SYNTHESI S METHOD FOR PREPARATION OF (S)-(2R,3R,11bR)-3-ISOBUTYL-9,10 DIMETHOXY-2,3,4,6,7,11b-HEXAHYDRO-1H-PYRIDO[2,1-a]ISOQUINOLINE-2-YL2-AMINO-3-METHYLBUTANOATE DI(4-METHYL BENZENE SULPHONATE)

Abstract

To provide a synthesis method for preparing a chemical compound.SOLUTION: A process for preparing (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido [2,1-a] isoquinoline-2-yl 2-amino-3-methyl butanoate di(4-methylbenzene sulfonate) or its solvation, a hydrate or a polymorph is provided in the present specification. In other embodiments, these methods provide (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido [2,1-a] isoquinoline-2-yl 2-amino-3-methyl butanoate di(4-methylbenzene sulfonate) having purity exceeding 95%.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Application No. 62 / 387,442, filed December 23, 2015, the disclosure of which is hereby incorporated by reference in its entirety.

[0002] (S)-(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 is provided herein.

Background Art

[0003] Movement disorders are characterized by excessive and abnormal involuntary movements. These neurological disorders include tremors, dystonia, ataxia, tics, akathisia, stereotypy, chorea, myoclonus and athetosis. The pathophysiology of these movement disorders is not fully understood, but dysregulation of neurotransmitters in the basal ganglia is thought to play an important role (Kenney et al., Expert Review Neurotherapeutics, 2005, 6, 7 - 17). Chronic use and high - dose administration of typical neuropletics or centrally acting dopamine receptor - blocking antiemetics make patients more likely to develop tardive syndromes. Tardive dyskinesia is one subtype of the latter syndrome and is characterized by rapid, repetitive and stereotyped involuntary movements of the face, limbs or trunk (Muller, Expert Opin. Investig. Drugs, 2015, 24, 737 - 742).

[0004] 3 - Isobutyl - 9,10 - dimethoxy - 1,3,4,6,7,11b - hexahydro - 2H - pyrido[2,1 - a]isoquinoline, also known as tetrabenazine (TBZ) Reversible inhibition of vesicular monoamine transporter-2 (VMAT2) by tetrabenazine (TBZ) improves the treatment of various hyperkinetic movement disorders. However, drawbacks of such treatment include variable response, the need for frequent dosing due to rapid metabolism of TBZ, and side effects. Side effects associated with TBZ include sedation, depression, akathisia, and parkinsonism.

[0005] Since TBZ contains two chiral centers, it is a racemic mixture of two stereoisomers and is rapidly and extensively metabolized in vivo to 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ol, also known as its reduced form, dihydrotetrabenazine (DHTBZ). DHTBZ is thought to exist as four individual isomers: (±)alpha-DHTBZ and (±)beta-DHTBZ. (2R,3R,11bR) or (+)alpha-DHTBZ is thought to be the absolute configuration of the active metabolite (Kilbourn et al., Chirality, 1997, 9, 59-62). Tetrabenazine is an orphan drug in the United States and is approved in certain European countries. Its use is also approved for the treatment of chorea in patients with Huntington's disease. However, since tetrabenazine is rapidly metabolized, it must be dosed frequently throughout the day (Muller, Expert Opin. Investig. Drugs, 2015, 24, 737-742). Therefore, there is a need to develop effective therapeutics for treating hyperkinetic movement disorders, including tardive dyskinesia, and the need remains unmet. Valbenazine, which is a prodrug of the (+)-α-isomer of dihydrotetrabenazine, i.e., (S)-2-amino-3-methyl-butanoic 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, has recently shown significant improvements in the treatment of hyperkinetic movement disorders, including the symptoms of tardive dyskinesia, with improved pharmacokinetic profiles and tolerability profiles. Methods for synthesizing (S)-2-amino-3-methyl-butanoic 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 are described in U.S. Patent Nos. 8,039,627 and 8,357,697 (the entire disclosures of each are incorporated herein by reference).

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Patent Document 2

Non-Patent Documents

[0007]

Patent Document 1

Patent Document 2

Patent Document 3

Summary of the Invention

Means for Solving the Problems

[0008] (S)-(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 is provided herein by a safe, efficient, cost-effective and / or readily scalable method. In other embodiments, those methods provide (S)-(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%.

[0009] The methods provided herein 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 with appropriately protected L-valine 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; (b) 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 (c) 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 bis(4-methylbenzenesulfonate) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0010] 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. Definitions

[0011] To facilitate the understanding of the disclosure presented in this specification, several terms are defined below.

[0012] Generally, the nomenclature used in this specification, as well as the test procedures in organic chemistry, pharmaceutical chemistry, and pharmacology described herein, are well-known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used in this specification shall generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0013] The term "alkyl" refers to a straight-chain or branched-chain monovalent saturated hydrocarbon radical, where the alkyl is optionally substituted with one or more substituents Q as described elsewhere in this specification. For example, C 1-6 alkyl refers to a straight-chain monovalent saturated hydrocarbon radical having 1 to 6 carbon atoms or a branched-chain monovalent saturated hydrocarbon radical having 3 to 6 carbon atoms. In certain embodiments, alkyl is a straight-chain monovalent saturated hydrocarbon radical having 1 to 20 (C 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 branched-chain monovalent saturated hydrocarbon radical 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, straight-chain C 1-6 alkyl groups and branched-chain C 3-6 alkyl groups are also referred to as "lower alkyl". Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomers), n-propyl, isopropyl, butyl (including all isomers), n-butyl, isobutyl, sec-butyl, t-butyl, pentyl (including all isomers), and hexyl (including all isomers).

[0014] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical containing one or more, in one embodiment 1 to 5, in another embodiment 1, carbon-carbon double bond(s), where the alkenyl is optionally substituted with one or more substituents Q as described elsewhere herein. The term "alkenyl" encompasses radicals having a "cis" or "trans" configuration or mixtures thereof, or alternatively, a "Z" or "E" configuration or mixtures thereof, as recognized by those skilled in the art. For example, C 2-6 "Alkenyl" refers to a linear monovalent unsaturated hydrocarbon radical of 2 to 6 carbon atoms or a branched monovalent unsaturated hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, alkenyl is a linear monovalent hydrocarbon radical of 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 branched monovalent hydrocarbon radical of 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.

[0015] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical containing one or more, in one embodiment 1 to 5, in another embodiment 1, carbon-carbon triple bond(s), where the alkynyl is optionally substituted with one or more substituents Q as described elsewhere herein. For example, C 2-6 "Alkynyl" refers to a linear monovalent unsaturated hydrocarbon radical of 2 to 6 carbon atoms or a branched monovalent unsaturated hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, alkynyl is a linear monovalent hydrocarbon radical of 2 to 20 (C2-20 ), 2 to 15 carbon atoms (C 2-15 ), 2 to 10 carbon atoms (C 2-10 ), or 2 to 6 carbon atoms (C 2-6 ) of a linear monovalent hydrocarbon radical, or 3 to 20 carbon atoms (C 3-20 ), 3 to 15 carbon atoms (C 3-15 ), 3 to 10 carbon atoms (C 3-10 ), or 3 to 6 carbon atoms (C 3-6 ) of a branched-chain monovalent hydrocarbon radical. Examples of alkynyl groups include ethynyl (-C≡CH), propynyl (including all isomers, e.g., 1-propynyl (-C≡CCH3) and propargyl (-CH2C≡CH)), butynyl (including all isomers, e.g., 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including all isomers, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomers, e.g., 1-hexyn-1-yl), but are not limited thereto.

[0016] The term "cycloalkyl" refers to a monovalent cyclic hydrocarbon radical, where the cycloalkyl is optionally substituted with one or more substituents Q as described elsewhere in this specification. In one embodiment, the cycloalkyl group may be saturated or unsaturated, but is a non-aromatic and / or spiro and / or non-spiro and / or bridged and / or non-bridged and / or fused bicyclic group. In certain embodiments, cycloalkyl has 3 to 20 carbon atoms (C 3-20 ), 3 to 15 carbon atoms (C 3-15 ), 3 to 10 carbon atoms (C 3-10 ), or 3 to 7 carbon atoms (C 3-7 ). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, and adamantyl, but are not limited thereto.

[0017] The term "aryl" refers to a monocyclic aromatic group and / or a polycyclic aromatic group containing at least one aromatic carbocyclic ring, where the aryl is optionally substituted with one or more substituents Q as described elsewhere herein. In certain embodiments, aryl has 6 to 20 carbon atoms (C 6-20 ), 6 to 15 carbon atoms (C 6-15 ) or 6 to 10 carbon atoms (C 6-10 ). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl and terphenyl. The term "aryl" also refers to bicyclic or tricyclic carbocyclic rings, where one of those rings is aromatic and the other ring may be saturated, partially unsaturated or aromatic, for example, dihydronaphthyl, indenyl, indanyl or tetrahydronaphthyl (tetralinyl).

[0018] The term "aralkyl" or "arylalkyl" refers to a monovalent alkyl group substituted with one or more aryl groups, where the aralkyl or arylalkyl is optionally substituted with one or more substituents Q as described elsewhere herein. In certain embodiments, aralkyl has 7 to 30 carbon atoms (C 7-30 ), 7 to 20 carbon atoms (C 7-20 ) or 7 to 16 carbon atoms (C 7-16 ). Examples of aralkyl groups include, but are not limited to, benzyl, 2-phenylethyl and 3-phenylpropyl.

[0019] The term "heteroaryl" refers to a monovalent monocyclic aromatic group and / or a monovalent polycyclic aromatic group containing at least one aromatic ring, where 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 attached 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, heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, 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, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl.In certain embodiments, the heteroaryl is optionally substituted with one or more substituents Q as described elsewhere herein.

[0020] The term "heterocyclyl" or "heterocyclic" refers to a monocyclic non-aromatic ring system and / or a polycyclic ring system of monovalent nature, containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms of these non-aromatic rings are heteroatoms independently selected from O, S, N and P; the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclyl group 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 group is attached to the remainder 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 spiro, fused or bridged, wherein a nitrogen atom or a sulfur atom may optionally be oxidized, a nitrogen atom may optionally be quatemized, and some of the rings may be partially or fully saturated or may be aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom that results in the formation of a stable compound.Examples of such a complex cyclic group include, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl, benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, 13-carbolinyl, chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl, dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl, isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiomorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described elsewhere herein.

[0021] The term "alkene" refers to a straight or branched chain hydrocarbon containing one or more, in one embodiment 1 to 5, in another embodiment 1, carbon-carbon double bond(s), wherein the alkene is optionally substituted with one or more substituents Q as described elsewhere herein. The term "alkene" encompasses compounds having the "cis" or "trans" configuration or mixtures thereof, or alternatively, the "Z" or "E" configuration or mixtures thereof, as recognized by those skilled in the art. For example, C 2-6An alkene refers to a straight-chain unsaturated hydrocarbon having 2 to 6 carbon atoms or a branched-chain unsaturated hydrocarbon having 3 to 6 carbon atoms. In certain embodiments, the alkene is a straight-chain hydrocarbon 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 branched-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.

[0022] The term "cycloalkene" refers to a cyclic hydrocarbon containing one or more, in one embodiment 1 to 5, in another embodiment 1, carbon-carbon double bond(s), where the cycloalkene is optionally substituted with one or more substituents Q as described elsewhere herein. In one embodiment, the cycloalkene can be non-aromatic and / or spiro and / or non-spiro and / or bridged and / or non-bridged and / or fused bicyclic. In certain embodiments, the cycloalkene 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.

[0023] The term "arene" refers to a monocyclic aromatic compound and / or a polycyclic aromatic compound containing at least one aromatic carbon ring, where 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 6-10has a ring atom of ( ). The term "arene" also refers to a bicyclic or tricyclic carbocyclic ring, where one of those rings is aromatic and the other(s) can be saturated, partially unsaturated or aromatic.

[0024] The term "heteroarene" refers to a monocyclic aromatic compound and / or a polycyclic aromatic compound containing at least one aromatic ring, where at least one aromatic ring contains one or more heteroatoms independently selected from O, S, N and P in that ring. Each ring of the heteroarene can 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 hetero atoms 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.

[0025] The term "heterocyclic ring" refers to a monocyclic non-aromatic ring system and / or a polycyclic non-aromatic ring system, where one or more non-aromatic ring atoms are heteroatoms, each of which is independently selected from O, S, N and P; the remaining ring atoms are carbon atoms. In certain embodiments, the heterocyclic ring 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 heterocyclic ring is a monocyclic, bicyclic, tricyclic or tetracyclic ring system that can be spiro, fused or bridged, where a nitrogen atom or a sulfur atom can be optionally oxidized, a nitrogen atom can be optionally quaternized, and some rings can be partially saturated or fully saturated. In certain embodiments, the heterocyclic ring is optionally substituted with one or more substituents Q as described elsewhere herein.

[0026] The term "alcohol" refers to alkyl-OH, alkenyl-OH, alkynyl-OH, cycloalkyl-OH, aryl-OH, aralkyl-OH, heteroaryl-OH or heterocyclyl-OH, where the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclyl are as defined herein, respectively.

[0027] The term "carboxylic acid" refers to alkyl-COOH, alkenyl-COOH, alkynyl-COOH, cycloalkyl-COOH, aryl-COOH, aralkyl-COOH, heteroaryl-COOH or heterocyclyl-COOH, where the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclyl are as defined herein, respectively.

[0028] The term "carboxylic acid ester" or "ester" refers to alkyl-COOR', alkenyl-COOR', alkynyl-COOR', cycloalkyl-COOR', aryl-COOR', aralkyl-COOR', heteroaryl COOR' or heterocyclyl-COOR', each R' being independently alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclyl are as defined herein, respectively.

[0029] The term "optionally substituted" is intended to mean that a group or substituent (e.g., an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl or heterocyclyl group) can be substituted with one or more substituents Q, each of those substituents Q being independently, for example, (a) oxo (=O), halo, cyano (-CN) and nitro (-NO2); (b) C 1-6 alkyl, C 2-6 alkenyl, C2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 1-15 Aralkyl, heteroaryl and heterocyclyl (each of which is further, in one embodiment, substituted with one or more, in one embodiment, 1, 2, 3 or 4 substituents Q a 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 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)(ORa )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)2NR b R c (wherein 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 optionally substituted with one or more, in one embodiment, 1, 2, 3 or 4, substituents Q a ); or (iii) R b and R e (where each of this R b and R e is optionally substituted with one or more, in one embodiment, 1, 2, 3 or 4, substituents Q a ) which together with the attached N atom form a heteroaryl or heterocyclyl). As used herein, unless otherwise specified, all groups that can be substituted are "optionally substituted".

[0030] The term "isotopically enriched" refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. "Isotopically enriched" can also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.

[0031] With respect to the compounds provided herein, when a particular atomic position is specified as having deuterium or "D", the abundance of deuterium at that position is understood to be substantially higher than the natural abundance of deuterium (which is about 0.015%). Positions specified as having deuterium typically, in certain embodiments, have a minimum isotopic enrichment factor of 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 deuterium position specified.

[0032] The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to those of skill in the art, including mass spectrometry, nuclear magnetic resonance spectroscopy and crystallography.

[0033] Isotope enrichment (e.g., deuteration) of pharmaceuticals to improve pharmacokinetic (PK), pharmacodynamic (PD), and toxicity profiles has been previously demonstrated for some classes of drugs. See, e.g., 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).

[0034] Isotope enrichment of a drug can be used, for example, (1) to reduce or eliminate unwanted metabolites, (2) to extend the half-life of the parent drug, (3) to reduce the number of doses required to achieve the desired effect, (4) to reduce the dose amount required to achieve the desired effect, (5) to increase the formation of active metabolites if any are formed, and / or (6) to reduce the formation of harmful metabolites in certain tissues, and / or to produce a more effective and / or safer drug for combination therapy whether or not combination therapy is intended.

[0035] When a particular atom is used in place of one of its isotopes, the reaction rate of a chemical reaction often changes. This phenomenon is known as the kinetic isotope effect ("KIE"). For example, when a C-H bond breaks in the rate-determining step of a chemical reaction (i.e., the step with the highest transition state energy), using deuterium instead of hydrogen for that hydrogen results in a decrease in the reaction rate, and the process slows down. This phenomenon is known as the deuterium kinetic isotope effect ("DKIE") (see, e.g., 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)).

[0036] The magnitude of the DKIE can be expressed as the ratio between the rate of a given reaction in which the C-H bond breaks and the rate of the same reaction using deuterium instead of hydrogen. The DKIE can range from approximately 1 (no isotope effect) to very large values (e.g., 50 or greater (which means that the reaction can be 50 times or more slower when using deuterium instead of hydrogen)). High DKIE values can be partially attributed to a phenomenon known as tunneling, which is a result of the uncertainty principle. Tunneling is thought to be due to the small mass of the hydrogen atom, such that the transition state involving the proton can sometimes occur in the absence of the required activation energy, and tunneling occurs. Since deuterium has a larger mass than hydrogen, the probability of this phenomenon occurring is statistically much lower.

[0037] Tritium ("T") is a radioactive isotope of hydrogen that is used in research, nuclear fusion reactors, neutron generators, and radiopharmaceuticals. Tritium is a hydrogen atom that has two neutrons in its nucleus and an atomic weight close to 3. Tritium occurs naturally in the environment at very low concentrations and is most commonly found 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 main hazard associated with this isotope, but large amounts would have to be ingested to pose a significant health risk. Compared to deuterium, tritium should consume less quantity before reaching dangerous levels. By using tritium ("T") instead of hydrogen, a stronger bond and a numerically larger isotope effect are brought about. Similarly, using isotopes instead of other elements (such as 13 C or 14 C, 33 S instead of sulfur, 34 S or 36 S, 15 N instead of nitrogen, and 17 O or 18 O instead of oxygen, although not limited to these) can bring about a similar kinetic isotope effect.

[0038] For example, DKIE was used to reduce the hepatotoxicity of halothane, perhaps by restricting the generation of reactive species such as trifluoroacetyl chloride. However, this method may not apply to all drug classes. For example, deuterium incorporation can lead to metabolic switching. The concept of metabolic switching posits that when a foreign substance (xenogen) is sequestered by a Phase I enzyme, it transiently binds and after rebinding in various conformations, can undergo a chemical reaction (e.g., oxidation). This hypothesis is supported by the relatively large-sized binding pockets in many Phase I enzymes and the promiscuous nature of many metabolic reactions. Metabolic switching can potentially result in different ratios of known metabolites as well as entirely new metabolites. This new metabolic profile can result in toxicity, to a greater or lesser extent.

[0039] Animal bodies express various enzymes for the purpose of eliminating foreign substances such as therapeutic drugs from their circulatory systems. Examples of such enzymes include cytochrome P450 enzymes ("CYP"), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, which react with these foreign substances to convert them into more polar intermediates or metabolites destined for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve oxidizing a carbon-hydrogen (C-H) bond to either a carbon-oxygen (C-O) or a carbon-carbon (C-C) π bond. The resulting metabolites may be stable or unstable under physiological conditions and can have substantially different pharmacokinetic profiles, pharmacodynamic profiles, as well as acute and long-term toxicity profiles compared to the parent compound. In the case of many drugs, such oxidation is rapid. Therefore, these drugs often require multiple-dose administration or high daily-dose administration.

[0040] Thus, the isotopic enrichment at certain positions of the compounds provided herein can result in detectable KIEs that affect the pharmacokinetic, pharmacological, and / or toxicological profiles of the compounds provided herein as compared to similar compounds having a natural isotopic composition.

[0041] The term "isotope variant" refers to such a therapeutic agent that contains isotopes in unnatural ratios in one or more atoms that make up the therapeutic agent. In certain embodiments, the therapeutic agent of "isotope variant" contains one or more isotopes in unnatural ratios, and such isotopes include 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), among others, but not limited thereto. In certain embodiments, the therapeutic agent of "isotope variant" contains one or more isotopes in non-natural ratios, and these isotopes include 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), among others, but not limited thereto.

[0042] When practicable according to the judgment of those skilled in the art, in a therapeutic agent, any hydrogen can be, for example 2 H, or any carbon can be, for example 13 C, or any nitrogen can be, for example 15 N, or any oxygen can be, for example 18 O. It is understood that in certain embodiments, a therapeutic agent of "isotope variant" contains a non-natural ratio of deuterium (D).

[0043] As used in this specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" include not only singular referents but also plural referents unless the context clearly dictates otherwise.

[0044] The term "about" or "approximately" means an acceptable error with respect to a particular value as determined by those skilled 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.

[0045] The term "solvate" refers to a complex or aggregate formed by molecules of one or more solutes, such as the compounds provided herein, and molecules of one or more solvents, present in stoichiometric or non-stoichiometric amounts. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is a pharmaceutically acceptable solvent. In one embodiment, the complex or aggregate is in crystalline form. In another embodiment, the complex or aggregate is in amorphous form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0046] The term "crystalline form" of a compound can refer to any crystalline form of the compound as a free acid, as a free base, as an acid addition salt of the compound, as a base addition salt of the compound, as a complex of the compound, as a solvate (including hydrate) of the compound, or as a co-crystal of the compound. The term "solid form" of a compound can refer to any crystalline form of the compound, or any amorphous form of the compound as a free acid, as a free base, as an acid addition salt of the compound, as a base addition salt of the compound, as a complex of the compound, or as a solvate (including hydrate) of the compound, or a coprecipitate of the compound. In many cases, the terms "crystalline form" and "solid form" can refer to pharmaceutically acceptable crystalline forms and solid forms (e.g., including crystalline forms and solid forms of pharmaceutically acceptable addition salts, pharmaceutically acceptable complexes, pharmaceutically acceptable solvates, pharmaceutically acceptable co-crystals, and pharmaceutically acceptable coprecipitates).

[0047] The term "hyperkinetic disorder" or "hyperkinetic movement disorder" or "hyperkinesis" refers to a disorder or disease characterized by excessive and abnormal involuntary movements. These neurological disorders include, but are not limited to, tremors, dystonia, ballism, tics, akathisia, stereotypy, chorea, myoclonus, and athetosis.

[0048] The term "VMAT2" refers to human monoamine transporter isoform 2, an endogenous membrane protein that functions to transport monoamines, particularly neurotransmitters (e.g., dopamine, norepinephrine, serotonin, and histamine) from the cytosol of a cell into synaptic vesicles.

[0049] "Pharmaceutically acceptable salts" refers to any salts of the compounds provided herein that retain their biological properties and are not toxic or otherwise undesirable for pharmaceutical use. Such salts can be obtained from a variety of organic and inorganic counterions well known in the art. Such salts include (1) organic or inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid, acetic acid, trifluoroacetic acid, tri Acid addition salts formed with acids such as dichloroacetic 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-hydroxybenzoyl)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, borneol acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, benzoic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, cyclohexylsulfamic acid, kinic acid, muconic acid, etc.; or (2) salts formed in any of the following cases: the acidic proton present in the parent compound is replaced by (a) metal ions such as alkali metal ions, alkaline earth metal ions or aluminum ions, or alkali metal hydroxides or alkaline earth metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, aluminum hydroxide, lithium hydroxide, zinc hydroxide and barium hydroxide), ammonia, or (b) coordinated with an organic base (e.g., aliphatic, alicyclic or aromatic organic amines such as ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, etc.), but not limited to these.

[0050] Merely as examples of pharmaceutically acceptable salts, there are sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, tetraalkylammonium salts, etc., and when the compound contains a basic functional group, salts of non-toxic organic acids or inorganic acids (e.g., hydrohalides, e.g., hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartrate, citrate, benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, benzoate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, etc.), but are not limited thereto.

[0051] The term "amino acid" refers to naturally occurring amino acids and synthetic α, β, γ, or δ amino acids, including, but not limited to, the amino acids found in proteins, namely 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, valinyl, leucinyl, isoleucinyl (isoleuccinyl), prolynyl, phenylalaninyl, tryptophanyl, methioninyl, glycyl, serynyl, threonyl, cysteinyl, tyrosyl, asparaginyl, glutaminyl, aspartoyl, glutaryl, lysinyl, arginyl, histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleucinyl, β-prolynyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycyl, β-serynyl, β-threonyl, β-cysteinyl, β-tyrosyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaryl, β-lysynyl, β-arginyl, or β-histidinyl. oleuccinyl), prolynyl, phenylalaninyl (phenylalaninyl), tryptophanyl, methioninyl (methioninyl), glycyl, serynyl, threonyl, cysteinyl, tyrosyl, asparaginyl, glutaminyl, aspartoyl, glutaryl, lysinyl, arginyl (argininyl), histidinyl, β-alanyl, β-valinyl, β-leucinyl, β-isoleucinyl, β-prolynyl, β-phenylalaninyl, β-tryptophanyl, β-methioninyl, β-glycyl, β-serynyl, β-threonyl, β-cysteinyl, β-tyrosyl, β-asparaginyl, β-glutaminyl, β-aspartoyl, β-glutaryl, β-lysynyl, β-arginyl, or β-histidinyl.

[0052] When referring to a composition "substantially free of" a particular compound, it means that the composition contains about 20 wt% or less, about 10 wt% or less, about 5 wt% or less, about 3 wt% or less, about 1 wt% or less, about 0.5 wt% or less, about 0.2 wt% or less, about 0.1 wt% or less, about 0.01 wt% or less, about 0.001 wt% or less, or about 0.0001 wt% or less of that compound.

[0053] When referring to a compound or composition, the term "substantially pure" means that the compound or composition has a purity of about 80% by weight or more, about 90% by weight or more, about 95% by weight or more, about 96% by weight or more, about 97% by weight or more, about 98% by weight or more, about 99% by weight or more, about 99.5% by weight or more, about 99.9% by weight or more, about 99.95% by weight or more, about 99.99% by weight or more, about 99.995% by weight or more, about 99.999% by weight or more (no less than), about 99.9995% by weight or more, or about 99.9999% by weight or more.

[0054] The terms "process" and "method" are used interchangeably to refer to the methods disclosed herein for preparing compounds. Modifications to the processes and methods disclosed herein that are well known to those skilled in the art (e.g., starting materials, reagents, protecting groups, solvents, temperature, reaction time, and / or purification) are also encompassed by this disclosure.

[0055] The terms "add", "react", and "mix" are used interchangeably to refer to contacting one reaction component (reactant), reagent, solvent, catalyst, or reactive group with another reaction component, reagent, solvent, catalyst, or reactive group. Unless otherwise specified, the reaction components, reagents, solvents, catalysts, and reactive groups can be added individually, simultaneously, or separately, and / or in any order. They can be added in the presence or absence of heat, and optionally, in an inert atmosphere (e.g., N2 or Ar). In certain embodiments, the term "react" can also refer to in situ formation or intramolecular reaction when the reactive groups are present in the same molecule.

[0056] When referring to a reaction, the term "substantially complete" means that the reaction contains about 50% or less, about 40% or less, about 30% or less, about 20% or less, about 10% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, about 0.5% or less, about 0.1% or less, or about 0.05% or less of residual starting material.

[0057] When the stereochemistry of a structure or a part thereof is not indicated, for example, by a bold or dashed line, the structure or the part thereof should be construed as encompassing all stereoisomers of the structure.

[0058] The phrase "its pharmaceutically acceptable salts, solvates, hydrates or polymorphs" has the same meaning as the phrase "the pharmaceutically acceptable salts, solvates, hydrates or polymorphs of the compound mentioned therein; or the pharmaceutically acceptable salts, solvates, hydrates or polymorphs of the enantiomer or enantiomer mixture of the compound mentioned therein". is acceptable. Process

[0059] Methods are 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 bis(4-methylbenzenesulfonate) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof with a purity of at least about 95%. In certain embodiments, the methods provided herein are safe, efficient, 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 bis(4-methylbenzenesulfonate) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof.

[0060] 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 bis(4-methylbenzenesulfonate) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof with a purity of at least about 95%. The method includes 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 bis(4-methylbenzenesulfonate) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof.

[0061] In one 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 bis(4-methylbenzenesulfonate) includes: (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.

[0062] 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.

[0063] In certain embodiments, the base includes an inorganic base. In some embodiments, the base includes a carbonate base. In some embodiments, the base includes sodium carbonate, sodium bicarbonate, potassium carbonate, or potassium bicarbonate. In some embodiments, the base is sodium bicarbonate.

[0064] In some embodiments, the solvent in step (a) (i.e., 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 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 heteroarene, a heterocycle, water, or a mixture thereof. In certain embodiments, the solvent is a chlorinated hydrocarbon. In still other embodiments, the solvent is dichloromethane.

[0065] 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 the base is carried out at a temperature in the range of about 0 to about 30 °C, about 5 to about 25 °C, about 5 to about 20 °C. In some embodiments, the reaction is carried out at a temperature in the range of about 20 to about 30 °C. In still other embodiments, the reaction is carried out at a temperature of about 25 °C.

[0066] In another embodiment, the reaction of the product of (a) with p-toluensufonic acid is carried out in a second solvent.

[0067] 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 heteroarene, a heterocycle, a carboxylic acid, a phosphoramide, carbon disulfide, water, or a mixture thereof.

[0068] 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-dichloroethene, 1,2-dichloroethene, chloroform, trichloroethane, trichloroethene, carbon tetrachloride, chlorobenzene, trifluoromethylbenzene, methanol, ethanol, isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, t-butanol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, diethyl ether, diisopropyl ether, methyl t-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 disulfide, water; or a mixture thereof.

[0069] 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 still other embodiments, the solvent is a mixture of dichloromethane and acetonitrile. In still other embodiments, the solvent is acet It is a nitrile.

[0070] In certain embodiments, the volume ratio of p-toluenesulfonic acid to acetonitrile ranges 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 ranges from about 1 to about 100. In certain embodiments, the volume ratio of p-toluenesulfonic acid to acetonitrile ranges from about 2 to about 50. In certain embodiments, the volume ratio of p-toluenesulfonic acid to acetonitrile ranges from about 5 to about 50. In certain embodiments, the volume ratio of p-toluenesulfonic acid to acetonitrile ranges from about 5 to about 25. In certain embodiments, the volume ratio of p-toluenesulfonic acid to acetonitrile ranges from about 10 to about 25. In certain embodiments, the volume ratio of p-toluenesulfonic acid to acetonitrile ranges 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.

[0071] In one 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) includes 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 with p-toluenesulfonic acid.

[0072] 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) involves a solvent.

[0073] 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-dichloroethene, 1,2-dichloroethene, chloroform, trichloroethane, trichloroethene, carbon tetrachloride, chlorobenzene, trifluoromethylbenzene, methanol, ethanol, isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, t-butanol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, diethyl ether, diisopropyl ether, methyl t-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-di It is tert - acetamide, 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.

[0074] 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 still other embodiments, the solvent is ethyl acetate.

[0075] 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 in the range of about 15 to about 70 °C, about 20 to about 70 °C, about 25 to about 70 °C. In still another embodiment, the reaction is carried out at a temperature of about 70 °C.

[0076] 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 ranges 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 ranges 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 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 the dihydrochloride 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 is about 4.2. In some embodiments, the molar ratio of p-toluenesulfonic acid to the dihydrochloride 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 is about 4.5. In certain embodiments, p-toluenesulf... 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 ranges 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 ranges 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.

[0077] 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 in the range of about 0 to about 100 °C, about 5 to about 90 °C, about 5 to about 80 °C, about 10 to about 70 °C, about 10 to about 60 °C, about 10 to about 50 °C, about 10 to about 40 °C, about 10 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 with p-toluenesulfonic acid is carried out at a temperature in the range of about 20 to about 60 °C, about 30 to about 60 °C, about 40 to about 60 °C, about 50 to about 60 °C. In still 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 in the range of about 40 to about 50 °C, about 45 to about 50 °C, about 40 to about 55 °C, about 45 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.

[0078] In one 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 bis(4-methylbenzenesulfonate) includes the step of 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.

[0079] In yet 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 bis(4-methylbenzenesulfonate) 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.

[0080] In certain embodiments, 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 solvate, hydrate or polymorph thereof prepared by the methods provided herein has a purity of about 95% by weight or greater, about 96% by weight or greater, about 97% by weight or greater, about 97.5% by weight or greater, about 98% by weight or greater, about 98.5% by weight or greater, about 99% by weight or greater, about 99.5% by weight or greater, about 99.6% by weight or greater, about 99.7% by weight or greater, about 99.8% by weight or greater or about 99.9% by weight or greater.

[0081] In other embodiments, methods are provided herein for preparing 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 solvate, hydrate or polymorph thereof at a purity of at least about 95%; the methods include 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 via a deprotection step under conditions suitable 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 prior to 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 with a base.

[0082] 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 with a purity of at least about 95%; the method 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-((tert-butoxycarbonyl)amino)-3-methylbutanoate via a deprotection step under conditions suitable 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 prior to 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 p-toluenesulfonic acid. Prior to 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, the method 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-((tert-butoxycarbonyl)amino)-3-methylbutanoate via a deprotection step under conditions suitable 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.

[0083] 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 an ether. In some embodiments , the acid includes a solution of hydrogen chloride in dioxane.

[0084] 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.

[0085] 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 heteroarene, a heterocycle, a carboxylic acid, a phosphoramide, carbon disulfide, water, or a mixture thereof. In certain embodiments, the solvent is a chlorinated hydrocarbon. In certain embodiments, the solvent is dichloromethane.

[0086] 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 in the range of about 0 to about 25 °C, about 0 to about 30 °C, about 5 to about 25 °C, about 5 to about 20 °C. In some embodiments, the reaction is carried out at a temperature in the range of about 20 to about 30 °C. In still other embodiments, the reaction is carried out at a temperature of about 25 °C.

[0087] 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.

[0088] 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.

[0089] In yet 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.

[0090] 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-dichloroethene, 1,2-dichloroethene, chloroform, trichloroethane, trichloroethene, carbon tetrachloride, chlorobenzene, trifluoromethylbenzene, methanol, ethanol, isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, t-butanol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, diethyl ether, diisopropyl ether, methyl t-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 disulfide, water; or a mixture thereof.

[0091] 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 still other embodiments, the solvent is dichloromethane, acetonitrile, or a mixture thereof. In still other embodiments, the solvent is dichloromethane.

[0092] 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 hydrogen chloride-ether solution. In some embodiments, the acid comprises a hydrogen chloride-dioxane solution. In some embodiments, the acid comprises a solution of hydrogen chloride in a C alcohol. 1-6 of hydrogen chloride in a C 1-6 alcohol)

[0093] In certain embodiments, the C 1-6 alcohol is a primary or secondary C 1-6 alcohol, each of which is optionally substituted with one or more substituents Q. In certain embodiments, the C 1-6 alcohol is a primary C 1-6 alcohol optionally substituted with one or more substituents Q. In certain embodiments, the hydrogen donor is a secondary C 1-6 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 mixtures thereof. In one embodiment, the C 1-6 alcohol is propan-2-ol.

[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 another solvent.

[0095] 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 still other embodiments, the solvent is acetonitrile.

[0096] In certain embodiments, the volume ratio of hydrogen chloride to dichloromethane ranges from about 1 to about 100, about 2 to about 50, about 5 to about 50, about 5 to about 25, about 10 to about 25, or about 15 to about 25. In certain embodiments, the volume ratio of hydrogen chloride to dichloromethane ranges from about 1 to about 100. In certain embodiments, the volume ratio of hydrogen chloride to dichloromethane ranges from about 2 to about 50. In certain embodiments, the volume ratio of hydrogen chloride to dichloromethane ranges from about 5 to about 50. In certain embodiments, the volume ratio of hydrogen chloride to dichloromethane ranges from about 5 to about 25. In certain embodiments, the volume ratio of hydrogen chloride to dichloromethane ranges from about 10 to about 25. In certain embodiments, the volume ratio of hydrogen chloride to dichloromethane ranges from about 15 to about 25. In certain embodiments, the volume ratio of p-toluenesulfonic acid to acetonitrile ranges 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.

[0097] 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 ranges from about 0.1 to about 10, from about 0.2 to about 5, and from about 0.5 to about 5. In certain embodiments, hydrogen chloride to (S)-(2R, 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 ranges 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 ranges from about 0.2 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 ranges 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 about 5.1, about 5.2, about 5.3, about 5.4 or about 5.5. 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 about 5, about 5.1 or about 5.2. 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.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 5.1. 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.

[0098] 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 is carried out at a temperature in the range of about 0 to about 30 °C, about 5 to about 80 °C, about 5 to about 70 °C, about 5 to about 60 °C, about 5 to about 50 °C, about 5 to about 40 °C, about 5 to about 30 °C, about 5 to about 25 °C, about 5 to about 20 °C. In some embodiments, the reaction is carried out at a temperature in the range of about 5 to about 80 °C. In some embodiments, the reaction is carried out at a temperature in the range of about 50 to about 70 °C.

[0099] 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, 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 further comprises 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.

[0100] 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 about 95% by weight or greater, about 96% by weight or greater, about 97% by weight or greater, about 97.5% by weight or greater, about 98% by weight or greater, about 98.5% by weight or greater, about 99% by weight or greater, about 99.5% by weight or greater, about 99.6% by weight or greater, about 99.7% by weight or greater, about 99.8% by weight or greater or about 99.9% by weight or greater.

[0101] In still 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 about 99.5% or greater, about 99.6% or greater, about 99.7% or greater, about 99.8% or greater, about 99.9% or greater pure.

[0102] In other embodiments, 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 in at least about 95% purity is provided herein; the method comprises 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 an amino acid protected with tert-butoxycarbonyl 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.

[0103] 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 an amino acid protected with tert-butoxycarbonyl 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 still 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.

[0104] 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 an amino acid protected with tert-butoxycarbonyl 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 involves an amino acid including valine or alanine. In some embodiments, the amino acid is valine. In still other embodiments, the amino acid protected with tert-butoxycarbonyl is L-valine.

[0105] 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.

[0106] 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.

[0107] 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 an amino acid protected with tert-butoxycarbonyl 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 reagent.

[0108] In certain embodiments, the coupling reagent is carbodiimide, 1,1'-carbonyldiimidazole (CDI), bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride (BOP-Cl), hexafluorophosphate (BOP reagent), PCh, PCl or 1-propanephosphonic acid cyclic anhydride. In certain embodiments, the coupling reagent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC or EDCI), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC hydrochloride), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC methiodide), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate or 1,3-dicyclohexylcarbodiimide (DCC). In certain embodiments, the coupling reagent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC or EDCI), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC hydrochloride), 1-[3-(dimethylamino)propyl]-3 -ethylcarbodiimide methiodide (EDC methiodide), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate or 1,3-dicyclohexylcarbodiimide (DCC). In some embodiments, the coupling reagent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC or EDCI).

[0109] 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.

[0110] 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 heteroarene, 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 some embodiments, the solvent is a cycloalkyl ether. In certain embodiments, the solvent is 2-methyltetrahydrofuran (MeTHF).

[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 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 in the range of about 0 to about 20 °C, about 0 to about 30 °C, about 5 to about 80 °C, about 5 to about 70 °C, about 5 to about 60 °C, about 5 to about 50 °C, about 5 to about 40 °C, about 5 to about 30 °C, about 5 to about 25 °C, about 5 to about 20 °C. In some embodiments, the reaction is carried out at a temperature in the range of about 0 to about 20 °C.

[0112] 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 solution in dichloromethane.

[0113] 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 with a purity of at least about 95%; the method comprises 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, and then reacting with an amino acid protected with tert-butoxycarbonyl. The process is included.

[0114] In certain embodiments, the chiral agent includes aminocaprolactamic acid, aminopropanol, anthryltrifluoroethanol, aspartic acid, benzodioxanecarboxylic acid, benzylamiocyclohexanemethanol, naphthylethylamine, binaphthyl hydrogen phosphate, bis-O-chlorobenzyl-L-tartrol, bis-hydroxyphenylethylenediamine, bis-phenylethylamine, bis-phenylethylphthalamic acid, bromocamphorsulfonic acid, camphorsulfonic acid, bromophenylethylamine, brucine, 2-butanol, camphanic acid, borneolic acid, chloromethylbenzylamine, cinchonidine, cinchonine, dehydroabityl amine, diacetyl tartaric acid, dibenzoyl tartaric acid, dibenzyltartaric acid, diethyl tartrate, diisopropyl tartrate, tartaric acid, quinine, quinic acid, strychnine, N,N-dimethylphenylethylamine, dimethylphenyltetrahydropyrimidine, pyroglutamic acid, phenylpropionic acid, naphthylethylsuccinamic acid, naphthylethyl isocyanate, malic acid, mandelic acid, menthyl chloroformate, glutamic acid or ephedrine. In certain embodiments, the chiral agent includes an acid. In some embodiments, the acid is a sulfonic acid. In still other embodiments, the acid is camphorsulfonic acid. In still other embodiments, the acid is (1S)-(+)-camphorsulfonic acid.

[0115] In other 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-forming 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 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 a C 1-6 alcohol as defined herein. In still other embodiments, the solvent mixture comprises water and ethanol. In certain embodiments, the solvent mixture comprises water and ethanol in a volume ratio in the range 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 ranges from about 1 to about 20. In certain embodiments, the volume ratio of water to ethanol ranges from about 1 to about 19. In certain embodiments, the volume ratio of water to ethanol ranges from about 1 to about 18. In certain embodiments, the volume ratio of water to ethanol ranges from about 1 to about 17. In certain embodiments, the volume ratio of water to ethanol ranges from about 1 to about 16. In certain embodiments, the volume ratio of water to ethanol ranges from about 1 to about 15. In certain embodiments, the volume ratio of water to ethanol ranges from about 1 to about 14. In certain embodiments, the volume ratio of water to ethanol ranges from about 1 to about 13. In certain embodiments, the volume ratio of water to ethanol ranges from about 1 to about 12. In certain embodiments, the volume ratio of water to ethanol ranges from about 1 to about 11. In certain embodiments, the volume ratio of water to ethanol ranges from about 1 to about 10.

[0116] 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 or a salt thereof 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 and a chiral resolving agent is carried out at a temperature in the range of about 0 to about 100 °C, about 5 to about 90 °C, about 5 to about 80 °C, about 10 to about 70 °C, about 10 to about 60 °C, about 10 to about 50 °C, about 10 to about 40 °C, about 10 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 or a salt thereof 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 and a chiral resolving agent is carried out at a temperature in the range of about 20 to about 80 °C, about 20 to about 70 °C, about 20 to about 60 °C, about 20 to about 70 °C. In other embodiments, the reaction is carried out at a temperature in the range of about 20 to about 65 °C or about 20 to about 75 °C.

[0117] 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 or a salt thereof 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 and a chiral resolving agent 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.

[0118] In certain 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 or a pharmaceutically acceptable salt thereof, or a solvate, hydrate or polymorph thereof prepared by the methods provided herein has a purity of about 95% by weight or greater, about 96% by weight or greater, about 97% by weight or greater, about 97.5% by weight or greater, about 98% by weight or greater, about 98.5% by weight or greater, about 99% by weight or greater, about 99.1% by weight or greater, about 99.2% by weight or greater, about 99.3% by weight or greater, about 99.4% by weight or greater, about 99.5% by weight or greater, about 99.6% by weight or greater, about 99.7% by weight or greater, about 99.8% by weight or greater or about 99.9% by weight or greater.

[0119] In certain embodiments, 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 with a purity of at least about 95% is provided herein; the method includes 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 and then reacting it with a chiral agent.

[0120] 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, examples of the Lewis acid include titanium tetrachloride (TiCl4); zinc dichloride (ZnCl2); boron trifluoride (BF3); aluminum halides and alkylaluminum 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 (C uCl2 and CuBr2)), but are not limited thereto. In certain embodiments, the acid is a lithium halide. In other embodiments, the acid is lithium chloride.

[0121] 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 a C 1-14 carboxylic acid optionally substituted with one or more substituents Q. In certain embodiments, the acid is a 2-hydroxy-C 1-14It is a carboxylic acid. 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.

[0122] 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.

[0123] 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 includes dichloromethane and alcohol. In certain embodiments, the alcohol is C as defined herein 1-6It is alcohol. In other embodiments, the solvent mixture includes dichloromethane and ethanol. In certain embodiments, the solvent mixture includes dichloromethane and ethanol in a volume ratio in the range 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 to ethanol is in the range of about 2 to about 30. In certain embodiments, the volume ratio of dichloromethane to ethanol is in the range of about 2 to about 20. In certain embodiments, the volume ratio of dichloromethane to ethanol is in the range of about 2 to about 10. In certain embodiments, the volume ratio of dichloromethane to ethanol is in the range of 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. In certain embodiments, the volume ratio of dichloromethane to ethanol is in the range of about 2 to about 14. In certain embodiments, the volume ratio of dichloromethane to ethanol is in the range of about 2 to about 16.

[0124] In certain embodiments, sodium borohydride to 3-isobutyl-9,10- 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 in the range of about 0.5 to about 100, about 1 to about 100, about 1 to about 50, about 1 to about 25, about 1 to about 20, about 1 to about 10, about 2 to about 50, about 5 to about 50, about 5 to about 25, about 10 to about 25, or 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 in the range of 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 in the range of 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 in the range of 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 in the range of 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 in the range of 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 in the range of 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 in the range of 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 ranges 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 ranges 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 ranges 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.

[0125] In certain 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 in the range of about 0.5 to about 100, about 1 to about 100, about 1 to about 50, about 1 to about 25, about 1 to about 20, about 1 to about 10, about 2 to about 50, about 5 to about 50, about 5 to about 25, about 10 to about 25, or about 15 to about 25. In certain 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 in the range of 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 in the range of about 1 to about 50. In certain embodiments, acetic acid to 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2, 1-a] 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 in the range of about 1 to about 25. In certain 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 in the range of about 1 to about 20. In certain 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 in the range of about 1 to about 10. In certain 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 in the range of about 2 to about 50. In certain 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 in the range of about 5 to about 50. In certain 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 in the range of about 5 to about 25. In certain 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 in the range of about 10 to about 25. In certain 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 in the range of about 15 to about 25. In certain 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 certain 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.

[0126] In certain 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 in the range of about 0.5 to about 100, about 1 to about 100, about 1 to about 50, about 1 to about 25, about 1 to about 20, about 1 to about 10, about 2 to about 50, about 5 to about 50, about 5 to about 25, about 10 to about 25, or about 15 to about 25. In certain 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 in the range of 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 ranges from about 1 to about 50. In certain 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 certain 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 certain 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 certain 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 certain 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 in the range of from about 5 to about 50. In certain embodiments, lithium chloride versus 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyridyl 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 in the range of about 5 to about 25. In certain 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 in the range of about 10 to about 25. In certain 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 in the range of about 15 to about 25. In certain 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 certain 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.

[0127] 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 in the range of about -5 to about -15 °C, about -5 to about -10 °C, about -5 to about -5 °C, about -5 to about 0 °C, about 0 to about 5 °C, about 0 to about 10 °C, about 0 to about 15 °C, about 0 to about 20 °C, about 0 to about 25 °C, about 5 to about 25 °C, about 5 to about 15 °C, about 5 to about 10 °C. In some embodiments, the reduction is carried out at a temperature in the range of about -5 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 in the temperature range 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 in the temperature range of about -10 °C.

[0128] In other embodiments, the reaction 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 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.

[0129] 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 thereof, or a solvate, hydrate or polymorph thereof prepared by the methods provided herein has a purity of about 95 wt% or greater, about 96 wt% or greater, about 97 wt% or greater, about 97.5 wt% or greater, about 98 wt% or greater, about 98.5 wt% or greater, about 99 wt% or greater. 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 about 97.5 wt% or greater, about 97.6 wt% or greater, about 97.7 wt% or greater, about 97.8 wt% or greater, about 97.9 wt% or greater, about 98.1 wt% or greater, about 98.2 wt% or greater, about 98.3 wt% or greater, about 98.4 wt% or greater, about 98.5 wt% or greater, about 98.6 wt% or greater, about 98.7 wt% or greater, about 98.8 wt% or greater or about 98.9 wt% or greater. 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 about 97.6 wt% or greater or about 98.1 wt% or greater.

[0130] 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 with at least about 95% purity; the method includes 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, followed by a reduction step.

[0131] 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.

[0132] 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 heteroarene, a heterocycle, a carboxylic acid, a phosphoramide, carbon disulfide, water or a mixture thereof.

[0133] 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-dichloroethene, 1,2-dichloroethene, chloroform, trichloroethane, trichloroethene, carbon tetrachloride, chlorobenzene, trifluoromethylbenzene, methanol, ethanol, isopropanol (IPA), 1-propanol, 1-butanol, 2-butanol, t-butanol, 3-methyl-1-butanol, 1-pentanol, 2-methoxyethanol, 2-ethoxyethanol, ethylene glycol, diethyl ether, diisopropyl ether, methyl t-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 disulfide, water; or a mixture thereof.

[0134] In certain embodiments, the solvent 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 comprises a mixture of a hydrocarbon and water. In certain embodiments, the solvent comprises a mixture of heptane and water.

[0135] In certain embodiments, the solvent mixture comprises heptane and water in a volume ratio in the range 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 in the range of about 2 to about 30. In certain embodiments, the volume ratio of heptane to water is in the range of about 2 to about 20. In certain embodiments, the volume ratio of heptane to water is in the range of about 2 to about 10. In certain embodiments, the volume ratio of heptane to water is in the range of 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 in the range of about 1.5 to about 3.

[0136] In certain embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is in the range of about 0.5 to about 100, about 1 to about 100, about 1 to about 50, about 1 to about 25, about 1 to about 20, about 1 to about 10, about 2 to about 50, about 5 to about 50, about 5 to about 25, about 10 to about 25, or about 15 to about 25. In certain embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is in the range of about 1 to about 100. In certain embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is in the range of about 1 to about 50. In certain embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is in the range of about 1 to about 25. In certain embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is in the range of about 1 to about 20. In certain embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is in the range of about 1 to about 10. In certain embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is in the range of about 2 to about 50. In certain embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is in the range of about 5 to about 50. In certain embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one is in the range of about 5 to about 25.In certain embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one ranges from about 10 to about 25. In certain embodiments, the molar ratio of 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof to 3-((dimethylamino)methyl)-5-methylhexan-2-one ranges from about 15 to about 25. In certain embodiments, 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 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 1.1.

[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 at a temperature in the range of about 0 to about 100 °C, about 5 to about 90 °C, about 5 to about 80 °C, about 10 to about 70 °C, about 10 to about 60 °C, about 10 to about 50 °C, about 10 to about 40 °C, about 10 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 or a salt thereof is carried out at a temperature in the range of about 20 to about 80 °C, about 20 to about 70 °C, about 20 to about 60 °C, about 20 to about 50 °C. In other embodiments, the reaction is carried out at a temperature in the range of about 30 to about 80 °C, about 30 to about 70 °C, about 30 to about 60 °C, about 30 to about 40 °C, about 30 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 or a salt thereof is carried out at a temperature in the range of about 30 to about 40 °C.

[0138] 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 reacting the 3-((dimethylamino)methyl)-5-methylhexan-2-one salt with a base and then reacting the resulting product with 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof.

[0139] In some embodiments, the 6,7-dimethoxy-3,4-dihydroisoquinoline salt comprises an inorganic acid salt. In certain embodiments, the inorganic acid salt comprises hydrogen chloride.

[0140] In some embodiments, the 3-((dimethylamino)methyl)-5-methylhexan-2-one salt comprises a carboxylate salt. In certain embodiments, the carboxylate salt comprises a fumarate, oxalate, citrate, or maleate salt. In other embodiments, the carboxylate salt comprises an oxalate or citrate salt.

[0141] In some embodiments, the reaction of the 3-((dimethylamino)methyl)-5-methylhexan-2-one salt with a base comprises an inorganic base. In still other embodiments, the base is a carbonate base, bicarbonate base, or hydroxide base. In other embodiments, the base is sodium carbonate.

[0142] 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-amino-3-methylbutanoate di(4-methyl Methods for preparing (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol benzenesulfonate or a pharmaceutically acceptable solvate, hydrate or polymorph thereof with at least about 95% purity are provided herein; the methods include (a) 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) 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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof.

[0143] In certain embodiments, steps (a) (i.e., the step of 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) (i.e., 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)) are carried out as described herein.

[0144] 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 in at least about 95% purity; the method comprising: (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 with a protected suitable 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) 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 (c) 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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof. comprising 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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof.

[0145] In certain embodiments, step (b) (i.e., the step of 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) and step (c) (i.e., 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 bis(4-methylbenzenesulfonate)) are carried out as described herein.

[0146] (S)-(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 with a purity of at least about 95%, the method comprising: (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 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.

[0147] 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.

[0148] 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 carried out as described in U.S. Provisional Application No. 62 / 249,074, filed October 30, 2015, the disclosure of which is incorporated herein by reference in its entirety.

[0149] In certain embodiments, 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 or a pharmaceutically acceptable solvate, hydrate or polymorph thereof prepared by the methods provided herein is substantially pure. In certain embodiments, 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 or a pharmaceutically acceptable solvate, hydrate or polymorph thereof prepared by the methods provided herein is suitable for use in humans (e.g., for treating, preventing and / or managing a disease, disorder or condition).

[0150] In certain embodiments, the overall yield of 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 is about 30% or greater, about 40% or greater, about 50% or greater, about 55% or greater, about 60% or greater, about 65% or greater, about 70% or greater, about 75% or greater, about 80% or greater, about 85% or greater, about 90% or greater or about 95% or greater, where the yield is calculated based on the starting materials.

[0151] In certain embodiments, 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 solvate, hydrate or polymorph thereof prepared by the methods provided herein is substantially pure. In certain embodiments, 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 solvate, hydrate or polymorph thereof prepared by the methods provided herein is suitable for use in humans (e.g., for treating, preventing and / or managing a disease, disorder or condition).

[0152] 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 are about 5 wt% or less, about 4 wt% or less, about 3 wt% or less, about 2.5 wt% or less, about 2 wt% or less, about 1.5 wt% or less, about 1 wt% or less, about 0.5 wt% or less, or about 0.1 wt% or less.

[0153] In certain embodiments, the impurities are detectable by HPLC (High Performance Liquid Chromatography). In certain embodiments, examples of the 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.

[0154] In certain embodiments, the impurities are metal-based impurities. In certain embodiments, the impurities are volatile organic compounds. In certain embodiments, the impurities are organic solvents. In certain embodiments, the impurities are sulfonates, dimethylamine, formaldehyde, ethyl chloride, or isopropyl chloride.

[0155] 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 about 5% by weight or less, about 4% by weight or less, about 3% by weight or less, about 2% by weight or less, about 1% by weight or less, about 0.9% by weight or less, about 0.8% by weight or less, about 0.7% by weight or less, about 0.6% by weight or less, about 0.5% by weight or less, about 0.4% by weight or less, about 0.3% by weight or less, about 0.2% by weight or less, or about 0.1% by weight or less.

Example

[0156] Certain embodiments are illustrated by the following non-limiting examples.

[0157] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius and all parts and percentages are by weight. Reagents can be purchased from commercial suppliers (e.g., Sigma-Aldrich® Chemical Co., etc.) and used without further purification unless otherwise indicated. Reagents can also be prepared according to standard literature procedures known to those skilled in the art. Solvents can be purchased, for example, from Sigma-Aldrich® and used as received or purified using standard methods known to those skilled in the art, unless otherwise indicated.

[0158] Unless otherwise specified, the reactions shown below were generally carried out at ambient temperature or room temperature. The reactions were terminated when the reactants were assayed by HPLC and judged by the consumption of starting materials.

[0159] The structures and purities of the compounds in the following examples were determined by the following methods: proton nuclear magnetic resonance ( 1 1H NMR) spectroscopy, 13Confirmed by one or more of the methods of 13C NMR spectroscopy, mass spectrometry, infrared spectroscopy, melting point, X-ray crystal structure analysis and / or HPLC. Using an NMR spectrometer operating at a specific field strength, 1 1H NMR spectra were measured. Chemical shifts are reported in parts per million (ppm, δ) downfield from an internal standard such as a standard, e.g., TMS. Alternatively, 1 1H NMR spectra were referenced to signals from residual protons in deuterated solvents as follows: CDCl3 = 7.26 ppm; DMSO-d6 = 2.50 ppm; C6D6 = 7.16 ppm; CD3OD = 3.31 ppm (J. Org. Chem. 1997, 62, 7513). Peak multiplicities are designated as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, triplet of doublets; q, quartet; br, broadened ); and m, multiplet. Coupling constants are expressed in Hertz (Hz). Mass spectrum (MS) data were obtained using a mass spectrometer equipped with APCI or ESI ionization. Example 1 (S)-(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) Preparation A. Preparation of 3-Isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one

Chemical formula

[0160] 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 between 15 and 25 °C, and the mixture was stirred at this temperature. By adding the previous sodium hydroxide / water solution, the pH was adjusted to 8 - 10, and the mixture was stirred for 30 - 60 minutes. Then, the aqueous layer was 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.

[0161] The 3-((dimethylamino)methyl)-5-methylhexan-2-one - heptane solution 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 about 30 °C. When less than 10% of 6,7-dimethoxy-3,4-dihydroisoquinoline remained relative to the standard solution, the reaction was judged to be complete. The mixture was cooled to room temperature, the solid was filtered, washed with water (176.5 L) and then n-heptane (277.4 L) (both stabilized at a temperature of 15 - 20 °C), and then dried under vacuum to obtain 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (139 kg, 79% yield). A1. Preparation of 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one starting from 3-((dimethylamino)methyl)-5-methylhexan-2-one free base

[0162] 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 about 35 °C for at least 48 hours until less than 10% of 6,7-dimethoxy-3,4-dihydroisoquinoline remained with respect to the standard solution. The solid was filtered, washed with water and then with heptane, and then dried under vacuum to obtain 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquin olin-2(11bH)-one (141.1 kg, 85.6% yield). B. Preparation of 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol [Chemical formula]

[0163] 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 mixture was stirred for several hours and monitored by HPLC for completion. When the reaction was complete, the mixture was warmed to 25 °C and saturated aqueous ammonium chloride solution (69.5 kg) was added to quench the reaction. The reaction mixture was distilled under vacuum at 40 ± 5 °C to concentrate to a minimum volume. 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 of water) were added at 20 ± 5 °C and the mixture was stirred for at least 15 minutes. The layers were separated, the organic layer was recovered, and the aqueous layer was back-extracted with dichloromethane. The combined organics were washed with water, separated, and then distilled under vacuum to a minimum volume. Isopropyl acetate (347.5 L) was added and the mixture was distilled under vacuum until a total of approximately 3 volumes remained, and the process was repeated. The slurry was heated to 85 ± 5 °C, held for 0.5 - 1 hour, then cooled to 65 °C to initiate crystallization. The mixture was further cooled to 20 °C and held for 1 hour. The solid was filtered, rinsed with isopropyl acetate, and then dried under vacuum to obtain 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (60 kg, 86% yield). For another batch, starting from 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (69.5 kg) and following the same procedure described herein, 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol was obtained (59.7 kg, 85% yield). 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

Chemical formula

[0164] 3-Isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (59.8 kg) and (1S )-(+)-camphorsulfonic acid (46 kg, 1 equivalent) were suspended in 19:1 ethanol:water (v / v), and then it was heated at about 75 °C until a solution was formed. The mixture was cooled to 53 ± 2 °C and held until crystallization occurred. If nucleation did not occur, seeds 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 were added to the batch. The mixture was cooled to 25 ± 5 °C over at least 14 hours. The slurry was filtered, washed with ethanol, and then dried under vacuum to obtain (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 as a crystalline solid (38.7 kg, 38% yield). For another batch, 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) and using the same procedure described herein, (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 was obtained (39.5 kg, 38% yield). 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

Chemical Structure

[0165] (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 then the mixture was stirred at 25 ± 5 °C. The organic matter was recovered, washed with additional sodium hydroxide solution, and then with water. The organic phase was recovered, dried over sodium sulfate, and then filtered to remove solids. Boc-L-valine (12.2 kg, 1.2 equivalents) and 4-dimethylaminopyridine (1.55 kg, 0.3 equivalents) were added to the organic phase, and then 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 by HPLC for completion. Once complete, water was added and the contents were stirred. After standing, the aqueous layer was discarded. The organic layer was washed with an aqueous citric acid solution (prepared from 5.2 kg of citric acid in 101 L of water), and then with water to obtain (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate as a solution in dichloromethane. Preparation of (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate dihydrochloride [Chemical formula]

[0166] A hydrogen chloride - dioxane solution (4 M, 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 - 10 °C. After the addition was complete, the mixture was stirred at 25 ± 5 °C for > 12 hours. When complete, an aqueous sodium hydrogen carbonate solution (217.6 kg) was slowly added and the mixture was stirred at 25 ± 5 °C until the pH > 7. The organic matter was recovered and washed with additional aqueous sodium hydrogen carbonate solution and then with water. Sodium sulfate was added to the organic layer and then the mixture was filtered to remove the solid. Then the organic layer was distilled to the minimum volume required for stirring. Acetonitrile (70 L) was added and the mixture was distilled again to the minimum volume. Acetonitrile was added until the solution totaled 10 volumes and then the solution was cooled to 10 ± 5 °C. A solution of hydrogen chloride in isopropanol (3.7 M, 26.4 L, 2.1 equivalents) was slowly added, then ethyl acetate (57 L) was added and then the mixture was heated to 50 ± 5 °C. After additional ethyl acetate was added, a seed crystal 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 was added 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 obtain (S)-(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).For another batch, starting from (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (24.4 kg), by performing using the same procedure described herein, (S)-(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 obtained (17 kg, 79% yield). 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-methylbutanoate di(4-methylbenzenesulfonate) [Chemical formula]

[0167] (S)-(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 an aqueous sodium hydrogen carbonate solution. The mixture was stirred at about 25 °C. The organic matter was recovered, washed with a further aqueous sodium hydrogen carbonate solution and then with water. The organic layer was recovered and acetonitrile was added to the solution in dichloromethane. The solution was distilled to the minimum volume necessary for stirring. Further acetonitrile was added and the mixture was distilled to the minimum volume. The mixture was tested for water content and then warmed to about 50 °C. To this mixture, an acetonitrile solution of p-toluenesulfonic acid (2 equivalents) was slowly added and the contents were stirred at about 50 °C for >8 h. The slurry was then cooled to about 25 °C, the solid was filtered off, 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). 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-methylbutanoate Di(4-methylbenzenesulfonate)

[0168] (S)-(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 an aqueous sodium hydrogen carbonate solution (245 kg) was added until the pH was > 6.5. Then, the mixture was stirred at 25 ± 5 °C. The organic matter was recovered, washed with a further aqueous sodium hydrogen carbonate solution, and then washed with water. Then, the solution was distilled to the minimum volume required for stirring. Acetonitrile (54 L) was added, and the mixture was distilled to the minimum volume, and this was repeated. Acetonitrile was added, and the mixture was tested for water content. When it was within the specification, it was heated to 50 ± 5 °C. To this mixture, a solution of p-toluenesulfonic acid (11.7 kg, 2 equivalents) in acetonitrile (55.5 L) was slowly added, and the contents were stirred at 50 ± 5 °C for > 8 hours. Then, the slurry was cooled to 25 ± 5 °C, the solid was filtered, washed with acetonitrile, and then dried under vacuum to obtain (S)-(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). 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-methylbutanoate di(4-methylbenzenesulfonate) [Chemical formula]

[0169] Into an Erlenmeyer flask, (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) (100 mL) in 2-methyltetrahydrofuran (MeTHF) was charged, and then an aqueous KOH solution (2 M, 110 mL) was added. 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 layer formed and this layer was partitioned with brine for better separation. The aqueous layer was discarded. To the organic layer, H2O (20 mL) was added and then shaken several times. After 15 minutes, the layers were separated and the aqueous layer was discarded.

[0170] Into a round-bottom flask, MeTH of the free based material Solution F (ca. 100 mL; from above) was added along with additional MeTHF (40 mL). N-Boc-(L)-Val-OH (1.2 eq) and DMAP (0.27 eq) were added, after which a clear yellow solution resulted. The solution was cooled to 0 to -10 °C using an acetone ice / H2O bath. After reaching temperature, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) (1.77 eq) was added and stirring was continued at 0 to -10 °C for 3 h. After 3 h, the ice bath was removed and the reaction was stirred for at least 5 h. After 18 h, analytical data showed complete conversion to (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate. 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 was isolated.

[0171] The 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 from above was transferred to a clean round-bottom flask together with additional MeTHF (110 mL). To that solution was added EtOAc (44 mL) and 3.7 N HCl / isopropanol (21 mL; other HCl solutions can also be used). The solution was heated to 45 °C, and a seed crystal 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 was added, and the mixture was stirred for half an hour. After half an hour, additional EtOAc (30 mL) was added, and the temperature was raised to 70 °C over 1 hour. After 1 hour, HPLC indicated that 8% of the starting material still remained. To the reaction mixture was added additional 3.7 N HCl / isopropanol (3 mL), and then it was heated at 70 °C for 2 hours. After 2 hours, the reaction was complete. Saturated aqueous NaHCO3 (30 mL) was slowly added, the mixture was stirred for half an hour, and then it was washed with H2O (60 mL). The resulting solution of the free basified material (HPLC >95% purity) was advanced to tosylate salt formation without further purification.

[0172] The free base solution from the above was evaporated, and solvent exchange was completed using acetonitrile (2 × 40 mL). The yellow residue was dissolved in acetonitrile (67 mL), heated to 45 - 55 °C, and then a solution of p-TsOH / acetonitrile (8.3 g / 139 mL) was added all at once. After stirring at 45 °C for 18 h, the slurry was cooled to 25 °C, the white solid was filtered, washed with EtOAc (2 × 10 mL), and then dried in a vacuum oven at 50 °C for 18 h to obtain (S)-(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). Purity (99.68%) and chirality (99.77%) were confirmed by analytical HPLC data.

[0173] In an alternative procedure, (S)-(2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl 2-amino-3-methylbutanoate dihydrochloride was isolated by filtration, then free basified and then converted to the ditosylate as described above. 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-methylbutanoate di(4-methylbenzenesulfonate)

Chemical Structure

[0174] (S)-(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 heating the mixture, p-TsOH (14 g, 4 equivalents) was added. During heating, the mixture became a homogeneous clear solution. The solution was allowed to stand at 70 °C for 2 - 3 hours. After 2 - 3 hours, a white solid precipitated and the heat 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 obtain (S)-(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. The H 1 -NMR was consistent with that obtained from Step G.

[0175] The embodiments described herein are intended to be merely illustrative, and those skilled in the art can recognize or confirm numerous equivalents of specific compounds, materials, and procedures using only routine experimental methods. All such equivalents are considered to be within the scope of the present disclosure.

[0176] All patents, patent applications, and publications referred to herein are hereby incorporated by reference in their entirety. The citation or identification of any reference in this application is not an admission that such reference is available as prior art to the present application. The full scope of the present disclosure is better understood in light of the appended claims. Examples of embodiments of the present disclosure include the following items. (Item 1) (S)-(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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof is prepared with a purity of at least about 95%, the method comprising 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 bis(4-methylbenzenesulfonate) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof. (Item 2) (S)-(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 bis(4-methylbenzenesulfonate) in the step described above comprises the steps of (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. The method according to item 1. (Item 3) The method according to item 2, wherein the base comprises an inorganic base. (Item 4) The method according to item 3, wherein the base comprises a carbonate base. (Item 5) The method according to item 4, wherein the base is sodium hydrogen carbonate. (Item 6) The method according to any one of items 2 to 5, wherein the step of contacting (S)-(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. (Item 7) The method according to item 6, wherein the first solvent contains a chlorinated hydrocarbon. (Item 8) The method according to item 7, wherein the first solvent is dichloromethane. (Item 9) The method according to any one of items 1 to 8, wherein the reaction between the product of (a) and p-toluenesulfonic acid is carried out in a second solvent. (Item 10) The method according to item 9, wherein the second solvent contains a nitrile. (Item 11) The method according to item 10, wherein the second solvent contains acetonitrile. (Item 12) The method according to any one of items 1 to 11, wherein the reaction between the product of (a) and p-toluenesulfonic acid is carried out at a temperature in the range of about 40 to about 60 °C. (Item 13) The method according to item 12, wherein the reaction is carried out at a temperature in the range of about 45 to about 55 °C. (Item 14) The method according to any one of items 1 to 13, further comprising an isolation step. (Item 15) (S)-(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 di(4-methylbenzenesulfonate) 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 method according to any one of items 1 to 14. (Item 16) (S)-(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 is at least about 96%, at least about 97%, at least about 98%, at least about 99% pure, the method according to any one of items 1 to 15. (Item 17) (S)-(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 is at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, at least about 99.9% pure, the method according to item 16. (Item 18) Before 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 with a base, 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, the method according to any one of items 1 to 17, further comprising 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 via a deprotection step. (Item 19) (S)-(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 method according to item 18, wherein the deprotection step is carried out in the presence of an acid. (Item 20) (S)-(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 method according to item 19, wherein the acid comprises a hydrogen chloride-dioxane solution or a 2-methyltetrahydrofuran solution. (Item 21) (S)-(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 method according to any one of items 19 or 20, wherein the reaction is carried out in the presence of a solvent. (Item 22) (S)-(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 method according to item 21, wherein the solvent comprises a chlorinated hydrocarbon. (Item 23) (S)-(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 method according to item 22, wherein the solvent comprises dichloromethane. (Item 24) (S)-(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 method according to any one of items 19 to 23, wherein the deprotection step is carried out at a temperature in the range of about 0 to about 25 °C. (Item 25) The method according to any one of items 18 to 24, further comprising a step of adding a base. (Item 26) The method according to item 25, wherein the base contains a carbonate. (Item 27) The method according to item 26, wherein the base is sodium hydrogen carbonate. (Item 28) The method according to item 27, further comprising a step of separating the solvent from the aqueous solution. (Item 29) The method according to item 28, further comprising a step of adding a second solvent. (Item 30) The method according to item 29, wherein the second solvent contains a nitrile solvent. (Item 31) The method according to item 30, wherein the second solvent contains acetonitrile. (Item 32) The method according to any one of items 18 to 31, further comprising a step of adding an acid. (Item 33) The method according to item 32, wherein the acid contains a solution of hydrogen chloride. (Item 34) The acid is hydrogen chloride·C 1-6 The method according to item 33, wherein the acid contains an alcohol solution. (Item 35) The method according to item 34, wherein the acid is a hydrogen chloride·propan-2-ol solution. (Item 36) The method according to any one of items 32 to 35, further comprising a step of adding another solvent. (Item 37) The method according to item 36, wherein the solvent contains acetonitrile or ethyl acetate. (Item 38) The method according to any one of items 32 to 38, wherein the reaction is carried out at a temperature in the range of about 5 to about 80 °C. (Item 39) (S)-(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 further comprising the step of crystallizing the same, the method according to any one of items 18 to 38. (Item 40) (S)-(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 is substantially pure, the method according to any one of items 18 to 39. (Item 41) (S)-(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 is about 96% or more, about 97% or more, about 98% or more, about 99% or more pure, the method according to any one of items 18 to 40. (Item 42) (S)-(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 is about 99.5% or more, about 99.6% or more, about 99.7% or more, about 99.8% or more, about 99.9% or more pure, the method according to any one of items 18 to 41. (Item 43) (S)-(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 formed under conditions suitable for forming the same, (2R,3R,11bR)-3-isobutyl-9,10 The method according to any one of items 1 to 42, further comprising a step of reacting -dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol or a salt thereof with an amino acid protected with tert-butoxycarbonyl. (Item 44) (S)-(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, 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 for forming the same 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, the method according to item 43. (Item 45) (2R,3R,11bR)-3-Isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol, wherein the salt thereof contains a sulfonate, the method according to item 44. (Item 46) (2R,3R,11bR)-3-Isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol, wherein the salt thereof 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, the method according to item 45. (Item 47) (S)-(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 (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 an amino acid protected with tert-butoxycarbonyl to form the same, is the method according to any one of items 43 to 46, which comprises valine or alanine. (Item 48) The method according to item 47, wherein the amino acid protected with tert-butoxycarbonyl is L-valine. (Item 49) (S)-(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 (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 an amino acid protected with tert-butoxycarbonyl to form the same, is the method according to any one of items 43 to 48, which is carried out in the presence of a base. (Item 50) The method according to item 49, wherein the base is 4-dimethylaminopyridine. (Item 51) (S)-(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 (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 an amino acid protected with tert-butoxycarbonyl to form the same, is the method according to any one of items 43 to 48, which is carried out in the presence of a base. The reaction is carried out in the presence of a coupling reagent, according to the method described in any one of items 43 to 50. (Item 52) The method according to item 51, wherein the coupling reagent is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. (Item 53) 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, according to the method described in any one of items 42 to 52. (Item 54) The method according to item 53, wherein the solvent contains dichloromethane. (Item 55) 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 in the range of about 0 to about 25 °C, according to the method described in any one of items 43 to 54. (Item 56) The method according to any one of items 43 to 55, 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 solution in dichloromethane. (Item 57) Before the reaction with the amino acid protected with tert-butoxycarbonyl, 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, the method according to any one of items 1 to 41. (Item 58) The method according to item 57, wherein the chiral agent contains an acid. (Item 59) The method according to item 58, wherein the acid contains camphorsulfonic acid. (Item 60) The method according to item 59, wherein the acid is (1S)-(+)-camphorsulfonic acid. (Item 61) (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, 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 the same is carried out in the presence of a solvent, the method according to any one of items 57 to 60. (Item 62) The method according to item 61, wherein the solvent contains water and alcohol. (Item 63) The method according to item 62, wherein the solvent contains water and ethanol. (Item 64) The method according to item 63, wherein the solvent ratio of water to ethanol is about 1:17 or about 1:19. (Item 65) The method according to any one of items 61 to 64, wherein the reaction is carried out at a temperature in the range of about 20 to about 75 °C. (Item 66) The method according to any one of items 61 to 65, wherein the reaction is carried out at a temperature in the range of about 20 to about 65 °C. (Item 67) The method according to any one of items 61 to 66, wherein the reaction is carried out at a temperature in the range of about 20 to about 50 °C. (Item 68) The method according to any one of items 57 to 67, 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)-(+)-camphorsulfonate. (Item 69) (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 or a pharmaceutically acceptable solvate, hydrate or polymorph thereof is substantially pure, according to any one of items 57 to 68. (Item 70) (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 or a pharmaceutically acceptable solvate, hydrate or polymorph thereof is at least about 96%, at least about 97%, at least about 98%, at least about 99% pure, according to any one of items 57 to 69. (Item 71) (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 or a pharmaceutically acceptable solvate, hydrate or polymorph thereof is at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, at least about 99.9% pure, according to any one of items 57 to 70. (Item 72) The method according to any one of items 1 to 71, further comprising the step of reacting with a chiral agent after 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. (Item 73) The method according to item 72, wherein the reduction is carried out in the presence of an acid. (Item 74) The method according to item 73, wherein the acid comprises a Lewis acid. (Item 75) The method according to item 74, wherein the Lewis acid is lithium chloride. (Item 76) The method according to item 72, wherein the acid is an organic acid selected from acetic acid, formic acid, oxalic acid, maleic acid, lactic acid, ascorbic acid, mandelic acid or a mixture thereof. (Item 77) The method according to item 76, wherein the acid is acetic acid. (Item 78) The method according to any one of items 72 to 77, wherein the reduction is carried out in the presence of a reducing agent. (Item 79) The method according to item 78, wherein the reducing agent comprises a borohydride. (Item 80) The method according to item 79, wherein the reducing agent is selected from sodium borohydride, lithium borohydride, calcium borohydride, magnesium borohydride, potassium borohydride, 9-BBN, cyanoboroydride, bis-triphenylphosphine borohydride, sodium triethylborohydride, tetrabutylammonium borohydride, tetramethylammonium borohydride, tetraethylammonium borohydride or lithium triethylborohydride. (Item 81) The method according to item 80, wherein the reducing agent is sodium borohydride. (Item 82) The method according to any one of items 72 to 81, wherein the reduction is carried out in the presence of a solvent. (Item 83) The method according to any one of items 72 to 82, wherein the solvent comprises dichloromethane and alcohol. (Item 84) The method according to item 83, wherein the solvent comprises dichloromethane and ethanol. (Item 85) The method according to any one of items 72 to 84, wherein the reaction is carried out at a temperature in the range of about -5 to about -15 °C. (Item 86) The method according to any one of items 72 to 85, further comprising a step of crystallizing 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol. (Item 87) The method according to any one of items 72 to 86, 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 or a pharmaceutically acceptable solvate, hydrate or polymorph thereof is substantially pure. (Item 88) The method according to any one of items 72 to 87, 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 or a pharmaceutically acceptable solvate, hydrate or polymorph thereof is about 96% or more, about 97% or more, about 98% or more, about 99% or more pure. (Item 89) The method according to any one of items 72 to 88, 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 or a pharmaceutically acceptable solvate, hydrate or polymorph thereof is about 97.6% or more or about 98.1% or more pure. (Item 90) Before the reduction step, 6,7-dimethoxy-3,4-dihydroisoquinoline or a salt thereof is reacted 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, and the method according to any one of items 1 to 89 further comprises this step. (Item 91) The method according to item 90, 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. (Item 92) The method according to any one of items 90 or 91, wherein the solvent contains heptane. (Item 93) The method according to any one of items 90 to 92, 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 in the range of about 30 to about 40 °C. (Item 94) The method according to any one of items 90 to 93 further comprises reacting the 3-((dimethylamino)methyl)-5-methylhexan-2-one salt with a base and then reacting it with 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride. (Item 95) The method according to item 93, wherein the 3-((dimethylamino)methyl)-5-methylhexan-2-one salt contains a carboxylate. (Item 96) The method according to item 95, wherein the carboxylate contains fumarate, oxalate, citrate or maleate. (Item 97) The method according to item 95, wherein the salt is oxalate or citrate. (Item 98) The method according to any one of items 94 to 97, wherein the base is sodium carbonate. (Item 99) (S)-(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 is prepared at a purity of at least about 95%, the method 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-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 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. (Item 100) 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 bis(4-methylbenzenesulfonate) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof with a purity of at least about 95%, the method comprising the step of 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 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 and reacting it with p-toluenesulfonic acid. (Item 101) The method according to item 100, wherein the reaction is carried out at a temperature in the range of about 20 to about 70 °C. (Item 102) The method according to item 101 or 102, further comprising a filtration step. (Item 103) The method according to any one of items 100 to 102, further comprising an isolation step. (Item 104) (S)-(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 at a purity of at least about 95%, the method comprising: (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 with a protected suitable 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) 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 (c) 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) or a pharmaceutically acceptable solvate, hydrate or polymorph thereof. (Item 105) (S)-(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 is prepared at a purity of at least about 95% by a method comprising: (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; 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 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. (Item 106) The method according to any one of Items 1 to 101, wherein the prepared (S)-(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 is substantially free of impurities.

Claims

【Claim 1】 Involuntary movement.

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