Synthetic 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-methylbutyrate di(4-methylbenzenesulfonate)

Abstract

Provided herein are methods 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-methylbutyrate di(4-methylbenzenesulfonate) or a solvate, hydrate, or polymorph thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 387,442, filed December 23, 2015; the disclosure of which is incorporated herein by reference in its entirety.

[0003] field

[0004] Provided herein are methods 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) or a pharmaceutically acceptable solvate, hydrate, or polymorph thereof.

[0005] background

[0006] Hyperkinetic disorder is characterized by excessive, abnormal involuntary movements. These neurological disorders include tremor, dystonia, twitching, convulsions, akathisia, stereotypies, chorea, myoclonus and athetosis. Although the pathophysiology of these movement disorders is poorly understood, it is believed that the imbalance of neurotransmitters in the basal ganglia plays an important role (Kenney et.al., Expert Review Neurotherapeutics, 2005, 6, 7-17). Long-term use and high doses of typical neuroleptics or centrally acting dopamine receptor blocking antiemetics easily cause patients to develop tardive syndrome. Tardive dyskinesia is a subtype of the latter syndrome, characterized by rapid, repetitive, stereotyped, involuntary movements of the face, limbs or trunk (Muller, Expert Opin. Investig. Drugs, 2015, 24, 737-742).

[0007] 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), has improved the treatment of various hyperkinetic movement disorders through its reversible inhibition of the vesicular monoamine transporter-2 system (VMAT2). However, disadvantages of this treatment include fluctuating responses, the need for frequent ingestion due to rapid TBZ metabolism, and side effects. Side effects associated with TBZ include sedation, depression, akathisia, and Parkinson's disease.

[0008] TBZ contains two chiral centers and is a racemic mixture of two stereoisomers. It 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 separate isomers: (±)α-DHTBZ and (±)β-DHTBZ. (2R,3R,11bR) or (+)α-DHTBZ is considered 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 some European countries. It is also used to treat chorea in patients with Huntington's disease. However, tetrabenazine is rapidly metabolized and must be administered frequently throughout the day (Muller, Expert Opin. Investig. Drugs, 2015, 24, 737-742). Therefore, there is an urgent need in the art to develop effective therapeutic agents for treating hyperkinetic movement disorders including tardive dyskinesia.

[0009] Valbenazine, (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1a]isoquinolin-2-yl ester, is a prodrug of the (+)-α-isomer of dihydrotetrabenazine that has recently shown significant improvement in the treatment of hyperkinetic movement disorders, including tardive dyskinesia, with improved pharmacokinetic profile and tolerability profile.

[0010] Methods for synthesizing (S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester have been described in U.S. Patent Nos. 8,039,627 and 8,357,697, the disclosures of each of which are incorporated herein by reference in their entireties.

[0011] Overview of public content

[0012] Provided herein are safe, efficient, cost-effective, and / or readily scalable methods 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) or a pharmaceutically acceptable solvate, hydrate, or polymorph thereof. In other embodiments, the method provides (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) with a purity greater than 95%.

[0013] The methods provided herein generally involve: (a) reacting (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof in a suitable solvent to form (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol; (b) reacting (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 with an appropriately protected L-valine under the following conditions: (a) deprotecting (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 to form ... (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 or a pharmaceutically acceptable solvate, hydrate or polymorph thereof; (c) (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 is converted into (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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof.

[0014] Detailed Description of the Invention

[0015] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.All publications and patents mentioned herein are incorporated herein by reference in their entirety.

[0016] definition

[0017] To facilitate understanding of the disclosure described herein, a number of terms are defined below.

[0018] Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly used in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0019] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, wherein the alkyl radical is optionally substituted with one or more substituents Q as described elsewhere herein. For example, C 1-6 Alkyl refers to a straight chain saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In certain embodiments, an alkyl group is a saturated monovalent hydrocarbon group having 1 to 20 carbon atoms. 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ) or 1 to 6 (C 1-6 )) carbon atoms, or a straight-chain saturated monovalent hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. As used herein, a straight-chain C 1-6 Alkyl and branched C 3-6 Alkyl is also referred to as "lower alkyl." Examples of alkyl include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms).

[0020] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical containing one or more (in one embodiment, one to five, in another embodiment, one) carbon-carbon double bonds, wherein the alkenyl group is optionally substituted with one or more substituents Q as described elsewhere herein. The term "alkenyl" includes groups having "cis" or "trans" configurations, or alternatively, groups having "Z" or "E" configurations, or mixtures thereof, as understood by one of ordinary skill in the art. For example, C 2-6Alkenyl refers to a linear unsaturated monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In certain embodiments, alkenyl is a group having 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or a linear monovalent hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

[0021] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical comprising one or more (in one embodiment, one to five, in another embodiment, one) carbon-carbon triple bonds, wherein the alkynyl radical is optionally substituted with one or more substituents Q as described elsewhere herein. For example, C 2-6 Alkynyl refers to a straight chain unsaturated monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In certain embodiments, alkynyl is a 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or a linear monovalent hydrocarbon group having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (—C═CH), propynyl (including all isomeric forms, such as 1-propynyl (—C═CCH ) and propargyl (—CH C═CH)), butynyl (including all isomeric forms, such as 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including all isomeric forms, such as 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomeric forms, such as 1-hexyn-1-yl).

[0022] The term "cycloalkyl" refers to a cyclic monovalent hydrocarbon group, wherein the cycloalkyl group is optionally substituted with one or more substituents Q as described elsewhere herein. In one embodiment, the cycloalkyl group can be a saturated or unsaturated but non-aromatic, and / or spirocyclic, and / or non-spirocyclic, and / or bridged, and / or non-bridged, and / or fused bicyclic group. In certain embodiments, the cycloalkyl group has 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 7 (C 3-7 ) carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decahydronaphthyl, and adamantyl.

[0023] The term "aryl" refers to a monovalent monocyclic aromatic group and / or a monovalent polycyclic aromatic group containing at least one aromatic carbocyclic ring, wherein the aryl group is optionally substituted with one or more substituents Q as described elsewhere herein. In certain embodiments, the aryl group has 6 to 20 (C 6-20 ), 6 to 15 (C 6-15 ), or 6 to 10 (C 6-10 ) ring atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, and terphenyl. The term "aryl" also refers to a bicyclic or tricyclic carbocycle in which one ring is aromatic and the other ring can be saturated, partially unsaturated, or aromatic, such as dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl).

[0024] The term "aralkyl" or "arylalkyl" refers to a monovalent alkyl group substituted with one or more aryl groups, wherein the aralkyl or arylalkyl group is optionally substituted with one or more substituents Q as described elsewhere herein. In certain embodiments, the aralkyl group has 7 to 30 (C 7-30 ), 7 to 20 (C 7-20 ) or 7 to 16 (C 7-16 ) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, 2-phenylethyl, and 3-phenylpropyl.

[0025] The term "heteroaryl" refers to a monovalent monocyclic aromatic group and / or a monovalent polycyclic aromatic group containing at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, N and P in the ring. The heteroaryl group is bonded to the rest of the molecule through the aromatic ring. Each ring of the heteroaryl group may contain one or two O atoms, one or two S atoms, one to four N atoms and / or one or two P atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl group has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridinyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl, and thienopyridinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perylene, phenanthrolinyl, phenanthridinyl, phenpyrazinyl, phenazine, phenothiazine, phenoxazinyl and xanthenyl. In certain embodiments, heteroaryl is optionally substituted with one or more substituents Q as described elsewhere herein.

[0026] The term "heterocyclyl" or "heterocyclic" refers to a monovalent monocyclic non-aromatic ring system and / or a monovalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, N, and P; the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. The heterocyclyl is bonded to the rest of the molecule through the non-aromatic ring. In certain embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be spirocyclic, fused, or bridged, and wherein the nitrogen or sulfur atoms may be optionally oxidized, the nitrogen atoms may be optionally quaternized, and some of the rings may be partially or fully saturated or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom, which results in a stable compound. Examples of such heterocyclic groups include, but are not limited to, azacycloheptatrienyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyronyl, benzopyranyl, chromanyl, chromanyl, benzotetrahydrothiophenyl, benzothiopyranyl, benzoxazinyl, 13-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisothiazinyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolane, 1,4-dihydro- ... Thianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothiophenyl, isochromanyl, isocoumarinyl, isodihydroindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolinyl, octahydroisoindolinyl, oxazolidinone, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidone, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothiophenyl, thiomorpholinyl, thiazolidinyl, tetrahydroquinolinyl and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl group is optionally substituted with one or more substituents Q as described elsewhere herein.

[0027] The term "olefin" refers to a linear or branched hydrocarbon containing one or more (in one embodiment, one to five, in another embodiment, one) carbon-carbon double bonds, wherein the olefin is optionally substituted with one or more substituents Q as described elsewhere herein. As will be understood by one of ordinary skill in the art, the term "olefin" includes compounds or mixtures thereof having a "cis" or "trans" configuration, or compounds or mixtures thereof having a "Z" or "E" configuration. For example, C 2-6 Olefins refer to straight chain unsaturated hydrocarbons having 2 to 6 carbon atoms or branched chain unsaturated hydrocarbons having 3 to 6 carbon atoms. In certain embodiments, olefins are hydrocarbons having 2 to 20 carbon atoms.2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ) or 2 to 6 (C 2-6 ) carbon atoms, or a straight chain hydrocarbon having 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms in a branched chain hydrocarbon.

[0028] The term "cycloolefin" refers to a cyclic hydrocarbon comprising one or more (in one embodiment, one to five, in another embodiment, one) carbon-carbon double bonds, wherein the cycloolefin is optionally substituted with one or more substituents Q as described elsewhere herein. In one embodiment, the cycloolefin can be a non-aromatic, and / or spirocyclic, and / or non-spirocyclic, and / or bridged, and / or non-bridged, and / or fused bicyclic ring. In certain embodiments, the cycloolefin has 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 7 (C 3-7 ) carbon atom.

[0029] The term "arene" refers to a monocyclic aromatic compound and / or a polycyclic aromatic compound containing at least one aromatic carbocyclic ring, wherein the arene is optionally substituted with one or more substituents Q as described elsewhere herein. In certain embodiments, the arene has 6 to 20 (C 6-20 ), 6 to 15 (C 6-15 ) or 6 to 10 (C 6-10 ) ring atoms. The term "arene" also refers to a bicyclic or tricyclic carbon ring in which one ring is aromatic and the other rings may be saturated, partially unsaturated or aromatic.

[0030] The term "heteroarene" refers to a monocyclic aromatic compound and / or a polycyclic aromatic compound containing at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms independently selected from O, S, N and P in the ring. Each ring of the heteroarene may contain one or two O atoms, one or two S atoms, one to four N atoms and / or one or two P atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring contains at least one carbon atom. In certain embodiments, the heteroarene has 5 to 20, 5 to 15 or 5 to 10 ring atoms. In certain embodiments, the heteroarene is optionally substituted with one or more substituents Q as described elsewhere herein.

[0031] The term "heterocycle" refers to a monocyclic non-aromatic ring system and / or a non-aromatic polycyclic ring system, wherein one or more non-aromatic ring atoms are heteroatoms, each heteroatom independently selected from O, S, N, and P; the remaining ring atoms are carbon atoms. In certain embodiments, the heterocycle has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In certain embodiments, the heterocycle is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be spirocyclic, fused, or bridged, wherein the nitrogen or sulfur atom may be optionally oxidized, the nitrogen atom may be optionally quaternized, and some rings may be partially saturated or fully saturated. In certain embodiments, the heterocycle is optionally substituted by one or more substituents Q as described elsewhere herein.

[0032] The term "alcohol" refers to an alkyl-OH, alkenyl-OH, alkynyl-OH, cycloalkyl-OH, aryl-OH, aralkyl-OH, heteroaryl-OH, or heterocyclyl-OH, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl are each as defined herein.

[0033] The term "carboxylic acid" refers to alkyl-COOH, alkenyl-COOH, alkynyl-COOH, cycloalkyl-COOH, aryl-COOH, aralkyl-COOH, heteroaryl-COOH, or heterocyclyl-COOH, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl are each as defined herein.

[0034] The term "carboxylate" or "ester" refers to alkyl-COOR', alkenyl-COOR', alkynyl-COOR', cycloalkyl-COOR', aryl-COOR', aralkyl-COOR', heteroarylCOOR' or heterocyclyl-COOR', and each R' is independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclyl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclyl is as defined herein.

[0035] The term "optionally substituted" is intended to mean that a group or substituent, such as an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl or heterocyclyl, may be substituted by one or more substituents Q, each substituent Q being independently selected from, for example, (a) oxo (=O), halo, cyano (-CN) and nitro (-NO2); (b) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 1-15 Aralkyl, heteroaryl and heterocyclyl, each of which is further substituted by one or more (in one embodiment, one, two, three or four) substituents Qa Optionally substituted; and (c) -C(O)R a 、-C(O)OR a 、-C(O)NR b R c 、-C(NR a )NR b R c 、-OR a 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR b R c 、-OC(=NRa)NR b R c 、-OS(O)R a 、-OS(O)2R a 、-OS(O)NR b R c 、-OS(O)2NR b R c 、-NR b R c 、-NR a C(O)R d 、-NR a C(O)OR d 、-NR a C(O)NR b R c 、-NR a C(=NR d )NR b R c 、-NR a S(O)R d 、-NR a S(O)2R / / 这里的“ / / ”是为了和原文格式一致,实际翻译中不需要 d 、-NR a S(O)NR b R c 、-NR a S(O)2N b R c 、-P(O)R a R d 、-P(O)(OR a )R d ,-P(O)(OR a )(OR d )、-SR a -S(O)R a 、-S(O)2R a 、-S(O)NR b R c and -S(O)2NRb R c , where each R a 、R b 、R e and R d are each independently (i) hydrogen; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl or heterocyclyl, each of which is substituted by one or more (in one embodiment, one, two, three or four) substituents Q a is optionally substituted; or (iii) R b and R e Together with the nitrogen atom to which they are attached, they form a heteroaryl or heterocyclyl group, wherein each group is substituted by one or more (in one embodiment, one, two, three or four) substituents Q a Optionally substituted. As used herein, unless otherwise indicated, all groups that can be substituted are "optionally substituted."

[0036] The term "isotopically enriched" refers to an atom having an isotopic composition that is different from the natural isotopic composition of the atom. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition that is different from the natural isotopic composition of the atom.

[0037] With respect to the compounds provided herein, when a particular atomic position is designated as having deuterium or "D," it is understood that the abundance of deuterium at that position is significantly greater than the natural abundance of deuterium, which is approximately 0.015%. Positions designated as having deuterium typically have a minimum isotopic enrichment factor, which in particular embodiments is at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position.

[0038] The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to those of ordinary skill in the art, including mass spectrometry, nuclear magnetic resonance spectroscopy, and crystallography.

[0039] It has been previously demonstrated with some classes of drugs that isotopic enrichment (eg, deuteration) of drugs can improve pharmacokinetic ("PK"), pharmacodynamic ("PD"), and toxicity profiles. See, for example, Lijinsky et.al., Food Cosmet. Toxicol., 20:393 (1982); Lijinsky et.al., J. Nat. Cancer Inst., 69:1127 (1982); Mangold et.al., Mutation Res. 308:33 (1994); Gordon et.al., Drug Metab. Dispos., 15:589 (1987); Zello et.al., Metabolism, 43:487 (1994); Gately et.al., J. Nucl. Med., 27:388 (1986); Wade D, Chem. Biol. Interact. 117:191 (1999).

[0040] Isotopic enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites, (2) increase the half-life of the parent drug, (3) reduce the number of doses required to achieve a desired effect, (4) reduce the amount of dose necessary to achieve a desired effect, (5) increase the formation of active metabolites, if any, and / or (6) reduce the production of deleterious metabolites in specific tissues and / or for combination therapy, to produce a more effective drug and / or a safer drug, whether or not the combination therapy is intended.

[0041] Replacing an atom with one of its isotopes typically results in a change in the reaction rate of a chemical reaction. This phenomenon is called the kinetic isotope effect ("KIE"). For example, if a C-H bond breaks during the rate-determining step (i.e., the step with the highest transition state energy) of a chemical reaction, replacing the hydrogen with deuterium will result in a reduced reaction rate, and the process will slow down. This phenomenon is called the deuterium kinetic isotope effect ("DKIE") (see, for example, Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol. 77, pp. 79-88 (1999)).

[0042] The magnitude of the DKIE can be expressed as the ratio between the rate of a given reaction in which a C-H bond is broken and the rate of the same reaction when deuterium replaces hydrogen. The DKIE can range from about 1 (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be slowed down 50 times or more when deuterium replaces hydrogen. High DKIE values ​​may be due in part to a phenomenon called tunneling, a consequence of the uncertainty principle. Tunneling occurs because of the small mass of hydrogen atoms and because transition states involving protons can sometimes form in the absence of the required activation energy. Because deuterium has a larger mass than hydrogen, its statistical probability of experiencing this phenomenon is much lower.

[0043] Tritium ("T") is a radioactive isotope of hydrogen used in research, fusion reactors, neutron generators, and radiopharmaceuticals. Tritium is a hydrogen atom with 2 neutrons in its nucleus and an atomic weight close to 3. It occurs naturally in the environment in very low concentrations, most commonly as T2O. Tritium decays slowly (half-life = 12.3 years) and emits low-energy beta particles that cannot penetrate the outer layer of human skin. Internal exposure is the primary hazard associated with this isotope, but large amounts must be ingested to pose a serious health risk. Compared to deuterium, smaller amounts of tritium must be consumed before dangerous levels are reached. Replacing hydrogen with tritium ("T") results in a stronger bond than deuterium and produces a numerically larger isotope effect. Similarly, isotopes substitute for other elements, including but not limited to 13 C or 14 C replaces carbon, 33 S. 34 S or 36 S replaces sulfur, 15 N replaces nitrogen, 17 O or 18 O replaces oxygen, which may lead to similar kinetic isotope effects.

[0044] For example, DKIE has been used to reduce the hepatotoxicity of halothane by potentially limiting the production of reactive species such as trifluoroacetyl chloride. However, this approach may not be applicable to all drug classes. For example, deuterium incorporation can lead to metabolic switching. The concept of metabolic switching asserts that when sequestered by phase I enzymes, xenogens can bind transiently and rebind in various conformations prior to a chemical reaction (e.g., oxidation). The relatively large size of the binding pockets in many phase I enzymes and the promiscuous nature of many metabolic reactions support this hypothesis. Metabolic switching can potentially result in varying proportions of known metabolites as well as entirely new metabolites. This new metabolic profile may produce more or less toxicity.

[0045] In order to eliminate foreign substances such as therapeutic agents from their circulatory system, animals express a variety of enzymes. Examples of such enzymes include cytochrome P450 enzymes ("CYP"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, which react with these foreign substances and convert them into more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of drug compounds involve the oxidation of carbon-hydrogen (CH) bonds to carbon-oxygen (CO) or carbon-carbon (CC) π bonds. The resulting metabolites can be stable or unstable under physiological conditions and can have significantly different pharmacokinetics, pharmacodynamics, and acute toxicity profiles and long-term toxicity profiles relative to the parent compound. For many drugs, this oxidation is rapid. Therefore, these drugs typically require multiple or high-dose administration.

[0046] Thus, isotopic enrichment at certain positions of the compounds provided herein can produce detectable KIEs compared to similar compounds having natural isotopic compositions, which will affect the pharmacokinetic, pharmacological and / or toxicological profiles of the compounds provided herein.

[0047] The term "isotopic variant" refers to a therapeutic agent that contains unnatural proportions of isotopes at one or more atoms that comprise the therapeutic agent. In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 (34 S), sulfur-35 ( 35 S), sulfur-36 (36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), chlorine-37( 37 Cl), bromine-79( 79 Br), bromine-81( 81 Br), iodine 123 ( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I) and iodine-131( 131 I). In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of one or more isotopes including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), oxygen-18 ( 18 O), fluorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 (34 S), sulfur-35 ( 35 S), sulfur-36 ( 36 S), chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), chlorine-37( 37 Cl), bromine-79( 79 Br), bromine-81( 81 Br), iodine 123 ( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I) and iodine-131(131 I).

[0048] It will be appreciated that, where feasible, according to the judgment of the skilled artisan, in the therapeutic agent any hydrogen may be, for example 2 H, or any carbon can be e.g. 13 C, or any nitrogen may be e.g. 15 N, or any oxygen may be e.g. 18 O. In certain embodiments, an "isotopic variant" of a therapeutic agent contains unnatural proportions of deuterium (D).

[0049] As used in the specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural as well as singular referents, unless the context clearly dictates otherwise.

[0050] The term "about" or "approximately" means the acceptable error for a particular value determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means 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. In certain embodiments, "about" or "approximately" with respect to temperature means within ± 0.5°C.

[0051] The term "solvate" refers to a complex or aggregate formed by one or more solute molecules (e.g., a compound provided herein) and one or more solvent molecules, present in a stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a non-crystalline form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, and pentahydrates.

[0052] The term "crystalline form" of a compound may refer to any crystalline form of the compound as a free acid, any crystalline form of the compound as a free base, any crystalline form of an acid addition salt of the compound, any crystalline form of a base addition salt of the compound, any crystalline form of a complex of the compound, any crystalline form of a solvate (including hydrates) of the compound, or any crystalline form of a co-crystal of the compound. The term "solid form" of a compound may refer to any crystalline form of the compound or any amorphous form of the compound as a free acid, any amorphous form of the compound as a free base, any amorphous form of an acid addition salt of the compound, any amorphous form of a base addition salt of the compound, any amorphous form of a complex of the compound, any amorphous form of a solvate (including hydrates) of the compound, or any amorphous form of a co-precipitate of the compound. In many cases, the terms "crystalline form" and "solid form" can refer to those crystalline forms and solid forms that are pharmaceutically acceptable, including, for example, crystalline forms and solid forms of pharmaceutically acceptable addition salts, crystalline forms and solid forms of pharmaceutically acceptable complexes, crystalline forms and solid forms of pharmaceutically acceptable solvates, crystalline forms and solid forms of pharmaceutically acceptable cocrystals, and crystalline forms and solid forms of pharmaceutically acceptable coprecipitates.

[0053] The term "hyperkinetic disorder" or "hyperkinetic movement disorder" or "hyperkinesia" refers to a disorder or disease characterized by excessive, abnormal, involuntary movements. These neurological conditions include, but are not limited to, tremors, dystonias, tics, seizures, akathisia, stereotypies, chorea, myoclonus, and athetosis.

[0054] The term "VMAT2" refers to human monoamine transporter isoform 2, which is an integral membrane protein that serves to transport monoamines, particularly neurotransmitters such as dopamine, norepinephrine, serotonin, and histamine, from the cell cytosol into synaptic vesicles.

[0055] "Pharmaceutically acceptable salt" refers to any salt of a compound provided herein which retains the biological properties of the compound and is not toxic or undesirable for pharmaceutical use. These salts may be derived from various organic and inorganic counterions known in the art. These salts include, but are not limited to: (1) acid addition salts formed with organic or inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, glutaric acid, pyruvic acid, lactic acid, malonic acid, succinic acid, sorbic acid, ascorbic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoic acid), benzoic acid, ... Benzoyl)benzoic acid, picric acid, cinnamic acid, mandelic acid, phthalic acid, lauric acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphoric acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid or (2) salts formed when an acidic proton present in the parent compound is replaced either (a) by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion) or an alkali metal hydroxide or an alkaline earth metal hydroxide (e.g., hydroxides of sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium) or ammonia, or (b) by a complex with an organic base. The salt formed when the organic base is in the position, such as an aliphatic, alicyclic or aromatic organic amine, for example, ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris (hydroxymethyl) -aminomethane, tetramethylammonium hydroxide and the like.

[0056] By way of example only, pharmaceutically acceptable salts also include, but are not limited to, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium salts, and the like, and, when the compound contains a basic functional group, non-toxic organic or inorganic acid salts, such as hydrohalides, e.g., hydrochlorides and hydrobromides, sulfates, phosphates, sulfamates, nitrates, acetates, trifluoroacetates, trichloroacetates, propionates, hexanoates, cyclopentylpropionates, glycolates, glutarates, pyruvates, lactates, malonates, succinates, sorbates, ascorbates, malates, maleates, fumarates, tartrates, citrates, benzoates, 3-(4-hydroxybenzoyl)benzoate , picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (benzenesulfonate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, pivalate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylaminosulfonate, quinate, muconate, etc.

[0057] The term "amino acid" refers to naturally occurring and synthetic α, β, γ or δ amino acids, including but not limited to those found in proteins, i.e., glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine and histidine. In one embodiment, the amino acid is in the L-configuration. Alternatively, the amino acid can be a derivative of alanyl, valyl, leucyl, isoleucyl, prolyl, phenylalanyl, tryptophanyl, methionyl, glycyl, seryl, threonyl, cysteinyl, tyrosyl, asparaginyl, glutaminyl, aspartyl, glutamyl, lysyl, arginyl, histidyl, β-alanyl, β-valyl, β-leucyl, β-isoleucyl, β-prolyl, β-phenylalanyl, β-tryptophanyl, β-methionyl, β-glycyl, β-seryl, β-threonyl, β-cysteinyl, β-tyrosyl, β-asparaginyl, β-glutaminyl, β-aspartyl, β-glutamyl, β-lysyl, β-arginyl, or β-histidyl.

[0058] When referring to a composition as being "substantially free" of a compound, the term "substantially free" means that the composition contains no more than about 20% by weight, no more than about 10% by weight, no more than about 5% by weight, no more than about 3% by weight, no more than about 1% by weight, no more than about 0.5% by weight, no more than about 0.2% by weight, no more than about 0.1% by weight, no more than about 0.01% by weight, no more than about 0.001% by weight, or no more than about 0.0001% by weight of the compound.

[0059] The term "substantially pure," when referring to a compound or composition, means that the compound or composition has a purity of not less than about 80% by weight, not less than about 90% by weight, not less than about 95% by weight, not less than about 96% by weight, not less than about 97% by weight, not less than about 98% by weight, not less than about 99% by weight, not less than about 99.5% by weight, not less than about 99.9% by weight, not less than about 99.95% by weight, not less than about 99.99% by weight, not less than about 99.995% by weight, not less than about 99.999% by weight, not less than about 99.9995% by weight, or not less than about 99.9999% by weight.

[0060] The terms "process" and "method" are used interchangeably to refer to methods disclosed herein for the preparation of compounds. The present disclosure also encompasses modifications to the processes and methods disclosed herein (e.g., starting materials, reagents, protecting groups, solvents, temperatures, reaction times, and / or purification) that are well known to those of ordinary skill in the art.

[0061] The terms "addition", "reaction" and "mixing" are used interchangeably to refer to contacting a reactant, reagent, solvent, catalyst or reactive group with another reactant, reagent, solvent, catalyst or reactive group. Unless otherwise indicated, reactants, reagents, solvents, catalysts and reactive groups can be added individually, simultaneously or separately, and / or can be added in any order. They can be added in the presence or absence of heating and can optionally be added under an inert atmosphere (e.g., N2 or Ar). In certain embodiments, the term "reaction" can also refer to in situ formation or intramolecular reaction, wherein the reactive groups are in the same molecule.

[0062] The term "substantially complete," when referring to a reaction, means that the reaction contains no more than about 50%, no more than about 40%, no more than about 30%, no more than about 20%, no more than about 10%, no more than about 5%, no more than about 4%, no more than about 3%, no more than about 2%, no more than about 1%, no more than about 0.5%, no more than about 0.1%, or no more than about 0.05% of the starting material remaining.

[0063] If the stereochemistry of a structure or portion thereof is not indicated, for example, by bold or dashed lines, the structure or portion thereof should be interpreted as encompassing all stereoisomers of the structure.

[0064] The phrase "a pharmaceutically acceptable salt, solvate, hydrate or polymorph thereof" has the same meaning as the phrase "a pharmaceutically acceptable salt, solvate, hydrate or polymorph of the compound mentioned therein; or a pharmaceutically acceptable salt, solvate, hydrate or polymorph of an enantiomer or mixture of enantiomers of the compound mentioned therein."

[0065] Craftsmanship

[0066] Provided herein are methods 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) or a pharmaceutically acceptable solvate, hydrate, or polymorph thereof having a purity of at least about 95%. In certain embodiments, the methods provided herein are safe, effective, cost-effective, and / or readily scalable. In certain embodiments, the methods provided herein are suitable for large-scale or commercial production 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) or a pharmaceutically acceptable solvate, hydrate, or polymorph thereof.

[0067] In one embodiment, provided herein is 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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof having a purity of at least about 95%; comprising: -dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate dihydrochloride is converted 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-amino-3-methylbutanoate di(4-methylbenzenesulfonate) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof.

[0068] In one embodiment, (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 is converted 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 The steps of preparing 2,1-a]isoquinolin-2-yl 2-amino-3-methylbutyrate di(4-methylbenzenesulfonate) include: (a) reacting (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-methylbutyrate dihydrochloride with a base, and (b) reacting the product of (a) with p-toluenesulfonic acid.

[0069] In another embodiment, (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 is contacted with a base in a first solvent.

[0070] In certain embodiments, the base comprises an inorganic base. In some embodiments, the base comprises a carbonate base. In some embodiments, the base comprises sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate. In some embodiments, the base is sodium bicarbonate.

[0071] In some embodiments, the solvent in step (a) (i.e., reacting (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 with a base) 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 heteroaromatic hydrocarbon, a heterocycle, water, or a mixture thereof. In certain embodiments, the solvent is a chlorinated hydrocarbon. In other embodiments, the solvent is dichloromethane.

[0072] In certain embodiments, the reaction 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 with a base is carried out at a temperature of about 0° C. to about 30° C., about 5° C. to about 25° C., or about 5° C. to about 20° C. In some embodiments, the reaction is carried out at a temperature of about 20° C. to about 30° C. In other embodiments, the reaction is carried out at a temperature of about 25° C.

[0073] In another embodiment, the reaction of the product of (a) with p-toluenesulfonic acid is carried out in a second solvent.

[0074] In some embodiments, the solvent is a hydrocarbon, a chlorinated hydrocarbon, an alcohol, an ether, a ketone, an ester, a carbonate, an amide, a nitrile, a sulfoxide, a sulfone, a nitro compound, a heteroaromatic hydrocarbon, a heterocycle, a carboxylic acid, a phosphoramide, carbon sulfide, water, or a mixture thereof.

[0075] In certain embodiments, the solvent is petroleum ether, pentane, hexane, heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin, cumene, dichloromethane (DCM), 1,2-dichloroethane, 1,1-dichloroethylene, 1,2-dichloroethylene, chloroform, trichloroethane, trichloroethylene, carbon tetrachloride, chlorobenzene, trifluorotoluene, methanol, ethanol, isopropyl alcohol (IPA), 1-propanol, 1-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, ethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane, bis(2-methoxyethyl) ether, 1,1-dimethoxyethane, Methoxymethane, 2,2-dimethoxypropane, anisole, acetone, butanone, methyl ethyl ketone (MEK), methyl isopropyl ketone, methyl butyl ketone, methyl isobutyl ketone (MIBK), methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, ethylene carbonate, propylene carbonate, formamide, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, acetonitrile (ACN), dimethyl sulfoxide (DMSO), sulfolane, nitromethane, nitrobenzene, N-methylpyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), dioxane, pyridine, formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, hexamethylphosphoramide, carbon sulfide, water; or a mixture thereof.

[0076] In certain embodiments, the solvent is a chlorinated hydrocarbon, a nitrile, or a mixture thereof. In other embodiments, the solvent is dichloromethane, acetonitrile, or a mixture thereof. In other embodiments, the solvent is a mixture of dichloromethane and acetonitrile. In other embodiments, the solvent is acetonitrile.

[0077] In certain embodiments, the volume ratio of p-toluenesulfonic acid to acetonitrile is from about 1 to about 100, from about 2 to about 50, from about 5 to about 50, from about 5 to about 25, from about 10 to about 25, or from about 15 to about 25. In certain embodiments, the volume ratio of p-toluenesulfonic acid to acetonitrile is from about 1 to about 100. In certain embodiments, the volume ratio of p-toluenesulfonic acid to acetonitrile is from about 2 to about 50. In certain embodiments, the volume ratio of p-toluenesulfonic acid to acetonitrile is from about 5 to about 50. In certain embodiments, the volume ratio of p-toluenesulfonic acid to acetonitrile is from about 5 to about 25. In certain embodiments, the volume ratio of p-toluenesulfonic acid to acetonitrile is from about 10 to about 25. In certain embodiments, the volume ratio of p-toluenesulfonic acid to acetonitrile is from about 15 to about 25. In certain embodiments, the volume ratio of p-toluenesulfonic acid to acetonitrile is about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25.

[0078] In one embodiment, (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 is converted 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-amino-3-methylbutanoate dihydrochloride. The step of preparing hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate bis(4-methylbenzenesulfonate) comprises reacting (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 with p-toluenesulfonic acid.

[0079] In another embodiment, the step of converting (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 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-amino-3-methylbutanoate di(4-methylbenzenesulfonate) comprises a solvent.

[0080] In certain embodiments, the solvent is petroleum ether, pentane, hexane, heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin, cumene, dichloromethane (DCM), 1,2-dichloroethane, 1,1-dichloroethylene, 1,2-dichloroethylene, chloroform, trichloroethane, trichloroethylene, carbon tetrachloride, chlorobenzene, trifluorotoluene, methanol, ethanol, isopropyl alcohol (IPA), 1-propanol, 1-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, ethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane, bis(2-methoxyethyl) ether, 1,1-dimethoxyethane, Methoxymethane, 2,2-dimethoxypropane, anisole, acetone, butanone, methyl ethyl ketone (MEK), methyl isopropyl ketone, methyl butyl ketone, methyl isobutyl ketone (MIBK), methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, ethylene carbonate, propylene carbonate, formamide, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, acetonitrile (ACN), dimethyl sulfoxide (DMSO), sulfolane, nitromethane, nitrobenzene, N-methylpyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), dioxane, pyridine, formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, hexamethylphosphoramide, carbon sulfide, water; or a mixture thereof.

[0081] In certain embodiments, the solvent is a hydrocarbon, a nitrile, or a mixture thereof. In other embodiments, the solvent is ethyl acetate, acetonitrile, or a mixture thereof. In other embodiments, the solvent is ethyl acetate.

[0082] In certain embodiments, the step of converting (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 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-amino-3-methylbutanoate di(4-methylbenzenesulfonate) is carried out at a temperature of about 15° C. to about 70° C., about 20° C. to about 70° C., or about 25° C. to about 70° C. In another embodiment, the reaction is carried out at a temperature of about 70° C.

[0083] In certain embodiments, the molar ratio of p-toluenesulfonic acid 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-amino-3-methylbutanoate dihydrochloride is from about 0.1 to about 10, from about 0.2 to about 5, from about 0.5 to about 5, from about 1 to about 4, from about 1 to about 3, or from about 1 to about 2. In certain embodiments, the molar ratio of p-toluenesulfonic acid 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-amino-3-methylbutanoate dihydrochloride is from about 1 to about 4. In certain embodiments, the molar ratio of p-toluenesulfonic acid 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-amino-3-methylbutanoate dihydrochloride is about 4, about 4.1, about 4.2, about 4.3, about 4.4, or about 4.5. In certain embodiments, the molar ratio of p-toluenesulfonic acid 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-amino-3-methylbutanoate dihydrochloride is about 4, about 4.1, or about 4.2. In certain embodiments, the molar ratio of p-toluenesulfonic acid 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-amino-3-methylbutanoate dihydrochloride is about 4. In certain embodiments, the molar ratio of p-toluenesulfonic acid 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-amino-3-methylbutanoate dihydrochloride is about 4.1. In certain embodiments, the molar ratio of p-toluenesulfonic acid 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-amino-3-methylbutanoate dihydrochloride is about 4.2. In some embodiments, the molar ratio of p-toluenesulfonic acid 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-amino-3-methylbutanoate dihydrochloride is about 4.5.In certain embodiments, the molar ratio of p-toluenesulfonic acid 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-amino-3-methylbutanoate dihydrochloride is from about 1 to about 3. In certain embodiments, the molar ratio of p-toluenesulfonic acid 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-amino-3-methylbutanoate dihydrochloride is from about 1 to about 2. In certain embodiments, the molar ratio of p-toluenesulfonic acid 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-amino-3-methylbutanoate dihydrochloride is about 2, about 2.1, about 2.2, about 2.3, about 2.4, or about 2.5. In certain embodiments, the molar ratio of p-toluenesulfonic acid 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-amino-3-methylbutanoate dihydrochloride is about 2, about 2.1, or about 2.2. In certain embodiments, the molar ratio of p-toluenesulfonic acid 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-amino-3-methylbutanoate dihydrochloride is about 2. In certain embodiments, the molar ratio of p-toluenesulfonic acid 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-amino-3-methylbutanoate dihydrochloride is about 2.1. In certain embodiments, the molar ratio of p-toluenesulfonic acid 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-amino-3-methylbutanoate dihydrochloride is about 2.2. In some embodiments, the molar ratio of p-toluenesulfonic acid 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-amino-3-methylbutanoate dihydrochloride is about 2.5.

[0084] In another embodiment, the reaction 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 and p-toluenesulfonic acid is carried out at a temperature of about 0°C to about 100°C, about 5°C to about 90°C, about 5°C to about 80°C, about 10°C to about 70°C, about 10°C to about 60°C, about 10°C to about 50°C, about 10°C to about 40°C, about 10°C to about 30°C. In some embodiments, the reaction 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 and p-toluenesulfonic acid is carried out at a temperature of about 20°C to about 60°C, about 30°C to about 60°C, about 40°C to about 60°C, or about 50°C to about 60°C. In other embodiments, the reaction 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 with p-toluenesulfonic acid is carried out at a temperature of about 40° C. to about 50° C., about 45° C. to about 50° C., about 40° C. to about 55° C., or about 45° C. to about 55° C. In another embodiment, the reaction 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 with p-toluenesulfonic acid is carried out at a temperature of about 50° C.

[0085] In one embodiment, (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 is converted 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-amino-3-methylbutanoate dihydrochloride. The step of preparing 1b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) comprises isolating (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.

[0086] In another embodiment, the reaction 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 is carried out without isolating (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. A step for converting 6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate dihydrochloride into (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).

[0087] In certain embodiments, (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) or a pharmaceutically acceptable solvate, hydrate, or polymorph thereof prepared by the methods provided herein has a purity of not less than about 95% by weight, not less than about 96% by weight, not less than about 97% by weight, not less than about 97.5% by weight, not less than about 98% by weight, not less than about 98.5% by weight, not less than about 99% by weight, not less than about 99.5% by weight, not less than about 99.6% by weight, not less than about 99.7% by weight, not less than about 99.8% by weight, or not less than about 99.9% by weight.

[0088] In other embodiments, provided herein is 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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof having a purity of at least about 95%; comprising: reacting (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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof by a deprotection step. A step of reacting 1-(tert-butoxycarbonyl)-3-methylbutanoate under conditions suitable for forming (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 then reacting (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 with a base.

[0089] In other embodiments, provided herein is 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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof having a purity of at least about 95%, comprising: reacting (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) with a deprotection step. The invention relates to a step of reacting (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 under conditions suitable for forming (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 then reacting (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 with p-toluenesulfonic acid.

[0090] In some embodiments, the deprotection step 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 is carried out in the presence of an acid. In certain embodiments, the acid is an inorganic acid. In some embodiments, the acid comprises a solution of hydrogen chloride. In some embodiments, the acid comprises a solution of hydrogen chloride in ether. In some embodiments, the acid comprises a solution of hydrogen chloride in dioxane.

[0091] In some embodiments, the deprotection step 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 is carried out in the presence of a solvent.

[0092] In some embodiments, the solvent is a hydrocarbon, a chlorinated hydrocarbon, an alcohol, an ether, a ketone, an ester, a carbonate, an amide, a nitrile, a sulfoxide, a sulfone, a nitro compound, a heteroaromatic hydrocarbon, a heterocycle, a carboxylic acid, a phosphoramide, a carbon sulfide, water, or a mixture thereof. In certain embodiments, the solvent is a chlorinated hydrocarbon. In certain embodiments, the solvent is dichloromethane.

[0093] In certain embodiments, the deprotection step 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 is carried out at a temperature of about 0° C. to about 25° C., about 0° C. to about 30° C., about 5° C. to about 25° C., about 5° C. to about 20° C. In some embodiments, the reaction is carried out at a temperature of about 20° C. to about 30° C. In other embodiments, the reaction is carried out at a temperature of about 25° C.

[0094] In some embodiments, the reaction 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 to form (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 further comprises the step of adding a base.

[0095] In certain embodiments, the base comprises an inorganic base. In some embodiments, the base comprises a carbonate base. In some embodiments, the base comprises sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate. In some embodiments, the base is sodium bicarbonate.

[0096] In another embodiment, the reaction 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 to form (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 further comprises the step of separating the solvent from the aqueous solution. In certain embodiments, the reaction 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 to form (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 further comprises the step of adding a second solvent.

[0097] In some embodiments, the second solvent is petroleum ether, pentane, hexane, heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin, cumene, dichloromethane (DCM), 1,2-dichloroethane, 1,1-dichloroethylene, 1,2-dichloroethylene, chloroform, trichloroethane, trichloroethylene, carbon tetrachloride, chlorobenzene, trifluorotoluene, methanol, ethanol, isopropyl alcohol (IPA), 1-propanol, 1-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, ethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane, bis(2-methoxyethyl) ether, 1,1 dimethoxymethane, 2,2-dimethoxypropane, anisole, acetone, butanone, methyl ethyl ketone (MEK), methyl isopropyl ketone, methyl butyl ketone, methyl isobutyl ketone (MIBK), methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, ethylene carbonate, propylene carbonate, formamide, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, acetonitrile (ACN), dimethyl sulfoxide (DMSO), sulfolane, nitromethane, nitrobenzene, N-methylpyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), dioxane, pyridine, formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, hexamethylphosphoramide, carbon sulfide, water; or a mixture thereof.

[0098] In certain embodiments, the second solvent is a chlorinated hydrocarbon, a nitrile, or a mixture thereof. In other embodiments, the solvent is dichloromethane, acetonitrile, or a mixture thereof. In other embodiments, the solvent is dichloromethane, acetonitrile, or a mixture thereof. In other embodiments, the solvent is dichloromethane, acetonitrile, or a mixture thereof. In other embodiments, the solvent is dichloromethane.

[0099] In certain embodiments, the reaction 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 to form (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 further comprises the step of adding an acid. In some embodiments, the acid comprises a solution of hydrogen chloride. In some embodiments, the acid comprises a solution of hydrogen chloride in ether. In some embodiments, the acid comprises a solution of hydrogen chloride in dioxane. In some embodiments, the acid comprises a solution of hydrogen chloride in C 1-6 Alcohol solution.

[0100] In certain embodiments, C 1-6 Alcohol is C1-6 Primary alcohol or C 1-6 secondary alcohols, each optionally substituted with one or more substituents Q. In certain embodiments, C 1-6 Alcohol is C 1-6 A primary alcohol, optionally substituted with one or more substituents Q. In certain embodiments, the hydrogen donor is C 1-6 A secondary alcohol, optionally substituted with one or more substituents Q. In certain embodiments, the hydrogen donor is methanol, ethanol, propan-1-ol, propan-2-ol (IPA), butan-1-ol, butan-2-ol, cyclopentanol, cyclohexanol, benzyl alcohol, menthol, or a mixture thereof. In one embodiment, C 1-6 The alcohol is propan-2-ol.

[0101] In some embodiments, the reaction 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 to form (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 further comprises the step of adding another solvent.

[0102] In certain embodiments, the solvent is a chlorinated hydrocarbon, a nitrile, an ester, or a mixture thereof. In other embodiments, the solvent is a nitrile. In other embodiments, the solvent is acetonitrile.

[0103] In certain embodiments, the volume ratio of hydrogen chloride to dichloromethane is from about 1 to about 100, from about 2 to about 50, from about 5 to about 50, from about 5 to about 25, from about 10 to about 25, or from about 15 to about 25. In certain embodiments, the volume ratio of hydrogen chloride to dichloromethane is from about 1 to about 100. In certain embodiments, the volume ratio of hydrogen chloride to dichloromethane is from about 2 to about 50. In certain embodiments, the volume ratio of hydrogen chloride to dichloromethane is from about 5 to about 50. In certain embodiments, the volume ratio of hydrogen chloride to dichloromethane is from about 5 to about 25. In certain embodiments, the volume ratio of hydrogen chloride to dichloromethane is from about 10 to about 25. In certain embodiments, the volume ratio of hydrogen chloride to dichloromethane is from about 15 to about 25. In certain embodiments, the volume ratio of p-toluenesulfonic acid to acetonitrile is from about 15 to about 25. In certain embodiments, the volume ratio of hydrogen chloride to dichloromethane is about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, or about 25.

[0104] In certain embodiments, the molar ratio of hydrogen chloride 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 is from about 0.1 to about 10, from about 0.2 to about 5, or from about 0.5 to about 5. In certain embodiments, the molar ratio of hydrogen chloride 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 is from about 0.1 to about 5. In certain embodiments, the molar ratio of hydrogen chloride 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 is from about 0.1 to about 5. In some embodiments, the molar ratio of hydrogen chloride 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 is from about 0.5 to about 5. In some embodiments, the molar ratio of hydrogen chloride 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 is from about 0.5 to about 5. In some embodiments, the molar ratio of hydrogen chloride 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 is about 5, about 5.1, or about 5.2. In some embodiments, the molar ratio of hydrogen chloride 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 is about 5, about 5.1, or about 5.2. In some embodiments, the molar ratio 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 is about 5. In some embodiments, the molar ratio 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 is about 5.1.In certain embodiments, the molar ratio of hydrogen chloride 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 is about 5.2. In some embodiments, the molar ratio of hydrogen chloride 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 is about 5.5.

[0105] In certain embodiments, (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 forms (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. The reaction of 4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate dihydrochloride is carried out at a temperature of about 0° C. to about 30° C., about 5° C. to about 80° C., about 5° C. to about 70° C., about 5° C. to about 60° C., about 5° C. to about 50° C., about 5° C. to about 40° C., about 5° C. to about 30° C., about 5° C. to about 25° C., about 5° C. to about 20° C. In some embodiments, the reaction is carried out at a temperature of about 5° C. to about 80° C. In some embodiments, the reaction is carried out at a temperature of about 50° C. to about 70° C.

[0106] In other embodiments, (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 forms (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. The reaction of 7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate dihydrochloride further includes the step of crystallizing (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.

[0107] In certain embodiments, (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 or a pharmaceutically acceptable solvate, hydrate or polymorph thereof prepared by the methods provided herein has a purity of not less than about 95% by weight, not less than about 96% by weight, not less than about 97% by weight, not less than about 97.5% by weight, not less than about 98% by weight, not less than about 98.5% by weight, not less than about 99% by weight, not less than about 99.5% by weight, not less than about 99.6% by weight, not less than about 99.7% by weight, not less than about 99.8% by weight, or not less than about 99.9% by weight.

[0108] In other embodiments, (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 or a pharmaceutically acceptable solvate, hydrate or polymorph thereof prepared by the methods provided herein has a purity of not less than about 99.5%, about 99.6%, about 99.7%, about 99.8%, about 99.9% pure.

[0109] In other embodiments, provided herein is 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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof having a purity of at least about 95%; comprising: reacting (2R,3R,11bR)-3-isobutyl- A step of reacting 9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof with a tert-butoxycarbonyl-protected amino acid under conditions suitable for forming (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.

[0110] In some embodiments, the step of reacting (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol with a tert-butoxycarbonyl-protected amino acid to form (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 is carried out using a salt of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol. In certain embodiments, the salt comprises a sulfonate. In other embodiments, the salt is a camphorsulfonate. In some embodiments, the (2R, 3R, 11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol salt is (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.

[0111] In certain embodiments, the reaction of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof with a tert-butoxycarbonyl protected amino acid to form (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 comprises valine or alanine amino acid. In some embodiments, the amino acid is valine. In other embodiments, the tert-butoxycarbonyl protected amino acid is L-valine.

[0112] In certain embodiments, the reaction of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof to form (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 is carried out in the presence of a base.

[0113] In some embodiments, the base is an organic base. In certain embodiments, the base is an inorganic base. In certain embodiments, the base is an organic base. In certain embodiments, the base is sodium bicarbonate, sodium carbonate, sodium citrate, sodium hydroxide, potassium hydroxide, or 4-dimethylaminopyridine. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide. In some embodiments, the base is 4-dimethylaminopyridine.

[0114] In certain embodiments, the reaction of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof with a tert-butoxycarbonyl-protected amino acid to form (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 further comprises a coupling agent.

[0115] In certain embodiments, the coupling agent is carbodiimide, 1,1'-carbonyldiimidazole (CDI), bis(2-oxo-3-oxazolidinyl)phosphinyl chloride (BOP-Cl), hexafluorophosphate (BOP reagent), PCh, PCls, or 1-propanephosphonic acid cyclic anhydride. In certain embodiments, the coupling agent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC or EDCI), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC hydrochloride), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methyl iodide (EDC methyl iodide), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide methyl p-toluenesulfonate, or 1,3-dicyclohexylcarbodiimide (DCC). In certain embodiments, the coupling agent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC or EDCI), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC hydrochloride), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methyl iodide (EDC methyl iodide), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide methyl p-toluenesulfonate, or 1,3-dicyclohexylcarbodiimide (DCC). In some embodiments, the coupling agent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC or EDCI).

[0116] In certain embodiments, the reaction of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof to form (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 is carried out in the presence of a solvent.

[0117] In some embodiments, the 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 heteroaromatic hydrocarbon, a heterocycle, water or a mixture thereof. In certain embodiments, the solvent is a chlorinated hydrocarbon solvent. In certain embodiments, the solvent is dichloromethane. In certain embodiments, the solvent is an ether. In certain embodiments, the solvent is a cycloalkyl ether. In certain embodiments, the solvent is 2-methyltetrahydrofuran (MeTHF).

[0118] In certain embodiments, the reaction of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof to form (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 is carried out at a temperature of about 0°C to about 20°C, about 0°C to about 30°C, about 5°C to about 80°C, about 5°C to about 70°C, about 5°C to about 60°C, about 5°C to about 50°C, about 5°C to about 40°C, about 5°C to about 30°C, about 5°C to about 25°C, about 5°C to about 20°C. In some embodiments, the reaction is carried out at a temperature of about 0°C to about 20°C.

[0119] In some embodiments, (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 prepared by the methods provided herein is obtained as a dichloromethane solution.

[0120] In other embodiments, provided herein is 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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof having a purity of at least about 95%; comprising reacting the mixture with tert-butyl Before the reaction of the oxycarbonyl-protected amino acid, 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol is reacted with a chiral resolving agent to form (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof.

[0121] In certain embodiments, the chiral reagent comprises aminocaprolactamic acid, aminopropanol, anthracenyltrifluoroethanol, aspartic acid, benzodioxanecarboxylic acid, benzylaminocyclohexanemethanol, naphthylethylamine, binaphthyl phosphate, bis-O-chlorobenzyl-L-threitol, bis-hydroxyphenylethylenediamine, bisphenylethylamine, bisphenylethyl o-aminobenzoic acid, bromocamphorsulfonic acid, camphorsulfonic acid, bromophenethylamine, strychnine, 2-butanol, camphanic acid, camphoric acid, chloromethylbenzylamine, cinchonidine, cinchonine, dehydroabietylamine, diacetyltartaric acid, In some embodiments, the chiral reagent comprises an acid. In some embodiments, the acid is a sulfonic acid. In other embodiments, the acid is camphorsulfonic acid. In other embodiments, the acid is (1S)-(+)-camphorsulfonic acid.

[0122] In other embodiments, the reaction of 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol with a chiral resolving agent to form (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is carried out in the presence of a solvent. In some embodiments, the solvent comprises water and an alcohol. In certain embodiments, the alcohol is C as defined herein. 1-6Alcohol. In other embodiments, the solvent mixture comprises water and ethanol. In certain embodiments, the solvent mixture comprises water and ethanol in a volume ratio of about 0.1 to about 100, about 0.2 to about 50, about 0.5 to about 25, about 1 to about 20, about 1 to about 10, about 1 to about 5, or about 1 to about 2. In certain embodiments, the volume ratio of water to ethanol is about 1 to about 20. In certain embodiments, the volume ratio of water to ethanol is about 1 to about 19. In certain embodiments, the volume ratio of water to ethanol is about 1 to about 18. In certain embodiments, the volume ratio of water to ethanol is about 1 to about 17. In certain embodiments, the volume ratio of water to ethanol is about 1 to about 16. In certain embodiments, the volume ratio of water to ethanol is about 1 to about 15. In certain embodiments, the volume ratio of water to ethanol is about 1 to about 14. In certain embodiments, the volume ratio of water to ethanol is about 1 to about 13. In certain embodiments, the volume ratio of water to ethanol is about 1 to about 12. In certain embodiments, the volume ratio of water to ethanol is about 1 to about 11. In certain embodiments, the volume ratio of water to ethanol is from about 1 to about 10.

[0123] In certain embodiments, the reaction of 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol with a chiral resolving agent to form (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is carried out at a temperature of about 0°C to about 100°C, about 5°C to about 90°C, about 5°C to about 80°C, about 10°C to about 70°C, about 10°C to about 60°C, about 10°C to about 50°C, about 10°C to about 40°C, about 10°C to about 30°C. In some embodiments, the reaction of 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol with a chiral resolving agent to form (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is carried out at a temperature of about 20° C. to about 80° C., about 20° C. to about 70° C., about 20° C. to about 60° C., about 20° C. to about 70° C. In other embodiments, the reaction is carried out at a temperature of about 20° C. to about 65° C. or at a temperature of about 20° C. to about 75° C.

[0124] In other embodiments, reacting 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol with a chiral resolving agent to form (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof further comprises the step of crystallizing (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof.

[0125] In certain embodiments, (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof, or a solvate, hydrate or polymorph thereof prepared by the methods provided herein has a purity of not less than about 95% by weight, not less than about 96% by weight, not less than about 97% by weight, not less than about 10% by weight, or not less than about 10% by weight. At least about 97.5 wt %, not less than about 98 wt %, not less than about 98.5 wt %, not less than about 99 wt %, not less than about 99.1 wt %, not less than about 99.2 wt %, not less than about 99.3 wt %, not less than about 99.4 wt %, not less than about 99.5 wt %, not less than about 99.6 wt %, not less than about 99.7 wt %, not less than about 99.8 wt %, or not less than about 99.9 wt %. In certain embodiments, provided herein is 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) or a pharmaceutically acceptable solvate, hydrate, or polymorph thereof having a purity of at least about 95%; comprising the step of reducing 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one to form 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol prior to reacting with a chiral reagent.

[0126] In other embodiments, the reduction of 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one to form 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol is carried out in the presence of an acid. In some embodiments, the acid comprises a Lewis acid. In other embodiments, the Lewis acid includes, but is not limited to, titanium tetrachloride (TiCl4), zinc dichloride (ZnCl2), boron trifluoride (BF3), aluminum halides, and alkyl aluminum halides (AlX3 and R n AlX 3-n ), phosphorus pentafluoride and antimony pentafluoride (PF5 and SbF5), and tin dichloride and tin tetrachloride (SnCl2 and SnCl4), lithium halides (LiX), including lithium chloride and lithium bromide (LiCl and LiBr), copper halides (CuX2), including copper chloride and copper bromide (CuCl2 and CuBr2). In certain embodiments, the acid is a lithium halide. In other embodiments, the acid is lithium chloride.

[0127] In other embodiments, the reduction of 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one to form 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol is carried out in the presence of an organic acid. In certain embodiments, the organic acid is a carboxylic acid. In certain embodiments, the organic acid is C optionally substituted with one or more substituents Q. 1-14 In certain embodiments, the acid is 2-hydroxy-C 1-14 Carboxylic acid, optionally substituted with one or more substituents Q. In certain embodiments, the hydrogen donor is acetic acid, formic acid, oxalic acid, maleic acid, lactic acid, ascorbic acid, mandelic acid, or a mixture thereof. In certain embodiments, the organic acid is acetic acid.

[0128] In some embodiments, the reduction of 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one to form 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol is carried out in the presence of a reducing agent. In other embodiments, the reducing agent is a borohydride. In certain 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. In other embodiments, the reducing agent is sodium borohydride.

[0129] In some embodiments, the reduction of 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one to form 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol is carried out in the presence of a solvent. In some embodiments, the solvent comprises dichloromethane and an alcohol. In certain embodiments, the alcohol is C as defined herein. 1-6 Alcohol. In other embodiments, the solvent mixture comprises dichloromethane and ethanol. In certain embodiments, the solvent mixture comprises dichloromethane and ethanol in a volume ratio of about 0.1 to about 100, about 0.2 to about 50, about 0.5 to about 25, about 1 to about 20, about 1 to about 10, about 1 to about 5, or about 1 to about 2. In certain embodiments, the volume ratio of dichloromethane and ethanol is about 2 to about 30. In certain embodiments, the volume ratio of dichloromethane and ethanol is about 2 to about 20. In certain embodiments, the volume ratio of dichloromethane and ethanol is about 2 to about 10. In certain embodiments, the volume ratio of dichloromethane and ethanol is about 2 to about 19, about 2 to about 18, about 2 to about 17, about 2 to about 16, about 2 to about 15, about 2 to about 14, about 2 to about 13, about 2 to about 12, about 2 to about 11, about 2 to about 10. The volume ratio of dichloromethane and ethanol is about 2 to about 14. In certain embodiments, the volume ratio of dichloromethane to ethanol is from about 2 to about 16.

[0130] In certain embodiments, the molar ratio of sodium borohydride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 0.5 to about 100, from about 1 to about 100, from about 1 to about 50, from about 1 to about 25, from about 1 to about 20, from about 1 to about 10, from about 2 to about 50, from about 5 to about 50, from about 5 to about 25, from about 10 to about 25, or from about 15 to about 25. In certain embodiments, the molar ratio of sodium borohydride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 1 to about 100. In certain embodiments, the molar ratio of sodium borohydride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 1 to about 50. In certain embodiments, the molar ratio of sodium borohydride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 1 to about 25. In certain embodiments, the molar ratio of sodium borohydride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 1 to about 20. In certain embodiments, the molar ratio of sodium borohydride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 1 to about 10. In certain embodiments, the molar ratio of sodium borohydride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 2 to about 50. In certain embodiments, the molar ratio of sodium borohydride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 5 to about 50. In certain embodiments, the molar ratio of sodium borohydride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 5 to about 25. In certain embodiments, the molar ratio of sodium borohydride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 10 to about 25. In certain embodiments, the molar ratio of sodium borohydride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 15 to about 25.In certain embodiments, the molar ratio of sodium borohydride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0. In certain embodiments, the molar ratio of sodium borohydride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is about 1.2.

[0131] In some embodiments, the molar ratio of acetic acid to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 0.5 to about 100, from about 1 to about 100, from about 1 to about 50, from about 1 to about 25, from about 1 to about 20, from about 1 to about 10, from about 2 to about 50, from about 5 to about 50, from about 5 to about 25, from about 10 to about 25, or from about 15 to about 25. In some embodiments, the molar ratio of acetic acid to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 1 to about 100. In some embodiments, the molar ratio of acetic acid to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 1 to about 50. In some embodiments, the molar ratio of acetic acid to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 1 to about 25. In some embodiments, the molar ratio of acetic acid to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 1 to about 20. In some embodiments, the molar ratio of acetic acid to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 1 to about 10. In some embodiments, the molar ratio of acetic acid to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 2 to about 50. In some embodiments, the molar ratio of acetic acid to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 5 to about 50. In some embodiments, the molar ratio of acetic acid to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 5 to about 25. In some embodiments, the molar ratio of acetic acid to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 10 to about 25. In some embodiments, the molar ratio of acetic acid to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 15 to about 25.In some embodiments, the molar ratio of acetic acid to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0. In some embodiments, the molar ratio of acetic acid to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is about 1.1.

[0132] In some embodiments, the molar ratio of lithium chloride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 0.5 to about 100, from about 1 to about 100, from about 1 to about 50, from about 1 to about 25, from about 1 to about 20, from about 1 to about 10, from about 2 to about 50, from about 5 to about 50, from about 5 to about 25, from about 10 to about 25, or from about 15 to about 25. In some embodiments, the molar ratio of lithium chloride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 1 to about 100. In some embodiments, the molar ratio of lithium chloride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 1 to about 50. In some embodiments, the molar ratio of lithium chloride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 1 to about 25. In some embodiments, the molar ratio of lithium chloride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 1 to about 20. In some embodiments, the molar ratio of lithium chloride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 1 to about 10. In some embodiments, the molar ratio of lithium chloride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 2 to about 50. In some embodiments, the molar ratio of lithium chloride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 5 to about 50. In some embodiments, the molar ratio of lithium chloride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 5 to about 25. In some embodiments, the molar ratio of lithium chloride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 10 to about 25. In some embodiments, the molar ratio of lithium chloride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is from about 15 to about 25.In some embodiments, the molar ratio of lithium chloride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0. In some embodiments, the molar ratio of lithium chloride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is about 1.

[0133] In certain embodiments, the reduction of 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one to form 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol 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 -5°C, about -5°C to about 0°C, about 0°C to about 5°C, about 0°C to about 10°C, about 0°C to about 15°C, about 0°C to about 20°C, about 0°C to about 25°C, about 5°C to about 25°C, about 5°C to about 15°C, about 5°C to about 10°C. In some embodiments, the reduction is carried out at a temperature of about -5°C to about -15°C. In certain embodiments, the reduction of 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one to form 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol is carried out at a temperature of about -20°C, about -15°C, about -10°C, about -5°C. In certain embodiments, the reduction of 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one to form 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol is carried out at a temperature of about -10°C.

[0134] In other embodiments, reacting 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one to form 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol further comprises the step of crystallizing 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol.

[0135] In certain embodiments, 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a pharmaceutically acceptable salt, or a solvate, hydrate, or polymorph thereof, prepared by the methods provided herein has a purity of not less than about 95% by weight, not less than about 96% by weight, not less than about 97% by weight, not less than about 97.5% by weight, not less than about 98% by weight, not less than about 98.5% by weight, or not less than about 99% by weight. In some embodiments, 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof, or a solvate, hydrate, or polymorph thereof, prepared by the methods provided herein has a purity of not less than about 97.5%, not less than about 97.6%, not less than about 97.7%, not less than about 97.8%, not less than about 97.9%, not less than about 98.1%, not less than about 98.2%, not less than about 98.3%, not less than about 98.4%, not less than about 98.5%, not less than about 98.6%, not less than about 98.7%, not less than about 98.8%, or not less than about 98.9%. In some embodiments, the purity of 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a pharmaceutically acceptable salt thereof, or a solvate, hydrate or polymorph thereof prepared by the methods provided herein is not less than about 97.6% by weight or not less than about 98.1% by weight.

[0136] In certain embodiments, provided herein is 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) or a pharmaceutically acceptable solvate, hydrate, or polymorph thereof having a purity of at least about 95%; comprising, prior to the reduction step, reacting 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof with 3-((dimethylamino)methyl)-5-methylhexan-2-one or a salt thereof to form 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one.

[0137] In some embodiments, the reaction of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof with 3-((dimethylamino)methyl)-5-methylhexan-2-one or a salt thereof to form 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is carried out in the presence of a solvent.

[0138] In some embodiments, the solvent is a hydrocarbon, a chlorinated hydrocarbon, an alcohol, an ether, a ketone, an ester, a carbonate, an amide, a nitrile, a sulfoxide, a sulfone, a nitro compound, a heteroaromatic hydrocarbon, a heterocycle, a carboxylic acid, a phosphoramide, carbon sulfide, water, or a mixture thereof.

[0139] In certain embodiments, the solvent is petroleum ether, pentane, hexane, heptane, octane, isooctane, cyclopentane, cyclohexane, methylcyclohexane, benzene, toluene, xylene, tetralin, cumene, dichloromethane (DCM), 1,2-dichloroethane, 1,1-dichloroethylene, 1,2-dichloroethylene, chloroform, trichloroethane, trichloroethylene, carbon tetrachloride, chlorobenzene, trifluoromethylbenzene, methanol, ethanol, isopropyl alcohol (IPA), 1-propanol, 1-butanol, 2-butanol, tert-butanol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, diethyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), diphenyl ether, 1,2-dimethoxyethane, bis(2-methoxyethyl) ether, 1,1-dimethoxyethyl Methoxymethane, 2,2-dimethoxypropane, anisole, acetone, butanone, methyl ethyl ketone (MEK), methyl isopropyl ketone, methyl butyl ketone, methyl isobutyl ketone (MIBK), methyl acetate, ethyl formate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, butyl acetate, ethylene carbonate, propylene carbonate, formamide, N,N-dimethylformamide (DMF), N,N-dimethylacetamide, acetonitrile (ACN), dimethyl sulfoxide (DMSO), sulfolane, nitromethane, nitrobenzene, N-methylpyrrolidone, 2-methyltetrahydrofuran, tetrahydrofuran (THF), dioxane, pyridine, formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, hexamethylphosphoramide, carbon disulfide, water; or a mixture thereof.

[0140] In certain embodiments, in the reaction of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof with 3-((dimethylamino)methyl)-5-methylhexan-2-one or a salt thereof to form 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one, the solvent comprises a mixture of hydrocarbons and water. In certain embodiments, the solvent comprises a mixture of heptane and water.

[0141] In certain embodiments, the solvent mixture comprises heptane and water in a volume ratio of about 0.1 to about 100, about 0.2 to about 50, about 0.5 to about 25, about 1 to about 20, about 1 to about 10, about 1 to about 5, about 1 to about 3, or about 1 to about 2. In certain embodiments, the volume ratio of heptane to water is about 2 to about 30. In certain embodiments, the volume ratio of heptane to water is about 2 to about 20. In certain embodiments, the volume ratio of heptane to water is about 2 to about 10. In certain embodiments, the volume ratio of heptane to water is about 1 to about 2, about 1 to about 2, about 1 to about 5, about 1.1 to about 2, about 1.1 to about 3, about 1.2 to about 2, about 1.2 to about 3, about 1.3 to about 2, about 1.3 to about 3, about 1.4 to about 2, about 1.4 to about 3, about 1.5 to about 2, about 1.5 to about 3. In certain embodiments, the volume ratio of heptane to water is about 1.5 to about 3.

[0142] In some embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline, or a salt thereof, to 3-((dimethylamino)methyl)-5-methylhexan-2-one is from about 0.5 to about 100, from about 1 to about 100, from about 1 to about 50, from about 1 to about 25, from about 1 to about 20, from about 1 to about 10, from about 2 to about 50, from about 5 to about 50, from about 5 to about 25, from about 10 to about 25, or from about 15 to about 25. In some embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline, or a salt thereof, to 3-((dimethylamino)methyl)-5-methylhexan-2-one is from about 1 to about 100. In some embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline, or a salt thereof, to 3-((dimethylamino)methyl)-5-methylhexan-2-one is from about 1 to about 50. In some embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is from about 1 to about 25. In some embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is from about 1 to about 20. In some embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is from about 1 to about 10. In some embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is from about 2 to about 50. In some embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is from about 5 to about 50. In some embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is from about 5 to about 25. In some embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is from about 10 to about 25. In some embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is from about 15 to about 25. In some embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is about 1, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0. In some embodiments, the molar ratio of sodium borohydride to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is about 1.1.

[0143] In some embodiments, the reaction of 6,7-dimethoxy-3,4-dihydroisoquinoline, or a salt thereof, with 3-((dimethylamino)methyl)-5-methylhexan-2-one, or a salt thereof, to form 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is carried out at a temperature of about 0°C to about 100°C, about 5°C to about 90°C, about 5°C to about 80°C, about 10°C to about 70°C, about 10°C to about 60°C, about 10°C to about 50°C, about 10°C to about 40°C, about 10°C to about 30°C. In some embodiments, the reaction of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof with 3-((dimethylamino)methyl)-5-methylhexan-2-one or a salt thereof to form 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is carried out at a temperature of about 20° C. to about 80° C., about 20° C. to about 70° C., about 20° C. to about 60° C., about 20° C. to about 50° C. In other embodiments, the reaction is carried out at a temperature of about 30° C. to about 80° C., about 30° C. to about 70° C., about 30° C. to about 60° C., about 30° C. to about 40° C., about 30° C. to about 50° C. In some embodiments, the reaction of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof with 3-((dimethylamino)methyl)-5-methylhexan-2-one or a salt thereof to form 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is carried out at a temperature of about 30°C to about 40°C.

[0144] In certain embodiments, the reaction of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof with 3-((dimethylamino)methyl)-5-methylhexan-2-one or a salt thereof to form 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one further comprises a step of reacting the 3-((dimethylamino)methyl)-5-methylhexan-2-one salt with a base prior to reacting with 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof.

[0145] In some embodiments, the 6,7-dimethoxy-3,4-dihydroisoquinoline salt comprises an inorganic acid salt. In certain embodiments, the inorganic acid salt comprises a hydrochloride salt.

[0146] In some embodiments, the 3-((dimethylamino)methyl)-5-methylhexan-2-one salt comprises a carboxylate. In certain embodiments, the carboxylate comprises a fumarate, an oxalate, a citrate, or a maleate. In other embodiments, the carboxylate comprises an oxalate or a citrate.

[0147] In some embodiments, the reaction of the 3-((dimethylamino)methyl)-5-methylhexan-2-one salt with a base comprises an inorganic base. In other embodiments, the base is a carbonate, bicarbonate, or hydroxide base. In other embodiments, the base is sodium carbonate.

[0148] In some embodiments, provided herein is 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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof having a purity of at least about 95%; comprising (a) converting (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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof to (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof 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-amino-3-methylbutanoate dihydrochloride; and (b) converting (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 into (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 or a pharmaceutically acceptable solvate, hydrate or polymorph thereof.

[0149] In certain embodiments, steps (a) (i.e., converting (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof 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-amino-3-methylbutanoate dihydrochloride) and (b) are performed as described herein. ) (i.e., converting (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 into (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)).

[0150] In other embodiments, provided herein is 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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof having a purity of at least about 95%; comprising the steps of: (a) reacting (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) with a purity of at least about 95%; 3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is reacted with an appropriately protected L-valine to form (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; (b) reacting (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; (c) deprotecting (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 to form (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 or a pharmaceutically acceptable solvate, hydrate or polymorph thereof; and (d) reacting (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 or a pharmaceutically acceptable solvate, hydrate or polymorph thereof. )-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 is converted into (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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof.

[0151] In certain embodiments, step (b) (i.e., deprotection 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) and step (c) (i.e., conversion 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) are performed as described herein. 0-Dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate dihydrochloride was converted 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-amino-3-methylbutanoate di(4-methylbenzenesulfonate).

[0152] 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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof having a purity of at least about 95% comprises the following steps: (a) crystallizing (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; (b) crystallizing (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; (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 or a pharmaceutically acceptable solvate, hydrate or polymorph thereof with a base; and (c) reacting the product of step (b) with p-toluenesulfonic acid to form (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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof.

[0153] In some embodiments, the crystallization step 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 is performed as described herein.

[0154] In other embodiments, the crystallization step 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 is performed as described in U.S. Provisional Application No. 62 / 249,074, filed on October 30, 2015; the disclosure of which is incorporated herein by reference in its entirety.

[0155] In certain embodiments, (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 or a pharmaceutically acceptable solvate, hydrate or polymorph thereof prepared by the methods provided herein is substantially pure. In certain embodiments, (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 or a pharmaceutically acceptable solvate, hydrate or polymorph thereof prepared by the methods provided herein is suitable for use in humans, e.g., for use in treating, preventing and / or managing a disease, disorder or condition.

[0156] In certain embodiments, the methods provided herein 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) or a pharmaceutically acceptable solvate, hydrate, or polymorph thereof, provide a total yield of not less than about 30%, not less than about 40%, not less than about 50%, not less than about 55%, not less than about 60%, not less than about 65%, not less than about 70%, not less than about 75%, not less than about 80%, not less than about 85%, not less than about 90%, or not less than about 95%, wherein the yield is calculated based on the starting material.

[0157] In certain embodiments, (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) or a pharmaceutically acceptable solvate, hydrate, or polymorph thereof prepared by the methods provided herein is substantially pure. In certain embodiments, (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) prepared by the methods provided herein, or a pharmaceutically acceptable solvate, hydrate, or polymorph thereof, is suitable for use in humans, e.g., for the treatment, prevention, and / or management of a disease, disorder, or condition.

[0158] In certain embodiments, the total impurities in 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-amino-3-methylbutanoate di(4-methylbenzenesulfonate) or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof prepared by the methods provided herein do not exceed about 5 weight %, not exceed about 4 weight %, not exceed about 3 weight %, not exceed about 2.5 weight %, not exceed about 2 weight %, not exceed about 1.5 weight %, not exceed about 1 weight %, not exceed about 0.5 weight %, or not exceed about 0.1 weight %.

[0159] In certain embodiments, impurities can be detected by HPLC (high performance liquid chromatography). In certain embodiments, impurities include, but are not limited to, (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof, (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-aminopropanoate, and (S)-(2S,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. In some embodiments, the impurity is (R)-(2R,3R,11bR)-3-isobutyl-9,10,11b-trimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate. In some embodiments, the impurity is 6,7-dimethoxy-3,4-dihydroisoquinoline. In some embodiments, the impurity is (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-7-oxo-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate.

[0160] In certain embodiments, the impurity is a metal-based impurity. In certain embodiments, the impurity is a volatile organic compound. In certain embodiments, the impurity is an organic solvent. In certain embodiments, the impurity is a sulfonate, dimethylamine, formaldehyde, ethyl chloride, or isopropyl chloride.

[0161] In certain embodiments, the loss on drying (LOD) 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), or a pharmaceutically acceptable salt, solvate, hydrate, or polymorph thereof, prepared by the methods provided herein, is no greater than about 5 wt%, no greater than about 4 wt%, no greater than about 3 wt%, no greater than about 2 wt%, no greater than about 1 wt%, no greater than about 0.9 wt%, no greater than about 0.8 wt%, no greater than about 0.7 wt%, no greater than about 0.6 wt%, no greater than about 0.5 wt%, no greater than about 0.4 wt%, no greater than about 0.3 wt%, no greater than about 0.2 wt%, or no greater than about 0.1 wt%. Example

[0162] Certain embodiments are illustrated by the following non-limiting examples.

[0163] In the following examples, all temperatures are expressed in degrees Celsius and all parts and percentages are by weight unless otherwise indicated. Reagents can be purchased from commercial suppliers such as Sigma-Aldrich. Chemical Co., and unless otherwise noted, the reagents were used without further purification. Reagents can also be prepared according to standard literature procedures known to those skilled in the art. Solvents can be purchased from, for example, Sigma-Aldrich. Unless otherwise indicated, they can be used as is or can be purified using standard methods known to those skilled in the art.

[0164] Unless otherwise stated, the following reactions were typically carried out at ambient or room temperature. Reactions were monitored by HPLC and terminated as judged by consumption of starting material.

[0165] The structures and purities 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. Use an NMR spectrometer operating at a certain field strength to determine 1 H NMR spectra. Chemical shifts are reported in parts per million (ppm, δ) relative to a standard (e.g., an internal standard such as TMS). Alternatively, 1 H NMR spectra are referenced to signals 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 assigned 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 given in Hertz (Hz). Mass spectral (MS) data were obtained using a mass spectrometer with APCI or ESI ionization.

[0166] Example 1

[0167] 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-methylbutyrate di(4-methylbenzenesulfonate)

[0168] A. Preparation of 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one

[0169]

[0170] 3-((dimethylamino)methyl)-5-methylhexan-2-one oxalate (174 kg) was suspended in a mixture of n-heptane (184 L) and water (757 L). A solution of sodium hydroxide (75.7 kg) in water (908 L) was added, the temperature was stabilized at 15°C-25°C, and the mixture was stirred at this temperature. The pH was adjusted to 8 to 10 by adding the previous sodium hydroxide / water solution, and the mixture was stirred for 30 to 60 minutes. The aqueous layer was then discarded. Alternatively, 3-((dimethylamino)methyl)-5-methylhexan-2-one citrate (242.1 kg) was used instead of 3-((dimethylamino)methyl)-5-methylhexan-2-one oxalate and the reaction was carried out in the same manner as described herein.

[0171] A solution of 3-((dimethylamino)methyl)-5-methylhexan-2-one in heptane was added to a solution of 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (126.1 kg) in water (315.2 L), and the mixture was stirred at approximately 30°C. The reaction was judged to be complete when less than 10% of 6,7-dimethoxy-3,4-dihydroisoquinoline remained relative to the standard solution. The mixture was cooled to room temperature, and the solid was filtered, washed with water (176.5 L), and then with n-heptane (277.4 L), both of which were stable at temperatures between 15°C and 20°C, and then dried under vacuum to provide 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (139 kg, 79% yield).

[0172] A1. Preparation of 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one from 3-((dimethylamino)methyl)-5-methylhexan-2-one free base

[0173] 6,7-Dimethoxy-3,4-dihydroisoquinoline hydrochloride (118.2 kg) was dissolved in water (3 volumes). 3-((dimethylamino)methyl)-5-methylhexan-2-one (99.1 kg) in n-heptane (1.5 volumes) was added, and the mixture was stirred vigorously at approximately 35°C for at least 48 hours, until less than 10% of 6,7-dimethoxy-3,4-dihydroisoquinoline remained relative to the standard solution. The solid was filtered, washed with water and then heptane, and then dried under vacuum to provide 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (141.1 kg, 85.6% yield).

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

[0175]

[0176] 3-Isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (69.5 kg) was dissolved in dichloromethane (145.9 L, 2.1 volumes). Acetic acid (13.9 L, 1.1 equivalents), lithium chloride (9 kg, 1 equivalent) and ethanol (208.5 L, 14 volumes) were added. The mixture was cooled to -10±5°C and a solution of sodium borohydride (9.73 kg, 1.2 equivalents) in ethanol (139 L, 5 volumes) was slowly added at -10±5°C. The reaction was stirred for several hours and monitored for completion by HPLC. Once the reaction was complete, the mixture was warmed to 25°C and saturated aqueous ammonium chloride (69.5 kg) was added to quench the reaction. The reaction mixture was concentrated to a minimum volume by vacuum distillation at 40±5°C. Water (139 L) was added and the distillation was repeated to a minimum volume. Dichloromethane (549 L) and 1N sodium hydroxide (10.4 kg dissolved in 250.2 L water) were added at 20 ± 5 ° C and stirred for at least 15 minutes. The layers were separated and the organic layer was collected while the aqueous layer was extracted with dichloromethane. The combined organics were washed with water, separated, and then distilled to a minimum volume under vacuum. Isopropyl acetate (347.5 L) was added and the mixture was distilled to about 3 volumes under vacuum and repeated. The slurry was heated to 85 ± 5 ° C, maintained for 0.5-1 hour, and then cooled to 65 ° C to induce crystallization. The mixture was further cooled to 20 ° C and maintained for 1 hour. The solid was filtered, rinsed with isopropyl acetate, and then vacuum dried to give 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (60 kg, 86% yield). Another batch was carried out starting from 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (69.5 kg) using the same procedure as described herein to give 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (59.7 kg, 85% yield).

[0177] C. 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

[0178]

[0179] 3-Isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (59.8 kg) and (S)-(+)-camphorsulfonic acid (46 kg, 1 equivalent) were suspended in 19:1 ethanol:water (v / v) and heated until a solution formed at ~75°C. The mixture was cooled to 53±2°C and held until crystallization occurred. If nucleation did not occur, the batch was seeded 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)-(+)-camphorsulfonic acid salt. The mixture was cooled to 25±5°C over at least 14 hours. The slurry was filtered, washed with ethanol, and then dried in vacuo 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 (1S)-(+)-camphorsulfonate (38.7 g, 38% yield) as a crystalline solid. Another batch was carried out starting from 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (59.6 kg) using the same method as described herein 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 (1S)-(+)-camsylate salt (39.5 kg, 38% yield).

[0180] D. 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-((tert-butoxycarbonyl)amino)-3-methylbutanoate

[0181]

[0182] (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), and the mixture was stirred at 25±5°C. The organics were collected and washed with additional sodium hydroxide solution, followed by water. The organic phase was collected, dried over sodium sulfate, and then filtered to remove solids. Boc-L-valine (12.2 kg, 1.2 equiv) and 4-dimethylaminopyridine (1.55 kg, 0.3 equiv) were added to the organic phase, and the mixture was cooled to approximately 0°C. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (15.8 kg, 1.8 equivalents) was added and the reaction was stirred for>3 hours. The reaction mixture was maintained at 0±5 ° C and monitored for completion by HPLC. Once completed, water was added and the contents were stirred. After sedimentation, the aqueous layer was discarded. The organic layer was washed with citric acid aqueous solution (prepared by 5.2 kg citric acid in 101 L water) and then washed with water to obtain a 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.

[0183] E. 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-methylbutyrate dihydrochloride

[0184]

[0185] A solution of hydrogen chloride in dioxane (4M, 57 L, 5 equivalents) was slowly added to a 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 in dichloromethane while maintaining the temperature between 5°C and 10°C. Once the addition was complete, the mixture was stirred at 25±5°C for >12 hours. Upon completion, aqueous sodium bicarbonate (217.6 kg) was slowly added and the mixture was stirred at 25±5°C until the pH was >7. The organics were collected and washed with additional aqueous sodium bicarbonate solution, followed by 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 for stirring. Acetonitrile (70 L) was added, and the mixture was distilled again to the minimum volume required. Acetonitrile was added until the total volume of the solution was 10, and the solution was then cooled to 10 ± 5° C. Hydrogen chloride in isopropanol (3.7 M, 26.4 L, 2.1 equiv) was slowly added, followed by ethyl acetate (57 L), and the mixture was heated to 50 ± 5° C. Additional ethyl acetate was added, followed by seeds 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, and the mixture was heated to 75 ± 5° C. for > 1 hour. The slurry was slowly cooled to 25 ± 5 ° C, 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 run 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-((tert-butoxycarbonyl)amino)-3-methylbutanoate (24.4 kg) using the same procedure as described herein 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).

[0186] F. 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-methylbutyrate di(4-methylbenzenesulfonate)

[0187]

[0188] (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 solution, followed by water. The organic layer was collected and acetonitrile was added to the dichloromethane solution. The solution was distilled to the minimum volume required for stirring. Additional acetonitrile was added and the mixture was distilled to the minimum volume required for stirring. 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% pure).

[0189] F1. 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-methylbutyrate di(4-methylbenzenesulfonate)

[0190] (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 the pH was >6.5, and the mixture was then stirred at 25°C ± 5°C. The organics were collected and washed with additional aqueous sodium bicarbonate, followed by water. The solution was then distilled to the minimum volume required for stirring. Acetonitrile (54 L) was added, and the mixture was distilled to the minimum volume and repeated. Acetonitrile was added and the water content of the mixture was tested. Once within the specified range, it was warmed to 50°C ± 5°C. To this mixture was slowly added a solution of p-toluenesulfonic acid (11.7 kg, 2 equivalents) in acetonitrile (55.5 L), and the contents were stirred at 50°C ± 5°C for >8 hours. The slurry was then cooled to 25°C ± 5°C, and the solid was filtered, washed with acetonitrile, and then dried under vacuum to afford (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% pure).

[0191] G. 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-methylbutyrate di(4-methylbenzenesulfonate)

[0192]

[0193] To an Erlenmeyer flask was added a solution of (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 minutes. The resulting two-phase solution was transferred to a separatory funnel and the layers were separated. An emulsion formed, which was broken up with brine for better separation. The aqueous layer was discarded. H2O (20 mL) was added to the organic layer, which was then shaken several times. After 15 minutes, the layers were separated and the aqueous layer was discarded.

[0194] To a round-bottom flask was added a solution of the free base material in MeTHF (-100 mL; from above) and additional MeTHF (40 mL). Boc-(L)-Val-OH (1.2 equiv) and DMAP (0.27 equiv) were added to give a clear yellow solution. The solution was cooled to 0°C to -10°C using an acetone ice / H2O bath. Once at temperature, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (1.77 equiv) was added and stirring was continued at 0°C to -10°C for 3 hours. After 3 hours, the ice bath was removed and the reaction was stirred for at least 5 hours. Analytical data indicated 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 hours. The reaction was quenched with 5% aqueous citric acid (78 mL), and the organic layer was washed with H2O (60 mL). The resulting organic solution consisted 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, which was carried forward to the deprotection step without further purification. In another 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 evaporation of the organic solution.

[0195] 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 this solution was added EtOAc (44 mL) and 3.7 N HCl / isopropanol (21 mL; additional HCl solution may 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 1 / 2 hour. After 1 / 2 hour, more EtOAc (30 mL) was added and the temperature was raised to 70°C for 1 hour. After 1 hour, HPLC showed that 8% of the starting material still remained. More 3.7N HCl / isopropanol (3 mL) was added to the reaction, which was then heated at 70°C for 2 hours. After 2 hours, the reaction was complete. Saturated aqueous NaHCO3 (30 mL) was slowly added, and the mixture was stirred for 1 / 2 hour, then washed with H2O (60 mL). The resulting solution of free base material (HPLC >95% purity) was subjected to tosylate formation without further purification.

[0196] The free base solution was evaporated and a solvent exchange was completed with acetonitrile (2 x 40 mL). The yellow residue was dissolved in acetonitrile (67 mL) and heated to 45-55°C, followed by the addition of a solution of p-TsOH in acetonitrile (8.3 g / 139 mL) in one portion. After stirring at 45°C for 18 hours, the slurry was cooled to 25°C, the white solid was filtered and washed with EtOAc (2 x 10 mL), and then dried in a vacuum oven at 50°C for 18 hours to afford (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 purity (99.68%) and chirality (99.77%).

[0197] In another 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 prior to free basification and then converted to the ditosylate salt as described above.

[0198] H. 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-methylbutyrate di(4-methylbenzenesulfonate)

[0199]

[0200] 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 heating, p-TsOH (14 g, 4 equiv) was added. During the heating process, the mixture became a clear, homogeneous solution. The solution was aged at 70°C for 2-3 hours. After 2-3 hours, a white solid precipitated and the heating source was removed. The suspension was stirred for 18 hours and then filtered. The solid was washed with EtOAc and then dried in a vacuum oven at 50°C for 18 hours 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 -NMR matched that of the sample from Step G.

[0201] The embodiments described herein are exemplary only, and those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific compounds, materials, and methods. All such equivalents are considered to be within the scope of this disclosure.

[0202] All patents, patent applications, and publications mentioned herein are incorporated herein in their entirety. The citation or identification of any document in this application is not an admission that such document is available as prior art to this application. The full scope of the present invention may be better understood by reference to the appended claims.

Claims

1. 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) having a purity of at least 95%; comprising: ,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutyrate dihydrochloride was converted 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-amino-3-methylbutyrate di(4-methylbenzenesulfonate).

2. The method according to claim 1, wherein the step of converting (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 into (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) comprises: (a) reacting (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 with a base, and (b) reacting the product of (a) with p-toluenesulfonic acid.

3. The method of claim 2, wherein the base comprises an inorganic base.

4. The method of claim 3, wherein the base comprises a carbonate base.

5. The process of claim 4, wherein the base is sodium bicarbonate.

6. The method according to claim 2, wherein the step of contacting 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-amino-3-methylbutanoate dihydrochloride with a base is carried out in a first solvent.

7. The method of claim 6, wherein the first solvent comprises a chlorinated hydrocarbon.

8. The method of claim 7, wherein the first solvent is dichloromethane.

9. The method of claim 2, wherein the reaction of the product of (a) with p-toluenesulfonic acid is carried out in a second solvent.

10. The method of claim 9, wherein the second solvent comprises a nitrile.

11. The method of claim 10, wherein the second solvent comprises acetonitrile.

12. The method of claim 2, wherein the reaction of the product of (a) with p-toluenesulfonic acid is carried out at a temperature of 40°C to 60°C.

13. The method of claim 12, wherein the reaction is carried out at a temperature of 45°C to 55°C.

14. The method of claim 1, further comprising a separation step.

15. The method of claim 1, wherein the step of reacting (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 is carried out without isolating (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. , the step of converting 3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutyrate dihydrochloride into (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-methylbutyrate di(4-methylbenzenesulfonate).

16. The method of claim 1, wherein 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-amino-3-methylbutanoate di(4-methylbenzenesulfonate) is not less than 96% pure.

17. The method of claim 1, wherein 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-amino-3-methylbutanoate di(4-methylbenzenesulfonate) is not less than 97% pure.

18. The method of claim 1, wherein 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-amino-3-methylbutanoate di(4-methylbenzenesulfonate) is not less than 98% pure.

19. The method of claim 1, wherein 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-amino-3-methylbutanoate bis(4-methylbenzenesulfonate) is not less than 99% pure.

20. The method of claim 19, wherein 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-amino-3-methylbutanoate bis(4-methylbenzenesulfonate) is not less than 99.5% pure.

21. The method of claim 19, wherein 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-amino-3-methylbutanoate bis(4-methylbenzenesulfonate) is not less than 99.6% pure.

22. The method of claim 19, wherein 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-amino-3-methylbutanoate bis(4-methylbenzenesulfonate) is not less than 99.7% pure.

23. The method of claim 19, wherein 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-amino-3-methylbutanoate bis(4-methylbenzenesulfonate) is not less than 99.8% pure.

24. The method of claim 19, wherein 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-amino-3-methylbutanoate bis(4-methylbenzenesulfonate) is not less than 99.9% pure.

25. The method according to claim 2, further comprising a deprotection step 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 before the step of reacting 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-amino-3-methylbutanoate dihydrochloride with a base. A step of reacting (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 to form (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.

26. The method of claim 25, wherein the deprotection step 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 is carried out in the presence of an acid.

27. The method of claim 26, wherein the acid comprises a solution of hydrogen chloride in dioxane or a solution of hydrogen chloride in 2-methyltetrahydrofuran.

28. The method of claim 26, wherein the reaction is carried out in the presence of a solvent.

29. The method of claim 28, wherein the solvent comprises a chlorinated hydrocarbon.

30. The method of claim 29, wherein the solvent comprises dichloromethane.

31. The method of claim 26, wherein the deprotection step is performed at a temperature of 0°C to 25°C.

32. The method of claim 25, further comprising the step of adding a base.

33. The method of claim 32, wherein the base comprises a carbonate.

34. The process of claim 33, wherein the base is sodium bicarbonate.

35. The method of claim 34, further comprising the step of separating the solvent from the aqueous solution.

36. The method of claim 35, further comprising the step of adding a second solvent.

37. The method of claim 36, wherein the second solvent comprises a nitrile solvent.

38. The method of claim 37, wherein the second solvent comprises acetonitrile.

39. The method of claim 25, further comprising adding an acid.

40. The method of claim 39, wherein the acid comprises a hydrogen chloride solution.

41. The method of claim 40, wherein the acid comprises a solution of hydrogen chloride in a C1-6 alcohol.

42. The method of claim 41, wherein the acid is a solution of hydrogen chloride in propan-2-ol.

43. The method of claim 39, further comprising adding another solvent.

44. The method of claim 43, wherein the solvent comprises acetonitrile and ethyl acetate.

45. The method of claim 39, wherein the reaction is carried out at a temperature of 5°C to 80°C.

46. ​​The method of claim 25, further comprising the step of crystallizing (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.

47. The method of claim 25, wherein 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-amino-3-methylbutanoate dihydrochloride is not less than 95% pure.

48. The method of claim 25, wherein 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-amino-3-methylbutanoate dihydrochloride is not less than 96% pure.

49. The method of claim 25, wherein 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-amino-3-methylbutanoate dihydrochloride is not less than 97% pure.

50. The method of claim 25, wherein 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-amino-3-methylbutanoate dihydrochloride is not less than 98% pure.

51. The method of claim 25, wherein 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-amino-3-methylbutanoate dihydrochloride is not less than 99% pure.

52. The method of claim 51, wherein 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-amino-3-methylbutanoate dihydrochloride is not less than 99.5% pure.

53. The method of claim 51, wherein 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-amino-3-methylbutanoate dihydrochloride is not less than 99.6% pure.

54. The method of claim 51, wherein 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-amino-3-methylbutanoate dihydrochloride is not less than 99.7% pure.

55. The method of claim 51, wherein 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-amino-3-methylbutanoate dihydrochloride is not less than 99.8% pure.

56. The method of claim 51, wherein 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-amino-3-methylbutanoate dihydrochloride is not less than 99.9% pure.

57. The method of claim 1, further comprising the step of reacting (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof with a tert-butoxycarbonyl-protected amino acid to form (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.

58. The method of claim 57, wherein the reaction of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol to form (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 is carried out using a salt of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol.

59. The method of claim 58, wherein the salt of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol comprises a sulfonate salt.

60. The method of claim 59, wherein the salt of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol is (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.

61. The method of claim 57, wherein the (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is reacted with a tert-butoxycarbonyl-protected amino acid to form (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.

62. The method of claim 61, wherein the tert-butoxycarbonyl-protected amino acid is tert-butoxycarbonyl-protected L-valine.

63. The method of claim 57, wherein the reaction of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is carried out in the presence of a base to form (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.

64. The method of claim 63, wherein the base is 4-dimethylaminopyridine.

65. The method of claim 57, wherein the reaction of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof with a tert-butoxycarbonyl-protected amino acid is carried out in the presence of a coupling agent to form (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.

66. The method of claim 65, wherein the coupling agent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.

67. The method of claim 57, wherein the reaction of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof to form (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 is carried out in a solvent.

68. The method of claim 67, wherein the solvent comprises dichloromethane.

69. The method of claim 57, wherein the reaction of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof to form (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 is carried out at a temperature of 0°C to 25°C.

70. The method of claim 57, wherein 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 is obtained as a dichloromethane solution.

71. The method of claim 57, further comprising the step of reacting 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol with a chiral resolving agent to form (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof before reacting with the tert-butoxycarbonyl-protected amino acid.

72. The process of claim 71, wherein the chiral resolving agent comprises an acid.

73. The method of claim 72, wherein the acid comprises camphorsulfonic acid.

74. The method of claim 73, wherein the acid is (1S)-(+)-camphorsulfonic acid.

75. The method of claim 71, wherein the reaction of 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol with a chiral resolving agent to form (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is carried out in the presence of a solvent.

76. The method of claim 75, wherein the solvent comprises water and an alcohol.

77. The method of claim 76, wherein the solvent comprises water and ethanol.

78. The method of claim 77, wherein the water to ethanol solvent ratio is 1:17 or 1:

19.

79. The process of claim 75, wherein the reaction is carried out at a temperature of 20°C to 75°C.

80. The method of claim 75, wherein the reaction is carried out at a temperature of 20°C to 65°C.

81. The method of claim 75, wherein the reaction is carried out at a temperature of 20°C to 50°C.

82. The method of claim 71, further comprising the step of crystallizing (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (1S)-(+)-camphorsulfonic acid.

83. The method of claim 71, wherein (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 95% pure.

84. The method of claim 71, wherein (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 96% pure.

85. The method of claim 71, wherein (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 97% pure.

86. The method of claim 71, wherein (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 98% pure.

87. The method of claim 71, wherein (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 99% pure.

88. The method of claim 87, wherein (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 99.2% pure.

89. The method of claim 87, wherein (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 99.3% pure.

90. The method of claim 87, wherein (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 99.4% pure.

91. The method of claim 87, wherein (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 99.5% pure.

92. The method of claim 87, wherein (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 99.6% pure.

93. The method of claim 87, wherein (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 99.7% pure.

94. The method of claim 87, wherein (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 99.8% pure.

95. The method of claim 87, wherein (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 99.9% pure.

96. The method of claim 71, further comprising the step of reducing 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one to form 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol prior to reacting with the chiral resolving agent.

97. The method of claim 96, wherein the reducing is performed in the presence of an acid.

98. The method of claim 97, wherein the acid comprises a Lewis acid.

99. The method of claim 98, wherein the Lewis acid is lithium chloride.

100. The method of claim 97, wherein the acid is an organic acid selected from acetic acid, formic acid, oxalic acid, maleic acid, lactic acid, ascorbic acid, mandelic acid, or mixtures thereof.

101. The method of claim 100, wherein the acid is acetic acid.

102. The method of claim 96, wherein the reducing is performed in the presence of a reducing agent.

103. The method of claim 102, wherein the reducing agent comprises a borohydride.

104. The method of claim 103, wherein the reducing agent is selected from sodium borohydride, lithium borohydride, calcium borohydride, magnesium borohydride, potassium borohydride, 9-BBN, cyanoborohydride, bistriphenylphosphine borohydride, sodium triethylborohydride, tetrabutylammonium borohydride, tetramethylammonium borohydride, tetraethylammonium borohydride, or lithium triethylborohydride.

105. The method of claim 104, wherein the reducing agent is sodium borohydride.

106. The method of claim 96, wherein the reducing is performed in the presence of a solvent.

107. The method of claim 96, wherein the solvent comprises dichloromethane and an alcohol.

108. The method of claim 107, wherein the solvent comprises dichloromethane and ethanol.

109. The method of claim 96, wherein the reaction is carried out at a temperature of -5°C to -15°C.

110. The method of claim 96, further comprising the step of crystallizing 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol.

111. The method of claim 96, wherein 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 95% pure.

112. The method of claim 96, wherein 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 96% pure.

113. The method of claim 96, wherein 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 97% pure.

114. The method of claim 96, wherein 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 98% pure.

115. The method of claim 96, wherein 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 99% pure.

116. The method of claim 96, wherein 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 97.6% pure.

117. The method of claim 96, wherein 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is not less than 98.1% pure.

118. The method of claim 96, further comprising, before the reducing step, a step of reacting 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof with 3-((dimethylamino)methyl)-5-methylhexan-2-one or a salt thereof to form 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one.

119. The method of claim 118, wherein the reaction of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof with 3-((dimethylamino)methyl)-5-methylhexan-2-one or a salt thereof to form 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is carried out in the presence of a solvent.

120. The method of claim 119, wherein the solvent comprises heptane.

121. The process of claim 118, wherein the reaction of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof with 3-((dimethylamino)methyl)-5-methylhexan-2-one or a salt thereof to form 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one is carried out at a temperature of 30°C to 40°C.

122. The method of claim 118, further comprising the step of reacting the 3-((dimethylamino)methyl)-5-methylhexan-2-one salt with a base prior to reacting with 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof.

123. The method of claim 121, wherein the salt of 3-((dimethylamino)methyl)-5-methylhexan-2-one comprises a carboxylate salt.

124. The method of claim 123, wherein the carboxylate comprises a fumarate, an oxalate, a citrate, or a maleate.

125. The method of claim 123, wherein the salt is oxalate or citrate.

126. The process of claim 122, wherein the base is sodium carbonate.

127. 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) having a purity of at least 95%; comprising the steps of: (a) converting (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) to (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof; 6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate dihydrochloride; and (b) converting (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 into (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.

128. 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) having a purity of at least 95%; comprising reacting (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 with p-toluenesulfonic acid.

129. The process of claim 128, wherein the reaction is carried out at a temperature of 20°C to 70°C.

130. The method of claim 128, further comprising a filtering step.

131. The method of claim 128, further comprising a separation step.

132. 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) having a purity of at least 95%; comprising the steps of: (a) reacting (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) with a purity of at least 95%; -1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof is reacted with protected L-valine to form (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; (b) reacting (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; ,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate to form (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 (c) reacting (S)-(2R,3R,11 (bR)-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 converted 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-amino-3-methylbutanoate di(4-methylbenzenesulfonate).

133. 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) having a purity of at least 95%; comprising the steps of: (a) crystallizing (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; b) reacting (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 with a base; and (c) reacting the product of step (b) with p-toluenesulfonic acid to form (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).

134. The method of claim 1, wherein 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-amino-3-methylbutanoate bis(4-methylbenzenesulfonate) is prepared without impurities.

135. The method of any one of claims 1-134, wherein 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-amino-3-methylbutanoate bis(4-methylbenzenesulfonate) is a polymorph.

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