e.g., prepared as described in step a)) and a compound of formula F3 in the presence of sodium iodide to obtain a compound of formula F4.

[0039] [ka]

[0040] In some embodiments, the molar ratio of sodium iodide to the compound of formula F3 is about 0.1:1 to 1:1. In some embodiments, the molar ratio of sodium iodide to the compound of formula F3 is about 0.1:1 to 0.5:1. In some embodiments, the molar ratio of sodium iodide to the compound of formula F3 is about 0.2:1 to 0.8:1. In some embodiments, the molar ratio of sodium iodide to the compound of formula F3 is about 0.2:1 to 0.6:1. In some embodiments, the molar ratio of sodium iodide to the compound of formula F3 is about 0.25:1 to 0.55:1. In some embodiments, the molar ratio of sodium iodide to the compound of formula F3 is about 0.3:1 to 0.5:1. In some embodiments, the molar ratio of sodium iodide to the compound of formula F3 is about 0.35:1 to 0.45:1. In some embodiments, the molar ratio of sodium iodide to the compound of Formula F3 is about 0.4:1.

[0041] In some embodiments, the cyclization of the compound of formula F2 with the compound of formula F3 in the presence of sodium iodide in step b) is carried out in a cyclization step solvent. The cyclization step solvent can be any suitable solvent. In some embodiments, the cyclization of the compound of formula F2 with the compound of formula F3 in the presence of sodium iodide in step b) is carried out in a cyclization step solvent comprising isopropanol (IPA) and water. In some embodiments, the cyclization of the compound of formula F2 with the compound of formula F3 in the presence of sodium iodide in step b) is carried out in isopropanol (IPA) and water.

[0042] In some embodiments, the volume ratio of IPA to water is about 1:1 to about 10:1. In some embodiments, the volume ratio of IPA to water is about 1:1 to about 5:1. In some embodiments, the volume ratio of IPA to water is about 1:1 to about 3:1. In some embodiments, the volume ratio of IPA to water is about 2:1 to about 3:1. In some embodiments, the volume ratio of IPA to water is about 2:1 to about 2.6:1. In some embodiments, the volume ratio of IPA to water is about 2.1:1 to about 2.5:1. In some embodiments, the volume ratio of IPA to water is about 2.2:1 to about 2.4:1. In some embodiments, the volume ratio of IPA to water is about 2.25:1 to about 2.35:1. In some embodiments, the volume ratio of IPA to water is about 2.3:1.

[0043] In some embodiments, the cyclization of the compound of formula F2 with the compound of formula F3 in the presence of sodium iodide in step b) is carried out at an elevated temperature (i.e., a temperature above ambient temperature). In some embodiments, the cyclization of the compound of formula F2 with the compound of formula F3 is carried out at a temperature ranging from about 20° C. to about 60° C. In some embodiments, the cyclization of the compound of formula F2 with the compound of formula F3 is carried out at a temperature ranging from about 25° C. to about 50° C. In some embodiments, the cyclization of the compound of formula F2 with the compound of formula F3 is carried out at a temperature ranging from about 30° C. to about 45° C. In some embodiments, the cyclization of the compound of formula F2 with the compound of formula F3 is carried out at a temperature ranging from about 35° C. to about 45° C. In some embodiments, the cyclization of the compound of formula F2 with the compound of formula F3 is carried out at a temperature ranging from about 36° C. to about 48° C. In some embodiments, the cyclization of the compound of formula F2 with the compound of formula F3 is carried out at a temperature ranging from about 39° C. to about 45° C. In some embodiments, the cyclization of the compound of formula F2 with the compound of formula F3 is carried out at a temperature ranging from about 41° C. to about 43° C. In some embodiments, the cyclization of the compound of formula F2 with the compound of formula F3 is carried out at a temperature of about 42° C.

[0044] In some embodiments, the cyclization of the compound of formula F2 with the compound of formula F3 is carried out for about 24 hours or more. In some embodiments, the cyclization of the compound of formula F2 with the compound of formula F3 is carried out for about 24 hours.

[0045] Step c) - Method for preparing 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (compound of formula F5)

[0046] In some embodiments, the compound of formula F5 is prepared by a method described herein that includes reducing a compound of formula F4 (e.g., prepared as described in step b)) with a reducing agent to obtain a compound of formula F5. [ka]

[0047] In some embodiments, the reduction of the compound of formula F4 in step c) with a reducing agent is carried out in a reduction step solvent. The reduction step solvent can be any suitable solvent. In some embodiments, the reduction of the compound of formula F4 in step c) with a reducing agent is carried out in a reduction step solvent comprising methyl tert-butyl ether (MTBE) and methanol. In some embodiments, the reduction of the compound of formula F4 in step c) with a reducing agent is carried out in methyl tert-butyl ether (MTBE) and methanol.

[0048] In some embodiments, the volume ratio of MTBE to methanol is about 1:1 to about 10:1. In some embodiments, the volume ratio of MTBE to methanol is about 1:1 to about 5:1. In some embodiments, the volume ratio of MTBE to methanol is about 3:1 to about 7:1. In some embodiments, the volume ratio of MTBE to methanol is about 3:1 to about 5:1. In some embodiments, the volume ratio of MTBE to methanol is about 4.4:1.

[0049] In some embodiments, the reduction of the compound of formula F4 with a reducing agent in step c) is carried out in the presence of an organic acid. In some embodiments, the acid is acetic acid, formic acid, oxalic acid, maleic acid, lactic acid, ascorbic acid, mandelic acid, or a mixture thereof. In some embodiments, the organic acid is acetic acid.

[0050] In some embodiments, the solvent comprising methyl tert-butyl ether (MTBE) and methanol further comprises an acid. In some embodiments, the acid comprises acetic acid. In some embodiments, the acid is acetic acid.

[0051] In some embodiments, the acetic acid is present in excess (on a molar basis) relative to the compound of formula F4.

[0052] In some embodiments, the reduction of 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.

[0053] In some embodiments, the molar ratio of acetic acid to the compound of formula F4 is about 0.5 to about 1.5. In some embodiments, the molar ratio of acetic acid to the compound of formula F4 is about 0.8 to about 1.3. In some embodiments, the molar ratio of acetic acid to the compound of formula F4 is about 0.9 to about 1.2. In some embodiments, the molar ratio of acetic acid to the compound of formula F4 is about 1.0 to about 1.2. In some embodiments, the molar ratio of acetic acid to the compound of formula F4 is about 1.1.

[0054] In some embodiments, the reducing agent is added to the compound of formula F4 as a slurry in MTBE. In some embodiments, the reducing agent is added to the compound of formula F4 as a solid. In some embodiments, the reducing agent is a borohydride reducing agent. In some embodiments, the reducing agent is borohydride. In some embodiments, the reducing agent is sodium borohydride, lithium borohydride, calcium borohydride, magnesium borohydride, potassium borohydride, 9-BBN, cyanoborohydride, bis-triphenylphosphine borohydride, sodium triethylborohydride, tetrabutylammonium borohydride, tetramethylammonium borohydride, tetraethylammonium borohydride, or lithium triethylborohydride.

[0055] In some embodiments, the reducing agent in step c) is sodium borohydride.

[0056] In some embodiments, the molar ratio of sodium borohydride to the compound of formula F4 is about 1.0 to about 10.0. In some embodiments, the molar ratio of sodium borohydride to the compound of formula F4 is about 1.0 to about 5.0. In some embodiments, the molar ratio of sodium borohydride to the compound of formula F4 is about 1.0 to about 3.0. In some embodiments, the molar ratio of sodium borohydride to the compound of formula F4 is about 1.5 to about 2.5. In some embodiments, the molar ratio of sodium borohydride to the compound of formula F4 is about 1.8 to about 2.2. In some embodiments, the molar ratio of sodium borohydride to the compound of formula F4 is about 1.9 to about 2.1. In some embodiments, the molar ratio of sodium borohydride to the compound of formula F4 is about 2.0.

[0057] In some embodiments, the reduction of compound of formula F4 with a reducing agent in step c) is carried out at a temperature of about -5°C to about -15°C, about -5°C to about -10°C, about -5°C to about 0°C, about 0°C to about 5°C, about 0 to about 10°C, about 0°C to about 15°C, about 0°C to about 25°C, about 0°C to about 30°C, about 5°C to about 30°C, about 10°C to about 30°C, about 20°C to about 30°C, about 20°C to about 25°C, about 20°C to about 24°C, and about 21°C to about 23°C during the addition of the reducing agent.

[0058] In some embodiments, the reduction of the compound of formula F4 in step c) with the reducing agent is carried out at a temperature of about 25° C. after the addition of the reducing agent. In some embodiments, the reduction of the compound of formula F4 in step c) is carried out for about 2 hours after the addition of the reducing agent. In some embodiments, the reduction of the compound of formula F4 in step c) is carried out at a temperature in the range of about 15° C. to about 30° C. for at least 1.5 hours after the addition of the reducing agent. In some embodiments, the reduction of the compound of formula F4 in step c) is carried out at a temperature in the range of about 15° C. to about 30° C. for about 1 hour to about 3 hours after the addition of the reducing agent. In some embodiments, the reduction of the compound of formula F4 in step c) is carried out at a temperature in the range of about 18° C. to about 28° C. for about 1.5 hours to about 2.5 hours after the addition of the reducing agent. In some embodiments, the reduction of the compound of formula F4 in step c) is carried out at a temperature in the range of about 20° C. to about 28° C. for about 1.8 hours to about 2.2 hours after the addition of the reducing agent.

[0059] In some embodiments, lithium chloride is not present in the reaction of the compound of Formula F4 with the reducing agent in step c).

[0060] Step d) - Method for preparing (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (S)-(+)-camphorsulfonate (compound of formula F6-CSA)

[0061] In some embodiments, the compound of formula F6-CSA is prepared by a method described herein comprising resolving a compound of formula F5 (e.g., prepared as described in step c)) with (S)-(+)-camphorsulfonic acid (CSA) to obtain a compound of formula F6-CSA. [ka]

[0062] In some embodiments, the molar ratio of CSA to the compound of formula F5 is about 0.6:1 to about 1:1. In some embodiments, the molar ratio of CSA to the compound of formula F5 is about 0.66:1 to about 0.99:1. In some embodiments, the molar ratio of CSA to the compound of formula F5 is about 0.70:1 to about 0.95:1. In some embodiments, the molar ratio of CSA to the compound of formula F5 is about 0.74:1 to about 0.91:1. In some embodiments, the molar ratio of CSA to the compound of formula F5 is about 0.76:1 to about 0.89:1. In some embodiments, the molar ratio of CSA to the compound of formula F5 is about 0.78:1 to about 0.87:1. In some embodiments, the molar ratio of CSA to the compound of formula F5 is about 0.80:1 to about 0.85:1. In some embodiments, the molar ratio of CSA to the compound of formula F5 is from about 0.81:1 to about 0.84:1.

[0063] In some embodiments, the resolution of the compound of formula F5 in step d) with (S)-(+)-camphorsulfonic acid (CSA) is carried out in a resolution step solvent. The resolution step solvent can be any suitable solvent. In some embodiments, the resolution of the compound of formula F5 in step d) with (S)-(+)-camphorsulfonic acid (CSA) is carried out in a resolution step solvent comprising alcohol and water. In some embodiments, the resolution of the compound of formula F5 in step d) with (S)-(+)-camphorsulfonic acid (CSA) is carried out in a resolution step solvent comprising ethanol and water. In some embodiments, the resolution of the compound of formula F5 in step d) with (S)-(+)-camphorsulfonic acid (CSA) is carried out in ethanol and water.

[0064] In some embodiments, the splitting step solvent comprises water and ethanol in a volume ratio of water to ethanol of about 1:5 to about 1:25. In some embodiments, the splitting step solvent comprises water and ethanol in a volume ratio of water to ethanol of about 1:10 to about 1:20. In some embodiments, the splitting step solvent comprises water and ethanol in a volume ratio of water to ethanol of about 1:14 to about 1:18. In some embodiments, the splitting step solvent comprises water and ethanol in a volume ratio of water to ethanol of about 1:15 to about 1:17. In some embodiments, the splitting step solvent comprises water and ethanol in a volume ratio of water to ethanol of about 1:15.5 to about 1:16.5. In some embodiments, the splitting step solvent comprises water and ethanol in a volume ratio of water to ethanol of about 1:16.

[0065] In some embodiments, the resolution step solvent is about 10 to about 14 volumes of ethanol and about 0.5 to about 1.0 volumes of water. In some embodiments, the resolution step solvent is about 11 to about 13 volumes of ethanol and about 0.65 to about 0.85 volumes of water. In some embodiments, the resolution step solvent comprises about 12 volumes of ethanol and about 0.75 volumes of water.

[0066] In some embodiments, the resolution of the compound of formula F5 with (S)-(+)-camphorsulfonic acid (CSA) in step d) is carried out at a temperature in the range of about 55° C. to about 78° C., about 60° C. to about 75° C., about 65° C. to about 73° C., about 67° C. to about 72° C., or about 69° C. to about 71° C. In some embodiments, the resolution of the compound of formula F5 is carried out at a temperature of about 70° C.

[0067] In some embodiments, the resolution of the compound of formula F5 further comprises the steps of 1) heating to a first temperature in the presence of CSA and 2) cooling to a second temperature. In some embodiments, the first temperature is a temperature in the range of about 55°C to about 78°C, about 60°C to about 75°C, about 65°C to about 73°C, about 67°C to about 72°C, or about 69°C to about 71°C. In some embodiments, the second temperature is a temperature in the range of about 10°C to about 32°C, about 12°C to about 30°C, about 15°C to about 28°C, about 18°C ​​to about 26°C, or about 20°C to about 24°C. In some embodiments, the cooling step is performed at a rate in the range of about 2°C / hr to about 4°C / hr. In some embodiments, the cooling step is performed at a rate of about 3°C / hr.

[0068] In some embodiments, the reaction mixture of formula F5 and CSA is cooled to about 22° C. In some embodiments, the reaction mixture is seeded with crystals of a compound of formula F6-CSA. In some embodiments, the compound of formula F6-CSA is vacuum dried at an elevated temperature (i.e., greater than 25° C.). In some embodiments, the compound of formula F6-CSA is vacuum dried at about 45° C. for 12 hours or more.

[0069] In some embodiments, the compound of formula F6-CSA prepared from step d) has an optical purity of about 95% or more, about 96% or more, about 97% or more, about 97.5% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.1% or more, about 99.2% or more, about 99.3% or more, about 99.4% or more, about 99.5% or more, about 99.6% or more, about 99.7% or more, about 99.8% or more, or about 99.9% or more. In some embodiments, the compound of formula F6-CSA has an optical purity of about 99% or more.

[0070] Step e) - Method for preparing (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (compound of formula F6, free base)

[0071] In some embodiments, the compound of formula F6 is prepared by a method described herein comprising step e) reacting a compound of formula F6-CSA (e.g., prepared as described in step d)) with a base to obtain a compound of formula F6. [ka]

[0072] In some embodiments, the step e)-base is an inorganic base. In some embodiments, the step e)-base is sodium bicarbonate, sodium carbonate, sodium citrate, sodium hydroxide, or potassium hydroxide. In some embodiments, the step e)-base is potassium hydroxide. In some embodiments, the step e)-base is aqueous potassium hydroxide. In some embodiments, the step e)-base is 2N aqueous potassium hydroxide. In some embodiments, the step e)-base is sodium hydroxide. In some embodiments, the step e)-base is aqueous sodium hydroxide. In some embodiments, the step e)-base is 1N aqueous sodium hydroxide.

[0073] In some embodiments, the reaction of the compound of formula F6-CSA with step e)-base is carried out in the presence of a step e)-solvent. The step e)-solvent can be any suitable solvent. In some embodiments, the step e)-solvent is a solvent comprising a hydrocarbon, a chlorinated hydrocarbon, an alcohol, an ether, an ester, a carbonate, an amide, a nitrile, a sulfoxide, a sulfone, a nitro compound, a heteroarenes, a heterocycle, water, or a mixture thereof. In some embodiments, the step e)-solvent is a chlorinated hydrocarbon solvent. In some embodiments, the step e)-solvent is an ether. In some embodiments, the step e)-solvent is a cycloalkyl ether. In some embodiments, the step e)-solvent is 2-methyltetrahydrofuran (MeTHF). In some embodiments, the step e)-solvent comprises water and a halogenated hydrocarbon solvent. In some embodiments, the halogenated hydrocarbon solvent is dichloromethane.

[0074] In some embodiments, the reaction of the compound of formula F6-CSA with step e)-base is carried out in the presence of a step e)-solvent comprising 2-methyltetrahydrofuran (MeTHF). In some embodiments, the reaction of the compound of formula F6-CSA with step e)-base is carried out in the presence of 2-methyltetrahydrofuran (MeTHF). In some embodiments, the reaction of the compound of formula F6-CSA with step e)-base is carried out in the presence of 2-methyltetrahydrofuran (MeTHF) and the step e)-base is potassium hydroxide. In some embodiments, the reaction of the compound of formula F6-CSA with step e)-base is carried out in the presence of 2-methyltetrahydrofuran (MeTHF) and the step e)-base is aqueous potassium hydroxide. In some embodiments, the reaction of the compound of formula F6-CSA with step e)-base is carried out in the presence of 2-methyltetrahydrofuran (MeTHF) and the step e)-base is 2N aqueous potassium hydroxide.

[0075] In some embodiments, the reaction of the compound of formula F6-CSA with step e)-base is carried out in the presence of 2-methyltetrahydrofuran (MeTHF) and water.

[0076] In some embodiments, the reaction of the compound of formula F6-CSA with step e)-base is carried out in the presence of a step e)-solvent comprising dichloromethane. In some embodiments, the reaction of the compound of formula F6-CSA with step e)-base is carried out in the presence of dichloromethane. In some embodiments, the reaction of the compound of formula F6-CSA with step e)-base is carried out in the presence of dichloromethane, and the step e)-base is sodium hydroxide. In some embodiments, the reaction of the compound of formula F6-CSA with step e)-base is carried out in the presence of dichloromethane, and the step e)-base is aqueous sodium hydroxide. In some embodiments, the reaction of the compound of formula F6-CSA with step e)-base is carried out in the presence of dichloromethane, and the step e)-base is aqueous 1N sodium hydroxide. In some embodiments, the step e)-base is 1N sodium hydroxide.

[0077] In some embodiments, the reaction of the compound of formula F6-CSA with step e)-base is carried out in the presence of a step e)-solvent comprising dichloromethane and water.

[0078] In some embodiments, the reaction of the compound of formula F6-CSA with step e)-base is carried out in the presence of dichloromethane. In some embodiments, the reaction of the compound of formula F6-CSA with step e)-base is carried out in the presence of dichloromethane and water.

[0079] In some embodiments, the reaction of the compound of formula F6-CSA with step e)-base is carried out at a temperature ranging from about 20°C to about 30°C, from about 21°C to about 29°C, from about 22°C to about 28°C, from about 23°C to about 27°C, from about 24°C to about 26°C, or at about 25°C.

[0080] In some embodiments, the compound of formula F6 is not isolated. Accordingly, in some embodiments, the reaction of the compound of formula F6-CSA with step e)-base is carried out in the presence of step e)-solvent, and after completion of the reaction, the mixture of the compound of formula F6 and step e)-solvent is used directly in step f). In some embodiments, the step e)-solvent is dichloromethane. In some embodiments, the step e)-solvent is 2-methyltetrahydrofuran (MeTHF).

[0081] Step f) - Method 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-((tert-butoxycarbonyl)amino)-3-methylbutanoate (compound of formula F8)

[0082] In some embodiments, the compound of formula F8 is prepared by a method described herein comprising coupling a compound of formula F6 (e.g., prepared as described in step e)) and a carboxylic acid of formula F7 with a coupling reagent to obtain a compound of formula F8. [ka]

[0083] In some embodiments, the coupling of the compound of formula F6 and the carboxylic acid of formula F7 with a coupling reagent in step f) is carried out in the presence of a coupling step base. In some embodiments, the coupling step base is an organic base.

[0084] In some embodiments, the coupling of the compound of formula F6 and the 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). In some embodiments, the coupling of the compound of formula F6 and the carboxylic acid of formula F7 with a coupling reagent in step f) is carried out in the presence of 4-dimethylaminopyridine (DMAP).

[0085] In some embodiments, the coupling step base is present in a catalytic amount (i.e., less than the molar amount of the compound of formula F6). In some embodiments, the molar ratio of the coupling step base to the compound of formula F6 is about 0.6:1.0, about 0.5:1.0, about 0.4:1.0, about 0.3:1.0, about 0.27:1.0, or about 0.25:1.0. In some embodiments, the molar ratio of 4-dimethylaminopyridine (DMAP) to the compound of formula F6 is about 0.6:1.0, about 0.5:1.0, about 0.4:1.0, about 0.3:1.0, about 0.27:1.0, or about 0.25:1.0.

[0086] In some embodiments, the coupling of the compound of formula F6 and the carboxylic acid of formula F7 with a coupling reagent in step f) is carried out in the presence of a coupling step solvent. The coupling step solvent can be any suitable solvent. In some embodiments, the coupling step solvent is a hydrocarbon, a chlorinated hydrocarbon, an alcohol, an ether, an ester, a carbonate, an amide, a nitrile, a sulfoxide, a sulfone, a nitro compound, a heteroarene, a heterocycle, water, or a mixture thereof. In some embodiments, the solvent is a chlorinated hydrocarbon solvent. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is an ether. In some embodiments, the solvent is a cycloalkyl ether. In some embodiments, the solvent is 2-methyltetrahydrofuran (MeTHF).

[0087] In some embodiments, the coupling of the compound of formula F6 and the 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. In some embodiments, the coupling of the compound of formula F6 and the carboxylic acid of formula F7 with a coupling reagent in step f) is carried out in the presence of dichloromethane. In some embodiments, the coupling of the compound of formula F6 and the 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). In some embodiments, the coupling of the compound of formula F6 and the carboxylic acid of formula F7 with a coupling reagent in step f) is carried out in the presence of 2-methyltetrahydrofuran (MeTHF).

[0088] In some embodiments, the coupling reagent is a carbodiimide, 1,1'-carbonyldiimidazole (CDI), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), hexafluorophosphate (BOP reagent), PCh, PCl, or 1-propanephosphonic acid cyclic anhydride. In some embodiments, the coupling reagent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC or EDCI), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC hydrochloride), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC methiodide), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate, or 1,3-dicyclohexylcarbodiimide (DCC). In some embodiments, the coupling reagent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC or EDCI), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC hydrochloride), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC methiodide), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate, or 1,3-dicyclohexycarbodiimide (DCC).

[0089] In some embodiments, the coupling reagent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC or EDCI). In some embodiments, the coupling reagent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC·HCl).

[0090] In some embodiments, the coupling of a compound of formula F6 and a carboxylic acid of formula F7 is carried out at a temperature less than about 25° C. In some embodiments, the coupling of a compound of formula F6 and a carboxylic acid of formula F7 is carried out at a temperature in the range of about −10° C. to about 30° C., about −10° C. to about 25° C., about −5° C. to about 20° C., about −5° C. to about 15° C., about −5° C. to about 10° C., or about −1° C. to about 25° C.

[0091] Step g) - Method 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 dihydrochloride (compound of formula F9-HCl)

[0092] In some embodiments, the compound of formula F9-HCl is prepared by a method described herein comprising the step of deprotecting a compound of formula F8 (e.g., prepared as described in step f)) with hydrogen chloride to obtain a compound of formula F9-HCl. [ka]

[0093] In some embodiments, the hydrogen chloride in step g) is hydrogen chloride gas. In some embodiments, the hydrogen chloride in step g) is an aqueous hydrogen chloride solution (i.e., hydrochloric acid). In some embodiments, the hydrogen chloride in step g) is a mixture of hydrogen chloride and any suitable organic solvent. In some embodiments, the hydrogen chloride in step g) comprises a hydrogen chloride isopropanol (IPA) mixture. In some embodiments, the hydrogen chloride in step g) is a hydrogen chloride isopropanol (IPA) mixture. In some embodiments, the hydrogen chloride in step g) is a 3.7 M hydrogen chloride isopropanol (IPA) mixture. In some embodiments, the hydrogen chloride in step g) is a 3.7 M hydrogen chloride in isopropanol (IPA) solution. In some embodiments, the hydrogen chloride in step g) comprises a hydrogen chloride dioxane mixture. In some embodiments, the hydrogen chloride in step g) is a hydrogen chloride dioxane mixture. In some embodiments, the hydrogen chloride in step g) is a 4 M hydrogen chloride dioxane mixture. In some embodiments, the hydrogen chloride in step g) is a 4 M hydrogen chloride in dioxane solution. In some embodiments, the hydrogen chloride in step g) is substantially anhydrous.

[0094] In some embodiments, the deprotection of the compound of formula F8 with hydrogen chloride in step g) is carried out in a deprotection step solvent. The deprotection step solvent can be any suitable solvent. In some embodiments, the deprotection of the compound of formula F8 with hydrogen chloride in step g) is carried out in a deprotection step solvent comprising dichloromethane. In some embodiments, the deprotection of the compound of formula F8 with hydrogen chloride in step g) is carried out in a deprotection step solvent comprising 2-methyltetrahydrofuran (MeTHF). In some embodiments, the deprotection of the compound of formula F8 with hydrogen chloride in step g) is carried out in a deprotection step solvent comprising ethyl acetate (EtOAc). In some embodiments, the deprotection of the compound of formula F8 with hydrogen chloride in step g) is carried out in a deprotection step solvent comprising 2-methyltetrahydrofuran (MeTHF) and ethyl acetate (EtOAc). In some embodiments, the deprotection of the compound of formula F8 with hydrogen chloride in step g) is carried out in dichloromethane. In some embodiments, the deprotection of the compound of formula F8 with hydrogen chloride in step g) is carried out in methyl tert-butyl ether (MTBE). In some embodiments, the deprotection of the compound of formula F8 with hydrogen chloride in step g) is carried out in methyl tert-butyl ether (MTBE) and ethyl acetate (EtOAc). In some embodiments, the deprotection of the compound of formula F8 with hydrogen chloride in step g) is carried out in dichloromethane and dioxane. In some embodiments, the deprotection of the compound of formula F8 with hydrogen chloride in step g) is carried out in dichloromethane and isopropanol. In some embodiments, the deprotection of the compound of formula F8 with hydrogen chloride in step g) is carried out in 2-methyltetrahydrofuran (MeTHF) and dioxane. In some embodiments, the deprotection of the compound of formula F8 with hydrogen chloride in step g) is carried out in 2-methyltetrahydrofuran (MeTHF) and dioxane. In some embodiments, the deprotection of the compound of formula F8 with hydrogen chloride in step g) is carried out in 2-methyltetrahydrofuran (MeTHF) and isopropanol. In some embodiments, the deprotection of the compound of formula F8 with hydrogen chloride in step g) is carried out in 2-methyltetrahydrofuran (MeTHF), ethyl acetate (EtOAc), and dioxane.In some embodiments, the deprotection of the compound of formula F8 with hydrogen chloride in step g) is carried out in 2-methyltetrahydrofuran (MeTHF), ethyl acetate (EtOAc), and isopropanol.

[0095] In some embodiments, step g) further comprises a "solvent exchange", where the solvent used in the deprotection of the compound of formula F8 is different from the solvent that results in the isolated compound of formula F9-HCl. It is understood that after deprotection with hydrogen chloride, the compound of formula F9-HCl is formed first and can be isolated as is or subsequently neutralized to form the free base (compound of formula F9) prior to the "solvent exchange". After solvent exchange, the free base can be converted to the compound of formula F9-HCl with hydrogen chloride. Accordingly, in some embodiments, after deprotection of the compound of formula F8 with hydrogen chloride, step g) comprises: 1) reacting a compound of formula F9-HCl with a base to obtain a compound of formula F9 (free base); [ka] 2) reacting a compound of formula F9 (free base) with hydrogen chloride to obtain a compound of formula F9-HCl; Further includes:

[0096] In some embodiments, for step g)-step 1), the base is an inorganic base. In some embodiments, the base is sodium bicarbonate, sodium carbonate, sodium citrate, sodium hydroxide, or potassium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is sodium bicarbonate. In some embodiments, the base is aqueous sodium bicarbonate. In some embodiments, for step g)-step 1), reacting the compound of formula F9-HCl with a base to obtain the compound of formula F9 (free base) is carried out in the presence of a solvent. In some embodiments, the solvent comprises dichloromethane. In some embodiments, the solvent comprises dichloromethane and dioxane. In some embodiments, the solvent is a mixture of dichloromethane and dioxane. In some embodiments, the compound of formula F9 (free base) is isolated as a mixture comprising dichloromethane.

[0097] In some embodiments, with regard to step g)-step 2), reacting the compound of formula F9 with hydrogen chloride to obtain a compound of formula F9-HCl is carried out in the presence of a solvent. In some embodiments, the solvent comprises acetonitrile. In some embodiments, the solvent comprises acetonitrile and isopropanol. In some embodiments, the solvent is a mixture of acetonitrile, isopropanol, and ethyl acetate. In some embodiments, the hydrogen chloride is a hydrogen chloride isopropanol mixture. In some embodiments, the hydrogen chloride is a 3.7M hydrogen chloride isopropanol mixture. In some embodiments, the hydrogen chloride is a 3.7M hydrogen chloride solution in isopropanol. In some embodiments, the hydrogen chloride is substantially anhydrous.

[0098] In some embodiments, after deprotecting the compound of formula F8 using hydrogen chloride, step g) comprises: 1) reacting a compound of formula F9-HCl with a base in a solvent comprising dichloromethane and dioxane to obtain a compound of formula F9 (free base); [ka] 2) reacting the compound of formula F9 (free base) with a mixture of hydrogen chloride and isopropanol in a solvent containing acetonitrile to obtain a compound of formula F9-HCl; Further includes:

[0099] In some embodiments, after deprotecting the compound of formula F8 using hydrogen chloride, step g) comprises: 1) reacting a compound of formula F9-HCl with aqueous sodium bicarbonate in the presence of a solvent comprising dichloromethane to obtain a compound of formula F9 (free base); 2) reacting the compound of formula F9 (free base) in a solvent containing acetonitrile with a mixture of hydrogen chloride and isopropanol to obtain a compound of formula F9-HCl; Further includes:

[0100] In some embodiments, after step g) and before step h), the method further comprises: 1) reacting a compound of formula F9-HCl with aqueous sodium bicarbonate in the presence of a solvent comprising dichloromethane to obtain a compound of formula F9 (free base); 2) reacting the compound of formula F9 (free base) in a solvent containing acetonitrile with a mixture of hydrogen chloride and isopropanol to obtain a compound of formula F9-HCl; Further includes:

[0101] In some embodiments, the compound of formula F9-HCl is isolated. In some embodiments, the compound of formula F9-HCl is a solid. In some embodiments, the compound of formula F9-HCl is crystalline. In some embodiments, the compound of formula F9-HCl is crystalline form I, crystalline form II, or an amorphous solid as described in WO 2017 / 075340, which is incorporated by reference in its entirety (see, for example, Formula II (valbenazine dihydrochloride) and Examples 14, 15, and 16 of WO 2017 / 075340). In some embodiments, the compound of formula F9-HCl is crystalline form I. In some embodiments, the compound of formula F9-HCl is crystalline form II. In some embodiments, the compound of formula F9-HCl is an amorphous solid.

[0102] In some embodiments, the compound of formula F9-HCl is not isolated and is used as is in step h).

[0103] Step h) - Method 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 (compound of formula F9, free base)

[0104] In some embodiments, the compound of formula F9 is prepared by a method described herein that includes the step of reacting a compound of formula F9-HCl (e.g., prepared as described in step g)) with step h)-base to obtain a compound of formula F9 (free base). [ka]

[0105] In some embodiments, the step h)-base is an inorganic base. In some embodiments, the step h)-base is sodium bicarbonate, sodium carbonate, sodium citrate, sodium hydroxide, or potassium hydroxide. In some embodiments, the step h)-base is potassium hydroxide. In some embodiments, the step h)-base is sodium hydroxide. In some embodiments, the step h)-base is sodium bicarbonate. In some embodiments, the step h)-base is aqueous sodium bicarbonate.

[0106] In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in the presence of a step h)-solvent. The step h)-solvent can be any suitable solvent. In some embodiments, the step h)-solvent is a solvent comprising a hydrocarbon, a chlorinated hydrocarbon, an alcohol, an ether, an ester, a carbonate, an amide, a nitrile, a sulfoxide, a sulfone, a nitro compound, a heteroarenes, a heterocycle, water, or a mixture thereof. In some embodiments, the step h)-solvent is an ether. In some embodiments, the step h)-solvent is a cycloalkyl ether. In some embodiments, the step h)-solvent is 2-methyltetrahydrofuran (MeTHF). In some embodiments, the step h)-solvent comprises water and a halogenated hydrocarbon solvent. In some embodiments, the halogenated hydrocarbon solvent is dichloromethane.

[0107] In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in the presence of a step h)-solvent comprising dichloromethane. In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in the presence of dichloromethane. In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in the presence of dichloromethane and water. In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in the presence of dichloromethane, and the step h)-base is aqueous sodium bicarbonate.

[0108] In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in the presence of a step h)-solvent comprising 2-methyltetrahydrofuran (MeTHF). In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in the presence of a step h)-solvent comprising ethyl acetate (EtOAc). In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in the presence of a step h)-solvent comprising 2-methyltetrahydrofuran (MeTHF) and ethyl acetate (EtOAc). In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in 2-methyltetrahydrofuran (MeTHF). In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in ethyl acetate (EtOAc). In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in 2-methyltetrahydrofuran (MeTHF).

[0109] In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in 2-methyltetrahydrofuran (MeTHF) and water. In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in ethyl acetate (EtOAc) and water. In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in 2-methyltetrahydrofuran (MeTHF), ethyl acetate (EtOAc), and water.

[0110] In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in 2-methyltetrahydrofuran (MeTHF) and the step h)-base is aqueous sodium bicarbonate. In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in ethyl acetate (EtOAc) and the step h)-base is aqueous sodium bicarbonate. In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in 2-methyltetrahydrofuran (MeTHF) and ethyl acetate (EtOAc) and the step h)-base is aqueous sodium bicarbonate.

[0111] In some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out at a temperature ranging from about 20° C. to about 30° C., from about 21° C. to about 29° C., from about 22° C. to about 28° C., from about 23° C. to about 27° C., from about 24° C. to about 26° C., or from about 25° C.

[0112] In some embodiments, the compound of formula F9 is not isolated.Accordingly, in some embodiments, the reaction of the compound of formula F9-HCl with step h)-base is carried out in the presence of step h)-solvent, and after completion of the reaction, the mixture of the compound of formula F9 and step h)-solvent is used directly in step i).In some embodiments, the step h)-solvent is dichloromethane.

[0113] Step i) - Method 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) (compound of formula I)

[0114] The compound of formula I can be prepared by any of the methods described herein, such as by reacting p-toluenesulfonic acid with either a compound of formula F9 (free base) or a compound of formula F9-HCl as described herein to obtain a compound of formula I (e.g., step ia) and step ib) respectively).

[0115] Step ia) Use of the compound of formula F9 (free base)

[0116] In some embodiments, the compound of formula I is prepared by a method described herein comprising reacting a compound of formula F9 (e.g., prepared as described in step h)) with p-toluenesulfonic acid to obtain the compound of formula I. [ka]

[0117] In some embodiments, the reaction of the compound of formula F9 with p-toluenesulfonic acid in step ia) is carried out in a suitable solvent. In some embodiments, the reaction of the compound of formula F9 with p-toluenesulfonic acid in step ia) is carried out in a solvent comprising dichloromethane.

[0118] In some embodiments, the reaction of the compound of formula F9 with p-toluenesulfonic acid in step ia) is carried out in a solvent comprising acetonitrile. In some embodiments, the solvent comprises acetonitrile and dichloromethane. In some embodiments, the reaction of the compound of formula F9 with p-toluenesulfonic acid in step ia) is carried out in acetonitrile.

[0119] In some embodiments, the compound of formula F9 is not isolated, but is present in a mixture with step h)-solvent prior to reaction with p-toluenesulfonic acid. In some embodiments, the step h)-solvent comprises dichloromethane. In some embodiments, the step h)-solvent is dichloromethane. In some embodiments, the step h)-solvent is "swapped" or replaced with a suitable solvent to carry out the reaction of the compound of formula F9 with p-toluenesulfonic acid. In some embodiments, the solvent comprises acetonitrile. In some embodiments, the solvent is acetonitrile.

[0120] In some embodiments, the p-toluenesulfonic acid is a solid. In some embodiments, the p-toluenesulfonic acid is a solution of p-toluenesulfonic acid in any suitable organic solvent. In some embodiments, the p-toluenesulfonic acid is a solution comprising p-toluenesulfonic acid and acetonitrile. In some embodiments, the p-toluenesulfonic acid is a solution of p-toluenesulfonic acid in acetonitrile.

[0121] In some embodiments, the reaction of the compound of formula F9 with p-toluenesulfonic acid in step i) is carried out at a temperature ranging from about 35° C. to about 65° C., from about 40° C. to about 60° C., from about 45° C. to about 55° C., from about 47° C. to about 53° C., from about 48° C. to about 52° C., or at about 50° C. In some embodiments, the reaction is carried out at a temperature ranging from about 48° C. to about 52° C. In some embodiments, the reaction is carried out at a temperature of about 50° C.

[0122] Step ib) Use of the compound of formula F9-HCl

[0123] In some embodiments, the compound of formula I is prepared by a method described herein comprising reacting a compound of formula F9-HCl (e.g., prepared as described in step g)) with p-toluenesulfonic acid to obtain the compound of formula I. [ka]

[0124] In some embodiments, the compound of formula F9-HCl is isolated prior to use in step ib). In some embodiments, the compound of formula F9-HCl prepared according to step g) is used without isolation.

[0125] In some embodiments, the reaction of the compound of formula F9-HCl with p-toluenesulfonic acid in step ib) is carried out in a suitable solvent. In some embodiments, the reaction of the compound of formula F9-HCl with p-toluenesulfonic acid in step ib) is carried out in a solvent comprising ethyl acetate (EtOAc).

[0126] In some embodiments, the reaction of the compound of formula F9-HCl with p-toluenesulfonic acid in step ib) is carried out in ethyl acetate (EtOAc). In some embodiments, the solvent is ethyl acetate and acetonitrile. In some embodiments, the solvent is ethyl acetate and dichloromethane.

[0127] In some embodiments, the compound of formula F9-HCl is not isolated, but is present in a mixture with step g)-solvent prior to reaction with p-toluenesulfonic acid. In some embodiments, the step g)-solvent comprises dichloromethane. In some embodiments, the step g)-solvent is dichloromethane. In some embodiments, the step g)-solvent is "swapped" or replaced with a suitable solvent to carry out the reaction of the compound of formula F9-HCl with p-toluenesulfonic acid. In some embodiments, the solvent comprises ethyl acetate (EtOAc). In some embodiments, the solvent comprises acetonitrile. In some embodiments, the solvent is ethyl acetate (EtOAc). In some embodiments, the solvent is acetonitrile.

[0128] In some embodiments, the p-toluenesulfonic acid is a solid. In some embodiments, the p-toluenesulfonic acid is a solution of p-toluenesulfonic acid in any suitable organic solvent. In some embodiments, the p-toluenesulfonic acid is a solution comprising p-toluenesulfonic acid and ethyl acetate (EtOAc). In some embodiments, the p-toluenesulfonic acid is a solution comprising p-toluenesulfonic acid and acetonitrile. In some embodiments, the p-toluenesulfonic acid is a solution of p-toluenesulfonic acid in ethyl acetate (EtOAc). In some embodiments, the p-toluenesulfonic acid is a solution of p-toluenesulfonic acid in acetonitrile.

[0129] In some embodiments, the reaction of the compound of Formula F9-HCl with p-toluenesulfonic acid in step ib) is carried out at a temperature ranging from about 25° C. to about 75° C., from about 30° C. to about 75° C., from about 40° C. to about 75° C., from about 50° C. to about 75° C., from about 60° C. to about 75° C., or from about 65° C. to about 75° C. In some embodiments, the reaction is carried out at a temperature of about 68° C. to about 72° C. In some embodiments, the reaction is carried out at a temperature of about 70° C.

[0130] In some embodiments, the compound of formula I is isolated. In some embodiments, the compound of formula I is isolated by filtration. In some embodiments, the compound of formula I is vacuum dried at elevated temperature. In some embodiments, the compound of formula I is vacuum dried at about 45°C to about 55°C. In some embodiments, the compound of formula I is vacuum dried at about 45°C to about 55°C for 12 hours or more. In some embodiments, the compound of formula I is vacuum dried at about 50°C for 12 hours or more. In some embodiments, the compound of formula I is isolated and vacuum dried at about 50°C for 12 hours or more.

[0131] In some embodiments, the compound of formula I has a purity of about 95% or more, about 96% or more, about 97% or more, about 97.5% or more, or about 98% or more by weight.

[0132] In some embodiments, the compound of formula I is crystalline.In some embodiments, the compound of formula I is crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V, crystalline form VI, or amorphous solid as described in WO2017 / 075340, which is incorporated by reference in its entirety (see, for example, WO2017 / 075340 formula I (valbenazine ditosylate) and examples 2, 3, 5, 6, 7, 8, 9, 10, 11, and 16, and associated figures).

[0133] In some embodiments, the compound of formula I is crystalline form I. In some embodiments, the compound of formula I is crystalline form II. In some embodiments, the compound of formula I is crystalline form III. In some embodiments, the compound of formula I is crystalline form IV. In some embodiments, the compound of formula I is crystalline form V. In some embodiments, the compound of formula I is crystalline form VI. In some embodiments, the compound of formula I is an amorphous solid.

[0134] Another aspect of the invention is a process for preparing a compound of formula I, comprising the steps of: [ka] a) reacting a compound of formula F1 with [ka] with aqueous potassium hydroxide in the presence of methyl tert-butyl ether (MTBE) to obtain a compound of formula F2; [ka] b) cyclizing a compound of formula F2 with a compound of formula F3 in the presence of sodium iodide, isopropanol (IPA), and water; [ka] obtaining a compound of formula F4; [ka] c) reducing the compound of formula F4 with sodium borohydride in the presence of methyl tert-butyl ether (MTBE), acetic acid, and methanol to obtain a compound of formula F5; [ka] d) resolving the compound of formula F5 using (S)-(+)-camphorsulfonic acid (CSA) in ethanol and water to obtain a compound of formula F6-CSA; [ka] e) reacting the compound of formula F6-CSA with aqueous sodium hydroxide in dichloromethane to obtain a compound of formula F6; [ka] f) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC·HCl) was used to prepare a compound of formula F6 and a carboxylic acid of formula F7. [ka] coupling in the presence of 4-dimethylaminopyridine (DMAP) and dichloromethane to give a compound of formula F8; [ka] g) deprotecting the compound of formula F8 using a mixture of hydrogen chloride and dioxane in the presence of dichloromethane to obtain a compound of formula F9-HCl; [ka] h) reacting the compound of formula F9-HCl with aqueous sodium bicarbonate in the presence of dichloromethane to obtain the compound of formula F9 (free base); [ka] i) reacting a compound of formula F9 (free base) with p-toluenesulfonic acid in the presence of acetonitrile to obtain a compound of formula I; The present invention provides a method comprising:

[0135] In some embodiments, after step g) and before step h), the method further comprises: 1) reacting a compound of formula F9-HCl with aqueous sodium bicarbonate in the presence of a solvent comprising dichloromethane to obtain a compound of formula F9 (free base); [ka] 2) reacting the compound of formula F9 (free base) in a solvent containing acetonitrile with a mixture of hydrogen chloride and isopropanol to obtain a compound of formula F9-HCl; Further includes:

[0136] In some embodiments, after step g) and before step h), the method further comprises: 1) reacting a compound of formula F9-HCl with aqueous sodium bicarbonate in the presence of a solvent comprising dichloromethane to obtain a compound of formula F9 (free base); [ka] 2) reacting the compound of formula F9 (free base) in a solvent containing acetonitrile with a mixture of hydrogen chloride and isopropanol to obtain a compound of formula F9-HCl; Further includes:

[0137] Another aspect of the invention is a process for preparing a compound of formula I, comprising the steps of: [ka] a) reacting a compound of formula F1 with [ka] with aqueous potassium hydroxide in the presence of methyl tert-butyl ether (MTBE) to obtain a compound of formula F2; [ka] b) cyclizing a compound of formula F2 with a compound of formula F3 in the presence of sodium iodide, isopropanol (IPA), and water; [ka] obtaining a compound of formula F4; [ka] c) reducing the compound of formula F4 with sodium borohydride in the presence of methyl tert-butyl ether (MTBE), acetic acid, and methanol to obtain a compound of formula F5; [ka] d) resolving the compound of formula F5 using (S)-(+)-camphorsulfonic acid (CSA) in ethanol and water to obtain a compound of formula F6-CSA; [ka] e) reacting the compound of formula F6-CSA with aqueous sodium hydroxide in dichloromethane to obtain a compound of formula F6; [ka] f) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC·HCl) was used to prepare a compound of formula F6 and a carboxylic acid of formula F7. [ka] coupling in the presence of 4-dimethylaminopyridine (DMAP) and dichloromethane to give a compound of formula F8; [ka] g) deprotecting the compound of formula F8 using a mixture of hydrogen chloride and dioxane in the presence of dichloromethane to give the compound of formula F9-HCl; [ka] Reacting the compound of formula F9-HCl with aqueous sodium bicarbonate in the presence of a solvent comprising dichloromethane to give the compound of formula F9 (free base); [ka] reacting a compound of formula F9 (free base) in a solvent comprising acetonitrile with a hydrogen chloride isopropanol mixture to obtain a compound of formula F9-HCl; h) reacting the compound of formula F9-HCl with aqueous sodium bicarbonate in the presence of dichloromethane to obtain the compound of formula F9 (free base); i) reacting a compound of formula F9 with p-toluenesulfonic acid in the presence of acetonitrile to obtain a compound of formula I; The present invention provides a method comprising:

[0138] Another aspect of the invention is a process for preparing a compound of formula I, comprising the steps of: [ka] a) reacting a compound of formula F1 with [ka] with aqueous potassium hydroxide in the presence of methyl tert-butyl ether (MTBE) to obtain a compound of formula F2; [ka] b) cyclizing a compound of formula F2 with a compound of formula F3 in the presence of sodium iodide, isopropanol (IPA), and water; [ka] obtaining a compound of formula F4; [ka] c) reducing the compound of formula F4 with sodium borohydride in the presence of methyl tert-butyl ether (MTBE), acetic acid, and methanol to obtain a compound of formula F5; [ka] d) resolving the compound of formula F5 using (S)-(+)-camphorsulfonic acid (CSA) in ethanol and water to obtain a compound of formula F6-CSA; [ka] e) reacting the compound of formula F6-CSA with aqueous potassium hydroxide in 2-methyltetrahydrofuran (MeTHF) to obtain a compound of formula F6; [ka] f) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI) is used to react a compound of formula F6 with a carboxylic acid of formula F7. [ka] coupling in the presence of 4-dimethylaminopyridine (DMAP) and 2-methyltetrahydrofuran (MeTHF) to obtain a compound of formula F8; [ka] g) deprotecting the compound of formula F8 using a mixture of hydrogen chloride and isopropanol in the presence of 2-methyltetrahydrofuran (MeTHF) and ethyl acetate (EtOAc) to obtain a compound of formula F9-HCl; [ka] h) reacting the compound of formula F9-HCl with aqueous sodium bicarbonate in the presence of 2-methyltetrahydrofuran (MeTHF) and ethyl acetate (EtOAc) to obtain the compound of formula F9 (free base); [ka] i) reacting a compound of formula F9 with p-toluenesulfonic acid in the presence of acetonitrile to obtain a compound of formula I; The present invention provides a method comprising:

[0139] Another aspect of the invention is a process for preparing a compound of formula I, comprising the steps of: [ka] a) reacting a compound of formula F1 with [ka] with aqueous potassium hydroxide in the presence of methyl tert-butyl ether (MTBE) to obtain a compound of formula F2; [ka] b) cyclizing a compound of formula F2 with a compound of formula F3 in the presence of sodium iodide, isopropanol (IPA), and water; [ka] obtaining a compound of formula F4; [ka] c) reducing the compound of formula F4 with sodium borohydride in the presence of methyl tert-butyl ether (MTBE), acetic acid, and methanol to obtain a compound of formula F5; [ka] d) resolving the compound of formula F5 using (S)-(+)-camphorsulfonic acid (CSA) in ethanol and water to obtain a compound of formula F6-CSA; [ka] e) reacting the compound of formula F6-CSA with aqueous sodium hydroxide in dichloromethane to obtain a compound of formula F6; [ka] f) N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC·HCl) was used to prepare a compound of formula F6 and a carboxylic acid of formula F7. [ka] coupling in the presence of 4-dimethylaminopyridine (DMAP) and dichloromethane to give a compound of formula F8; [ka] g) deprotecting the compound of formula F8 using a mixture of hydrogen chloride and dioxane in the presence of dichloromethane to obtain a compound of formula F9-HCl; [ka] h) reacting the compound of formula F9-HCl with p-toluenesulfonic acid in a solvent containing ethyl acetate (EtOAc) to obtain a compound of formula I; The present invention provides a method comprising:

[0140] In some embodiments, after step g) and before step h), the method further comprises: 1) reacting a compound of formula F9-HCl with aqueous sodium bicarbonate in the presence of a solvent comprising dichloromethane to obtain a compound of formula F9 (free base); [ka] 2) reacting the compound of formula F9 (free base) in a solvent containing acetonitrile with a mixture of hydrogen chloride and isopropanol to obtain a compound of formula F9-HCl; Further includes:

[0141] Another aspect of the present invention provides a compound of formula I prepared by any of the processes described herein.

[0142] Another aspect of the invention provides a method of preparing a pharmaceutical composition comprising preparing a compound of formula I according to any of the methods described herein and formulating the compound of formula I with a pharma- ceutically acceptable carrier and / or diluent.

[0143] In some embodiments, the pharmaceutical composition comprises the compound of formula I (i.e., valbenazine ditosylate salt); at least one water-insoluble filler; at least one water-soluble diluent; at least one binder; at least one disintegrant; and at least one lubricant. In some embodiments, the pharmaceutical composition comprises the compound of formula I with about 40% w / w%, at least one water-insoluble filler with about 25% w / w%, at least one water-soluble diluent with about 20% w / w%, at least one binder with about 5% w / w%, at least one disintegrant with about 7.5% w / w%, and at least one lubricant with about 2.5% w / w%.

[0144] In some embodiments, the pharma- ceutically acceptable carrier and / or diluent in the pharmaceutical composition comprises silicified microcrystalline cellulose; isomalt; hydroxypropyl methylcellulose; partially pregelatinized corn starch; and magnesium stearate. In some embodiments, the pharmaceutical composition comprises the compound of formula I with about 40% w / w%, silicified microcrystalline cellulose with about 25% w / w%, isomalt with about 20% w / w%, hydroxypropyl methylcellulose with about 5% w / w%, partially pregelatinized corn starch with about 7.5% w / w%, and magnesium stearate with about 2.5% w / w%.

[0145] In some embodiments, the pharma- ceutically acceptable carriers and / or diluents in the pharmaceutical composition include silicified microcrystalline cellulose; isomalt; hydroxypropyl methylcellulose; partially pregelatinized maize starch; and magnesium stearate.

[0146] Another aspect of the invention provides a method of preparing a unit dosage form, the method comprising the steps of preparing a compound of formula I according to any of the methods described herein and formulating the compound of formula I with a pharma- ceutically acceptable carrier and / or diluent.

[0147] In some embodiments, the unit dosage form comprises a compound of formula I (i.e., valbenazine ditosylate salt); at least one water-insoluble filler; at least one water-soluble diluent; at least one binder; at least one disintegrant; and at least one lubricant. In some embodiments, the unit dosage form comprises a compound of formula I with about 40% w / w%, at least one water-insoluble filler with about 25% w / w%, at least one water-soluble diluent with about 20% w / w%, at least one binder with about 5% w / w%, at least one disintegrant with about 7.5% w / w%, and at least one lubricant with about 2.5% w / w%.

[0148] In some embodiments, the pharma- ceutically acceptable carrier and / or diluent in the unit dosage form comprises silicified microcrystalline cellulose; isomalt; hydroxypropyl methylcellulose; partially pregelatinized corn starch; and magnesium stearate. In some embodiments, the unit dosage form comprises the compound of formula I with about 40% w / w%, silicified microcrystalline cellulose with about 25% w / w%, isomalt with about 20% w / w%, hydroxypropyl methylcellulose with about 5% w / w%, partially pregelatinized corn starch with about 7.5% w / w%, and magnesium stearate with about 2.5% w / w%.

[0149] In some embodiments, pharma- ceutically acceptable carriers and / or diluents in unit dosage forms include silicified microcrystalline cellulose; isomalt; hydroxypropyl methylcellulose; partially pregelatinized maize starch; and magnesium stearate.

[0150] In some embodiments, the compound of formula I in the unit dosage form is present in an amount ranging from about 20 mg to 160 mg, measured as the free base (i.e., the compound of formula F9). In some embodiments, 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, measured as the free base. In some embodiments, the compound of formula I in the unit dosage form is present in an amount of 40 mg, 60 mg, or 80 mg, measured as the free base. In some embodiments, the compound of formula I in the unit dosage form is present in an amount of 20 mg, measured as the free base. In some embodiments, the compound of formula I in the unit dosage form is present in an amount of 40 mg, measured as the free base. In some embodiments, the compound of formula I in the unit dosage form is present in an amount of 60 mg, measured as the free base. In some embodiments, the compound of formula I in the unit dosage form is present in an amount of 80 mg, measured as the free base. In some embodiments, the unit dosage form is suitable for oral administration. In some embodiments, the unit dosage form is formulated for once-daily administration. In some embodiments, the unit dosage form is in the form of a capsule. In some embodiments, the capsule is size 1 or smaller. In some embodiments, the capsule is size 1, 2, or 3. In some embodiments, the capsule is size 1. In some embodiments, the capsule is size 2. In some embodiments, the capsule is size 3.

[0151] Some embodiments relate to a pharmaceutical composition prepared by any of the methods described herein.

[0152] Some embodiments relate to unit dosage forms prepared by any of the methods described herein.

[0153] Another aspect of the present application provides a method of inhibiting monoamine transporter isoform 2 (VMAT2) in a patient in need of inhibiting VMAT2, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or unit dosage form, where the pharmaceutical composition and unit dosage form may be prepared according to any of the methods described herein. Another aspect of the present application provides a method of treating a neurological or psychiatric disease or disorder in a patient in need of treating the neurological or psychiatric disease or disorder, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or unit dosage form, where the pharmaceutical composition and unit dosage form may be prepared according to any of the methods described herein. Another aspect of the present application provides a method of treating a hyperactivity disorder in a patient in need of treating the hyperactivity disorder, comprising administering to the patient a therapeutically effective amount of a pharmaceutical composition or unit dosage form, where the pharmaceutical composition and unit dosage form may be prepared according to any of the methods described herein.

[0154] Another aspect of the present application provides a use of a pharmaceutical composition or unit dosage form for manufacturing a medicament for inhibiting monoamine transporter isoform 2 (VMAT2) in a patient in need of inhibiting monoamine transporter isoform 2 (VMAT2), where the pharmaceutical composition and unit dosage form can be prepared according to any of the methods described herein. Another aspect of the present application provides a use of a pharmaceutical composition or unit dosage form for manufacturing a medicament for treating a neurological or psychiatric disease or disorder in a patient in need of treating a neurological or psychiatric disease or disorder, where the pharmaceutical composition and unit dosage form can be prepared according to any of the methods described herein. Another aspect of the present application provides a use of a pharmaceutical composition or unit dosage form for manufacturing a medicament for treating a hyperactivity disorder in a patient in need of treating a hyperactivity disorder, where the pharmaceutical composition and unit dosage form can be prepared according to any of the methods described herein.

[0155] In some embodiments, the VMAT2 inhibitor is administered to a patient to treat a neurological or psychiatric disease or disorder. In some embodiments, the neurological or psychiatric disease or disorder is hyperkinesia disorder, mood disorder, bipolar disorder, schizophrenia, schizoaffective disorder, manic episodes in mood disorders, depressive episodes in mood disorders, refractory obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor ataxia syndrome, autism spectrum disorder, Rett syndrome, or acanthocyocytosis. In some embodiments, the neurological or psychiatric disease or disorder is a disease or disorder in patients with intellectual and developmental disabilities (IDD).

[0156] In some embodiments, the neurological or psychiatric disease or disorder is a hyperkinetic disorder. In some embodiments, the hyperkinetic disorder is tardive dyskinesia. In some embodiments, the hyperkinetic disorder is a tic disorder. In some embodiments, the tic disorder is Tourette's syndrome. In some embodiments, the hyperkinetic disorder is Huntington's disease. In some embodiments, the hyperkinetic disorder is chorea-like movements, generalized dystonia, focal dystonia, and myoclonic movements. In some embodiments, the hyperkinetic disorder is chorea associated with Huntington's disease. In some embodiments, the hyperkinetic disorder is ataxia, chorea, dystonia, Huntington's disease, myoclonus, restless legs syndrome, or tremor. In some embodiments, the hyperkinetic disorder is a disease or disorder other than Huntington's disease. In some embodiments, the hyperkinetic disorder described herein is not a disorder in patients with intellectual and developmental disabilities (IDD). In some embodiments, the hyperkinesia disorder described herein is a disorder in an intellectual or developmental disability (IDD) patient, e.g., in some embodiments, the hyperkinesia disorder is tardive dyskinesia in an intellectual or developmental disability (IDD) patient.

[0157] definition For the sake of clarity and consistency, the following definitions are used throughout this patent document.

[0158] As used in this specification and the appended claims, the indefinite articles "a" and "an," and the definite article "the," include plural referents as well as singular referents, unless the context clearly indicates otherwise.

[0159] The term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In some embodiments, the term "about" or "approximately" refers to within 1, 2, 3, or 4 standard deviations. In some embodiments, the term "about" or "approximately" refers to within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0160] The term "crystalline form" of a compound refers to any crystalline form of a compound as a free acid, a compound as a free base, an acid addition salt of a compound, a base addition salt of a compound, a complex of a compound, a solvate (including hydrates) of a compound, or a co-crystal of a compound. The term "solid form" of a compound can refer to any crystalline form of a compound, or any amorphous form of a compound as a free acid, a compound as a free base, an acid addition salt of a compound, a base addition salt of a compound, a complex of a compound, or a solvate (including hydrates) of a compound, or a co-precipitate of a compound. In many cases, the terms "crystalline form" and "solid form" can refer to pharma- ceutically acceptable, including, for example, pharma- ceutically acceptable addition salts, pharma-ceutically acceptable complexes, pharma-ceutically acceptable solvates, pharma-ceutically acceptable co-crystals, and pharma-ceutically acceptable co-precipitates.

[0161] The terms "process" and "method" are used interchangeably to refer to the methods disclosed herein for preparing compounds. Modifications to the processes and methods disclosed herein that are known to those of skill in the art (e.g., starting materials, reagents, protecting groups, solvents, temperatures, reaction times, and / or purification) are also encompassed by the disclosure.

[0162] The terms "adding," "reacting," and "mixing" are used interchangeably to refer to contacting one reactant, reagent, solvent, catalyst, or reactive group with another reactant, reagent, solvent, catalyst, or reactive group. Unless otherwise specified, reactants, reagents, solvents, catalysts, and reactive groups can be added individually, simultaneously, or separately, and / or in any order. They can be added with or without heat, and can be added under an inert atmosphere (e.g., N2 or Ar) if necessary. In some embodiments, the term "reacting" can also refer to in situ formation or intramolecular reactions where reactive groups are present in the same molecule.

[0163] The term "substantially anhydrous" refers to a solution, mixture, solid (crystalline, or amorphous, or mixtures thereof), and the like having a percent water content of 5% or less, 4% or less, 3% or less, 2% or less, 1% or less, 0.5% or less, 0.1% or less at or below the limit of detection as determined by analytical methods known in the art, such as a Karl Fischer titrator.

[0164] The present application also includes salts of the compounds described herein. As used herein, "salt" refers to derivatives of the disclosed compounds, which modify the parent compound by converting an acid or base moiety present therein to its salt form. Examples of salts include, but are not limited to, mineral (HCl, HBr, H2SO4, etc.) or organic (acetic acid, benzoic acid, trifluoroacetic acid, etc.) salts of basic residues such as amines; alkali (Li, Na, K, Mg, Ca, etc.) or organic (trialkylammonium, etc.) salts of acidic residues such as carboxylic acids; and the like. The salts of the present application can be synthesized by conventional chemical methods from the parent compounds containing basic or acidic moieties. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (ACN) are preferred.

[0165] The methods described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectroscopic methods such as spectrometry (e.g., UV-visible), or mass spectrometry; or chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography. The compound obtained by the reaction can be purified by any suitable method known in the art. For example, (medium pressure) chromatography on a suitable adsorbent (e.g., silica gel, alumina, etc.), HPLC, or preparative thin layer chromatography; distillation; sublimation, trituration, or recrystallization. The purity of a compound is generally determined by physical methods such as measuring the melting point (if solid), obtaining an NMR spectrum, or performing an HPLC separation. A compound is said to be purified if the melting point is reduced, if undesired signals in the NMR spectrum are reduced, or if irrelevant peaks in the HPLC trace are eliminated. In some embodiments, the compound is substantially purified.

[0166] The reactions of the methods described herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, which can range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the reaction step, a suitable solvent for that particular reaction step can be selected. Suitable solvents include water, alkanes (such as pentane, hexane, heptane, cyclohexane, etc., or mixtures thereof), aromatic solvents (e.g., benzene, toluene, xylene, etc.), alcohols (e.g., methanol, ethanol, isopropanol, etc.), ethers (e.g., dialkyl ethers, methyl tert-butyl ether (MTBE); substituted and unsubstituted cycloalkyl ethers, 2-methyltetrahydrofuran (MeTHF), tetrahydrofuran (THF), dioxane, etc.), esters (e.g., ethyl acetate, butyl acetate, etc.), halogenated hydrocarbon solvents (dichloromethane (DCM), chloroform, dichloroethane, tetrachloroethane, etc.), dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetone, acetonitrile (ACN), hexamethylphosphoramide (HMPA), and N-methylpyrrolidone (NMP). Such solvents may be used in wet or anhydrous form.

[0167] The crystals used for seeding can be obtained from previous syntheses, see, for example, WO 2017 / 112857 and WO 2021 / 050977. EXAMPLES

[0168] The present disclosure will be described in more detail by specific examples. The following examples are presented for illustrative purposes and are not intended to limit the present disclosure in any way. Those skilled in the art will readily recognize various non-critical parameters that can be changed or modified to obtain essentially the same results. Unless otherwise specified, the reactions described below were generally carried out at ambient or room temperature. The reactions were assayed by HPLC and terminated as determined by the consumption of starting material.

[0169] The structure and purity of the compounds in the following examples were confirmed by one or more of the following methods: proton nuclear magnetic resonance ( 1 H NMR) spectroscopy, 13 C NMR spectroscopy, mass spectrometry, infrared spectroscopy, melting point, X-ray crystallography, and / or HPLC. 1 H NMR spectra were determined using an NMR spectrometer operating at a particular magnetic field strength. Chemical shifts are reported in parts per million (ppm, δ) downfield from a standard, e.g., an internal standard, such as TMS. Alternatively, 1 H NMR spectra were referenced to signals derived from residual protons in deuterated solvents as follows: CDCl3 = 7.26 ppm; DMSOd6 = 2.50 ppm; C6D6 = 7.16 ppm; CD3OD = 3.31 ppm (J. Org. Chem. 1997, 62, 7513). Peak multiplicities are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, doublet of triplets; q, quartet; br, broad; and m, multiplet. Coupling constants are reported in Hertz (Hz). Mass spectral (MS) data were obtained using a mass spectrometer with APCI or ESI ionization.

[0170] The compounds described herein above and below are named according to MarvinSketch 18.24.0 or ChemDraw Professional 18.2.0.48. In certain cases, when common names are used, it is understood that these common names will be recognized by those skilled in the art.

[0171] Example 1 Synthesis of (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) (Formula I)

[0172] Step A: Synthesis of 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one [ka]

[0173] The reactor was charged with demineralized water (231 L, 6.30 V), 3-((dimethylamino)methyl)-5-methylhexan-2-one oxalate (Formula F1, 52.6 kg, 202 mol; 1.25 eq.) and methyl tert-butyl ether (95 L, 2.60 V). The resulting mixture was heated to about 22° C., the pH was adjusted to 11 with 10 wt. % potassium hydroxide solution (210.8 kg, 376 mol, 2.33 eq.) and stirred for not less than 15 minutes ("NLT"). The resulting layers were separated and the organic layer containing the free base (Formula F2) was washed with demineralized water (39 L, 1.05 V). The solvent was exchanged with isopropanol (129 L, 3.50 V) by put and take distillation at 1.50 V. The mixture was cooled to about 22 °C (19-25 °C) and charged with demineralized water (55 L, 1.50 V), sodium iodide (9.7 kg, 65 mol, 0.40 equiv.), and 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (Formula F3, 36.7 kg, 161 mmol, 1.00 equiv.) and heated to about 42 °C with stirring for not less than 24 h. The mixture was cooled to about 22 °C and stirred for not less than 1 h. The resulting solid was isolated by filtration and the filter cake was washed with isopropanol (91.8 L, 2.50 V). The isolated solid was dried under vacuum at about 40 °C for not less than 12 h to provide 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (Formula F4). Yield: 45.3 kg, 143 mol, 88.5%, purity 99.2%.

[0174] Step B: Synthesis of 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol [ka]

[0175] The reactor was charged with 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (Formula F4, 44.3 kg, 139 mol, 1.00 equiv.), methyl tert-butyl ether (195 L, 4.40 V), acetic acid (9.3 kg, 155 mol, 1.11 equiv.), and methanol (44 L, 1.00 V). The mixture was charged with a suspension of sodium borohydride (10.5 kg, 279 mol, 2.00 equiv.) in methyl tert-butyl ether (44 L, 1.00 V) while maintaining a temperature of about 22° C. The preparation vessel and transfer lines were rinsed with methyl tert-butyl ether (2×13 L, 2×0.30 V). The resulting mixture was stirred at about 25° C. for 2 hours and 1N sodium hydroxide solution (230 kg, 222 mol, 1.59 equiv.) was added (about 25° C.). The mixture was heated to about 47° C. with stirring (about 3 hours) and cooled to about 15° C. with stirring (about 30 minutes). The resulting solid was isolated by filtration. The filter cake was washed with water (4×44 L, 4×1.00 V) and methyl tert-butyl ether (44 L, 1.00 V) and dried under vacuum at about 40° C. for not less than 12 hours to provide 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (Formula F5). Yield: 35.6 kg, 111 mol, 80.1%, purity 99.0%.

[0176] Step C: Synthesis of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (S)-(+)-camphorsulfonate [ka]

[0177] The reactor was charged with absolute ethanol (428 L, 12.00 V), camphor D-(+)-sulfonic acid (21.4 kg, 92 mol, 0.825 equiv.), 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (formula F5, 35.7 kg, 112 mol, 1.00 equiv.), and demineralized water (0.75 V). The mixture was heated to about 70° C. (about 30 min) with stirring, cooled to about 22° C. at about 3° C. / hr, and stirred for about 2 h. Seed crystals of F6 CSA (0.2 kg, 0.5 wt. %) were then added if the product had not crystallized. The resulting crystalline solid was isolated by filtration. The filter cake was washed with absolute ethanol (36 L, 1.00 V) and dried under vacuum at about 45° C. for not less than 12 hours to give (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (S)-(+)-camphorsulfonate (formula F6-CSA). Yield: 23.0 kg, 42 mol, 37.3%, purity 99.6%.

[0178] Step D: Synthesis of (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-((tert-butoxycarbonyl)amino)-3-methylbutanoate [ka]

[0179] (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (1S)-(+)-camphorsulfonate (25.9 kg) was dissolved in dichloromethane (129.5 L, 5 volumes) and 1N sodium hydroxide (11.1 kg dissolved in 282.2 L of water) (pH>10), then the mixture was stirred at 25±5° C. The organics were collected and washed with additional sodium hydroxide solution and then with water. The organic phase was collected, dried over sodium sulfate, then filtered to remove solids. Boc-L-valine (12.2 kg, 1.2 equiv.) and 4-dimethylaminopyridine (1.55 kg, 0.3 equiv.) were charged to the organic phase, then the mixture was cooled to about 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (15.8 kg, 1.8 equiv.) was charged and the reaction was stirred for >3 hours. The reaction mixture was maintained at 0±5°C and monitored for completion by HPLC. Upon completion, water was added and the contents were stirred. After settling, the aqueous layer was drained. The organic layer was washed with aqueous citric acid (prepared from 5.2 kg citric acid in 101 L water) and then with water to give (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-((tert-butoxycarbonyl)amino)-3-methylbutanoate as a dichloromethane solution.

[0180] Step E: Synthesis of (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 dihydrochloride [ka]

[0181] Hydrogen chloride in dioxane (4 M, 57 L, 5 equiv.) was added slowly to the dichloromethane solution of (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-((tert-butoxycarbonyl)amino)-3-methylbutanoate while maintaining the temperature between 5-10 °C. Upon completion of the addition, the mixture was stirred at 25 ± 5 °C for > 12 hours. Upon completion, aqueous sodium bicarbonate (217.6 kg) was added slowly and the mixture was stirred at 25 ± 5 °C until pH > 7. The organics were collected and washed with additional aqueous sodium bicarbonate, then water. Sodium sulfate was added to the organic layer and the mixture was then filtered to remove solids. The organic layer was then distilled to the minimum volume required to stir. Acetonitrile (70 L) was added and the mixture was distilled again to a minimum volume. Acetonitrile was added until the solution was 10 volumes total, then the solution was cooled to 10±5°C. Hydrogen chloride in isopropanol (3.7 M, 26.4 L, 2.1 equiv) was added slowly, then ethyl acetate (57 L) was added, then the mixture was heated to 50±5°C. Additional ethyl acetate was added, then (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 dihydrochloride seeds were added, and the mixture was heated to 75±5°C for >1 hour. The slurry was slowly cooled to 25±5° C. and the solid was filtered, washed with ethyl acetate and then dried under vacuum to give (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 dihydrochloride (16.8 kg, 73% yield).Another batch was carried out using the same procedure described herein starting with (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 (24.4 kg) to give (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 dihydrochloride (17 kg, 79% yield).

[0182] Step F (Method 1): Synthesis of (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) [ka]

[0183] (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 dihydrochloride (10.2 kg) was dissolved in dichloromethane (9 volumes) and aqueous sodium bicarbonate. The mixture was stirred at approximately 25° C. The organics were collected and washed with additional aqueous sodium bicarbonate and then with water. The organic layer was collected and acetonitrile was added to the dichloromethane solution. The solution was distilled to the minimum volume required to stir. Additional acetonitrile was added and the mixture was distilled down to the minimum volume. The mixture was tested for water content and then warmed to approximately 50° C. To this mixture was slowly added a solution of p-toluenesulfonic acid (2 equivalents) in acetonitrile and the contents were stirred at approximately 50° C. for >8 hours. The slurry was then cooled to about 25° C., and the solids were filtered, washed with acetonitrile, and then dried under vacuum to give (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) (14.7 kg, 92.8% yield, 99.9% purity).

[0184] Step F (Method 2): Synthesis of (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)

[0185] (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 dihydrochloride (15 kg) was suspended in dichloromethane (136.5 L, 9 volumes) and aqueous sodium bicarbonate (245 kg) was added until pH>6.5, then the mixture was stirred at 25±5° C. The organics were collected and washed with additional aqueous sodium bicarbonate and then with water. The solution was then distilled to the minimum volume required to stir. Acetonitrile (54 L) was added and the mixture was distilled down to the minimum volume and repeated. Acetonitrile was added and the mixture was tested for water content and, if within specification, warmed to 50±5° C. To this mixture was slowly added a solution of p-toluenesulfonic acid (11.7 kg, 2 equiv.) in acetonitrile (55.5 L) and the contents were stirred for >8 hours at 50±5° C. The slurry was then cooled to 25±5° C. and the solids were filtered, washed with acetonitrile, and then dried under vacuum to give (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) (20.6 kg, 88% yield, ≧98% purity).

[0186] Example 2 Preparation of (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) (Formula I) [ka] [ka]

[0187] An Erlenmeyer flask was charged with (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (1S)-(+)-camphorsulfonate (20 g) in 2-methyltetrahydrofuran (MeTHF) (100 mL) followed by aqueous KOH (2M, 110 mL). The mixture was stirred for 15 min. The resulting biphasic solution was transferred to a separatory funnel and the layers were allowed to separate. An emulsion layer formed and was broken up by adding brine for better separation. The aqueous layer was discarded. H2O (20 mL) was added to the organic layer and then shaken several times. After 15 min, the layers were separated and the aqueous layer was discarded.

[0188] To a round bottom flask was added a solution of the free based material in MeTHF (approximately 100 mL; from above) along with additional MeTHF (40 mL). N-Boc-(L)-Val-OH (1.2 equiv.) and DMAP (0.27 equiv.) were added, followed by a clear yellow solution. The solution was cooled to 0-10°C using an acetone ice / H2O bath. After reaching temperature, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (1.77 equiv.) was added and stirring was continued at 0-10°C for 3 h. After 3 h, the ice bath was removed and the reaction was stirred for at least 5 h. Analytical data showed complete conversion to (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-((tert-butoxycarbonyl)amino)-3-methylbutanoate after 18 h. The reaction was quenched with 5% aqueous citric acid (78 mL) and then the organic layer was washed with HO (60 mL). The resulting organic solution, consisting of (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-((tert-butoxycarbonyl)amino)-3-methylbutanoate, was carried forward to the deprotection step without further purification. In an alternative procedure, (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-((tert-butoxycarbonyl)amino)-3-methylbutanoate was isolated by evaporating the organic solution.

[0189] The (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-((tert-butoxycarbonyl)amino)-3-methylbutanoate solution from above was transferred to a clean round-bottom flask along with additional MeTHF (110 mL). To the solution was added EtOAc (44 mL) and 3.7 N HCl / isopropanol (21 mL; other HCl solutions can be used). The solution was heated to 45° C., seeded with (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 dihydrochloride, and stirred for ½ h. After ½ h, additional EtOAc (30 mL) was added and the temperature was raised to 70° C. for 1 h. After 1 h, HPLC showed that 8% starting material still remained. To the reaction was added additional 3.7N HCl / isopropanol (3 mL) and then heated at 70° C. for 2 h. After 2 h, the reaction was complete. Saturated aqueous NaHCO3 (30 mL) was added slowly and the mixture was stirred for ½ h, then washed with H2O (60 mL). The resulting solution of the free based material (HPLC purity >95%) was carried on to the tosylate salt formation without further purification.

[0190] The free base solution from above was evaporated and solvent exchange was completed with acetonitrile (2×40 mL). The yellow residue was dissolved in acetonitrile (67 mL) and heated to 45-55 °C, after which a solution of p-TsOH / acetonitrile (8.3 g / 139 mL) was added in one portion. After stirring at 45 °C for 18 h, the slurry was cooled to 25 °C and the white solid was filtered, washed with EtOAc (2×10 mL), then dried in a vacuum oven at 50 °C for 18 h to give (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) (14.5 g, 53% overall isolated yield). Analytical HPLC data confirmed the purity (99.68%) and chirality (99.77%).

[0191] In an alternative procedure, (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 dihydrochloride was isolated by filtration, then free-based and converted to the ditosylate salt as described above.

[0192] Example 3 Preparation of (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) [ka]

[0193] The isolated (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 dihydrochloride (10 g, 0.02 mol) was suspended in EtOAc (500 mL) and then heated to 70 °C. While the mixture was heated, p-TsOH (14 g, 4 equiv.) was added. During heating, the mixture became a clear homogenous solution. The solution was aged at 70 °C for 2-3 h. After 2-3 h, a white solid precipitated and the heat source was removed. The suspension was stirred for 18 h and then filtered. The solid was washed with EtOAc and then dried in a vacuum oven at 50 °C for 18 h to give (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) (13.2 g, 88% isolated yield) as a white solid. 1 1 H-NMR matched that obtained from Example 2.

[0194] Example 4 p-Toluenesulfonic acid determination

[0195] Determination of the area % of p-toluenesulfonic acid in a sample of a compound of Formula I can be determined using reverse phase HPLC methods as described in WO 2021 / 050977.

[0196] Example 5 Preparation of capsules containing 40 mg and 80 mg of valbenazine

[0197] Capsules containing 40 mg and 80 mg of valbenazine (measured as the free base) can be prepared according to the methods described in WO 2019 / 060322, which is incorporated herein by reference in its entirety.

[0198] The ingredients of an exemplary 40 mg capsule are set forth in Table 1 below. [Table 1]

[0199] The ingredients of an exemplary 80 mg capsule are set forth in Table 2 below. [Table 2]

[0200] From the above description, various modifications of the embodiments will be apparent to those skilled in the art in addition to those described herein. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, and publications cited in this application, is hereby incorporated by reference in its entirety.

Claims

1. A method for preparing a compound of formula I comprising the steps of: 【Chemistry 108】 a) reacting a compound of formula F1 【Chemistry 109】 with aqueous potassium hydroxide in the presence of methyl tert-butyl ether (MTBE) to obtain a compound of formula F2; 【Chemistry 110】 b) cyclizing said compound of formula F2 with a compound of formula F3 in the presence of sodium iodide, isopropanol (IPA), and water; 【Chemistry 111】 Obtaining a compound of formula F4; 【Chemistry 112】 c) reducing said compound of formula F4 with sodium borohydride in the presence of methyl tert-butyl ether (MTBE), acetic acid, and methanol to obtain a compound of formula F5; 【Chemistry 113】 d) resolving said compound of formula F5 using (S)-(+)-camphorsulfonic acid (CSA) in ethanol and water to obtain a compound of formula F6-CSA; 【Chemistry 114】 e) reacting said compound of formula F6-CSA with aqueous sodium hydroxide in dichloromethane to obtain a compound of formula F6; 【Chemistry 115】 f) reacting the compound of formula F6 with a carboxylic acid of formula F7 using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl); 【Chemistry 116】 coupling in the presence of 4-dimethylaminopyridine (DMAP) and dichloromethane to give a compound of formula F8; 【Chemistry 117】 g) deprotecting said compound of formula F8 using a mixture of hydrogen chloride and dioxane in the presence of dichloromethane to obtain a compound of formula F9-HCl; 【Chemistry 118】 h) reacting said compound of formula F9-HCl with aqueous sodium bicarbonate in the presence of dichloromethane to obtain a compound of formula F9 (free base); 【Chemistry 119】 i) reacting said compound of formula F9 with p-toluenesulfonic acid in the presence of acetonitrile to obtain said compound of formula I; The method includes:

2. After step g) and before step h), 1) reacting said compound of formula F9-HCl with aqueous sodium bicarbonate in the presence of a solvent comprising dichloromethane to obtain a compound of formula F9 (free base); 【Chemistry 120】 2) reacting said compound of formula F9 (free base) in a solvent comprising acetonitrile with a hydrogen chloride isopropanol mixture to obtain said compound of formula F9-HCl; The method of claim 1 further comprising:

3. A method for preparing a compound of formula I comprising the steps of: 【Chemistry 121】 a) reacting a compound of formula F1 【Chemistry 122】 with aqueous potassium hydroxide in the presence of methyl tert-butyl ether (MTBE) to obtain a compound of formula F2; 【Chemistry 123】 b) cyclizing said compound of formula F2 with a compound of formula F3 in the presence of sodium iodide, isopropanol (IPA), and water; 【Chemistry 124】 Obtaining a compound of formula F4; 【Chemistry 125】 c) reducing said compound of formula F4 with sodium borohydride in the presence of methyl tert-butyl ether (MTBE), acetic acid, and methanol to obtain a compound of formula F5; 【Chemistry 126】 d) resolving said compound of formula F5 using (S)-(+)-camphorsulfonic acid (CSA) in ethanol and water to obtain a compound of formula F6-CSA; 【Chemistry 127】 e) reacting said compound of formula F6-CSA with aqueous sodium hydroxide in dichloromethane to obtain a compound of formula F6; 【Chemistry 128】 f) reacting the compound of formula F6 with a carboxylic acid of formula F7 using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl); 【Chemistry 129】 coupling in the presence of 4-dimethylaminopyridine (DMAP) and dichloromethane to give a compound of formula F8; 【Chemistry 130】 g) deprotecting said compound of formula F8 using a mixture of hydrogen chloride and dioxane in the presence of dichloromethane to obtain a compound of formula F9-HCl; 【Chemistry 131】 reacting said compound of formula F9-HCl with aqueous sodium bicarbonate in the presence of a solvent comprising dichloromethane to give a compound of formula F9 (free base); 【Chemistry 132】 reacting said compound of formula F9 (free base) in a solvent comprising acetonitrile with a hydrogen chloride isopropanol mixture to obtain said compound of formula F9-HCl; h) reacting said compound of formula F9-HCl with aqueous sodium bicarbonate in the presence of dichloromethane to obtain a compound of formula F9 (free base); i) reacting said compound of formula F9 with p-toluenesulfonic acid in the presence of acetonitrile to obtain said compound of formula I; The method includes:

4. A method for preparing a compound of formula I comprising the steps of: 【Chemistry 133】 a) reacting a compound of formula F1 【Chemistry 134】 with aqueous potassium hydroxide in the presence of methyl tert-butyl ether (MTBE) to obtain a compound of formula F2; 【Chemistry 135】 b) cyclizing said compound of formula F2 with a compound of formula F3 in the presence of sodium iodide, isopropanol (IPA), and water; 【Chemistry 136】 Obtaining a compound of formula F4; 【Chemistry 137】 c) reducing said compound of formula F4 with sodium borohydride in the presence of methyl tert-butyl ether (MTBE), acetic acid, and methanol to obtain a compound of formula F5; 【Chemistry 138】 d) resolving said compound of formula F5 using (S)-(+)-camphorsulfonic acid (CSA) in ethanol and water to obtain a compound of formula F6-CSA; 【Chemistry 139】 e) reacting said compound of formula F6-CSA with aqueous potassium hydroxide in 2-methyltetrahydrofuran (MeTHF) to obtain a compound of formula F6; 【Chemistry 140】 f) reacting said compound of formula F6 with a carboxylic acid of formula F7 using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI); 【Chemistry 141】 coupling in the presence of 4-dimethylaminopyridine (DMAP) and 2-methyltetrahydrofuran (MeTHF) to give a compound of formula F8; 【Chemistry 142】 g) deprotecting said compound of formula F8 using a mixture of hydrogen chloride and isopropanol in the presence of 2-methyltetrahydrofuran (MeTHF) and ethyl acetate (EtOAc) to obtain a compound of formula F9-HCl; 【Chemistry 143】 h) reacting said compound of formula F9-HCl with aqueous sodium bicarbonate in the presence of 2-methyltetrahydrofuran (MeTHF) and ethyl acetate (EtOAc) to obtain a compound of formula F9 (free base); 【Chemistry 144】 i) reacting said compound of formula F9 with p-toluenesulfonic acid in the presence of acetonitrile to obtain said compound of formula I; The method includes:

5. A method for preparing a compound of formula I comprising the steps of: 【Chemistry 145】 a) reacting a compound of formula F1 【Chemistry 146】 with aqueous potassium hydroxide in the presence of methyl tert-butyl ether (MTBE) to obtain a compound of formula F2; 【Chemistry 147】 b) cyclizing said compound of formula F2 with a compound of formula F3 in the presence of sodium iodide, isopropanol (IPA), and water; 【Chemistry 148】 Obtaining a compound of formula F4; 【Chemistry 149】 c) reducing said compound of formula F4 with sodium borohydride in the presence of methyl tert-butyl ether (MTBE), acetic acid, and methanol to obtain a compound of formula F5; 【Chemistry 150】 d) resolving said compound of formula F5 using (S)-(+)-camphorsulfonic acid (CSA) in ethanol and water to obtain a compound of formula F6-CSA; 【Chemistry 151】 e) reacting said compound of formula F6-CSA with aqueous sodium hydroxide in dichloromethane to obtain a compound of formula F6; 【Chemistry 152】 f) reacting the compound of formula F6 with a carboxylic acid of formula F7 using N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl); 【Chemistry 153】 coupling in the presence of 4-dimethylaminopyridine (DMAP) and dichloromethane to give a compound of formula F8; 【Chemistry 154】 g) deprotecting said compound of formula F8 using a mixture of hydrogen chloride and dioxane in the presence of dichloromethane to obtain a compound of formula F9-HCl; 【Chemistry 155】 h) reacting said compound of formula F9-HCl with p-toluenesulfonic acid in a solvent containing ethyl acetate (EtOAc) to obtain said compound of formula I; The method includes:

6. After step g) and before step h), 1) reacting said compound of formula F9-HCl with aqueous sodium bicarbonate in the presence of a solvent comprising dichloromethane to obtain a compound of formula F9 (free base); 【Chemistry 156】 2) reacting said compound of formula F9 (free base) in a solvent comprising acetonitrile with a mixture of hydrogen chloride isopropanol to obtain said compound of formula F9-HCl; The method of claim 4 or 5, further comprising:

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