Processes for synthesis of valbenazine

Abstract

To provide processes for synthesis of valbenazine.SOLUTION: The present application relates to processes for making (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl (S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), which is an inhibitor of vesicular monoamine transporter 2 (VMAT2) useful in the treatment of hyperkinetic movement disorders such as tardive dyskinesia (TD).SELECTED DRAWING: None

Description

[Technical Field]

[0001] background Technical Field The present application relates to a method for making (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), an inhibitor of vesicular monoamine transporter 2 (VMAT2) useful in the treatment of hyperkinetic movement disorders, such as tardive dyskinesia (TD). [Background technology]

[0002] 2. Description of Related Art Ingrezza®, the first FDA-approved treatment for patients with tardive dyskinesia, a hyperkinetic movement disorder, contains valbenazine present as valbenazine ditosylate. Valbenazine [(S)-2-amino-3-methyl-butyric acid (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-yl ester], a potent and selective VMAT2 inhibitor, is a purified prodrug of the (+)-α-isomer of dihydrotetrabenazine. The structure of valbenazine ditosylate is depicted herein as Formula I.

[0003] Valbenazine and its preparation and use are described in U.S. Patent Nos. 8,039,627; 8,357,697; and 10,160,757, each of which is incorporated herein by reference in its entirety. Certain salts and crystalline forms of valbenazine are described in International Publication No. 2017 / 075340, and certain formulations of valbenazine are described in International Publication No. 2019 / 060322, each of which is incorporated herein by reference in its entirety. Due to the high demand and utility of Ingrezza, there is a need to develop new methods for its production, particularly more environmentally friendly methods. It is to this need and others that the present application is made. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] U.S. Patent No. 8,039,627 [Patent Document 2] U.S. Patent No. 8,357,697 [Patent Document 3] U.S. Patent No. 10,160,757 [Patent Document 4] International Publication No. 2017 / 075340 [Patent Document 5] International Publication No. 2019 / 060322 Summary of the Invention [Means for solving the problem]

[0005] overview The present application relates inter alia to compounds of formula I: [ka] The present invention provides a method for preparing a compound of formula (I).

[0006] In some embodiments, the present application provides a compound of Formula I: [ka] 1. A method for preparing a compound of formula (I), comprising: Formula F8: [ka] with p-toluenesulfonic acid in a solvent comprising acetonitrile or isopropyl acetate to obtain a compound of formula I.

[0007] In some embodiments, the present application provides a compound of Formula I: [ka] 1. A method for preparing a compound of formula (I), comprising: Formula F8: [ka] with p-toluenesulfonic acid in a solvent comprising acetonitrile or isopropyl acetate to obtain a material comprising the compound of formula I.

[0008] The method is as follows: [ka] in a solvent with a compound of formula F7: [ka] with a carboxylic acid of formula F8 to give a compound of formula F9.

[0009] The method is as follows: [ka] with a base to provide a compound of formula F6.

[0010] The method is as follows: [ka] with (S)-(+)-camphorsulfonic acid (CSA) to obtain a compound of formula F6-CSA.

[0011] The method is as follows: [ka] with a reducing agent in a solvent comprising methyl tert-butyl ether (MTBE) and methanol to provide a compound of formula F5.

[0012] The method is as follows: [ka] is reacted with a compound of formula F2: [ka] to give a compound of formula F4.

[0013] The method is as follows: [ka] with a base to obtain a compound of formula F2.

[0014] The method comprises the step of crystallizing a compound of formula I, a) dissolving a material comprising a compound of formula I in a solvent mixture comprising methanol and acetonitrile; and b) crystallizing the compound of formula I from a solvent mixture to obtain a compound of formula I: [ka] The method may further comprise the step of obtaining a compound of formula (I).

[0015] The present application describes a method for preparing a crystalline compound of formula I, comprising: a) dissolving a material comprising a compound of formula I in a solvent mixture comprising methanol and acetonitrile; and b) crystallizing the compound of formula I from a solvent mixture to obtain a compound of formula I: [ka] The present invention further provides a method comprising the step of obtaining a crystalline compound of formula (I).

[0016] The present application provides compounds of formula I: [ka] 1. A method for preparing a material comprising a compound of a) Formula F6-CSA: [ka] with a base to form a compound of formula F6: [ka] obtaining a compound of formula (I); b) reacting a compound of formula F6 with a compound of formula F7: [ka] with a carboxylic acid of formula F8: [ka] forming a compound of c) reacting a compound of formula F8 with p-toluenesulfonic acid in a solvent comprising acetonitrile or isopropyl acetate to obtain a material comprising a compound of formula I.

[0017] The present application relates to a compound of formula F6-CSA: [ka] 1. A method for preparing a compound of formula (I), comprising: Formula F5: [ka] with (S)-(+)-camphorsulfonic acid (CSA) to obtain a compound of formula F6-CSA, wherein the molar ratio of CSA to the compound of formula F5 is between 0.7:1 and 0.9:1.

[0018] The present application provides compounds of formula F5: [ka] 1. A method for preparing a compound of formula (I), comprising: Formula F4: [ka] with a reducing agent in a solvent comprising methyl tert-butyl ether (MTBE) and methanol to provide a compound of formula F5.

[0019] The present application provides compounds of formula F4: [ka] 1. A method for preparing a compound of formula (I), comprising: a) Formula F1: [ka] with a base to form a compound of formula F2: [ka] obtaining a compound of formula (I); b) Transforming a compound of formula F2 into a compound of formula F3: [ka] to obtain a compound of formula F4.

[0020] The present application provides compounds of formula I: [ka] 1. A method for preparing a crystalline compound of a) Formula F1: [ka] with a base to form a compound of formula F2: [ka] obtaining a compound of formula (I); b) Formula F3: [ka] is reacted with a compound of formula F2 in a solvent comprising isopropanol (IPA) and water to give a compound of formula F4: [ka] obtaining a compound of formula (I); c) reacting the compound of formula F4 with a reducing agent in a solvent comprising methyl tert-butyl ether (MTBE) and methanol to give a compound of formula F5: [ka] obtaining a compound of formula (I); d) reacting the compound of formula F5 with (S)-(+)-camphorsulfonic acid (CSA) to give the compound of formula F6-CSA: [ka] obtaining a compound of formula (I); e) reacting a compound of formula F6-CSA with a base to form a compound of formula F6: [ka] obtaining a compound of formula (I); f) reacting a compound of formula F6 with a compound of formula F7: [ka] with a carboxylic acid of formula F8: [ka] obtaining the product; g) reacting the product of formula F8 with p-toluenesulfonic acid in acetonitrile or isopropyl acetate to obtain a material comprising a compound of formula I; and h) crystallizing the material comprising the compound of formula I, i) dissolving a material comprising a compound of formula I in a solvent mixture comprising methanol and acetonitrile; and ii) crystallizing the compound of formula I from a solvent mixture to obtain a compound of formula I: [ka] obtaining a compound of formula (I) Further provided is a method comprising:

[0021] In an alternative embodiment of the method described above, steps g) and h) are as follows: g) reacting the product of formula F8 with p-toluenesulfonic acid in acetonitrile or isopropyl acetate to obtain a mixture containing a compound of formula I; and h) crystallizing the compound of formula I from the mixture to obtain the compound of formula I.

[0022] The present application further provides one or more of the processes as described herein above or below, in separate or all of steps a) through h), which are useful in the preparation of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of formula I).

[0023] The present application further provides a step of formulating a compound of Formula I to form a pharmaceutical composition. The present application further provides a step of formulating a compound of Formula I to form a pharmaceutical composition comprising silicified microcrystalline cellulose; isomalt; hydroxypropyl methylcellulose; partially pregelatinized corn starch; and magnesium stearate. In some embodiments, the formulating step comprises combining the compound of Formula I with a pharmaceutically acceptable carrier and / or diluent to form a pharmaceutical composition comprising the compound of Formula I.

[0024] The present application further provides for formulating a crystalline form of the compound of Formula I to form a pharmaceutical composition. The present application further provides for formulating a crystalline form of the compound of Formula I to form a pharmaceutical composition comprising silicified microcrystalline cellulose; isomalt; hydroxypropyl methylcellulose; partially pregelatinized corn starch; and magnesium stearate. In some embodiments, the formulating step comprises combining the crystalline form of the compound of Formula I with a pharmaceutically acceptable carrier and / or diluent to form a pharmaceutical composition comprising the crystalline form of the compound of Formula I.

[0025] The present application further provides a method for preparing a pharmaceutical composition, the method comprising preparing a compound of formula I according to the methods provided herein above and below, and formulating the compound of formula I with a pharmaceutically acceptable carrier and / or diluent.

[0026] The present application further provides methods for preparing the crystalline compound of Formula I. In some embodiments, the crystalline compound of Formula I is Form I, as described in more detail herein. In certain embodiments, for example, the following items are provided: (Item 1) Formula I: [ka] 1. A method for preparing a compound of formula (I), comprising: Formula F8: [ka] with p-toluenesulfonic acid in a solvent comprising acetonitrile or isopropyl acetate to obtain the compound of formula I. (Item 2) Item 10. The method according to item 1, wherein the ratio of p-toluenesulfonic acid to the compound of formula F8 is about 2.0:1 to about 2.2:1 molar equivalents. (Item 3) Item 10. The method of claim 1, wherein the ratio of p-toluenesulfonic acid to the compound of formula F8 is about 2.1:1 molar equivalents. (Item 4) 4. The method according to any one of items 1 to 3, wherein the step of reacting the compound of formula F8 with p-toluenesulfonic acid is carried out at a temperature of about 50°C to about 75°C. (Item 5) 4. The method according to any one of items 1 to 3, wherein the step of reacting the compound of formula F8 with p-toluenesulfonic acid is carried out at a temperature of about 64°C to about 66°C. (Item 6) 6. The method of any one of items 1 to 5, wherein the step of reacting the compound of formula F8 with p-toluenesulfonic acid is carried out for a period of time sufficient to reduce the presence of the compound of formula F8 to at least 3% as determined by HPLC. (Item 7) 6. The method of any one of items 1 to 5, wherein the step of reacting the compound of formula F8 with p-toluenesulfonic acid is carried out for a period of about 10 hours to about 14 hours. (Item 8) 8. The method of any one of items 1 to 7, wherein after the step of reacting the compound of formula F8 with p-toluenesulfonic acid, the method further comprises a step of cooling to a temperature of about 18°C ​​to about 22°C. (Item 9) 9. The method according to item 8, wherein the temperature is maintained for about 1.8 hours to about 2.2 hours. (Item 10) 10. The method of claim 9, wherein the temperature is maintained with stirring. (Item 11) 11. The method according to any one of items 1 to 10, wherein the compound of formula I is isolated by washing with acetonitrile and drying under vacuum at elevated temperature. (Item 12) The compound of formula F8 may be a compound of formula F6: [ka] in a solvent [ka] 12. The method according to any one of items 1 to 11, wherein the compound is prepared by a process comprising the step of reacting a compound of formula F8 with a carboxylic acid of formula F8. (Item 13) Item 13. The method of claim 12, wherein the step of reacting the compound of formula F6 with a carboxylic acid of formula F7 is carried out in a solvent comprising a halogenated hydrocarbon solvent. (Item 14) 13. The method of claim 12, wherein the halogenated hydrocarbon solvent is dichloromethane. (Item 15) 15. The method according to any one of items 12 to 14, wherein the step of reacting the compound of formula F6 with the carboxylic acid of formula F7 is carried out in the presence of a coupling reagent and a catalytic base. (Item 16) Item 16. The method according to item 15, wherein the coupling reagent present in the step of reacting the compound of formula F6 with the carboxylic acid of formula F7 is EDC-HCl. (Item 17) 17. The method according to item 15 or 16, wherein the catalytic base present in the step of reacting the compound of formula F6 with the carboxylic acid of formula F7 is DMAP. (Item 18) The compound of formula F6 has the formula F6-CSA: [ka] 18. The method according to any one of items 12 to 17, wherein the compound is prepared by a process comprising the step of reacting a compound of formula F6 with a base to obtain the compound of formula F6. (Item 19) Item 19. The method of item 18, wherein the base reacted with the compound of formula F6-CSA is sodium hydroxide. (Item 20) 20. The method according to item 18 or 19, wherein the step of reacting the compound of formula F6-CSA with a base is carried out in a solvent comprising water and a halogenated hydrocarbon solvent. (Item 21) 21. The method of claim 20, wherein the halogenated hydrocarbon solvent is dichloromethane. (Item 22) 22. The method according to any one of items 18 to 21, wherein the step of reacting the compound of formula F6-CSA with a base is carried out at a temperature of about 22°C to about 28°C. (Item 23) The compound of formula F6-CSA may be prepared from a compound of formula F5: [ka] 23. The method according to any one of items 18 to 22, wherein the compound of formula F6 is prepared by a process comprising the step of reacting the compound of formula F6 with (S)-(+)-camphorsulfonic acid (CSA) to obtain the compound of formula F6-CSA. (Item 24) Item 24. The method according to item 23, wherein the molar ratio of CSA to the compound of formula F5 is about 0.7:1 to about 0.9:1. (Item 25) Item 24. The method according to item 23, wherein the molar ratio of CSA to the compound of formula F5 is about 0.80:1 to about 0.85:1. (Item 26) 26. The method according to any one of items 23 to 25, wherein the step of reacting the compound of formula F5 is carried out in a solvent comprising ethanol and water. (Item 27) 27. The method according to item 26, wherein the solvent is a mixture comprising water and ethanol in a volume ratio of water to ethanol of about 1:14 to about 1:18. (Item 28) 27. The method according to item 26, wherein the solvent is a mixture comprising water and ethanol in a volume ratio of water to ethanol of about 1:15.5 to about 1:16.5. (Item 29) 29. The method according to any one of items 23 to 28, wherein the compound of formula F6-CSA has an optical purity of more than 99%. (Item 30) The compound of formula F5 may be a compound of formula F4: [ka] with a reducing agent in a solvent comprising methyl tert-butyl ether (MTBE) and methanol to obtain the compound of formula F5. (Item 31) 31. The method of claim 30, wherein the solvent comprising methyl tert-butyl ether (MTBE) and methanol further comprises an acid. (Item 32) 32. The method of claim 31, wherein the acid comprises acetic acid. (Item 33) Item 33. The method of claim 32, wherein the acetic acid is present in about 1.0 to about 1.2 equivalents relative to the compound of formula F4. (Item 34) 34. The method of any of items 30 to 33, wherein the reducing agent is sodium borohydride. (Item 35) 35. The method according to any one of items 30 to 34, wherein the step of reacting the compound of formula F4 with a reducing agent is carried out at a temperature of about 20°C to about 27°C. (Item 36) The compound of formula F4 may be a compound of formula F3: [ka] is reacted with a compound of formula F2: [ka] to obtain said compound of formula F4. (Item 37) Item 37. The method according to item 36, wherein the volume ratio of IPA to water is about 2.2:1 to about 2.4:1. (Item 38) 38. The method according to item 36 or 37, wherein the step of reacting the compound of formula F2 with the compound of formula F3 is carried out in the presence of sodium iodide. (Item 39) Item 39. The method according to item 38, wherein the molar ratio of sodium iodide to the compound of formula F3 is about 0.3:1 to 0.5:1. (Item 40) 40. The method of any one of items 36 to 39, wherein the step of reacting the compound of formula F3 with the compound of formula F2 is carried out at a temperature of about 36°C to about 48°C. (Item 41) The compound of formula F2 is a compound of formula F1: [ka] with a base to obtain the compound of formula F2. (Item 42) Item 42. The method of item 41, wherein the base reacted with the compound of formula F1 is potassium hydroxide. (Item 43) 43. The method according to item 41 or 42, wherein the step of reacting the compound of formula F1 is carried out in a solvent comprising water and an organic solvent. (Item 44) Item 44. The method according to item 43, wherein the organic solvent used in the step of reacting the compound of formula F1 is MTBE. (Item 45) 45. The method according to any one of items 41 to 44, wherein the solvent used in the step of reacting the compound of formula F1 is removed after completion of the reaction and replaced with isopropanol. (Item 46) 46. ​​The method of any one of items 1 to 45, further comprising formulating said compound of formula I to form a pharmaceutical composition. (Item 47) 46. ​​The method of any one of items 1 or 45, further comprising formulating the compound of formula I to form a pharmaceutical composition comprising silicified microcrystalline cellulose; isomalt; hydroxypropyl methylcellulose; partially pregelatinized maize starch; and magnesium stearate. (Item 48) Formula I [ka] 1. A method for preparing a crystalline compound of a) dissolving the compound of formula I in a solvent mixture comprising an alcohol and acetonitrile; and b) crystallizing said compound of formula I to obtain a crystalline form of said compound of formula I. (Item 49) Item 49. The method according to item 48, wherein the volume ratio of alcohol to acetonitrile in the solvent mixture is about 1:1.8 to about 1:2.2. (Item 50) 50. The method of claim 48 or 49, wherein the crystallization in step b) comprises seeding the resulting mixture of solvent and compound with crystals of the compound of formula I to form a seed mixture. (Item 51) 51. The method of claim 50, wherein the seed mixture is heated to a temperature of about 39° C. to about 45° C. before and / or during seeding. (Item 52) 52. The method of claim 51, wherein after heating the seed mixture, the resulting seed mixture is cooled to a temperature of about 17°C to about 23°C. (Item 53) 53. The method of any one of items 48 to 52, wherein the alcohol is methanol. (Item 54) 53. The method of any one of items 48 to 52, wherein the crystalline form of the compound of formula I is isolated and dried under vacuum at elevated temperature. (Item 55) 55. The method according to any one of items 48 to 54, wherein the crystalline form of the compound of formula I is Form I. (Item 56) 56. The method of any one of items 48 to 55, further comprising formulating the crystalline form of the compound of formula I to form a pharmaceutical composition. (Item 57) 56. The method of any one of items 48 to 55, further comprising formulating the compound of formula I to form a pharmaceutical composition comprising silicified microcrystalline cellulose; isomalt; hydroxypropyl methylcellulose; partially pregelatinized maize starch; and magnesium stearate. (Item 58) Formula I: [ka] 1. A method for preparing a compound of formula (I), comprising: a) Formula F6-CSA: [ka] with a base to form a compound of formula F6: [ka] obtaining a compound of formula (I); b) reacting the compound of formula F6 with a compound of formula F7: [ka] with a carboxylic acid of formula F8: [ka] forming a compound of c) reacting said compound of formula F8 with p-toluenesulfonic acid in a solvent comprising acetonitrile or isopropyl acetate to obtain a compound of formula I. (Item 59) Item 59. The method of item 58, wherein the ratio of p-toluenesulfonic acid to the compound of formula F8 is about 2.0:1 to about 2.2:1 molar equivalents. (Item 60) 59. The method of claim 58, wherein the ratio of p-toluenesulfonic acid to the compound of formula F8 is about 2.1:1 molar equivalents. (Item 61) 61. The method of any one of items 58 to 60, wherein the step of reacting the compound of formula F8 with p-toluenesulfonic acid is carried out at a temperature of about 50°C to about 75°C. (Item 62) 61. The method of any one of items 58 to 60, wherein the step of reacting the compound of formula F8 with p-toluenesulfonic acid is carried out at a temperature of about 64°C to about 66°C. (Item 63) 63. The method of any one of items 58 to 62, wherein the step of reacting the compound of formula F8 with p-toluenesulfonic acid is carried out for a period of time sufficient to reduce the presence of the compound of formula F8 to at least 3% as determined by HPLC. (Item 64) 64. The method of any one of items 58 to 63, wherein the step of reacting the compound of formula F8 with p-toluenesulfonic acid is carried out for a period of about 10 hours to about 14 hours. (Item 65) 65. The method of any one of items 58 to 64, further comprising the step of cooling to a temperature of about 18°C ​​to about 22°C after the step of reacting the compound of formula F8 with p-toluenesulfonic acid. (Item 66) Item 66. The method according to item 65, wherein the temperature is maintained for about 1.8 hours to about 2.2 hours. (Item 67) 67. The method of claim 66, wherein the temperature is maintained with stirring. (Item 68) 68. The method of any one of items 58 to 67, wherein the compound of formula I is isolated by washing with acetonitrile and drying under vacuum at elevated temperature. (Item 69) 69. The method of any one of items 58 to 68, wherein the step of reacting the compound of formula F6 with a carboxylic acid of formula F7 is carried out in a solvent comprising a halogenated hydrocarbon solvent. (Item 70) 69. The method of any one of items 58 to 68, wherein the halogenated hydrocarbon solvent is dichloromethane. (Item 71) 71. The method according to any one of items 58 to 70, wherein the step of reacting the compound of formula F6 with the carboxylic acid of formula F7 is carried out in the presence of a coupling reagent and a catalytic base. (Item 72) 72. The method of claim 71, wherein the coupling reagent present in the step of reacting the compound of formula F6 with the carboxylic acid of formula F7 is EDC-HCl. (Item 73) 73. The method according to item 71 or 72, wherein the catalytic base present in the step of reacting the compound of formula F6 with the carboxylic acid of formula F7 is DMAP. (Item 74) 74. The method according to any one of items 58 to 73, wherein the base reacted with the compound of formula F6-CSA is sodium hydroxide. (Item 75) Item 75. The method according to item 74, wherein the step of reacting the compound of formula F6-CSA with a base is carried out in a solvent comprising water and a halogenated hydrocarbon solvent. (Item 76) 76. The method of claim 75, wherein the halogenated hydrocarbon solvent is dichloromethane. (Item 77) 77. The method of any one of items 58 to 76, wherein the step of reacting the compound of formula F6-CSA with a base is carried out at a temperature of about 22°C to about 28°C. (Item 78) Formula F6-CSA: [ka] 1. A method for preparing a compound of formula (I), comprising: Formula F5: [ka] with (S)-(+)-camphorsulfonic acid (CSA) to obtain the compound of formula F6-CSA, wherein the molar ratio of CSA to the compound of formula F5 is between 0.7:1 and 0.9:1. (Item 79) Item 79. The method according to item 78, wherein the molar ratio of CSA to the compound of formula F5 is about 0.7:1 to about 0.9:1. (Item 80) Item 79. The method according to item 78, wherein the molar ratio of CSA to the compound of formula F5 is about 0.80:1 to about 0.85:1. (Item 81) 81. The method according to any one of items 78 to 80, wherein the step of reacting the compound of formula F5 is carried out in a solvent comprising ethanol and water. (Item 82) Item 82. The method according to item 81, wherein the solvent is a mixture comprising water and ethanol in a volume ratio of water to ethanol of about 1:14 to about 1:18. (Item 83) Item 83. The method according to item 82, wherein the solvent is a mixture comprising water and ethanol in a volume ratio of water to ethanol of about 1:15.5 to about 1:16.5. (Item 84) 84. The method according to any one of items 78 to 83, wherein the compound of formula F6-CSA has an optical purity of more than 99%. (Item 85) Formula F5: [ka] 1. A method for preparing a compound of formula (I), comprising: Formula F4: [ka] with a reducing agent in a solvent comprising methyl tert-butyl ether (MTBE) and methanol to obtain the compound of formula F5. (Item 86) 86. The method of claim 85, wherein the solvent comprising methyl tert-butyl ether (MTBE) and methanol further comprises an acid. (Item 87) 87. The method of claim 86, wherein the acid comprises acetic acid. (Item 88) Item 88. The method of item 87, wherein the acetic acid is present in about 1.0 to about 1.2 equivalents relative to the compound of formula F4. (Item 89) 89. The method of any of items 85 to 88, wherein the reducing agent is sodium borohydride. (Item 90) 89. The method of any of items 85 to 89, wherein the step of reacting the compound of formula F4 with a reducing agent is carried out at a temperature of about 20°C to about 27°C. (Item 91) Formula F4: [ka] 1. A method for preparing a compound of formula (I), comprising: a) Formula F1: [ka] with a base to form a compound of formula F2: [ka] obtaining a compound of formula (I); b) reacting the compound of formula F2 with a compound of formula F3: [ka] to obtain said compound of formula F4. (Item 92) Item 92. The method according to Item 91, wherein the volume ratio of IPA to water is about 2.2:1 to about 2.4:1. (Item 93) Item 93. The method according to item 91 or 92, wherein the molar ratio of sodium iodide to the compound of formula F3 is about 0.3:1 to 0.5:1. (Item 94) 94. The method of any one of items 91 to 93, wherein the step of reacting the compound of formula F3 with the compound of formula F2 is carried out at a temperature of about 36°C to about 48°C. (Item 95) 95. The method of any one of items 91 to 94, wherein the base reacted with the compound of formula F1 is potassium hydroxide. (Item 96) 96. The method of any one of items 91 to 95, wherein the step of reacting the compound of formula F1 is carried out in a solvent comprising water and an organic solvent. (Item 97) Item 97. The method according to item 96, wherein the organic solvent used in the step of reacting the compound of formula F1 is MTBE. (Item 98) 98. The method according to item 96 or 97, wherein the solvent used in the step of reacting the compound of formula F1 is removed after completion of the reaction and replaced with isopropanol. (Item 99) Formula I: [ka] 1. A method for preparing a compound of formula (I), comprising: a) Formula F1: [ka] with a base to form a compound of formula F2: [ka] obtaining a compound of formula (I); b) Formula F3: [ka] with the compound of formula F2 in a solvent comprising isopropanol (IPA) and water to give a compound of formula F4: [ka] obtaining a compound of formula (I); c) reacting the compound of formula F4 with a reducing agent in a solvent comprising methyl tert-butyl ether (MTBE) and methanol to obtain a compound of formula F5: [ka] obtaining a compound of formula (I); d) reacting the compound of formula F5 with (S)-(+)-camphorsulfonic acid (CSA) to obtain the compound of formula F6-CSA: [ka] obtaining a compound of formula (I); e) reacting said compound of formula F6-CSA with a base to form a compound of formula F6: [ka] obtaining a compound of formula (I); f) reacting the compound of formula F6 with a compound of formula F7: [ka] with a carboxylic acid of formula F8: [ka] obtaining the product; g) reacting the product of formula F8 with p-toluenesulfonic acid in acetonitrile or isopropyl acetate to obtain a material comprising a compound of formula I; and h) crystallizing said material comprising said compound of formula I, i) dissolving the material comprising the compound of formula I in a solvent mixture comprising methanol and acetonitrile; and ii) crystallizing said compound of formula I from said solvent mixture to obtain said compound of formula I. A method comprising: (Item 100) Item 99. The method of item 99, wherein the compound of formula I is in crystalline form I. (Item 101) A method for preparing a pharmaceutical composition, the method comprising the steps of preparing a compound of formula I according to any one of items 1 to 45, 48 to 55, 58 to 77, 99 and 100, and formulating said compound of formula I with a pharmaceutically acceptable carrier and / or diluent. (Item 102) 102. The method according to item 101, wherein the compound of formula I is prepared by the method according to items 1, 48, 58 or 100. (Item 103) 103. The method of claim 101 or 102, wherein the pharmaceutically acceptable carrier and / or diluent comprises silicified microcrystalline cellulose; isomalt; hydroxypropyl methylcellulose; partially pregelatinized maize starch; and magnesium stearate. [Brief explanation of the drawings]

[0027] [Figure 1] FIG. 1 shows a representative X-ray powder diffraction (XRPD, Cu(Kα) radiation) pattern for a sample of crystalline Form I of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I) prepared according to Example 1.

[0028] [Figure 2] FIG. 2 shows a representative differential scanning calorimetry (DSC) trace for a sample of crystalline Form I of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I) prepared according to Example 1.

[0029] [Figure 3] FIG. 3 shows the general preparation of 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (compound of formula F4) from 3-((dimethylamino)methyl)-5-methylhexan-2-one oxalate (compound of formula F1), referred to and described herein as Step A.

[0030] [Figure 4] FIG. 4 illustrates the general preparation of 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (compound of formula F5) from 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (compound of formula F4), referred to and described herein as Step B; and 1 shows the preparation of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (S)-(+)-camphorsulfonate (compound of formula F6-CSA) from 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (compound of formula F5), which has been named and described.

[0031] [Figure 5] FIG. 5 shows the general preparation of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (Formula I intermediate) from (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (S)-(+)-camphorsulfonate (compound of Formula F6-CSA), referred to and described herein as Step D.

[0032] [Figure 6] FIG. 6 shows the general preparation of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (compound of Formula I) from (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (Formula I intermediate), referred to and described herein as Step E.

[0033] [Figure 7] FIG. 7 shows the preparation of 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (compound of formula F4) from 3-((dimethylamino)methyl)-5-methylhexan-2-one oxalate (compound of formula F1), referred to and described herein as Step A.

[0034] [Figure 8]FIG. 8 illustrates the preparation of 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (compound of formula F5) from 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (compound of formula F4), referred to and described herein as Step B; and This shows the preparation of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (S)-(+)-camphorsulfonate (compound of formula F6-CSA) from 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (compound of formula F5), as described in

[0035] [Figure 9] FIG. 9 shows the preparation of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (Formula I intermediate) from (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (S)-(+)-camphorsulfonate (compound of Formula F6-CSA), referred to and described herein as Step D.

[0036] [Figure 10]FIG. 10 shows the preparation of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (compound of Formula I) from (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (Formula I intermediate), referred to and described herein as Step E. DETAILED DESCRIPTION OF THE INVENTION

[0037] Detailed Description Although some of the method steps are illustrated in Figures 3 and 7 (step A), 4 and 8 (steps B and C), 5 and 9 (step D), and 6 and 10 (step E), it is contemplated that the individual method steps may be claimed separately or in any combination (i.e., steps A, B, C, D, and E may be claimed individually or in any combination thereof). It is not intended that the methods described herein be limited to entire methods having every step as shown in Figures 3, 4, 5, 6, 7, 8, 9, and 10.

[0038] Although the synthesis of compounds of formula I as described in US 10,160,757 B2 (hereinafter referred to as the "previous synthesis") is highly selective and robust, opportunities exist for greater efficiency through minimization of process operations, shortening of manufacturing time, and reducing waste and the environmental footprint of the overall process. The methods disclosed herein are based on the principles of green chemistry (Warner, JC; Anastas, PT; Green Chemistry Theory and Practice. Oxford Univ. Press, 1998; Pharmaceutical Green Chemistry (Tucker, JL, OPRD (2006), 10(2), 315-319; Tucker, JL, OPRD (2010), 14(2), 328-331; Tucker, JL; Faul, MM; Nature (2016), 534(7605), 27-29). The methods described herein offer greater efficiency and sustainability by reducing manufacturing operations, manufacturing time, and material use (waste, E-factors (Sheldon, RA Organic Synthesis Past, Present, and Future. Chem. Ind. (London) 1992)), while improving overall process yield and reducing water use over previous syntheses.

[0039] Corresponding to Step A of the previous synthesis (described in US Pat. No. 10,160,757), the synthesis begins with cleavage of the salt of aminoketone oxalate (Formula F1) using aqueous NaOH / n-heptane, followed by partitioning and water washing to obtain the free base in n-heptane to produce tetrabenazine (Formula F4). The free base solution is then combined with the HCl salt of dihydroisoquinoline (Formula F3) in water. The biphasic mixture is stirred at 30-40°C for at least 48 hours until less than 10% of dihydroisoquinoline (Formula F3) remains. The solids are filtered and dried under vacuum to give compounds of Formula F4 in 79% and 86% yields (US Pat. No. 10,160,757, Examples 1, A and A1, respectively).

[0040] Step A of the previous synthesis was performed using low solvent volumes and showed excellent atom efficiency, but the method suffered from long stirring times at 30–40 °C due to biphasic conditions, followed by limited mass transfer. In the new iteration described herein, the solvent mixture was designed to enhance reaction homogeneity, accelerate reaction kinetics, and reduce overall waste. In contrast to the previous synthesis, Step A herein also uses sodium iodide in an initially homogeneous reaction with a smaller overall volume of isopropanol (IPA) / water rather than the previously used water / heptane. The accelerated overall reaction kinetics achieves ≥95% reactant conversion (≤5% remaining Formula F3) in 24 h, compared to the previous synthesis, which required at least 48 h for less than 10% remaining dihydroisoquinoline (Formula F3). Atom efficiency remains high, and tetrabenazine (Formula F4) precipitates directly from the reaction mixture as the reaction proceeds. Upon completion, the slurry is simply cooled, filtered, washed with IPA, and dried under vacuum.

[0041] Thus, one improvement with Step A is the reduction in reaction / plant time compared to previous syntheses. In addition, Step A now also produces tetrabenazine in >99% purity and 88% yield.

[0042] Step B as described herein (FIGS. 4 and 8) is a sodium borohydride (NaBH4) mediated reduction of a compound of formula F4 to give a mixture of four formula F5 isomers (i.e., carbonyl to 2° alcohol). The four formula F5 isomers are shown below: [ka]

[0043] A previous synthesis (described in US Pat. No. 10,160,757) used 1.2 equivalents of NaBH4, 1.0 equivalents of lithium chloride (LiCl), and 1.1 equivalents of acetic acid (AcOH) in 19 volumes of ethanol (EtOH) and 2.1 volumes of methylene chloride (CHCl) at -10 ± 5 °C (i.e., -15 °C to -5 °C). During development, it was discovered that LiCl, AcOH, and temperature showed a favorable effect on selectivity for the desired isomer 1 (i.e., formula F6). Upon reaction completion, the mixture was warmed to 25 °C and quenched with saturated ammonium chloride. After stirring, the EtOH was removed under vacuum, and fresh CHCl was added to aid in partitioning during workup. After adjusting the pH with aqueous NaOH, the lower organic layer was separated. The aqueous material was extracted twice with CHCl, and the combined organic layers were washed with water. The CHCl solution was then replaced (put and take) with isopropyl acetate (i-PrOAc) under vacuum to a total volume of 3 L / kg. The mixture was heated to dissolution and cooled to 65°C, forming a suspension, which was further cooled to 20°C. After stirring, the suspension was filtered, washed with i-PrOAc, and dried under vacuum. The yields for the two examples were 86% and 85%, respectively (US 10,160,757, Example 1B).

[0044] Although the previous procedure was robust, drawbacks included the extensive effort required to manage the water-miscible solvent and the overall use of excess materials. Ethanol was used to solubilize LiCl and transfer NaBH4 as a slurry. This necessitated the distillation of EtOH and CHCl2 before extractive isolation of the product after quenching. Additionally, EtOH reacted with NaBH4 during slurry preparation prior to loading, thereby limiting the possible holding time before use and exacerbating hydrogen gas evolution in the secondary reactor system. Subsequent workup also required significant energy and time expenditures to replace CHCl2 with i-PrOAc for effective crystallization and isolation.

[0045] Due to the volume of reaction solvents, the variety of solvents used, and the large number of operations, this step generated the most waste of all the chemical steps for producing valbenazine ditosylate (Formula I), and required excessive manpower and plant time.

[0046] Step B as described herein (see Figures 4 and 8) is carried out by first adding the compound of formula F4 to methyl tert-butyl ether (MTBE) and methanol (MeOH) along with 0.9 equivalents of AcOH. To this mixture, 1.7 equivalents of NaBH4 are then added (as a slurry) in MTBE to obtain a complete reaction at 20-30°C for 4 hours. This solvent volume and ratio, combined with ambient temperature, provided ideal solubility and kinetics for a safe and reliable reduction. Providing NaBH4 in MTBE (rather than reactive EtOH) prevented unwanted hydrogen gas emissions, and the ambient temperature eliminated the need for energy-intensive vessel cooling. The mixture also eliminated the need for LiCl, which does not provide the additional desired selectivity over AcOH alone in this solvent system. At the end of the reaction, the slurry was diluted to 1M The reaction is quenched with aqueous sodium hydroxide (NaOH) and heated to 45-50°C for 3 hours to decompose any residual boron-amine complexes. The slurry is then cooled to 15°C, stirred for 1-2 hours, and directly isolated by filtration. The solid product is then washed with water followed by MTBE and dried in a vacuum oven to give the compound of formula F5 in 80% yield. Overall, the simplification of the process enhances efficiency, requiring only 4 days versus the previous 8 days, and significantly reduces waste.

[0047] Step C is the resolution of the single diastereomers of dihydrotetrabenazine with the (+)-(1S)-camphor-10-sulfonic acid (CSA) salt.

[0048] A previous synthesis (described in US Pat. No. 10,160,757) involved the formation of a suspension of racemic F5 and (+)-(1S)-camphor-10-sulfonic acid (1.0 equiv.) in ethanol:water (19:1, v / v). The mixture was heated to 75°C to obtain a solution, which was then cooled to 53°C ± 2°C (i.e., 51°C to 55°C) and held until crystallization occurred, or seed crystals were added if nucleation did not occur. The aged slurry was stirred and then cooled to 25°C ± 5°C over 14 hours at a rate of approximately 2°C per hour. The slurry was filtered, washed with ethanol, and dried under vacuum. The two reported yields for the previous synthesis were both 38% (US Pat. No. 10,160,757, Example 1C), and the material had a diastereoselectivity of >99%.

[0049] Step C, as disclosed herein (see Figures 4 and 8), involved experiments evaluating temperature, solvent ratio and volume, and CSA stoichiometry to arrive at a method that significantly reduced overall waste in Step C. The compound of formula F5 was combined with 0.825 equivalents of CSA, EtOH, and water. The mixture was heated to 70 °C until dissolution and cooled to 50–55 °C, where initial crystallization occurred. The slurry was then cooled to 20 °C at 3 °C per hour, after which the product was filtered, washed with 2 volumes of EtOH, and dried under vacuum. Recovery was 37% with a diastereomeric purity of >99%. While the time, labor, and yield remained similar to the previous synthesis, the waste generated and volume required (previously the step with the highest processing volume / lowest concentration) were optimized, allowing for greater efficiency in labor and processing waste, producing 56% more isolated compound of formula F6-CSA from the same volume of vessel compared to the previous synthesis.

[0050] Step D of the previous synthesis (described in US Pat. No. 10,160,757) can be thought of as four separate, shortened chemical processes: 1) cleavage of the F6-CSA salt, 2) coupling of the free base F6 to F7, 3) Boc deprotection of the intermediate of formula F8, and 3) isolation of the di-HCl salt of valbenazine. Step D of the previous synthesis is labor-intensive. The first step requires combining 1 M NaOH with F6-CSA in CHCl to cleave the camsylate salt. The mixture is stirred, precipitated, and separated. The lower organic layer is washed with water to obtain the free base of F6 in a total of 6 volumes of CHCl. ​​Boc-L-valine (1.2 equivalents) and dimethylaminopyridine (DMAP, 0.3 equivalents) are added to the free base solution, which is then cooled to approximately 0°C. To the mixture, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride was added, maintaining the temperature at 0°C ± 5°C. The mixture was stirred for at least 3 hours, with the reaction typically being complete after 5 hours. The reaction was quenched with aqueous citric acid and washed with water to obtain the coupled product as a CHCl solution. The solution was cooled to 5-10°C, and 5 equivalents of 4M HCl in dioxane were added for Boc deprotection. The reaction was warmed to 20-30°C and stirred for at least 12 hours. Upon completion, the pH was adjusted using aqueous sodium bicarbonate, and the product was then extracted into the organic layer and washed with water. The organic layer was then replaced with acetonitrile (ACN) under vacuum, cooled to 5-15°C, and 2.1 equivalents of 3.7M HCl in IPA were added to generate the di-HCl salt. Ethyl acetate was then charged, and the mixture was warmed to 45-55°C before seeding. Additional EtOAc is then added and the slurry is warmed to 65-75°C and stirred for 1 hour before being cooled to 20-30°C and granulated for an additional 3 hours. Filtration and washing with EtOAc affords valbenazine di-HCl in 79% yield (US Pat. No. 10,160,757, Example 1E).

[0051] In Step D as provided herein (see Figures 5 and 9), the organic layer of the crude product of F8 is replaced with ACN, which is then used as the solvent for the Boc deprotection and isolation of the Formula I intermediate.

[0052] The compound of Formula I is generated in Step D by Boc deprotection using p-toluenesulfonic acid (p-TSA or TsOH) directly in ACN rather than HCl / dioxane as in previous syntheses. The use of a single reagent (TsOH) serves as both the acid catalyst and the isolation counterion for Boc deprotection to directly access the compound of Formula I (the ditosylate salt), thus eliminating the need to isolate valbenazine diHCl as an intermediate as described in previous syntheses. The new and improved method reduces process steps, time (i.e., plant and personnel), and waste, and is highly atom-economical. During deprotection, the di-TsOH salt of valbenazine (Formula I) crystallizes directly from the reaction mixture to produce the intermediate compound of Formula I in high purity, thereby eliminating further work to isolate the HCl salt intermediate, the use of toxic HCl / dioxane reagent, the need to quench the acidic mixture with CO2 outgassing, and the significant time and energy required for distillation of ACN into EtOAc under vacuum as employed in previous syntheses.

[0053] Deprotection in Step D, as described herein, is accomplished by simply adding 2.1 equivalents of p-TSA to the intermediate of formula F8 and warming. The resulting intermediate, valbenazine ditosylate (Formula I), was filtered, washed, and dried to give an 86% yield with a purity of >99%. Overall, this step requires only 4 days of processing versus the previous 8 days due to the elimination of numerous operations, while improving recovery by 10% and reducing waste.

[0054] Step E of the previous synthesis (described in US 10,160,757) involved first cleaving the salt of valbenazine diHCl in CHCl and aqueous sodium bicarbonate, followed by displacing it into ACN and polish filtration of the solution. 2.0 equivalents of TsOH were then dissolved in ACN, and the TsOH solution was added to the solution of valbenazine (as the free base) through a polish filter. The solution was added at an elevated temperature at a controlled rate and held to ensure control of polymorphism and particle size. After the hold, the slurry was cooled to 25°C, filtered, washed with ACN, and dried to give the crystalline compound of Formula I in 92.8% and 88% yields (US 10,160,757, Examples 1F and 1F1).

[0055] Step E (see Figures 6 and 10) as provided herein is the recrystallization of the intermediate compound of Formula I prepared in Step D. The process begins with dissolving the intermediate compound of Formula I in MeOH and ACN, followed by abrasive filtration into a second vessel. Crystallization is then induced by removing MeOH by constant volume distillation while adding 4 volumes of ACN. After removing a portion of the solvent, the batch is seeded, and after the solvent exchange is complete, 1 volume of ACN is used to rinse the vessel before the suspension is cooled, filtered, washed, and dried. The dried product was obtained in 97% yield with quality consistent with previous syntheses. Step E also provides control of attributes such as particle size and crystal morphology, and the implementation of a robust and unwanted impurity control strategy.

[0056] Due to the presence of TsOH and methanol in the initial dissolution of the compound of Formula I prior to crystallization, the formation of a potentially genotoxic impurity (i.e., methyl toluenesulfonate) was a concern. Removal of excess (free) TsOH from the methanol / ACN solution was found to prevent ester formation below 50°C. Additionally, when the solution was spiked with 0.1 equivalents of excess TsOH, the ester (i.e., methyl toluenesulfonate) formed at levels up to 2700 ppm in solution. However, even at this level, crystallization was shown to be effective in purging the ester to <5 ppm in the isolated valbenazine ditosylate (Formula I). ​​Because it was preferable to completely avoid the formation of methyl toluenesulfonate, a simple and sensitive HPLC test was established to detect any excess TsOH upstream of the isolated solid crude valbenazine di-TsOH (obtained from Step D) to allow for reprocessing (if necessary) prior to dissolution in methanol in Step E. See Example 2.

[0057] Following adoption of the methods provided herein, method-related metrics demonstrated favorable impacts from environmental, economic, and strategic management perspectives compared to previous syntheses. In addition to reducing waste and costs, the methods provided herein allow for rapid production of batches of valbenazine ditosylate (i.e., the compound of formula F1) for rapid adaptation to patient needs.

[0058] Thus, the present application provides compounds of formula I: [ka] 1. A method for preparing a compound of formula (I), comprising: Formula F8: [ka] with p-toluenesulfonic acid in a solvent comprising acetonitrile or isopropyl acetate to obtain a material comprising the compound of formula I.

[0059] In some embodiments, the present application also provides compounds of Formula I: [ka] 1. A method for preparing a compound of formula (I), comprising: Formula F8: [ka] with p-toluenesulfonic acid in a solvent comprising acetonitrile or isopropyl acetate to obtain a compound of formula I.

[0060] In some embodiments, the solvent does not include acetonitrile. In some embodiments, the solvent does not include isopropyl acetate. In some embodiments, the solvent does not include acetonitrile or isopropyl acetate.

[0061] In some embodiments, the solvent is selected from the group consisting of 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 sulfide, water; or a mixture thereof. In some embodiments, the solvent is isopropanol. In some embodiments, the solvent is a mixture of dichloromethane and acetonitrile. In some embodiments, the solvent is acetonitrile. In some embodiments, the solvent is isopropyl acetate.

[0062] In some embodiments, the step of reacting the compound of Formula F8 with p-toluenesulfonic acid is carried out at an elevated temperature. In some embodiments, the step of reacting the compound of Formula F8 with p-toluenesulfonic acid is carried out at a temperature of about 35°C to about 80°C. In some embodiments, the step of reacting the compound of Formula F8 with p-toluenesulfonic acid is carried out at a temperature of about 35°C to about 75°C. In some embodiments, the step of reacting the compound of Formula F8 with p-toluenesulfonic acid is carried out at a temperature of about 40°C to about 75°C. In some embodiments, the step of reacting the compound of Formula F8 with p-toluenesulfonic acid is carried out at a temperature of about 45°C to about 75°C. In some embodiments, the step of reacting the compound of Formula F8 with p-toluenesulfonic acid is carried out at a temperature of about 50°C to about 75°C. In some embodiments, the step of reacting the compound of Formula F8 with p-toluenesulfonic acid is carried out at a temperature of about 55°C to about 75°C. In some embodiments, the step of reacting the compound of Formula F8 with p-toluenesulfonic acid is carried out at a temperature of about 60°C to about 70°C. In some embodiments, the step of reacting the compound of Formula F8 with p-toluenesulfonic acid is carried out at a temperature of about 62°C to about 68°C. In some embodiments, the step of reacting the compound of Formula F8 with p-toluenesulfonic acid is carried out at a temperature of about 63°C to about 67°C. In some embodiments, the step of reacting the compound of Formula F8 with p-toluenesulfonic acid is carried out at a temperature of about 64°C to about 66°C. In some embodiments, the step of reacting the compound of Formula F8 with p-toluenesulfonic acid is carried out at a temperature of about 65°C.

[0063] In some embodiments, the reacting of the compound of Formula F8 with p-toluenesulfonic acid is carried out for a period of time sufficient to reduce the presence of the compound of Formula F8 to at least 10%, as determined by HPLC. In some embodiments, the reacting of the compound of Formula F8 with p-toluenesulfonic acid is carried out for a period of time sufficient to reduce the presence of the compound of Formula F8 to at least 5%, as determined by HPLC. In some embodiments, the reacting of the compound of Formula F8 with p-toluenesulfonic acid is carried out for a period of time sufficient to reduce the presence of the compound of Formula F8 to at least 4%, as determined by HPLC. In some embodiments, the reacting of the compound of Formula F8 with p-toluenesulfonic acid is carried out for a period of time sufficient to reduce the presence of the compound of Formula F8 to at least 3%, as determined by HPLC. In some embodiments, the reacting of the compound of Formula F8 with p-toluenesulfonic acid is carried out for a period of time sufficient to reduce the presence of the compound of Formula F8 to at least 2%, as determined by HPLC. In some embodiments, the step of reacting the compound of Formula F8 with p-toluenesulfonic acid is carried out over a period of about 6 hours to about 18 hours. In some embodiments, the step of reacting the compound of Formula F8 with p-toluenesulfonic acid is carried out over a period of about 8 hours to about 16 hours. In some embodiments, the step of reacting the compound of Formula F8 with p-toluenesulfonic acid is carried out over a period of about 10 hours to about 14 hours. In some embodiments, the step of reacting the compound of Formula F8 with p-toluenesulfonic acid is carried out over a period of about 12 hours. In some embodiments, after the step of reacting the compound of Formula F8 with p-toluenesulfonic acid, the method further comprises cooling to a temperature of about 10°C to about 30°C. In some embodiments, after the step of reacting the compound of Formula F8 with p-toluenesulfonic acid, the method further comprises cooling to a temperature of about 15°C to about 25°C. In some embodiments, after reacting the compound of Formula F8 with p-toluenesulfonic acid, the method further comprises cooling to a temperature of about 18° C. to about 22° C. In some embodiments, the temperature is maintained for about 1 hour to about 3 hours.In some embodiments, the temperature is maintained for about 1.5 hours to about 2.5 hours. In some embodiments, the temperature is maintained for about 1.8 hours to about 2.2 hours. In some embodiments, the temperature is maintained with stirring.

[0064] In some embodiments, a reaction mixture is obtained by reacting a compound of Formula F8 with p-toluenesulfonic acid in a solvent. In some embodiments, the reaction mixture is further cooled to about 10°C to about 30°C. In some embodiments, the reaction mixture is further cooled to about 15°C to about 25°C. In some embodiments, the reaction mixture is further cooled to about 18°C ​​to about 22°C. In some embodiments, the reaction mixture is further cooled and stirred for about 1 hour to about 3 hours. In some embodiments, the reaction mixture is further cooled and stirred for about 1.5 hours to about 2.5 hours. In some embodiments, the reaction mixture is further cooled and stirred for about 2 hours. In some embodiments, the reaction mixture is further cooled to about 18°C ​​to about 22°C and stirred for about 1.5 hours to about 2.5 hours. In some embodiments, the reaction mixture is further cooled to about 20°C and stirred for about 2 hours.

[0065] In some embodiments, the ratio of p-toluenesulfonic acid to the compound of Formula F8 ranges from about 1.9:1 to about 2.3:1 molar equivalents. In some embodiments, the ratio of p-toluenesulfonic acid to the compound of Formula F8 ranges from about 2.0:1 to about 2.2:1 molar equivalents. In some embodiments, the ratio of p-toluenesulfonic acid to the compound of Formula F8 ranges from about 2.1:1 molar equivalents. In some embodiments, excess p-toluenesulfonic acid is undetectable in the material comprising the compound of Formula I. In some embodiments, excess p-toluenesulfonic acid is undetectable in the material comprising the compound of Formula I, as determined by HPLC.

[0066] In some embodiments, the compound of Formula I is isolated by washing with acetonitrile and drying under vacuum at elevated temperature, hi some embodiments, the compound of Formula I is dried under vacuum at about 50° C. for about 12 hours or more.

[0067] In some embodiments, reacting the compound of Formula F8 with p-toluenesulfonic acid further comprises formulating the compound of Formula I to form a pharmaceutical composition. In some embodiments, the formulating comprises combining the compound of Formula I with a pharmaceutical excipient, a pharmaceutically acceptable carrier and / or a diluent.

[0068] In some embodiments, any unacceptable excess p-toluenesulfonic acid detected in the material comprising the compound of Formula I is removed. In some embodiments, any unacceptable excess p-toluenesulfonic acid detected in the material comprising the compound of Formula I is removed by recrystallizing the material containing the unacceptable excess p-toluenesulfonic acid in the presence of a recrystallizing solvent. In some embodiments, the recrystallization solvent comprises acetonitrile. In some embodiments, the recrystallization solvent is acetonitrile.

[0069] In some embodiments, the compound of formula F8 has formula F6: [ka] in a solvent [ka] with a carboxylic acid of formula (I).

[0070] In some embodiments, the step of reacting the compound of formula F6 with the carboxylic acid of formula F7 is carried out in a solvent that is a hydrocarbon, a chlorinated hydrocarbon, an alcohol, an ether, an ester, a carbonate, an amide, a nitrile, a sulfoxide, a sulfone, a nitro compound, a heteroarene, a heterocycle, water, or a mixture thereof. In some embodiments, the solvent is a chlorinated hydrocarbon solvent. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is an ether. In some embodiments, the solvent is a cycloalkyl ether. In some embodiments, the solvent is 2-methyltetrahydrofuran (M eTHF).

[0071] In some embodiments, the step of reacting the compound of Formula F6 with the carboxylic acid of Formula F7 is carried out in a solvent comprising a halogenated hydrocarbon solvent, hi some embodiments, the halogenated hydrocarbon solvent is dichloromethane.

[0072] In some embodiments, the step of reacting the compound of formula F6 with the carboxylic acid of formula F7 is carried out in the presence of a coupling reagent. In some embodiments, the step of reacting the compound of formula F6 with the carboxylic acid of formula F7 is carried out in the presence of a base. In some embodiments, the step of reacting the compound of formula F6 with the carboxylic acid of formula F7 is carried out in the presence of a catalytic base. In some embodiments, the step of reacting the compound of formula F6 with the carboxylic acid of formula F7 is carried out in the presence of a coupling reagent and a base. In some embodiments, the step of reacting the compound of formula F6 with the carboxylic acid of formula F7 is carried out in the presence of a coupling reagent and a catalytic base.

[0073] In some embodiments, the coupling reagent is carbodiimide, 1,1'-carbonyldiimidazole (CDI), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), hexafluorophosphate (BOP reagent), PCh, PCls, or 1-propanephosphonic acid cyclic anhydride. In some embodiments, the coupling reagent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC or EDCI), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC hydrochloride), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC methiodide), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate, or 1,3-dicyclohexylcarbodiimide (DCC). In some embodiments, the coupling reagent is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC or EDCI), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC hydrochloride), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (EDC methiodide), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate, or 1,3-dicyclohexylcarbodiimide (DCC). In some embodiments, the coupling reagent present in the step of reacting a compound of formula F6 with a carboxylic acid of formula F7 is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC or EDCI). In some embodiments, the coupling reagent present in the step of reacting a compound of formula F6 with a carboxylic acid of formula F7 is N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC hydrochloride).

[0074] In some embodiments, the base is a catalytic base. In some embodiments, the molar ratio of the catalytic base to the compound of Formula F6-CSA is about 0.6:1.0, about 0.5:1.0, about 0.4:1.0, about 0.3:1.0, about 0.27:1.0, or about 0.25:1.0. In some embodiments, the catalytic base present during the step of reacting the compound of Formula F6 with the carboxylic acid of Formula F7 is an organic base. In some embodiments, the catalytic base is an inorganic base. In some embodiments, the catalytic base is an organic base. In some embodiments, the catalytic base is sodium bicarbonate, sodium carbonate, sodium citrate, sodium hydroxide, potassium hydroxide, or 4-dimethylaminopyridine. In some embodiments, the catalytic base is sodium hydroxide. In some embodiments, the catalytic base is potassium hydroxide. In some embodiments, the catalytic base present during the step of reacting the compound of Formula F6 with the carboxylic acid of Formula F7 is dimethylaminopyridine (DMAP).

[0075] In some embodiments, the step of reacting the compound of Formula F6 with the carboxylic acid of Formula F7 is carried out at a temperature less than about 25°C. In some embodiments, the step of reacting the compound of Formula F6 with the carboxylic acid of Formula F7 is carried out at a temperature ranging from about -10°C to about 25°C. In some embodiments, the step of reacting the compound of Formula F6 with the carboxylic acid of Formula F7 is carried out at a temperature ranging from about -5°C to about 20°C. In some embodiments, the step of reacting the compound of Formula F6 with the carboxylic acid of Formula F7 is carried out at a temperature ranging from about -5°C to about 15°C. In some embodiments, the step of reacting the compound of Formula F6 with the carboxylic acid of Formula F7 is carried out at a temperature ranging from about -5°C to about 10°C. In some embodiments, the step of reacting the compound of Formula F6 with the carboxylic acid of Formula F7 is carried out at a temperature ranging from about -1°C to about 25°C. In some embodiments, the step of reacting the compound of Formula F6 with the carboxylic acid of Formula F7 is carried out at a temperature ranging from -1°C to 25°C.

[0076] In some embodiments, the method comprises crystallizing a material comprising a compound of formula I, a) dissolving a material comprising a compound of formula I in a solvent mixture comprising an alcohol and acetonitrile; and b) crystallizing the compound of formula I from a solvent mixture to obtain a compound of formula I: [ka] The method further comprises obtaining a compound of formula (I).

[0077] In some embodiments, the method comprises crystallizing a compound of formula I, a) dissolving a compound of formula I in a solvent mixture comprising an alcohol (e.g., methanol) and acetonitrile; and b) crystallizing the compound of formula I to obtain a crystalline form of the compound of formula I.

[0078] In some embodiments, the volume ratio of alcohol to acetonitrile in the solvent mixture is about 1:1 to about 1:3.5. In some embodiments, the volume ratio of alcohol to acetonitrile in the solvent mixture is about 1:1.5 to about 1:3. In some embodiments, the volume ratio of alcohol to acetonitrile in the solvent mixture is about 1:1.7 to about 1:2.7. In some embodiments, the volume ratio of alcohol to acetonitrile in the solvent mixture is about 1:1.8 to about 1:2.2. In some embodiments, the volume ratio of alcohol to acetonitrile in the solvent mixture is about 1:1.9 to about 1:2.1. In some embodiments, the volume ratio of alcohol to acetonitrile in the solvent mixture is about 1:2.

[0079] In some embodiments, the ratio of alcohol to acetonitrile in the solvent mixture is approximately 1:2 v / v. In some embodiments, the alcohol is ethanol or methanol. In some embodiments, the alcohol is methanol.

[0080] In some embodiments, the crystallization in step b) comprises seeding the resulting solvent and compound mixture with crystals of the compound of Formula I to form a seed mixture. In some embodiments, the crystallization in step b) comprises seeding the resulting solvent and compound mixture with crystals of the compound of Formula I to form a seed mixture and cooling the seeded mixture. In some embodiments, the crystallization in step b) comprises removing about 10% to about 99% of the alcohol (e.g., methanol) by weight or volume, based on the initial amount of alcohol (e.g., methanol). In some embodiments, the seed mixture is heated to a temperature of about 30° C. to about 50° C. before and / or during seeding. In some embodiments, the seed mixture is heated to a temperature of about 37° C. to about 47° C. before and / or during seeding. In some embodiments, the seed mixture is heated to a temperature of about 39° C. to about 45° C. before and / or during seeding. In some embodiments, the seed mixture is heated to a temperature of about 41°C to about 43°C before and / or during seed addition. In some embodiments, the seed mixture is heated to a temperature of about 42°C before and / or during seed addition. In some embodiments, after heating the seed mixture, the resulting seed mixture is cooled to a temperature of about 15°C to about 25°C. In some embodiments, after heating the seed mixture, the resulting seed mixture is cooled to a temperature of about 16°C to about 24°C. In some embodiments, after heating the seed mixture, the resulting seed mixture is cooled to a temperature of about 17°C to about 23°C. In some embodiments, after heating the seed mixture, the resulting seed mixture is cooled to a temperature of about 18°C ​​to about 22°C. In some embodiments, after heating the seed mixture, the resulting seed mixture is cooled to a temperature of about 19°C to about 21°C. In some embodiments, after heating the seed mixture, the resulting seed mixture is cooled to a temperature of about 20°C.

[0081] In some embodiments, the crystalline form of the compound of Formula I is isolated and dried under vacuum at elevated temperature. In some embodiments, the crystalline form of the compound of Formula I is Form I as described herein.

[0082] In some embodiments, the crystallization in step b) of crystallizing the material comprising the compound of Formula I comprises seeding the resulting mixture of solvent and compound with crystals of the compound of Formula I and cooling the seeded mixture. In some embodiments, the mixture of solvent and compound is heated to between about 30° C. and about 50° C. before or during seeding. In some embodiments, the mixture of solvent and compound is cooled to between about 15° C. and about 25° C. immediately after heating.

[0083] In some embodiments, the crystallization in step b) of the crystallization of the material comprising the compound of Formula I comprises removing 5%, 10%, 12%, 14%, 16%, 18%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 99.5% by weight or volume of alcohol based on the initial amount or an amount within a range defined by either the initial amount or the preceding amount. In some embodiments, the crystallization in step b) of the crystallization of the material comprising the compound of Formula I comprises removing about 10% to about 99% by weight or volume of alcohol based on the initial amount of alcohol. In some embodiments, the alcohol is a C1-C6 alcohol. In some embodiments, the alcohol is ethanol or methanol. In some embodiments, the alcohol is methanol.

[0084] In some embodiments, the compound of Formula I is dried under vacuum at elevated temperatures. In some embodiments, the compound of Formula I is dried under vacuum at about 50° C. for 12 hours or more.

[0085] In some embodiments, the compound of formula I has a purity of about 95% by weight or more, about 96% by weight or more, about 97% by weight or more, about 97.5% by weight or more, about 98% by weight or more, about 98.5% by weight or more, about 99% by weight or more, about 99.1% by weight or more, about 99.2% by weight or more, about 99.3% by weight or more, about 99.4% by weight or more, about 99.5% by weight or more, about 99.6% by weight or more, about 99.7% by weight or more, about 99.8% by weight or more, or about 99.9% by weight or more. In some embodiments, the compound of formula F6-CSA has a purity of at least 99.5%.

[0086] In some embodiments, the compound of formula F6 has the formula F6-CSA: [ka] with a base to give a compound of formula F6.

[0087] In some embodiments, the base reacted with the compound of formula F6-CSA is an inorganic base. In some embodiments, the base is sodium bicarbonate, sodium carbonate, sodium citrate, sodium hydroxide, or potassium hydroxide. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide.

[0088] In some embodiments, the step of reacting the compound of Formula 6-CSA with a base is carried out in a solvent comprising a hydrocarbon, a chlorinated hydrocarbon, an alcohol, an ether, an ester, a carbonate, an amide, a nitrile, a sulfoxide, a sulfone, a nitro compound, a heteroarene, a heterocycle, water, or a mixture thereof. In some embodiments, the solvent is a chlorinated hydrocarbon solvent. In some embodiments, the solvent is dichloromethane. In some embodiments, the solvent is an ether. In some embodiments, the solvent is a cycloalkyl ether. In some embodiments, the solvent is 2-methyltetrahydrofuran (MeTHF). In some embodiments, the solvent comprises water and a halogenated hydrocarbon solvent. In some embodiments, the halogenated hydrocarbon solvent is dichloromethane.

[0089] In some embodiments, the step of reacting the compound of formula F6-CSA with a base is carried out at a temperature of about 20°C to about 30°C. In some embodiments, the step of reacting the compound of formula F6-CSA with a base is carried out at a temperature of about 21°C to about 29°C. In some embodiments, the step of reacting the compound of formula F6-CSA with a base is carried out at a temperature of about 22°C to about 28°C. In some embodiments, the step of reacting the compound of formula F6-CSA with a base is carried out at a temperature of about 23°C to about 27°C. In some embodiments, the step of reacting the compound of formula F6-CSA with a base is carried out at a temperature of about 24°C to about 26°C. In some embodiments, the step of reacting the compound of formula F6-CSA with a base is carried out at a temperature of about 25°C.

[0090] In some embodiments, the compound of formula F6-CSA has formula F5: [ka] with (S)-(+)-camphorsulfonic acid (CSA) to give a compound of formula F6-CSA.

[0091] In some embodiments, the molar ratio of CSA to the compound of Formula F5 is about 0.7:1 to about 1:1. In some embodiments, the molar ratio of CSA to the compound of Formula F5 is about 0.75:1 to about 0.95:1. In some embodiments, the molar ratio of CSA to the compound of Formula F5 is about 0.7:1 to about 0.9:1. In some embodiments, the molar ratio of CSA to the compound of Formula F5 is about 0.8:1 to about 0.9:1. In some embodiments, the molar ratio of CSA to the compound of Formula F5 is about 0.8:1 to about 0.85:1. In some embodiments, the molar ratio of CSA to the compound of Formula F5 is about 0.8:1. In some embodiments, the molar ratio of CSA to the compound of Formula F5 is 0.825:1.

[0092] In some embodiments, the molar ratio of CSA to the compound of Formula F5 is from about 0.66:1 to about 0.99:1. In some embodiments, the molar ratio of CSA to the compound of Formula F5 is from about 0.70:1 to about 0.95:1. In some embodiments, the molar ratio of CSA to the compound of Formula F5 is from about 0.74:1 to about 0.91:1. In some embodiments, the molar ratio of CSA to the compound of Formula F5 is from about 0.76:1 to about 0.89:1. In some embodiments, the molar ratio of CSA to the compound of Formula F5 is from about 0.78:1 to about 0.87:1. In some embodiments, the molar ratio of CSA to the compound of Formula F5 is from about 0.80:1 to about 0.85:1. In some embodiments, the molar ratio of CSA to the compound of Formula F5 is from about 0.81:1 to about 0.84:1.

[0093] In some embodiments, the step of reacting the compound of Formula F5 is carried out in a solvent comprising water and an alcohol. In some embodiments, the alcohol is a C1-C6 alcohol. In some embodiments, the solvent is a solvent mixture. In some embodiments, the solvent mixture comprises water and ethanol. In some embodiments, the solvent mixture comprises water and ethanol in a volume ratio of water to ethanol of about 1:5 to about 1:25. In some embodiments, the solvent mixture comprises water and ethanol in a volume ratio of water to ethanol of about 1:10 to about 1:20. In some embodiments, the solvent mixture comprises water and ethanol in a volume ratio of water to ethanol of about 1:14 to about 1:18. In some embodiments, the solvent mixture comprises water and ethanol in a volume ratio of water to ethanol of about 1:15 to about 1:17. In some embodiments, the solvent mixture comprises water and ethanol in a volume ratio of water to ethanol of about 1:15.5 to about 1:16.5. In some embodiments, the solvent mixture comprises water and ethanol in a volume ratio of water to ethanol of about 1:16. In some embodiments, the solvent mixture comprises water and ethanol in a volume ratio ranging from about 0.1 to about 100, from about 0.2 to about 50, from about 0.5 to about 25, from about 1 to about 20, from about 1 to about 16, from about 1 to about 10, from about 1 to about 5, or from about 1 to about 2. In some embodiments, the solvent comprising ethanol and water comprises about 10 to 14 volumes of ethanol and about 0.5 to 1.0 volumes of water. In some embodiments, the solvent comprising ethanol and water comprises about 12 volumes of ethanol and about 0.75 volumes of water.

[0094] In some embodiments, the step of reacting the compound of Formula F5 is carried out at a temperature ranging from about 20 to about 80°C, about 20 to about 70°C, about 20 to about 60°C, or about 20 to about 70°C. In other embodiments, the reaction is carried out at a temperature ranging from about 20 to about 65°C, or about 20 to about 75°C. In some embodiments, the step of reacting the compound of Formula F5 is carried out at a temperature of about 70°C. In some embodiments, the reaction of the compound is cooled to about 70°C to about 55°C and crystallized. In some embodiments, the reaction mixture of Formula F5 and CSA is cooled to about 22°C. In some embodiments, the reaction mixture is seeded with crystals of the compound of Formula F6-CSA. In some embodiments, the compound of Formula F6-CSA is dried under vacuum at elevated temperature. In some embodiments, the compound of Formula F6-CSA is dried under vacuum at about 45°C for at least 12 hours.

[0095] In some embodiments, the compound of formula F6-CSA has an optical purity of about 95% or more, about 96% or more, about 97% or more, about 97.5% or more, about 98% or more, about 98.5% or more, about 99% or more, about 99.1% or more, about 99.2% or more, about 99.3% or more, about 99.4% or more, about 99.5% or more, about 99.6% or more, about 99.7% or more, about 99.8% or more, or about 99.9% or more. In some embodiments, the compound of formula F6-CSA has an optical purity greater than 99%.

[0096] In some embodiments, the compound of formula F5 has formula F4: [ka] with a reducing agent in a solvent comprising methyl tert-butyl ether (MTBE) and methanol to provide a compound of formula F5.

[0097] In some embodiments, the solvent comprises MTBE and an alcohol that is not methanol. In some embodiments, the alcohol is a C2-C6 alcohol (containing 2-6 carbon atoms). In still other embodiments, the solvent mixture comprises MTBE and ethanol. In some embodiments, the step of reacting the compound of Formula F4 is carried out in the presence of an organic acid. In some embodiments, the organic acid is a carboxylic acid. In some embodiments, the organic acid is a C, optionally substituted with one or more substituents Q. 1~14 In some embodiments, the acid is a 2-hydroxy-C, optionally substituted with one or more substituents Q. 1~14 The one or more substituents Q are each independently selected from the group consisting of: (a) oxo (O=O), halo, cyano (-CN), and nitro (-NO2); (b) C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 6~14 Aryl, C 1~15 Aralkyl, heteroaryl, and heterocyclyl, each of which may further optionally contain one or more, in one embodiment one, two, three, or four, substituents Q a 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(=NR a )NR b R c , -OS(O)R a , -OS(O)2R a , -OS(O)NR b Rc , -OS(O)2NR b R c , -NR b R c , -NR a C(O)R d , -NR a C(O)R d , -NR a (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)(OR a )R d , -P(O)(OR a )(OR d ), -SR a -S(O)R a , -S(O)2R a , -S(O)NR b R c and -S(O)NR b R c (where each R a , R b , R c and R d are 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 optionally contains one or more, in one embodiment one, two, three, or four, substituents Q a or (iii) R b and Rc together with the N atom to which they are attached form a heteroaryl or heterocyclyl, each of which optionally contains one or more, in one embodiment one, two, three or four, substituents Q a substituted with ).

[0098] In some embodiments, the acid is acetic acid, formic acid, oxalic acid, maleic acid, lactic acid, ascorbic acid, mandelic acid, or a mixture thereof, hi some embodiments, the organic acid is acetic acid.

[0099] In some embodiments, the volume ratio of MTBE to methanol ranges from about 1:1 to about 10:1. In some embodiments, the volume ratio of MTBE to methanol ranges from about 1:1 to about 5:1. In some embodiments, the volume ratio of MTBE to methanol ranges from about 3:1 to about 7:1. In some embodiments, the volume ratio of MTBE to methanol ranges from about 3:1 to about 5:1. In some embodiments, the volume ratio of MTBE to methanol is about 4.4:1.

[0100] In some embodiments, the solvent comprising methyl tert-butyl ether (MTBE) and methanol further comprises an acid. In some embodiments, the acid comprises acetic acid. In some embodiments, the acid is acetic acid.

[0101] In some embodiments, the acid is present in excess relative to the compound of Formula F4. In some embodiments, the acid includes acetic acid. In some embodiments, the acetic acid is present in about 0.5 to about 1.5 equivalents relative to the compound of Formula F4. In some embodiments, the acid includes acetic acid. In some embodiments, the acetic acid is present in about 0.8 to about 1.3 equivalents relative to the compound of Formula F4. In some embodiments, the acid includes acetic acid. In some embodiments, the acetic acid is present in about 0.9 to about 1.2 equivalents relative to the compound of Formula F4. In some embodiments, the acid includes acetic acid. In some embodiments, the acetic acid is present in about 1.0 to about 1.2 equivalents relative to the compound of Formula F4. In some embodiments, the acetic acid is present in about 0.7 to about 1.0 equivalents relative to the compound of Formula F4. In some embodiments, the acetic acid is present in about 0.9 equivalents relative to the compound of Formula F4. In some embodiments, the acetic acid is present in about 0.8 equivalents relative to the compound of Formula F4.

[0102] In some embodiments, the reducing agent is first added to the compound of Formula F4 as a slurry in MTBE. In some embodiments, the reducing agent is first added to the compound of Formula F4 as a solid. In some embodiments, the reducing agent is a borohydride reducing agent. In some embodiments, the reducing agent is borohydride. In some embodiments, the reducing agent is sodium borohydride, lithium borohydride, calcium borohydride, magnesium borohydride, potassium borohydride, 9-BBN, cyanoborohydride, bis-triphenylphosphine borohydride, sodium triethylborohydride, tetrabutylammonium borohydride, tetramethylammonium borohydride, tetraethylammonium borohydride, or lithium triethylborohydride. In some embodiments, the borohydride reducing agent is sodium borohydride. In some embodiments, the reducing agent is sodium borohydride and is first added as a solid. In some embodiments, the molar ratio of sodium borohydride to the compound of Formula F4 ranges from about 1.0 to about 10.0. In some embodiments, the molar ratio of sodium borohydride to the compound of Formula F4 ranges from about 1.0 to about 5.0. In some embodiments, the molar ratio of sodium borohydride to the compound of Formula F4 ranges from about 1.0 to about 3.0. In some embodiments, the molar ratio of sodium borohydride to the compound of Formula F4 ranges from about 1.5 to about 2.5. In some embodiments, the molar ratio of sodium borohydride to the compound of Formula F4 ranges from about 1.8 to about 2.2. In some embodiments, the molar ratio of sodium borohydride to the compound of Formula F4 ranges from about 1.9 to about 2.1. In some embodiments, the molar ratio of sodium borohydride to the compound of Formula F4 is about 2.0.

[0103] In some embodiments, lithium chloride is not present during the step of reacting the compound of Formula F4.

[0104] In some embodiments, the step of reacting the compound of Formula F4 with a reducing agent is carried out at a temperature ranging from about minus 5°C to about minus 15°C, about minus 5°C to about minus 10°C, about minus 5°C to about 0°C, about 0°C to about 5°C, about 0 to about 10°C, about 0°C to about 15°C, about 0°C to about 25°C, about 0°C to about 30°C, about 5°C to about 30°C, about 10°C to about 30°C, about 20°C to about 30°C, about 20°C to about 25°C, about 20°C to about 24°C, and about 21°C to about 23°C.

[0105] In some embodiments, the step of reacting the compound of Formula F4 with the reducing agent is carried out at a temperature of about 15° C. to about 30° C. In some embodiments, the step of reacting the compound of Formula F4 with the reducing agent is carried out at a temperature of about 20° C. to about 27° C. In some embodiments, the step of reacting the compound of Formula F4 with the reducing agent is carried out at a temperature of about 21° C. to about 26° C. In some embodiments, the step of reacting the compound of Formula F4 with the reducing agent is carried out at a temperature of about 22° C. to about 25° C.

[0106] In some embodiments, the step of reacting the compound of Formula F4 with the reducing agent is carried out at a temperature of about 25° C. In some embodiments, the step of reacting the compound of Formula F8 with the reducing agent is carried out for a period of about 2 hours. In some embodiments, the step of reacting the compound of Formula F8 with the reducing agent is carried out at a temperature ranging from about 15° C. to about 30° C. and for a period of at least 1.5 hours. In some embodiments, the step of reacting the compound of Formula F8 with the reducing agent is carried out at a temperature ranging from about 15° C. to about 30° C. and for a period of about 1 hour to about 3 hours. In some embodiments, the step of reacting the compound of Formula F8 with the reducing agent is carried out at a temperature ranging from about 18° C. to about 28° C. and for a period of about 1.5 hours to about 2.5 hours. In some embodiments, the step of reacting the compound of Formula F8 with the reducing agent is carried out at a temperature ranging from about 20° C. to about 28° C. and for a period of about 1.8 hours to about 2.2 hours.

[0107] In some embodiments, the compound of formula F4 has formula F3: [ka] is reacted with a compound of formula F2: [ka] to give a compound of formula F4.

[0108] In some embodiments, the volume ratio of IPA to water ranges from about 1:1 to about 10:1. In some embodiments, the volume ratio of IPA to water ranges from about 1:1 to about 5:1. In some embodiments, the volume ratio of IPA to water ranges from about 1:1 to about 3:1. In some embodiments, the volume ratio of IPA to water ranges from about 2:1 to about 3:1. In some embodiments, the volume ratio of IPA to water is about 2:1 to about 2.6:1. In some embodiments, the volume ratio of IPA to water is about 2.1:1 to about 2.5:1. In some embodiments, the volume ratio of IPA to water is about 2.2:1 to about 2.4:1. In some embodiments, the volume ratio of IPA to water is about 2.25:1 to about 2.35:1. In some embodiments, the volume ratio of IPA to water is about 2.3:1.

[0109] In some embodiments, the step of reacting a compound of Formula F3 with a compound of Formula F2 is in a solvent other than IPA and water, hi 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 sulfide, water, or a mixture thereof. In some embodiments, the solvent is selected from the group consisting of 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 sulfide, water; or mixtures thereof.

[0110] In some embodiments, the step of reacting the compound of Formula F3 with the compound of Formula F2 is carried out in the presence of sodium iodide. In some embodiments, the molar ratio of sodium iodide to the compound of Formula F3 ranges from about 0.1:1 to 1:1. In some embodiments, the molar ratio of sodium iodide to the compound of Formula F3 ranges from about 0.1:1 to 0.5:1. In some embodiments, the molar ratio of sodium iodide to the compound of Formula F3 is about 0.2:1 to 0.8:1. In some embodiments, the molar ratio of sodium iodide to the compound of Formula F3 is about 0.2:1 to 0.6:1. In some embodiments, the molar ratio of sodium iodide to the compound of Formula F3 is about 0.25:1 to 0.55:1. In some embodiments, the molar ratio of sodium iodide to the compound of Formula F3 is about 0.3:1 to 0.5:1. In some embodiments, the molar ratio of sodium iodide to the compound of Formula F3 is about 0.35:1 to 0.45:1. In some embodiments, the molar ratio of sodium iodide to the compound of Formula F3 is about 0.4:1.

[0111] In some embodiments, the step of reacting a compound of Formula F3 with a compound of Formula F2 is carried out at an elevated temperature. In some embodiments, the step of reacting a compound of Formula F3 with a compound of Formula F2 is carried out at a temperature of about 20°C to about 60°C. In some embodiments, the step of reacting a compound of Formula F3 with a compound of Formula F2 is carried out at a temperature of about 25°C to about 50°C. In some embodiments, the step of reacting a compound of Formula F3 with a compound of Formula F2 is carried out at a temperature of about 30°C to about 45°C. In some embodiments, the step of reacting a compound of Formula F3 with a compound of Formula F2 is carried out at a temperature of about 35°C to about 45°C. In some embodiments, the step of reacting a compound of Formula F3 with a compound of Formula F2 is carried out at a temperature of about 36°C to about 48°C. In some embodiments, the step of reacting a compound of Formula F3 with a compound of Formula F2 is carried out at a temperature of about 39°C to about 45°C. In some embodiments, the step of reacting the compound of Formula F3 with the compound of Formula F2 is carried out at a temperature of about 41° C. to about 43° C. In some embodiments, the step of reacting the compound of Formula F3 with the compound of Formula F2 is carried out at a temperature of about 42° C.

[0112] In some embodiments, the step of reacting the compound of Formula F3 with the compound of Formula F2 is carried out for about 24 hours or more. In some embodiments, the step of reacting the compound of Formula F3 with the compound of Formula F2 is carried out for about 24 hours.

[0113] In some embodiments, the compound of formula F2 has formula F1: [ka] with a base to give a compound of formula F2.

[0114] In some embodiments, the base reacted with the compound of Formula I comprises an inorganic base. In some embodiments, the base is a carbonate, hydrogen carbonate, or hydroxide base. In other embodiments, the base is sodium carbonate. In some embodiments, the base reacted with the compound of Formula F1 is potassium hydroxide.

[0115] In some embodiments, the reaction of the compound of Formula F1 with a base is carried out in a suitable solvent. In some embodiments, the suitable solvent is a mixture of solvents. In some embodiments, the mixture of solvents comprises water and an organic solvent. In some embodiments, the mixture of solvents comprises water and an ether solvent. In some embodiments, the organic solvent used in the step of reacting the compound of Formula F1 is MTBE (i.e., methyl tert-butyl ether). In some embodiments, the mixture of solvents comprises water and MTBE. In some embodiments, the step of reacting the compound of Formula F1 with a base is carried out in a solvent comprising water and an organic solvent. In some embodiments, the mixture of solvents comprises water and MTBE. In some embodiments, the volume ratio of water to MTBE is from about 1:1 to about 4:1. In some embodiments, the volume ratio of water to MTBE is from about 1.3:1 to about 3.5:1. In some embodiments, the volume ratio of water to MTBE is from about 1.8:1 to about 3:1. In some embodiments, the volume ratio of water to MTBE is from about 2.0:1 to about 2.8:1. In some embodiments, the volume ratio of water to MTBE is about 2.3:1 to about 2.5:1. In some embodiments, the volume ratio of water to MTBE is about 2.35:1 to about 2.45:1. In some embodiments, the volume ratio of water to MTBE is 2.4:1. In some embodiments, the solvent used in the step of reacting the compound of Formula F1 is removed after completion of the reaction and replaced with isopropanol.

[0116] In some embodiments, the present application provides a compound of Formula I: [ka] 1. A method for preparing a compound of formula (I), comprising: a) Formula F1: [ka] with a base to form a compound of formula F2: [ka] obtaining a compound of formula (I); b) Formula F3: [ka] is reacted with a compound of formula F2 in a solvent comprising isopropanol (IPA) and water to give a compound of formula F4: [ka] obtaining a compound of formula (I); c) reacting the compound of formula F4 with a reducing agent in a solvent comprising methyl tert-butyl ether (MTBE) and methanol to give a compound of formula F5: [ka] obtaining a compound of formula (I); d) reacting the compound of formula F5 with (S)-(+)-camphorsulfonic acid (CSA) to give the compound of formula F6-CSA: [ka] obtaining a compound of formula (I); e) reacting a compound of formula F6-CSA with a base to form a compound of formula F6: [ka] obtaining a compound of formula (I); f) reacting a compound of formula F6 with a compound of formula F7: [ka] with a carboxylic acid of formula F8: [ka] obtaining the product; g) reacting the product of formula F8 with p-toluenesulfonic acid in acetonitrile or isopropyl acetate to obtain a material comprising a compound of formula I; and h) crystallizing the material comprising the compound of formula I, i) dissolving a material comprising a compound of formula I in a solvent mixture comprising methanol and acetonitrile; and ii) crystallizing the compound of formula I from a solvent mixture to obtain a compound of formula I: [ka] obtaining a compound of formula (I) The present invention provides a method comprising:

[0117] In some embodiments, the present application provides a method for preparing a crystalline compound of formula I, comprising: a) dissolving a material comprising a compound of formula I in a solvent mixture comprising methanol and acetonitrile; and b) crystallizing the compound of formula I from a solvent mixture to obtain a compound of formula I: [ka] The present invention provides a method for producing a crystalline compound of formula (I).

[0118] In some embodiments, the crystalline compound of Formula I is Form I as described herein, see, eg, Table 1, Table 2, Table 3, Figure 1, and Figure 2. In some embodiments, the present application provides a compound of Formula I: [ka] 1. A method for preparing a compound of formula (I), comprising: a) Formula F6-CSA: [ka] with a base to form a compound of formula F6: [ka] obtaining a compound of formula (I); b) reacting a compound of formula F6 with a compound of formula F7: [ka] with a carboxylic acid of formula F8 to form a compound of formula F8; and c) Formula F8: [ka] with p-toluenesulfonic acid in a solvent comprising acetonitrile or isopropyl acetate to obtain a material comprising the compound of formula I.

[0119] In some embodiments, the present application provides a compound of formula F6-CSA: [ka] 1. A method for preparing a compound of formula (I), comprising: Formula F5: [ka] with (S)-(+)-camphorsulfonic acid (CSA) to obtain a compound of formula F6-CSA, wherein the molar ratio of CSA to the compound of formula F5 is between 0.7:1 and 0.9:1. In some embodiments, the present application provides a compound of formula F5: [ka] 1. A method for preparing a compound of formula (I), comprising: Formula F4: [ka] with a reducing agent in a solvent comprising methyl tert-butyl ether (MTBE) and methanol to obtain a compound of formula F5.

[0120] In some embodiments, the present application provides a compound of formula F4: [ka] 1. A method for preparing a compound of formula (I), comprising: a) Formula F1: [ka] with a base to form a compound of formula F2: [ka] obtaining a compound of formula (I); b) Transforming a compound of formula F2 into a compound of formula F3: [ka] to give a compound of formula F4.

[0121] In another embodiment, a pharmaceutical composition containing a compound of formula I is disclosed. For the purpose of administration, the compound of formula I can be formulated as a pharmaceutical composition. The pharmaceutical composition disclosed herein comprises a compound of formula I and a pharmaceutically acceptable carrier and / or diluent. The compound of formula I is present in the composition in an amount effective for treating a specific disorder, i.e., sufficient to reduce the supply of monoamines in the central nervous system, and preferably in an amount with acceptable toxicity to patients. Appropriate concentrations and dosages can be easily determined by those skilled in the art.

[0122] Pharmaceutically acceptable carriers and / or diluents are well known to those skilled in the art. For compositions formulated as liquid solutions, acceptable carriers and / or diluents include physiological saline and sterilized water, and may include antioxidants, buffers, bacteriostatic agents, and other common additives as needed. The compositions can also be formulated as pills, capsules, granules, or tablets, containing diluents, dispersants and surfactants, binders, and lubricants in addition to the compound of formula I. Those skilled in the art can further formulate the compound of formula I in an appropriate manner and according to generally accepted practices, such as those disclosed in Remington's Pharmaceutical Sciences, Gennaro, Ed., Mack Publishing Co., Easton, Pa. 1990.

[0123] Pharmaceutical compositions can be formulated for systemic administration, including oral and parenteral methods of administration. For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets, and capsules, as well as liquids, syrups, suspensions, and emulsions. These compositions may contain flavorants, preservatives, suspending agents, thickeners, and emulsifiers, and other pharmaceutically acceptable additives. For parenteral administration, For administration, the compounds of Formula I can be prepared in aqueous injection solutions which may contain, in addition to the compounds of Formula I, buffers, antioxidants, bacteriostats and other additives commonly employed in such solutions.

[0124] In some embodiments, the present application provides a method of preparing a pharmaceutical composition, the method comprising preparing a compound of formula I as provided herein, and formulating the compound of formula I with a pharmaceutically acceptable carrier and / or diluent.

[0125] In some embodiments, the compound of Formula I in the pharmaceutical composition is a) Formula F1: [ka] with a base to form a compound of formula F2: [ka] obtaining a compound of formula (I); b) Formula F3: [ka] is reacted with a compound of formula F2 in a solvent comprising isopropanol (IPA) and water to give a compound of formula F4: [ka] obtaining a compound of formula (I); c) reacting the compound of formula F4 with a reducing agent in a solvent comprising methyl tert-butyl ether (MTBE) and methanol to give a compound of formula F5: [ka] obtaining a compound of formula (I); d) reacting the compound of formula F5 with (S)-(+)-camphorsulfonic acid (CSA) to give the compound of formula F6-CSA: [ka] obtaining a compound of formula (I); e) reacting a compound of formula F6-CSA with a base to form a compound of formula F6: [ka] obtaining a compound of formula (I); f) reacting a compound of formula F6 with a compound of formula F7: [ka] with a carboxylic acid of formula F8: [ka] obtaining the product; g) reacting the product of formula F8 with p-toluenesulfonic acid in acetonitrile or isopropyl acetate to obtain a material comprising a compound of formula I; and h) crystallizing the material comprising the compound of formula I, i) dissolving a material comprising a compound of formula I in a solvent mixture comprising methanol and acetonitrile; and ii) crystallizing the compound of formula I from a solvent mixture to obtain a compound of formula I: [ka] obtaining a compound of formula (I) It is prepared by a method comprising:

[0126] In some embodiments, the compound of Formula I in the pharmaceutical composition has Formula F8: [ka] with p-toluenesulfonic acid in a solvent comprising acetonitrile or isopropyl acetate to give a material comprising the compound of formula I.

[0127] In some embodiments, the pharmaceutical composition comprises: a compound of Formula I (i.e., valbenazine ditosylate); at least one water-insoluble filler; at least one water-soluble diluent; at least one binder; at least one disintegrant; and at least one lubricant. In some embodiments, the pharmaceutical composition comprises: a compound of Formula I (i.e., valbenazine ditosylate) having about 40% w / w%, at least one water-insoluble filler having about 25% w / w%, at least one water-soluble diluent having about 20% w / w%, at least one binder having about 5% w / w%, at least one disintegrant having about 7.5% w / w%, and at least one lubricant having about 2.5% w / w%. In some embodiments, the pharmaceutical composition comprises: a compound of formula I (i.e., valbenazine ditosylate) having about 40% w / w%; silicified microcrystalline cellulose having about 25% w / w%; isomalt having about 20% w / w%; hydroxypropyl methylcellulose having about 5% w / w%; partially pregelatinized corn starch having about 7.5% w / w%; and magnesium stearate having about 2.5% w / w%.

[0128] In some embodiments, the pharmaceutically acceptable carrier and / or diluent of the pharmaceutical composition comprises: silicified microcrystalline cellulose; isomalt; hydroxypropyl methylcellulose; partially pregelatinized maize starch; and magnesium stearate.

[0129] In some embodiments, the present application provides a compound of formula I, prepared by any of the methods as described hereinabove and below. [ka] which provides a compound of the formula Formula F8: [ka] with p-toluenesulfonic acid in a solvent comprising acetonitrile or isopropyl acetate to give a material comprising the compound of formula I.

[0130] In some embodiments, the application provides: a) Formula F8: [ka] reacting the product of with p-toluenesulfonic acid in acetonitrile or isopropyl acetate to obtain a material comprising the compound of formula I; and b) crystallizing a material comprising a compound of formula I, i) dissolving a material comprising a compound of formula I in a solvent mixture comprising methanol and acetonitrile; and ii) crystallizing the compound of formula I from a solvent mixture to obtain a compound of formula I: [ka] obtaining a compound of formula (I) The present invention provides a compound of formula I prepared by a process comprising:

[0131] In some embodiments, the present application provides a compound of Formula I: [ka] which provides a compound of the formula a) Formula F1: [ka] with a base to form a compound of formula F2: [ka] obtaining a compound of formula (I); b) Formula F3: [ka] is reacted with a compound of formula F2 in a solvent comprising isopropanol (IPA) and water to give a compound of formula F4: [ka] obtaining a compound of formula (I); c) reacting the compound of formula F4 with a reducing agent in a solvent comprising methyl tert-butyl ether (MTBE) and methanol to give a compound of formula F5: [ka] obtaining a compound of formula (I); d) reacting the compound of formula F5 with (S)-(+)-camphorsulfonic acid (CSA) to give the compound of formula F6-CSA: [ka] obtaining a compound of formula (I); e) reacting a compound of formula F6-CSA with a base to form a compound of formula F6: [ka] obtaining a compound of formula (I); f) reacting a compound of formula F6 with a compound of formula F7: [ka] with a carboxylic acid of formula F8: [ka] obtaining the product; g) reacting the product of formula F8 with p-toluenesulfonic acid in acetonitrile or isopropyl acetate to obtain a material comprising a compound of formula I; and h) crystallizing the material comprising the compound of formula I, i) dissolving a material comprising a compound of formula I in a solvent mixture comprising methanol and acetonitrile; and ii) crystallizing the compound of formula I from a solvent mixture to obtain a compound of formula I: [ka] obtaining a compound of formula (I) It is prepared by a method comprising:

[0132] A crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of formula I).

[0133] In some embodiments, the present application provides a crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I). Crystalline forms of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I) can be identified by unique solid-state signatures, such as by differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and other solid-state methods. Further characterization of the water or solvent content of the crystalline form can be determined by any of the following methods, such as thermogravimetric analysis (TGA), DSC, etc.

[0134] For DSC, it is known that the observed temperature for a thermal event depends on the purity of the sample and may also depend on the rate of temperature change, as well as the sample preparation technique and instrumentation employed. Thus, values ​​reported herein for DSC thermograms may vary by plus or minus about 5°C (i.e., ± about 5°C). Values ​​reported herein for DSC thermograms may vary by plus or minus about 20 joules per gram (i.e., ± about 20 joules per gram).

[0135] For XRPD, the relative intensities of peaks may vary depending on the sample preparation technique, sample loading procedure, and instrument employed. Furthermore, instrument changes and other factors can often affect 2θ values. Thus, peak identification in a diffraction pattern may vary by plus or minus about 0.2° (i.e., ± about 0.2°). For TGA, the temperature profiles reported herein may vary by plus or minus about 5°C (i.e., ± about 5°C). The TGA percent weight change over a particular temperature range reported herein may vary by plus or minus about 2% weight change (i.e., ± about 2% weight change) due to, for example, variations in sample quality and sample size. All powder X-ray diffraction patterns (diffractograms) were obtained using Cu-Kα radiation.

[0136] Further characterization of the hygroscopicity of the crystalline form can be measured, for example, by gravimetric vapor sorption (GVS). GVS properties can vary by plus or minus about 5% relative humidity (i.e., ± about 5% relative humidity). GVS properties can also vary by plus or minus about 2% weight change (i.e., ± about 2% weight change). One aspect of the present invention relates to novel crystalline forms of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I), and methods relating thereto.

[0137] Representative physical properties of crystalline forms for the compound of Formula I are summarized in Tables 1, 2 and 3. [Table 1]

[0138] Certain other XRPD peaks for (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I) are shown in Table 2 below. [Table 2]

[0139] One aspect of the present invention relates to a crystalline form of substantially anhydrous (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I). ​​Anhydrous crystals of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I) refer to a crystalline form containing 2% or less water. In some embodiments, the anhydrous crystalline form contains 1% or less water. In some embodiments, the water content is determined by Karl Fischer (KF) analysis.

[0140] One aspect of the present invention relates to a crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I), wherein the crystalline form has an X-ray powder diffraction pattern comprising at least one peak selected from the group consisting of 6.3°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 19.9°±0.2°, and 22.6°±0.2° in terms of two-theta, or selected from the group consisting of the peaks in Table 2. In some embodiments, the crystalline form of compound 1 of Formula I has an X-ray powder diffraction pattern comprising at least two peaks selected from the group consisting of 6.3°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 19.9°±0.2°, and 22.6°±0.2° in terms of two-theta, or selected from the group consisting of the peaks in Table 2. In some embodiments, the crystalline form of compound 1 of Formula I has an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 6.3°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 19.9°±0.2°, and 22.6°±0.2° in terms of two-theta, or selected from the group consisting of the peaks in Table 2. In some embodiments, the crystalline form of compound 1 of Formula I has an X-ray powder diffraction pattern comprising at least four peaks selected from the group consisting of 6.3°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 19.9°±0.2°, and 22.6°±0.2° in terms of two-theta, or selected from the group consisting of the peaks in Table 2.In some embodiments, the crystalline form of compound 1 of Formula I has an X-ray powder diffraction pattern comprising at least five peaks selected from the group consisting of 6.3°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 19.9°±0.2°, and 22.6°±0.2° in terms of two-theta, or selected from the group consisting of the peaks in Table 2. In some embodiments, the crystalline form of compound 1 of Formula I has an X-ray powder diffraction pattern comprising at least six peaks selected from the group consisting of 6.3°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 19.9°±0.2°, and 22.6°±0.2° in terms of two-theta, or selected from the group consisting of the peaks in Table 2. In some embodiments, the crystalline form of compound 1 of formula I has an X-ray powder diffraction pattern comprising at least seven peaks selected from the group consisting of 6.3°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 19.9°±0.2°, and 22.6°±0.2° in terms of two-theta, or selected from the group consisting of the peaks in Table 2.

[0141] One aspect of the present invention relates to a crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I), having a powder X-ray diffraction pattern including a peak at 6.3°±0.2° in terms of two-theta. In some embodiments, the crystalline form of the compound of Formula I has a powder X-ray diffraction pattern including a peak at 19.7°±0.2° in terms of two-theta. In some embodiments, the crystalline form of the compound of Formula I has a powder X-ray diffraction pattern including a peak at 17.8°±0.2° in terms of two-theta. In some embodiments, the crystalline form of the compound of Formula I has a powder X-ray diffraction pattern including peaks at 6.3°±0.2° and 19.7°±0.2° in terms of two-theta. In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern comprising peaks at 6.3°±0.2° and 17.8°±0.2° in terms of two-theta. In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern comprising peaks at 6.3°±0.2°, 17.8°±0.2°, and 19.7°±0.2° in terms of two-theta. In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern comprising peaks at 6.3°±0.2°, 16.5°±0.2°, 17.8°±0.2°, and 19.7°±0.2° in terms of two-theta. In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern comprising peaks at 6.3°±0.2°, 17.8°±0.2°, 19.7°±0.2°, and 22.6°±0.2° in terms of two-theta. In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern comprising peaks at 6.3°±0.2°, 17.8°±0.2°, 19.7°±0.2°, and 19.9°±0.2° in terms of two-theta. In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern comprising peaks at 6.3°±0.2°, 17.8°±0.2°, 18.3°±0.2°, and 19.7°±0.2° in terms of two-theta.In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern comprising peaks at 6.3°±0.2°, 15.5°±0.2°, 17.8°±0.2°, and 19.7°±0.2° in terms of two-theta. In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern comprising peaks at 6.3°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 19.7°±0.2°, and 22.6°±0.2° in terms of two-theta. In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern comprising peaks at 6.3°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 19.7°±0.2°, and 19.9°±0.2° in terms of two-theta. In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern comprising peaks at 6.3°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 18.3°±0.2°, and 19.7°±0.2° in terms of two-theta. In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern comprising peaks at 6.3°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 17.8°±0.2°, and 19.7°±0.2° in terms of two-theta. In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern comprising peaks at 6.3°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 19.7°±0.2°, 19.9°±0.2°, and 22.6°±0.2° in terms of two-theta. In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern comprising peaks at 6.3°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 19.7°±0.2°, and 22.6°±0.2° in terms of two-theta. In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern comprising peaks at 6.3°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 19.7°±0.2°, and 22.6°±0.2° in terms of two-theta.In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern comprising peaks at 6.3°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 19.9°±0.2°, and 22.6°±0.2° in terms of two theta. In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern comprising peaks at 6.3°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 19.7°±0.2°, 19.9°±0.2°, and 22.6°±0.2° in terms of two theta. In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern comprising peaks at 6.3°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 19.9°±0.2°, and 22.6°±0.2° in terms of 2θ. In some embodiments, the crystalline form of the compound of Formula I has an X-ray powder diffraction pattern substantially as shown in Figure 1, where "substantially" means that the reported peaks may vary by about ±0.2° 2θ.

[0142] It is understood that peak intensities may vary from diffractogram to diffractogram for the same crystalline form based on any number of factors known to those skilled in the art, such as preferred orientation effects, preparation techniques, sample loading procedures, instrumentation employed, etc. In some cases, peak intensities may be rather dramatic. Thus, the diffraction peak intensities shown herein are exemplary, and identical diffraction peak intensities are not necessarily required. Furthermore, it is understood that one skilled in the art can readily compare the diffractograms provided herein with diffractograms generated for unknown crystalline forms to determine whether the diffractograms characterize the same crystalline form as those provided herein, or a different form.

[0143] One aspect of the present invention relates to a crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I), having a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an extrapolated onset temperature of about 237.9°C to about 243.9°C. In some embodiments, the crystalline form of the compound of Formula I has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 238.4°C to about 243.4°C. In some embodiments, the crystalline form of the compound of Formula I has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 238.9°C to about 242.9°C. In some embodiments, the crystalline form of the compound of Formula I has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 239.4° C. to about 242.4° C. In some embodiments, the crystalline form of the compound of Formula I has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 239.9° C. to about 241.9° C. In some embodiments, the crystalline form of the compound of Formula I has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 240.4° C. to about 241.4° C.

[0144] One aspect of the present invention relates to a crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I), having a differential scanning calorimetry (DSC) thermogram comprising an endotherm with a peak temperature of about 240.8°C to about 246.8°C. In some embodiments, the crystalline form of the compound of Formula I has a differential scanning calorimetry thermogram comprising an endotherm with a peak temperature of about 241.3°C to about 246.3°C. In some embodiments, the crystalline form of the compound of Formula I has a differential scanning calorimetry thermogram comprising an endotherm with a peak temperature of about 241.8°C to about 245.8°C. In some embodiments, the crystalline form of the compound of Formula I has a differential scanning calorimetry thermogram comprising an endotherm with a peak temperature of about 242.3° C. to about 245.3° C. In some embodiments, the crystalline form of the compound of Formula I has a differential scanning calorimetry thermogram comprising an endotherm with a peak temperature of about 242.8° C. to about 244.8° C. In some embodiments, the crystalline form of the compound of Formula I has a differential scanning calorimetry thermogram comprising an endotherm with a peak temperature of about 243.3° C. to about 244.3° C.

[0145] One aspect of the present invention relates to a crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I), having a differential scanning calorimetry (DSC) thermogram comprising an endotherm with an extrapolated onset temperature of about 237.9° C. to about 243.9° C. and a peak temperature of about 240.8° C. to about 246.8° C. In some embodiments, the crystalline form of the compound of Formula I has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 238.4° C. to about 243.4° C. and a peak temperature of about 241.3° C. to about 246.3° C. In some embodiments, the crystalline form of the compound of Formula I has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 238.9° C. to about 242.9° C. and a peak temperature of about 241.8° C. to about 245.8° C. In some embodiments, the crystalline form of the compound of Formula I has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 239.4° C. to about 242.4° C. and a peak temperature of about 242.3° C. to about 245.3° C. In some embodiments, the crystalline form of the compound of Formula I has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 239.9° C. to about 241.9° C. and a peak temperature of about 242.8° C. to about 244.8° C. In some embodiments, the crystalline form of the compound of Formula I has a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature of about 240.4° C. to about 241.4° C. and a peak temperature of about 243.3° C. to about 244.3° C. In some embodiments, the crystalline form of the compound of Formula I has a differential scanning calorimetry thermogram substantially as shown in Figure 2, where "substantially" means that the reported DSC profile may vary by about ±5° C.

[0146] One aspect of the present invention is a crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I),

[0147] an X-ray powder diffraction pattern comprising at least one peak selected from the group consisting of 6.3°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 19.9°±0.2°, and 22.6°±0.2° in terms of 2θ; a differential scanning calorimetry (DSC) thermogram containing an endotherm with an extrapolated onset temperature of about 237.9°C to about 243.9°C; and / or The crystalline form has a differential scanning calorimetry (DSC) thermogram that includes an endotherm with a peak temperature of about 240.8°C to about 246.8°C.

[0148] One aspect of the present invention is a crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I),

[0149] an X-ray powder diffraction pattern comprising at least two peaks selected from the group consisting of 6.3°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 19.9°±0.2°, and 22.6°±0.2° in terms of 2θ; a differential scanning calorimetry thermogram containing an endotherm with an extrapolated onset temperature of about 238.4°C to about 243.4°C; and / or It relates to a crystalline form having a differential scanning calorimetry thermogram that includes an endotherm with a peak temperature of about 241.3°C to about 246.3°C.

[0150] One aspect of the present invention is a crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I), an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 6.3°±0.2°, 15.5°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 19.9°±0.2°, and 22.6°±0.2° in terms of 2θ; a differential scanning calorimetry thermogram containing an endotherm with an extrapolated onset temperature of about 238.9°C to about 242.9°C; and / or The crystalline form has a differential scanning calorimetry thermogram that includes an endotherm with a peak temperature of about 241.8°C to about 245.8°C.

[0151] One aspect of the present invention is a crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I), a powder X-ray diffraction pattern containing a peak at 6.3°±0.2° in terms of 2θ; a differential scanning calorimetry (DSC) thermogram containing an endotherm with an extrapolated onset temperature of about 237.9°C to about 243.9°C; and / or The crystalline form has a differential scanning calorimetry (DSC) thermogram that includes an endotherm with a peak temperature of about 240.8°C to about 246.8°C.

[0152] One aspect of the present invention is a crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I), a powder X-ray diffraction pattern containing peaks at 6.3°±0.2° and 19.7°±0.2° in terms of 2θ; a differential scanning calorimetry thermogram containing an endotherm with an extrapolated onset temperature of about 238.4°C to about 243.4°C; and / or It relates to a crystalline form having a differential scanning calorimetry thermogram that includes an endotherm with a peak temperature of about 241.3°C to about 246.3°C.

[0153] One aspect of the present invention is a crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I), a powder X-ray diffraction pattern containing peaks at 6.3°±0.2°, 17.8°±0.2°, and 19.7°±0.2° in terms of 2θ; a differential scanning calorimetry thermogram containing an endotherm with an extrapolated onset temperature of about 238.9°C to about 242.9°C; and / or The crystalline form has a differential scanning calorimetry thermogram that includes an endotherm with a peak temperature of about 241.8°C to about 245.8°C.

[0154] One aspect of the present invention is a crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I), a powder X-ray diffraction pattern containing peaks at 6.3°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 19.7°±0.2°, and 22.6°±0.2° in terms of 2θ; a differential scanning calorimetry thermogram containing an endotherm with an extrapolated onset temperature of about 239.4°C to about 242.4°C; and / or The crystalline form has a differential scanning calorimetry thermogram that includes an endotherm with a peak temperature of about 242.3°C to about 245.3°C.

[0155] One aspect of the present invention is a crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I), a powder X-ray diffraction pattern containing peaks at 6.3°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 19.7°±0.2°, 19.9°±0.2°, and 22.6°±0.2° in terms of 2θ; a differential scanning calorimetry thermogram containing an endotherm with an extrapolated onset temperature of about 239.9°C to about 241.9°C; and / or It relates to a crystalline form having a differential scanning calorimetry thermogram that includes an endotherm with a peak temperature of about 242.8°C to about 244.8°C.

[0156] One aspect of the present invention is a crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I), a powder X-ray diffraction pattern containing peaks at 6.3°±0.2°, 16.5°±0.2°, 17.8°±0.2°, 18.3°±0.2°, 19.7°±0.2°, 19.9°±0.2°, and 22.6°±0.2° in terms of 2θ; a differential scanning calorimetry thermogram containing an endotherm with an extrapolated onset temperature of about 240.4°C to about 241.4°C; and / or The crystalline form has a differential scanning calorimetry thermogram that includes an endotherm with a peak temperature of about 243.3°C to about 244.3°C.

[0157] One aspect of the present invention is a crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I), a powder X-ray diffraction pattern substantially as shown in Figure 1; and / or It relates to a crystalline form having a differential scanning calorimetry thermogram substantially as shown in FIG.

[0158] In some embodiments, the crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I) can be isolated in a crystalline purity of at least about 75% by weight, as described herein. In some embodiments, about 80% by weight. In some embodiments, about 85% by weight. In some embodiments, about 90% by weight. In some embodiments, about 95% by weight. In some embodiments, about 96% by weight. In some embodiments, about 97% by weight. In some embodiments, about 98% by weight. In some embodiments, about 99% by weight.

[0159] A manufacturing batch of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I) was prepared in a manner similar to that described herein and had the following particle size distribution characteristics, as shown in Table 3: [Table 3]

[0160] In some embodiments, the crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) has a particle size D10 of about 1 μM to about 8 μM. In some embodiments, the crystalline form of the compound of Formula I has a particle size D10 of about 1 μM to about 7 μM. In some embodiments, the crystalline form of the compound of Formula I has a particle size D10 of about 2 μM to about 6 μM. In some embodiments, the crystalline form of the compound of Formula I has a particle size D10 of about 2 μM to about 5 μM. In some embodiments, the crystalline form of the compound of Formula I has a particle size D10 of about 2 μM to about 4 μM.

[0161] In some embodiments, the crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) has a particle size D50 of about 4 μM to about 27 μM. In some embodiments, the crystalline form of the compound of Formula I has a particle size D50 of about 6 μM to about 20 μM. In some embodiments, the crystalline form of the compound of Formula I has a particle size D50 of about 8 μM to about 18 μM. In some embodiments, the crystalline form of the compound of Formula I has a particle size D50 of about 10 μM to about 16 μM. In some embodiments, the crystalline form of the compound of Formula I has a particle size D50 of about 12 μM to about 15 μM.

[0162] In some embodiments, the crystalline form of 4-(2-chloro-4-methoxy-5-methylphenyl)-N-[(1S)-2-cyclopropyl-1-(3-fluoro-4-methylphenyl)ethyl]-5-methyl-N-prop-2-ynyl-1,3-thiazol-2-amine (Compound 1, free base) has a particle size D90 of about 19 μM to about 62 μM. In some embodiments, the crystalline form of the compound of Formula I has a particle size D90 of about 28 μM to about 58 μM. In some embodiments, the crystalline form of the compound of Formula I has a particle size D90 of about 35 μM to about 55 μM. In some embodiments, the crystalline form of the compound of Formula I has a particle size D90 of about 40 μM to about 51 μM. In some embodiments, the crystalline form of the compound of Formula I has a particle size D90 of about 41 μM to about 50 μM.

[0163] Pharmaceutical compositions and pharmaceutical products comprising compounds of formula I. One aspect of the present invention relates to a pharmaceutical composition comprising (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (i.e., the compound of Formula I) and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet or capsule. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of a capsule.

[0164] One aspect of the present invention relates to a pharmaceutical product selected from a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each comprising a (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (compound of Formula I) composition as described herein.

[0165] One aspect of the invention relates to a method for preparing a pharmaceutical composition, the method comprising admixing a (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (compound of Formula I) composition, as described herein, and a pharmaceutically acceptable carrier.

[0166] One aspect of the present invention relates to a method for preparing a pharmaceutical composition, comprising the step of admixing a crystalline form of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (compound of Formula I) composition with a pharmaceutically acceptable carrier, wherein the anhydrous crystalline form is prepared by any of the methods described herein.

[0167] A composition comprising a compound of formula I. One aspect of the present invention is a. (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (compound of formula I); and b. (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl(2S)-2-aminopropanoate (compound 2A); (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (compound 2B); 3-Isobutyl-9,10-dimethoxy-6,7-dihydropyrido[2,1-a]isoquinolin-5-ium salt (compound 2C); (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-7-oxo-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl(2S)-2-amino-3-methylbutanoate (compound 2D); (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl(2R)-2-amino-3-methylbutanoate (compound 2E); acetonitrile; ethanol; dichloromethane; and At least one compound selected from methanol The present invention relates to a composition comprising:

[0168] In some embodiments, the composition comprising a compound of Formula I is (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl(2S)-2-aminopropanoate (Compound 2A); (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (Compound 2B); 3-isobutyl-9,10-dimethoxy-6,7-dihydropyrido[2,1-a]isoquinolin-5-ium salt (Compound 2C); (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (Compound 2B); 3-isobutyl-9,10-dimethoxy-6,7-dihydropyrido[2,1-a]isoquinolin-5-ium salt (Compound 2C); At least two compounds are selected from the group consisting of methoxy-3-(2-methylpropyl)-7-oxo-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl(2S)-2-amino-3-methylbutanoate (Compound 2D); (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl(2R)-2-amino-3-methylbutanoate (Compound 2E); acetonitrile; ethanol; dichloromethane; and methanol (for brevity, the above group of compounds is referred to as the "List" in this paragraph). In some embodiments, the composition comprises a compound of Formula I and at least three compounds selected from the "List." In some embodiments, the composition comprises a compound of formula I and at least four compounds selected from the "List." In some embodiments, the composition comprises a compound of formula I and at least five compounds selected from the "List." In some embodiments, the composition comprises at least six compounds selected from the compound of formula I and the "List." In some embodiments, the composition comprises at least seven compounds selected from the compound of formula I and the "List." In some embodiments, the composition comprises at least eight compounds selected from the compound of formula I and the "List."

[0169] In some embodiments, the composition contains at least 97% (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (compound of Formula I) as determined by HPLC. In some embodiments, the composition contains at least 98% (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (compound of Formula I) as determined by HPLC. In some embodiments, the composition contains at least 99% (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (compound of formula I), as determined by HPLC.

[0170] In some embodiments, the composition contains 0.3% or less of (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl(2S)-2-aminopropanoate (Compound 2A) as determined by HPLC. In some embodiments, the composition contains 0.2% or less of (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl(2S)-2-aminopropanoate (Compound 2A) as determined by HPLC. In some embodiments, the composition contains 0.1% or less of (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl(2S)-2-aminopropanoate (Compound 2A), as determined by HPLC.

[0171] In some embodiments, the composition contains 0.3% or less of (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (Compound 2B) as determined by HPLC. In some embodiments, the composition contains 0.2% or less of (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (Compound 2B) as determined by HPLC. In some embodiments, the composition contains 0.1% or less of (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (Compound 2B) as determined by HPLC.

[0172] In some embodiments, the composition contains 0.2% or less of 3-isobutyl-9,10-dimethoxy-6,7-dihydropyrido[2,1-a]isoquinolin-5-ium salt (Compound 2C) as determined by HPLC. In some embodiments, the composition contains 0.1% or less of 3-isobutyl-9,10-dimethoxy-6,7-dihydropyrido[2,1-a]isoquinolin-5-ium salt (Compound 2C) as determined by HPLC. In some embodiments, the composition contains 0.05% or less of 3-isobutyl-9,10-dimethoxy-6,7-dihydropyrido[2,1-a]isoquinolin-5-ium salt (Compound 2C) as determined by HPLC.

[0173] In some embodiments, the composition contains 0.3% or less of (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-7-oxo-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl(2S)-2-amino-3-methylbutanoate (Compound 2D) as determined by HPLC. In some embodiments, the composition contains 0.2% or less of (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-7-oxo-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl(2S)-2-amino-3-methylbutanoate (Compound 2D) as determined by HPLC. In some embodiments, the composition contains 0.1% or less of (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-7-oxo-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl(2S)-2-amino-3-methylbutanoate (Compound 2D), as determined by HPLC.

[0174] In some embodiments, the composition contains 0.5% or less of (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl(2R)-2-amino-3-methylbutanoate (Compound 2E) as determined by HPLC. In some embodiments, the composition contains 0.4% or less of (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl(2R)-2-amino-3-methylbutanoate (Compound 2E) as determined by HPLC. In some embodiments, the composition contains 0.3% or less of (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl(2R)-2-amino-3-methylbutanoate (Compound 2E), as determined by HPLC. In some embodiments, the composition contains 0.2% or less of (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl(2R)-2-amino-3-methylbutanoate (Compound 2E), as determined by HPLC. In some embodiments, the composition contains 0.1% or less of (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl(2R)-2-amino-3-methylbutanoate (Compound 2E), as determined by HPLC.

[0175] In some embodiments, the composition contains 410 ppm or less of acetonitrile as determined by gas chromatography. In some embodiments, the composition contains 300 ppm or less of acetonitrile as determined by gas chromatography. In some embodiments, the composition contains 100 ppm or less of acetonitrile as determined by gas chromatography. In some embodiments, the composition contains 50 ppm or less of acetonitrile as determined by gas chromatography.

[0176] In some embodiments, the composition contains 5000 ppm or less of ethanol as determined by gas chromatography. In some embodiments, the composition contains 3000 ppm or less of ethanol as determined by gas chromatography. In some embodiments, the composition contains 1000 ppm or less of ethanol as determined by gas chromatography. In some embodiments, the composition contains 100 ppm or less of ethanol as determined by gas chromatography.

[0177] In some embodiments, the composition contains 600 ppm or less of dichloromethane as determined by gas chromatography. In some embodiments, the composition contains 400 ppm or less of dichloromethane as determined by gas chromatography. In some embodiments, the composition contains 100 ppm or less of dichloromethane as determined by gas chromatography. In some embodiments, the composition contains 30 ppm or less of dichloromethane as determined by gas chromatography.

[0178] In some embodiments, the composition contains 3000 ppm or less of methanol as determined by gas chromatography. In some embodiments, the composition contains 1000 ppm or less of methanol as determined by gas chromatography. In some embodiments, the composition contains 500 ppm or less of methanol as determined by gas chromatography. In some embodiments, the composition contains 60 ppm or less of methanol as determined by gas chromatography.

[0179] In some embodiments, (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (compound of Formula I) is crystalline. In some embodiments, (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (compound of Formula I) is Form I as described herein.

[0180] Abbreviation / Definition As used herein, "stable" refers to a compound that is sufficiently robust to survive isolation from a reaction mixture with a useful degree of purity, and preferably amenable to formulation into an effective therapeutic agent.

[0181] As used in this specification and the appended claims, the indefinite articles "a" and "an" and the definite article "the" include plural referents as well as singular, unless the context clearly dictates otherwise.

[0182] The term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art and depends in part on how the value is measured or determined. In some embodiments, the term "about" or "approximately" refers to within 1, 2, 3, or 4 standard deviations. In some embodiments, the term "about" or "approximately" refers to within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0183] The term "crystalline form" of a compound can refer to any crystalline form of the compound, such as the compound as a free acid, the compound as a free base, an acid addition salt of the compound, a base addition salt of the compound, a complex of the compound, a solvate (including hydrates) of the compound, or 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, such as the compound as a free acid, the compound as a free base, an acid addition salt of the compound, a base addition salt of the compound, a complex of the compound, or a solvate (including hydrates) of the compound, or a coprecipitate of the compound. In many cases, the terms "crystalline form" and "solid form" can refer to pharmaceutically acceptable forms, including, for example, pharmaceutically acceptable addition salts, pharmaceutically acceptable complexes, pharmaceutically acceptable solvates, pharmaceutically acceptable co-crystals, and pharmaceutically acceptable coprecipitates.

[0184] The terms "process" and "method" are used interchangeably to refer to methods for preparing the compounds disclosed herein. Modifications to the processes and methods disclosed herein (e.g., starting materials, reagents, protecting groups, solvents, temperatures, reaction times, and / or purification) that are known to one of ordinary skill in the art are also encompassed by the present disclosure.

[0185] The terms "adding," "reacting," and "mixing" are used interchangeably to refer to contacting one reactant, reagent, solvent, catalyst, or reactive group with another reactant, reagent, solvent, catalyst, or reactive group. Unless otherwise specified, reactants, reagents, solvents, catalysts, and reactive groups can be added individually, simultaneously, or separately, and / or in any order. They can be added with or without heat, and can be added under an inert atmosphere (e.g., N or Ar) if necessary. In some embodiments, the term "reacting" can also refer to in situ formation, or intramolecular reaction if the reactive groups are in the same molecule.

[0186] It will be further understood that certain features that are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0187] The compounds disclosed herein may also include all isotopes of atoms occurring in intermediates or final compounds.Isotopes include atoms with the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

[0188] In some embodiments, the compounds disclosed herein and their salts are substantially isolated. By "substantially isolated" is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compounds disclosed herein. Substantial separation can include a composition containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds disclosed herein or their salts. Methods for isolating compounds and their salts are conventional in the art.

[0189] The present application also includes salts of the compounds described herein. As used herein, "salt" refers to a derivative of the disclosed compound in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of salts include, but are not limited to, mineral acid (e.g., HCl, HBr, H2SO4) or organic acid (e.g., acetic acid, benzoic acid, trifluoroacetic acid) salts of basic residues, such as amines; alkali (e.g., Li, Na, K, Mg, Ca) or organic (e.g., trialkylammonium) salts of acidic residues, such as carboxylic acids; and the like. The salts of the present application can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (ACN) are preferred.

[0190] This application also includes pharmaceutically acceptable salts of the compounds described herein. "Pharmaceutically acceptable salts" includes a subset of "salts" as defined above, which are conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety. The phrase "pharmaceutically acceptable" is employed herein to refer to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0191] The methods described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic methods, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C), infrared spectroscopy, spectrophotometry (e.g., ultraviolet-visible), or mass spectrometry; or chromatography, such as high-performance liquid chromatography (HPLC) or thin-layer chromatography. The compound obtained by the reaction can be purified by any suitable method known in the art. For example, chromatography (medium pressure) on a suitable adsorbent (e.g., silica gel, alumina, etc.), HPLC, or preparative thin-layer chromatography; distillation; sublimation, trituration, or recrystallization. The purity of a compound is generally determined by physical methods, such as measuring the melting point (if solid), obtaining an NMR spectrum, or performing HPLC separation. A compound can be said to be purified if the melting point is reduced, if undesired signals in the NMR spectrum are reduced, or if extraneous peaks in the HPLC trace are eliminated. In some embodiments, the compound is substantially purified.

[0192] Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Greene's Protective Groups in Organic Synthesis, 4th Ed., John Wiley & Sons: New York, 2006. and is incorporated herein by reference in its entirety.

[0193] The reactions of the methods described herein can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, i.e., a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the reaction step, a suitable solvent for a particular reaction step can be selected. Suitable solvents include water, alkanes (e.g., pentane, hexane, heptane, cyclohexane, etc., or mixtures thereof), aromatic solvents (e.g., benzene, toluene, xylene, etc.), alcohols (e.g., methanol, ethanol, isopropanol, etc.), ethers (e.g., dialkyl ethers, methyl tert-butyl ether (MTBE), tetrahydrofuran (THF), dioxane, etc.), esters (e.g., ethyl acetate, butyl acetate, etc.), halogenated hydrocarbon solvents (e.g., dichloromethane (DCM), chloroform, dichloroethane, tetrachloroethane), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, acetonitrile (ACN), hexamethylphosphoramide (HMPA), and N-methylpyrrolidone (NMP). Such solvents can be used in either wet or anhydrous form.

[0194] Resolution of racemic mixtures of compounds can be achieved by any of numerous methods known in the art. One example of a method is fractional recrystallization using a "chiral resolving acid," which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization are, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or the D- and L-forms of various optically active camphorsulfonic acids. Resolution of racemic mixtures can also be achieved by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art.

[0195] The crystals used for seeding can be obtained from a previous synthesis, for example as described in US Pat. No. 10,160,757 B2. [Example]

[0196] The present disclosure will be described in more detail using specific examples. The following examples are presented for illustrative purposes and are not intended to limit the present disclosure in any way. Those skilled in the art will readily recognize a variety of non-essential parameters that can be changed or modified to achieve essentially the same results.

[0197] In the following examples, all temperatures are listed in degrees Celsius, and all parts and percentages are by weight unless otherwise noted. Reagents can be purchased from commercial sources, such as Sigma-Aldrich® Chemical Co., and can be used without further purification unless otherwise noted. 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 can be used as received unless otherwise noted, or can be purified using standard methods known to those skilled in the art.

[0198] Unless otherwise specified, the reactions described below were generally carried out at ambient or room temperature. Reactions were assayed by HPLC and were complete as judged by consumption of starting material.

[0199] The structure and purity of the compounds in the following examples were determined by the following method: proton nuclear magnetic resonance ( 1 H NMR) spectroscopy, 13 Confirmed by one or more of C NMR spectroscopy, mass spectroscopy, infrared spectroscopy, melting point, X-ray crystallography and / or HPLC. 1 H NMR spectra were determined using an NMR spectrometer operating at a specific field strength. Chemical shifts are reported in parts per million (ppm, δ) downfield from a standard, e.g., an internal standard, e.g., TMS. Alternatively,1 H NMR spectra were referenced to signals from residual protons in deuterated solvents as follows: CDCl3 = 7.26 ppm; DMSOd6 = 2.50 ppm; CD6D6 = 7.16 ppm; CD3OD = 3.31 ppm (J Org. Chem. 1997, 62, 7513). Peak multiplicities are indicated as follows: s, singlet; d, doublet; dd, doublet of doublets; t, triplet; dt, triplet of doublets; q, quartet; br, broad line; and m, multiplet. Coupling constants are given in Hertz (Hz). Mass spectral (MS) data were obtained using a mass spectrometer with APCI or ESI ionization.

[0200] Example 1 Synthesis of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (Formula I).

[0201] Step A: Synthesis of 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (Formula F4, see Figures 3 and 7). Demineralized water (231 L, 6.30 V), 3-((dimethylamino)methyl)-5-methylhexan-2-one oxalate (formula F1, 52.6 kg, 202 mol; 1.25 eq.), and tert-butyl methyl ether (95 L, 2.60 V) are charged to reactor A. Heat to approximately 22°C and adjust the pH to 11 with 10 wt% potassium hydroxide solution (210.8 kg, 376 mol, 2.33 eq.). Stir for not less than 15 minutes ("NLT") and separate the layers. Wash the organic layer with demineralized water (39 L, 1.05 V). Solvent exchange with isopropanol by addition and removal distillation at 1.50 V with isopropanol (129 L, 3.50 V). Cool to approximately 22°C (19-25°C) and charge demineralized water (55 L, 1.50 V), sodium iodide (9.7 kg, 65 mol, 0.40 equiv.), and 6,7-dimethoxy-3,4-dihydroisoquinoline hydrochloride (Formula F3, 36.7 kg, 161 mmol, 1.00 equiv.). Heat to approximately 42°C and stir for at least 24 hours. Cool to approximately 22°C and stir for at least 1 hour. Isolate the solid by filtration. Wash the cake with isopropanol (91.8 L, 2.50 V). Dry the wet 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (Formula F4) product under vacuum at approximately 40°C for at least 12 hours. Yield: 45.3 kg, 143 mol, 88.5%, purity 99.2%.

[0202] Step B: Synthesis of 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (Formula F5, see Figures 4 and 8). 3-Isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one (Formula F4, 44.3 kg, 139 mol, 1.00 eq), tert-butyl methyl ether (195 L, 4.40 V), acetic acid (9.3 kg, 155 mol, 1.11 eq), and methanol (44 L, 1.00 V) are charged to Reactor A. A suspension of sodium borohydride (10.5 kg, 279 mol, 2.00 eq) in tert-butyl methyl ether (44 L, 1.00 V) is charged, maintaining the temperature at approximately 22 °C. The preparation vessel and transfer line are rinsed with tert-butyl methyl ether (2 × 13 L, 2 × 0.30 V). Stir at approximately 25 °C for 2 hours. Add 1N sodium hydroxide solution (230 kg, 222 mol, 1.59 eq) at about 25°C. Heat to about 47°C and stir for about 3 hours. Cool to about 15°C and stir for about 30 minutes. Isolate the solid by filtration. Wash the cake with water (4 x 44 L, 4 x 1.00 V) and tert-butyl methyl ether (44 L, 1.00 V). Dry the wet 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (Formula F5) product under vacuum at about 40°C for not less than 12 hours. Yield: 35.6 kg, 111 mol, 80.1%, purity 99.0%.

[0203] Step C: Synthesis of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (S)-(+)-camphorsulfonate (Formula F6-CSA, see Figure 4 and Figure 8). Charge reactor A with absolute ethanol (428 L, 12.00 V), camphor D-(+)-sulfonic acid (21.4 kg, 92 mol, 0.825 equiv.), 3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (formula F5, 35.7 kg, 112 mol, 1.00 equiv.), and demineralized water (0.75 V). Heat to approximately 70°C and stir for approximately 30 minutes. Cool to approximately 22°C at approximately 3°C / hour. Ensure product crystallizes. If not, seed with F6 CSA (0.2 kg, 0.5 wt%). Cool to approximately 22°C at approximately 3°C / hour and stir for approximately 2 hours. Isolate the solid by filtration. The cake is washed with absolute ethanol (36 L, 1.00 V). The wet (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (S)-(+)-camphorsulfonate (formula F6-CSA) product is dried under vacuum at approximately 45°C for ≥12 hours. Yield: 23.0 kg, 42 mol, 37.3%, purity 99.6%.

[0204] Step D: Synthesis of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (Formula I intermediate, see Figure 5 and Figure 9). Methylene chloride (120 L, 5.50 V) and (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol (S)-(+)-camphorsulfonate (formula F6-CSA, 21.8 kg, 40 mol, 1.00 equiv.) are charged to Reactor A. 1N sodium hydroxide (14.8 kg, 111 mol, 2.80 equiv.) is added at approximately 25°C. Stir for 15 minutes or more and separate the layers. The organic layer is washed with demineralized water (33 L, 1.50 V). Boc-L-valine (Formula F7, 10.2 kg, 47 mol, 1.19 eq) and 4-dimethylaminopyridine (1.3 kg, 11 mol, 0.27 eq) are charged, cooled to approximately 2°C, and inertized by four nitrogen compression / decompression cycles and sparging with nitrogen. EDC.HCl (13.3 kg, 69 mol, 1.75 eq) is charged in portions, maintaining the temperature at approximately 2°C. The mixture is heated to approximately 25°C and stirred for approximately 2 hours. 0.15 N citric acid solution (112.5 kg, 17 mol, 0.42 eq) is added, stirred for 15 minutes or more, and the layers are separated. The organic layer is washed with demineralized water (65 L, 3.00 V). The solvent is exchanged for acetonitrile by two addition-removal distillations at 3.00 V with acetonitrile (109 L, 5.00 V x 2). Charge a solution of para-toluenesulfonic acid (15.8 kg, 83 mol, 2.10 equiv.) in acetonitrile (76 L, 3.50 V). Heat to about 65° C. and stir for about 12 hours, then cool to about 20° C. and stir for about 2 hours. Isolate the solid by filtration. Wash the cake with acetonitrile (65 L, 3.00 V). Dry the wet (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (Formula I) material under vacuum at about 50° C. for at least 12 hours. Yield: 26.2 kg, 34 mol, 85.8%, 99.1% purity.

[0205] Step E: Synthesis of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (Formula I, see Figure 6 and Figure 10). Methanol (25 L, 1.00 V), (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (Formula I) material from Step D (24.5 kg, 32 mol, 1.00 equiv.), and acetonitrile (49 L, 2.00 V) are charged to Reactor A. Heat to approximately 25 °C and polish filter the solution into Reactor B. Rinse Reactor A, the filter, and the transfer line with a mixture of methanol (5 L, 0.20 V) and acetonitrile (10 L, 0.40 V). Charge acetonitrile (39 L, 1.60 V) to Reactor B. Distill at about 42°C, Pi = 400-200 mbar while adding acetonitrile (37 L, 1.50 V) and keeping the volume constant at 135 L (5.50 V). Seed with compound of formula I (0.02 kg, 0.1 wt%). Distill at about 42°C, Pi = 400-200 mbar while adding acetonitrile (86 L, 3.50 V) and keeping the volume constant at 135 L (5.50 V). Charge acetonitrile (25 L, 1.00 V) at about 42°C. Cool to about 20°C over 4 hours and stir for 2 hours. Isolate the solid by filtration. Wash the cake with acetonitrile (74 L, 3.00 V). Wet (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) (Formula I) compound (DS) is dried under vacuum at about 50° C. for 12 hours or more. Yield: 23.7 kg, 31 mol, 97.1%, purity 99.5%, powder X-ray diffraction (XRPD, see FIG. 1), and differential scanning calorimetry (DSC, see FIG. 2).

[0206] Four additional batches (i.e., 084, 085, 086, and 087) were prepared similarly as above, with the peak temperatures for each being shown in Table 4 below. [Table 4]

[0207] Example 2 Determination of p-toluenesulfonic acid. The determination of the % area of ​​p-toluenesulfonic acid in the compound of formula I prepared by step D is carried out by HPLC. The separation is based on a gradient reversed-phase HPLC method with ultraviolet (UV) detection.

[0208] Equipment and equipment conditions: To perform the HPLC method for the assay determination of compounds of Formula I, the following equipment is required:

[0209] HPLC system, or equivalent, equipped with a UV variable wavelength or photodiode array detector, gradient capability, and electronic data acquisition and processing. Column: Phenomenex Kinetex XB-C18, 4.6mm x 150mm, 2.6μm Column heater capable of controlling the temperature at 50°C ± 2°C Autosampler capable of injecting 3 μL A balance capable of accurately weighing 0.1 mg Analytical balance capable of weighing 0.01 mg accurately Water purification system, Milli-Q or equivalent Ultrasonic processor 0.45μm membrane filter pH meter Class A volumetric glassware

[0210] The parameters and conditions used for the HPLC method are listed in Table 5. The gradient conditions are listed in Table 6. [Table 5]

[0211] [Table 6] Reagents and reference standards:

[0212] The reagents and reference standards used in this method are listed in Table 7. [Table 7]

[0213] Preparation of solutions: Note: The preparation may be adjusted as needed.

[0214] Mobile phase A (50 mM ammonium formate, 0.1% formic acid in DI water). Accurately weigh approximately 3.15 grams of ammonium formate into a suitable container and add 500 mL of DI water. Using a transfer pipette, add 1.0 mL of formic acid to the container and swirl to mix until all solids are dissolved. Add an additional 500 mL of DI water and record the pH of the solution. If the pH of the solution is not between 3.90 and 4.00, re-adjust or adjust the pH with either formic acid or ammonium formate. Filter the solution through a 0.45 μm membrane filter and degas it.

[0215] Diluent (DI water:acetonitrile, 50:50, v / v). Add 500 mL of DI water and 500 mL of acetonitrile into a suitable container and mix thoroughly.

[0216] Preparation of standard solutions: Note: The standard solution is stable for 4 days at ambient laboratory conditions.

[0217] Working solution (4 mg / mL of compound of formula I). Accurately weigh approximately 100 mg of compound of formula I RS into a 25 mL volumetric flask. Add approximately 20 mL of diluent to the flask and mix thoroughly by swirling. Sonicate if necessary to dissolve solids. Dilute to volume with diluent and mix thoroughly by inversion.

[0218] Preparation of sample solution: Note: Sample solutions are stable for 4 days at ambient laboratory conditions.

[0219] Sample solution (4 mg / mL of compound of formula I). Approximately 100 mg of a compound of Formula I sample is accurately weighed into a 25 mL volumetric flask. Approximately 20 mL of diluent is added to the flask and mixed thoroughly by swirling.

[0220] Sonicate if necessary to dissolve solids. Dilute to volume with diluent and mix thoroughly by inversion.

[0221] procedure: Equilibrate the HPLC column at the gradient starting conditions for at least 1 hour or until a stable baseline is achieved (see Table 6). Inject samples and standards using the sequence in Table 8. [Table 8] System stability:

[0222] Blank - There should be no interfering peaks (>0.05%) at the retention time of the peak of interest.

[0223] Working solution - The response factors and % relative standard deviations (RSDs) of retention times for the compound of Formula I and PTSA in the first five injections must be 1.0% or less (NMT). The tailing factor of the peak for the compound of Formula I in the first five injections must be 2.0 or less. calculation: PTSA % area in sample solution (p-toluenesulfonic acid): PTSA% area=(A PTSA)÷(A API +A PTSA ) x 100 (In the formula, A PTSA = Area response for PTSA (area measurement) A API = area response (area measurement) for compounds of formula I Reporting the results: PTSA% area The PTSA % area of ​​40.35% to 41.21% area indicates a PTSA / Formula I stoichiometry of 2.0. A PTSA % area > 41.21% area indicates that there is an excess of PTSA. A PTSA % area of ​​42.35% area indicates that there is an excess of 0.1 equivalents of PTSA. A PTSA % area < 40.35% area indicates insufficient PTSA reacted with the compound of formula F8, resulting in a low yield.

[0224] The PTSA determination results are summarized in Table 9, where the PTSA / DS ratio refers to the PTSA / Formula I stoichiometry. [Table 9]

[0225] Example 3 Analytical characterization of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate), the compound of formula I.

[0226] Four separate batches of (2R,3R,11bR)-3-isobutyl-9,10-dimethoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-yl(S)-2-amino-3-methylbutanoate di(4-methylbenzenesulfonate) were produced in accordance with cGMP for applicable GLP use in a manner similar to that described herein (i.e., Example 1). Certain data for Example 1, Step E (i.e., Batch 073) and four batches (i.e., Batches 084, 085, 086, and 087) are shown in Table 10 below. [Table 10] [ka] [ka]

[0227] A representative list of specifications for each of the tests used to analyze the four batches is provided below in Table 11. [Table 11]

[0228] In addition to those described herein, various modifications of the present disclosure will become apparent to those skilled in the art from the preceding description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this application, including all patents, patent applications, and publications, is hereby incorporated by reference in its entirety.

Claims

[Claim 1] The invention described in the specification.

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