Synthesis of Substituted Heterocyclic Condensed Gamma-Carbolines

Abstract

This provides a more efficient method for producing enantiomerically pure substituted heterocyclic condensed gamma-carbolins. [Solution] A method is provided for producing a compound represented by the following formula, either in free form or salt form. JPEG2026086861000051.jpg4446 [In the formula, R is H or C] 1-4 It is an alkyl group (for example, methyl).

Description

[Technical Field]

[0001] Cross-citation of related applications This application is an international application claiming priority and benefits under U.S. Provisional Application 62 / 683,411 filed June 11, 2018, and U.S. Provisional Application 62 / 780,742 filed December 17, 2018, each of which is incorporated herein by reference in whole.

[0002] Field of Invention The present invention relates to methods for producing substituted heterocyclic condensed gamma-carbolins, intermediates useful for their production, methods for producing such intermediates, and compositions containing such compounds produced by these methods. [Background technology]

[0003] Background of the Invention Substituted heterocyclic condensed gamma-carbolins are useful as agonists or antagonists of 5-HT2 receptors, particularly 5-HT2A and 5-HT2C receptors, in the treatment of central nervous system disorders, including obesity, anxiety, depression, mental illness, schizophrenia, sleep disorders, sexual disorders, migraines, headaches and related symptoms, social phobias, and gastrointestinal disorders such as gastrointestinal motility dysfunction. [Overview of the project] [Problems that the invention aims to solve]

[0004] Conventional methods for the production of enantiomerically pure substituted heterocyclic condensed gamma-carbolins involve the Fischer indole cyclization of appropriately substituted cyclic ketones (e.g., piperidine-4-one) with an arylhydrazine (e.g., dihydroquinoxaline-1-(2H)-amine, 2H-benzo[b][1,4]oxazine-4(3H)-amine, or 2H-benzo[b][1,4]thiadin-4(3H)-amine) to obtain a tetracyclic indole compound (e.g., 1,3,7,8,9,10-hexahydro-1H-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline). This indole core is then reduced to a cis or trans tetracyclic dihydroindole (i.e., cis or trans tetracyclic indoline) product, which requires thorough purification methods such as chiral column chromatography to obtain an enantiomerically pure product. This method is inefficient overall because it requires excess reactants and a racemic intermediate as a reaction intermediate, and even after purifying such products in the final step, a yield of 25-50% can only be achieved. Therefore, a more efficient method is needed to produce enantiomerically pure substituted heterocyclic condensed gamma-carbolins.

[0005] Substituted heterocyclic condensed gamma-carbolins in free or pharmaceutically acceptable salt forms, intermediates used for their manufacture, such as enantiomerically pure 2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole-type intermediates, methods for manufacturing said intermediates, and said substitute heterocyclic condensed gamma-carbolins are disclosed in U.S. Patents 7,183,282, 8,309,722, 8,779,139, 9,315,504, and 9,751,883, each of which is incorporated herein by reference in its entirety. [Means for solving the problem]

[0006] Summary of the Invention The present invention discloses methods for producing substituted heterocyclic condensed gamma-carbolins in free form or pharmaceutically acceptable salt form, intermediates used in their production, such as an enantiomerically pure 2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole-type intermediate, a method for producing the intermediate, and the substituted heterocyclic condensed gamma-carbolins. The substituted heterocyclic condensed gamma-carbolins produced by the present invention and their pharmaceutically acceptable salts are of formulas 1J and 2J [ka] [In the formula, R is H and C] 1-4 Selected from alkyl groups, Q is selected from 4-(4-fluorophenyl)-4-oxobutyl and 3-(4-fluorophenoxy)propyl. The core structure is represented as shown. In the compounds of formula 1J (and similar formulas of class 1 as used herein), the stereochemistry shown is understood to be absolute stereochemistry, corresponding, for example, to the 4aS,9bR configuration of the compounds of formula 1I and the 6bR,10aS configuration of the compounds of formula 1J. In contrast, in the compounds of formula 2J (and similar formulas of class 2 as used herein), the stereochemistry is understood to be relative stereochemistry of two adjacent stereocenters. Therefore, for example, in the compounds of formula 2J, the formula represents both a compound having a 6bR,4aS configuration and a compound having a 6bS,4aR configuration, or a combination thereof.

[0007] Other exemplary representative examples of the compounds of the present invention or related compounds are described in U.S. Patents 6,552,017; 6,548,493; 6,713,471; and 6,849,619, 7,071,186, 7,081,455 and U.S. Reissue Patents 39,680 and 38,679, the contents of each of which are incorporated herein by reference in their entirety. These compounds have been found to be useful as 5-HT2 receptor agonists and antagonists, serotonin transporter antagonists and modulators of dopamine D1 and / or D2 receptor function. These compounds can be used in the treatment of central nervous system disorders including obesity, anxiety, depression, mental disorders, schizophrenia, sleep disorders, sexual disorders, migraine, symptoms associated with headache, social phobia and gastrointestinal disorders including gastrointestinal motility dysfunction.

[0008] These compounds have also recently been shown to have unique pharmacological properties associated with indirect enhancement of AMPA and NMDA signaling via the D1 receptor pathway and enhancement of mTOR signaling. Such properties are described in detail in U.S. Provisional Applications 62 / 644,355, 62 / 682,582 and 62 / 780,004 and International Application PCT / US2019 / 022480, the contents of each of which are incorporated herein by reference in their entirety.

[0009] In certain embodiments, the present invention provides a compound of Formula 1I in free or salt form, which may be useful, for example, as an intermediate in the production of a compound of Formula 1J: In free or salt form, for example, acid addition salt form, optionally in solid form, of Formula 1I [Chemical formula] [Wherein, R is H or C 1-4 alkyl (e.g., methyl). ] of the compound.

[0010] The present invention further provides a compound of the following formula: 1.1 Formula 1I, wherein R is C1-C4 alkyl. 1.2 Formula 1I, wherein R is methyl. 1.3 Formula 1I, 1.1 or 1.2, wherein the compound is in free base form. 1.4 Formula 1I, 1.1 or 1.2, wherein the compound is in acid addition salt form. 1.5 Formula 1.4, wherein the acid addition salt form is a hydrohalide salt form (such as hydrochloride, hydrobromide, hydroiodide or hydrofluoride with a base to acid molar ratio of 1:1 to 3:1). 1.6 Formula 1.5, wherein the acid addition salt form is hydrochloride. 1.7 Any of the preceding formulas, wherein the compound is in solid form, such as solid amorphous form or solid crystalline form. 1.8 Any of the preceding formulas, wherein the compound has at least 70%, preferably at least 80%, more preferably at least 90%, most preferably 95% to 100% of the cis stereoisomer relative to all other stereoisomers and / or the compound has an enantiomeric excess (e.e.) of at least 70%, preferably at least 80%, more preferably at least 90%, most preferably more than 95% or more than 97% or more than 99% or more than 99.5% or 99.9% - 100% (i.e., for the above 4aS, 9bR enantiomer).

[0011] In certain embodiments, the present invention provides a compound of the following Formula 2I in free form or salt form, which may be useful, for example, as an intermediate for the preparation of a compound of Formula 2J: Formula 2I in free form or salt form, such as acid addition salt form, optionally in solid form

Chemical formula

[0012] The present invention further provides a compound of the following formula: 2.1 Formula 2I, where R is a C1-C4 alkyl group. 2.2 Formula 2I, where R is methyl. 2.3 The compound is in the form of a free base, formula 2I, 2.1, or 2.2. 2.4 Compounds in the form of an acid addition salt, formula 2I, 2.1, or 2.2. 2.5 Formula 2.4, where the acid addition salt form is a hydrohalide salt form (base-to-acid molar ratio of 1:1 to 3:1, e.g., hydrochloride, hydrobromide, hydroiodide, or hydrofluoride). 2.6 The acid addition salt form is hydrochloride, formula 2.5. 2.7 The compound is in solid form, for example, solid amorphous form or solid crystalline form, according to one of the above formulas. 2.8 Any of the above formulas, wherein the compound is at least 70%, preferably at least 80%, more preferably at least 90%, and most preferably 95% to 100% cis stereoisomer of all other stereoisomers.

[0013] The present invention further provides the following compounds that can be formed as impurities in a method for producing the compound of formula 1J. [ka] [ka] [ka] [In the formula, in any of the compounds 1K, 1L, 1M, 1N, 1O, 1P, and 1Q, the group R is H and C] 1-4 The alkyl group (e.g., methyl) is selected, and the group Q is selected from -O- and -(C=O)-.

[0014] The present invention further provides the following compounds that can be formed as impurities in a method for producing compounds of formula 2J. [ka] [ka] [ka] [In the formula, in any of the compounds 2K, 2L, 2M, 2N, 2P, and 2Q, the group R is H and C] 1-4 The alkyl group (e.g., methyl) is selected, and the group Q is selected from -O- and -(C=O)-.

[0015] method In one embodiment, the present invention relates to a method for producing a compound of formula 1J, as shown in the following scheme. [ka] Here, independently of each of compounds 1A to 1J: (i) A is selected from Br, Cl and I, (ii) R is H and C 1-4 Selected from alkyl groups (e.g., methyl), (iii) B is a protecting group as defined herein, and (iv) Q is selected from 4-(4-fluorophenyl)-4-oxobutyl and 3-(4-fluorophenoxy)propyl, Here, each of compounds 1A, 1B, 1C, 1D, 1E, 1F, 1H, 1I, and 1J is independently in free base form or salt form (e.g., acid addition salt form). It is understood that compound 1B contains substantially equal amounts of two cis enantiomers, i.e., an essential or complete racemic cis isomer, i.e., any trans isomer is substantially or completely excluded. It is further understood that compound 1C is substantially, essentially or completely a single compound 1C, with the opposite cis enantiomer or any trans stereoisomer substantially or completely excluded.

[0016] In one embodiment, the present invention relates to a method for producing a compound of formula 2J, as shown in the following scheme. [ka] Here, independently of each of compounds 2A to 2J: (i) A is selected from Br, Cl and I, (ii) R is H and C 1-4 Selected from alkyl groups (e.g., methyl), (iii) B is a protecting group as defined herein, and (iv) Q is selected from 4-(4-fluorophenyl)-4-oxobutyl and 3-(4-fluorophenoxy)propyl. Here, each of the compounds 1A, 1B, 2C, 2D, 2E, 2F, 2H, 2I, and 2JJ is independently in free base form or salt form (e.g., acid addition salt form). Compound 1B is understood to contain substantially, essential, or complete racemic cis isomers, i.e., two cis enantiomers in substantially or completely excluded amounts. Compound 2C is further understood to be substantially, essentially, or completely a single compound 2C, with the opposite cis enantiomer or any trans stereoisomer substantially or completely excluded.

[0017] In one embodiment, the present invention relates to a method for producing the compound of formula 1J in free form or salt form, as described below: 3.1 Equation 1J, where R is H. 3.2 R is C 1-4 Formula 1J is alkyl. 3.3 Formula 1J, where R is methyl. 3.4 The formula 1J or one of 3.1-3.3, where Q is 4-(4-fluorophenyl)-4-oxobutyl. 3.5 Q is 3-(4-fluorophenoxy)propyl, either formula 1J or one of 3.1-3.3. 3.6 Either formula 1J or one of 3.1-3.4, where R is methyl and Q is 4-(4-fluorophenyl)-4-oxobutyl. 3.7 The compound of formula 1J is in the form of a free base, either formula 1J or one of the compounds in 3.1-3.6. 3.8 Any of Formula 1J or 3.1 - 3.6, wherein the compound of Formula 1J is in salt form. 3.9 Any of Formula 1J or 3.1 - 3.6, wherein the compound of Formula 1J is in acid addition salt form. 3.10 Any of Formula 1J or 3.1 - 3.6, wherein the compound of Formula 1J is in tosylate or hydrochloride form, for example, in a free base to acid ratio of 1:1 to 1:3. 3.11 Any of Formula 1J or 3.1 - 3.10, wherein the compound of Formula 1J is in solid form (e.g., solid amorphous form or solid crystalline form). 3.12 Any of Formula 1J or 3.1 - 3.10, wherein the compound of Formula 1J is in solid crystalline form, for example, solid crystalline free base form or solid crystalline salt form. 3.13 Formula 3.12, wherein the compound of Formula 1J is in solid crystalline tosylate form (monotosylate, ditosylate, or tritosylate or any combination thereof) as described in any of U.S. 8,648,077, U.S. 9,199,995, and U.S. 9,586,960 (or their continuing re - publication applications, 16 / 294,607) (the contents of each of which are incorporated herein by reference in their entirety). 3.14 Any of Formula 1J or 3.1 - 3.13, wherein the compound of Formula 1J is a cis stereoisomer that is more than at least 70%, preferably at least 80%, more preferably at least 90%, most preferably more than 95% and up to 100% with respect to all other stereoisomers. 3.15 Any of Formula 1J or 3.1 - 3.14, wherein the compound of Formula 1J is in a substantially enantiomerically pure form, for example, at least 90% e.e., preferably at least 95% e.e., or at least 97% e.e., or at least 99% e.e., or at least 99.5% e.e., or at least 99.9% e.e. to 100% e.e.

[0018] In certain embodiments, the present invention relates to a method for producing the compound of Formula 2J in free form or salt form as follows. 4.1 Formula 2J, wherein R is H. 4.2 R is C 1-4 alkyl, Formula 2J. 4.3 Formula 2J, where R is methyl. 4.4 The formula 2J or one of the formulas in 4.1-4.3, where Q is 4-(4-fluorophenyl)-4-oxobutyl. 4.5 Any of formulas 2J or 4.1-4.3, where Q is 3-(4-fluorophenoxy)propyl. 4.6 Any of formulas 2J or 4.1-4.4, where R is methyl and Q is 4-(4-fluorophenyl)-4-oxobutyl. 4.7 The compound of formula 2J is in the free base form, either formula 2J or one of the compounds in 4.1-4.6. 4.8 The compound of formula 2J is in salt form, either formula 2J or one of the compounds in 4.1-4.6. 4.9 The compound of formula 2J is in the form of an acid addition salt, either formula 2J or one of 4.1-4.6. 4.10 The compound of formula 2J is, for example, in the form of a tosylate or hydrochloride salt with a free base-to-acid ratio of 1:1 to 1:3, either of formula 2J or any of 4.1 to 4.6. 4.11 The compound of formula 2J is in solid form (e.g., solid amorphous form or solid crystalline form), either formula 2J or one of 4.1-4.10. 4.12 The compound of formula 2J is in solid crystalline form, e.g., solid crystalline free base form or solid crystalline salt form, either formula 2J or any of 4.1-4.10. 4.13 The compound of formula 2J is in the form of a solid crystalline tosylate (monotosylate, ditosylate, or tritosylate or a combination thereof) as described in any of U.S. 8,648,077, U.S. 9,199,995 and U.S. 9,586,960 (or its continuing republication application, 16 / 294,607) (the contents of each of these are incorporated herein by reference as a whole), formula 4.12. 4.14 The compound of formula 2J is a cis stereoisomer of at least 70%, preferably at least 80%, more preferably at least 90%, most preferably more than 95%, and up to 100% of all other stereoisomers, such as formula 2J or any of 4.1 to 4.13. 4.15 The compound of formula 2J is in a substantially enantiomerically pure form, e.g., at least 90% ee, preferably at least 95% ee, or at least 97% ee, or at least 99% ee, or at least 99.5% or at least 99.9% ee to 100% ee, either formula 2J or any of 4.1 to 4.14.

[0019] In a first embodiment, the present invention provides a method for producing a compound of formula 1I in free form or a salt form, or any of 1.1 to 1.8, comprising the steps of: (a) reacting a compound of formula 1E in free form or a salt form with (i) a transition metal catalyst selected from the group consisting of groups 8 to 11 of the periodic table, (ii) optionally a base, (iii) optionally an alkali metal iodide (e.g., potassium iodide), and (iv) optionally a monodentate ligand or a bidentate ligand to form a free form or a salt form of an intermediate of formula 1F; (b) reducing the amide carbonyl of the compound of formula 1F to obtain a free form or a salt form of an intermediate of formula 1H; and (c) deprotecting the piperidine nitrogen of the compound of formula 1H to obtain a compound of formula 1I in free form or a salt form (or any of 1.1 to 1.8).

[0020] In another embodiment of the first aspect, the present invention provides a method for producing a compound of formula 2I in free form or a salt form, or any of 2.1 to 2.8, comprising the steps of: (a) reacting a compound of formula 2E in free form or a salt form with (i) a transition metal catalyst selected from the group consisting of groups 8 to 11 of the periodic table, (ii) optionally a base, (iii) optionally an alkali metal iodide (e.g., potassium iodide), and (iv) optionally a monodentate ligand or a bidentate ligand to form a free form or a salt form of a 2F intermediate; (b) reducing the amide carbonyl of the compound of formula 2F to obtain a free form or a salt form of a 2H intermediate; and (c) deprotecting the piperidine nitrogen of the compound of formula 2H to obtain a compound of formula 2I in free form or a salt form (or any of 2.1 to 2.8).

[0021] In a second aspect, the present invention involves (a) reacting a compound of formula 1E in free or salt form with (i) a transition metal catalyst selected from the group consisting of groups 8 to 11 of the periodic table, (ii) optionally a base, (iii) optionally an alkali metal iodide (e.g., potassium iodide), and (iv) optionally a monodentate or bidentate ligand to form an intermediate of formula 1F in free or salt form, (b) reducing the amide carbonyl of the compound of formula 1F to obtain an intermediate of formula 1H in free or salt form, and (c) deprotecting the piperidine nitrogen of the compound of formula 1H to obtain the free form The present invention provides a method for producing a compound of formula 1J in free form or salt form or any of 3.1 to 3.15, comprising the steps of (d) alkylating the piperidine nitrogen of the compound of formula 1I with a suitable alkylating agent to obtain a compound of formula 1J in free form or salt form (or any of 3.1 to 3.15), and optionally (e) converting the compound of formula 1J in free form to a salt form, for example, an acid addition salt form (for example, a tosylate form) of the compound of formula 1J (or any of 3.1 to 3.15).

[0022] In another embodiment of the second aspect of the present invention, (a) react a compound of formula 2E in free or salt form with (i) a transition metal catalyst selected from the group consisting of groups 8 to 11 of the periodic table, (ii) optionally a base, (iii) optionally an alkali metal iodide (e.g., potassium iodide), and (iv) optionally a monodentate or bidentate ligand to form an intermediate of formula 2F in free or salt form, (b) reduce the amide carbonyl of the compound of formula 2F to obtain an intermediate of formula 2H in free or salt form, and (c) deprotect the piperidine nitrogen of the compound of formula 2H The present invention provides a method for producing a compound of formula 2J in free form or a salt form or any of 4.1 to 4.15, comprising the steps of: (d) obtaining a compound of formula 2I in free form or a salt form (or any of 2.1 to 2.8); (d) alkylating the piperidine nitrogen of a compound of formula 1I with a suitable alkylating agent to obtain a compound of formula 2J in free form or a salt form (or any of 4.1 to 4.15); and optionally (e) converting the compound of formula 2J in free form to a salt form, for example, an acid addition salt form (for example, a tosylate form) of a compound of formula 2J (or any of 4.1 to 4.15).

[0023] In another embodiment, the present invention provides the use of a compound of formula 1I or any of the compounds from 1.1 onwards in a method for producing a compound of formula 1J or any of the methods from 3.1 to 3.15.

[0024] In another embodiment, the present invention provides the use of a compound of formula 2I or any of the compounds from 2.1 onwards in a method for producing a compound of formula 2J or any of the methods from 4.1 to 4.15.

[0025] In other embodiments, the present invention provides active pharmaceutical compositions comprising, in substantially pure form, a compound of formula 1J or 2J or any of 3.1-3.15 or 4.1-4.15.

[0026] Detailed description of the invention In a first embodiment, the present invention provides a method for producing a compound of formula 1I in free form or a salt form, or any of 1.1 to 1.8, comprising the steps of: (a) reacting a compound of formula 1E in free form or a salt form with (i) a transition metal catalyst selected from the group consisting of groups 8 to 11 of the periodic table, (ii) optionally a base, (iii) optionally an alkali metal iodide (e.g., potassium iodide), and (iv) optionally a monodentate ligand or a bidentate ligand to form a free form or a salt form of an intermediate of formula 1F; (b) reducing the amide carbonyl of the compound of formula 1F to obtain a free form or a salt form of an intermediate of formula 1H; and (c) deprotecting the piperidine nitrogen of the compound of formula 1H to obtain a compound of formula 1I in free form or a salt form (or any of 1.1 to 1.8).

[0027] Preferably, steps (a), (b), and (c) are carried out without isolating or purifying the intermediates of formula 1F and 1H. In one embodiment, steps (a), (b), and (c) are carried out sequentially in a single reaction vessel or in a set of connected reaction vessels.

[0028] In another embodiment of the first aspect, the present invention provides a method for producing a compound of formula 2I in free form or a salt form, or any of 2.1 to 2.8, comprising the steps of: (a) reacting a compound of formula 2E in free form or a salt form with (i) a transition metal catalyst selected from the group consisting of groups 8 to 11 of the periodic table, (ii) optionally a base, (iii) optionally an alkali metal iodide (e.g., potassium iodide), and (iv) optionally a monodentate ligand or a bidentate ligand to form a free form or a salt form of a 2F intermediate; (b) reducing the amide carbonyl of the compound of formula 2F to obtain a free form or a salt form of a 2H intermediate; and (c) deprotecting the piperidine nitrogen of the compound of formula 2H to obtain a compound of formula 2I in free form or a salt form (or any of 2.1 to 2.8).

[0029] Preferably, steps (a), (b), and (c) are carried out without isolation or purification of the intermediates of formula 2F and 2H. In one embodiment, steps (a), (b), and (c) are carried out sequentially in a single reaction vessel or in a set of connected reaction vessels.

[0030] A transition metal catalyst useful in step (a) of Method 1I or 2I may be an atom, ion, salt, or complex of a transition metal selected from groups 8-11 of the periodic table (e.g., palladium, copper, nickel, platinum, ruthenium, or rhodium). Examples of such transition metal catalysts are copper catalysts such as CuI, CuCl, CuBr, CuBr2, Cu(II) acetate, Cu2Cl2, Cu2O, Cu, CuSO4, Cu2SO4, or Pd / C, PdCl2, Pd(OAc)2, ( The catalysts include, but are not limited to, palladium or nickel catalysts such as CH3CN)2PdCl2, Pd[P(C6H5)3]4, bis(dibenzylideneacetone)palladium[Pd(dba)2], tris(dibenzylideneacetone)dipalladium[Pd2(dba)3], Ni(acetylacetonate)2, NiCl2[P(C6H5)]2, and Ni(1,5-cyclooctadiene)2. In preferred embodiments, the transition metal catalyst is a copper catalyst. In particularly preferred embodiments, the catalyst is CuI.

[0031] Bases useful in step (a) of Method 1I or 2I may be Brønsted bases or Lewis bases, including, but merely as examples, amine bases (e.g., triethylamine, trimethylamine, N,N'-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,4-diazabicyclo[2.2.2]octane (DABCO)), hydrides (e.g., sodium, lithium, or potassium hydrides), alkoxides (e.g., sodium or potassium tert-butoxide), carbonates (e.g., sodium carbonate or sodium bicarbonate, potassium carbonate, or cesium), or phosphates (e.g., potassium phosphate). In a preferred embodiment, the base is a carbonate of an alkali or alkaline earth metal (e.g., sodium, potassium, cesium, barium, etc.). In a particularly preferred embodiment, the base is potassium carbonate.

[0032] In one embodiment, the base in step (a) can be omitted by using a ligand in step (a) that is itself basic, such as an amine ligand (e.g., DBU, DBN, or 1,2-diamine), as described below. In such an embodiment, step (a) may not include the base (ii) but may include the ligand (iv).

[0033] A desired monodentate or bidentate ligand useful in step (a) of Method 1I or 2I is a ligand known to bond with a transition metal catalyst. Examples of such ligands include, but are not limited to, phenolic or amine ligands, such as optionally substituted aryl alcohols, 1,2-diamines, 1,2-amino alcohols, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), imidazolium carbenes, 4-(dimethylamino)pyridine, 2-(aminomethyl)pyridine, 4,7-diphenyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 5-chloro-1,10-phenanthroline, and 5-nitro-1,10-phenanthroline. Examples of phenol ligands or amine ligands are found in U.S. Patents 6,759,554B2; 6,395,916B1; 6,307,087B1, Klapars, A. et al., J. Am. Chem. Soc. (2002) 124, 7421-7428; Kang, S., et al., Synlett, 3, 427-430 (2002); Sugahara, M. and Ukita, T., Chem. Pharm. Bull. (1997) 45. 2-phenylphenol, 2,6-dimethylphenol, 2-isopropylphenol, 1-naphthol, 8-hydroxyquinoline, 8-aminoquinoline, DBU, DBN, DABCO, 2-(dimethylamino)ethanol, N,N-diethylsalicylamide, 2-(dimethylamino)glycine, N,N,N',N'-tetramethyl-1,2-diaminoethane, 4,7-diphenyl-1,10-phenanthroline, 4,7-dimethyl-1,10-phenanthroline, 5-methyl-1,10-phenanthroline, 5-chloro-1,10-phenanthroline, 5-nitro-1,10-phenanthroline, 4-(dimethylamino)pyridine, 2-(aminomethyl)pyridine, (methylimide)diacetic acid, cis-1,2-diaminocyclohexane, trans-1,2-diaminocyclohexane, mixtures of cis- and trans-1,2-diaminocyclohexane, cis-N,N'-dimethyl-1,2-diaminocyclohexane, trans-N,N'-dimethyl-1,2-diaminocyclohexane, mixtures of cis- and trans-N,N'-dimethyl-1,2-diaminocyclohexane, cis-N-tolyl-1,2-diaminocyclohexane, trans-N-tolyl-1,2-diaminocyclohexane, mixtures of cis- and trans-N-tolyl-1,2-diaminocyclohexane, ethanol Ligands include, but are not limited to, luamine, 1,2-diaminoethane, N,N'-dimethyl-1,2-diaminoethane, N,N-dimethyl-2-hydroxybenzamide, N,N-diethyl-2-hydroxybenzamide, fluoro-N,N-diethyl-2-hydroxybenzamide, chloro-N,N'-diethyl-2-hydroxybenzamide, (2-hydroxyphenyl)(pyrrolidin-1-yl)methanone, biphenyl-2-ol, 2-pyridylphenol, 1,2-benzenediamine, ammonia, N,N-dimethylformamide, dimethyl sulfoxide, and 1-methyl-2-pyrrolidinone. In particularly preferred embodiments, the ligand is DBU, DBN, N,N'-dimethyl-1,2-diaminoethane, trans-N,N'-dimethyl-1,2-diaminocyclohexane, or N-butylethylenediamine. Without being bound by any theory, the ligand is thought to facilitate the reaction by stabilizing and solubilizing the metal catalyst.

[0034] Other monodentate or bidentate ligands useful in step (a) of Method 1I or 2I include phosphine ligands (including phosphine oxide ligands), such as those commonly known as Buchwald ligands. Such ligands include triphenylphosphine, trimethylphosphine, triethylphosphine, tri-n-butylphosphine, tri-t-butylphosphine, tri-n-octylphosphine, tricyclohexylphosphine, tri-o-tolylphosphine, dimethylphenylphosphine, diphenylmethylphosphine, tri-2-furylphosphine, APhos(di-t-butyl-4'(N,N-dimethylphenyl)-phosphine), diphenyl-2-pyridylphosphine, tris(hydroxymethyl)phosphine, dicyclohexylphosphine, diphenylphosphine, diisopropylphosphine, dichlorophenylphosphine (PhPCl2), chlorodiphenylphosphine (Ph2PCl), chlorodiethylphosphine, di-t-butylphosphine, chlorodi-t-butylphosphine, and chlorodicyclohexylphosphine. Sphin, trimethoxyphosphine, triethoxyphosphine, triphenoxyphosphine, 2-chloro-4,4,5,5-tetramethyl-1,3,2-dioxaphosphoran, di-t-butyl-N,N-diisopropylphosphoramidite, bis(diisopropylamino)chlorophosphine, HMPT (hexamethylphosphinetriamine), tris(diethylamino)phosphine, tris(trimethylsilyl)phosphine, TriPhos, BippyPhos, QPhos, PTA, bis-(p-sulfonatophenyl)phenylphosphine dihydrate dipotassium salt, 6-DPPon, Xantphos, Xanphos, DPEPhos, BINAP (racemic, (+) or (-)), SEGPHOS (racemic, (S) or (R)), DPP-benz, DPPF, DMPE, DPPM, DPPE, DPPP, DPPB, 1,2-Bis(dichlorophosphino)ethane, DCPE, Dt-BPF, DNPF, Cyclohexyl JohnPhos, DavePhos, XPhos, SPhos, MePhos, RuPhos, BrettPhos, s-SPhos, PhDavePhos, tBuXPhos, JohnPhos, Tetramethyldi-t-Bu-XPhos, t-BuMePhos, t-BuBrettPhos, t-BuDavePhos, JackiePhos, cataCXium ligand (e.g., di-adamantine) This includes, but is not limited to, phenylalkylphosphines and their analogues, MeDalPhos, Mor-DalPhos, di(1-adamantyl)-1-piperidinyl-phenylphosphine and any of the above P-oxides, such as triphenylphosphine oxide, TOPO (tri-n-octyl-phosphine oxide), diphenylphosphine oxide, chlorodiphenylphosphine oxide, dichlorophenylphosphine oxide, and any other analogues thereof. Such ligands are known to those skilled in the art and are exemplified, for example, in the Sigma Aldrich Phosphine Ligand Application Guide (Sigma Aldrich, 2013). In certain embodiments, the ligand may be selected from the bidentate biarylphosphine ligand family, for example, XantPhos, Xanphos, BINAP, SEGPHOS, cyclohexyl JohnPhos, DavePhos, XPhos, SPhos, MePhos, RuPhos, BrettPhos, s-SPhos, PhDavePhos, tBuXPhos, JohnPhos, tetramethyldi-t-Bu-XPhos, t-BuMePhos, t-BuBrettPhos, t-BuDavePhos, JackiePhos, for example, XantPhos, XanPhos, BINAP, XPhos, SPhos, RuPhos, or BrettPhos.

[0035] Step (a) of Method 1I or 2I may be carried out with some suitable organic solvent, such as dioxane, dimethoxyethane, toluene, xylene, chlorobenzene, etc.

[0036] The reduction in step (b) of Method 1I or 2I may be carried out by the use of any suitable reducing agent, for example, a reducing agent selected from metal hydrides (e.g., diisobutylaluminum hydride (DIBAL), sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), or sodium cyanobolohydride), boranes (e.g., borane-THF, borane-dimethyl sulfide, diborane, borane-ammonia), or organoboranes (e.g., bis(benzyloxy)borane, BBN, trialkylboranes). Alternatively, such transformations can be achieved through the use of a reducing agent selected from among those used in catalytic hydrogenation with hydrogen in the presence of a noble transition metal catalyst such as nickel, platinum, palladium, rhodium, or ruthenium catalysts (e.g., palladium / carbon, platinum oxide, Raney nickel, etc.), Wolf-Kishner reduction by heating of ketones and hydrazine hydrate in the presence of a base such as sodium hydroxide or potassium hydroxide (see Todd, Org. React. 4, 378-422 (1948)), or Clemsen reduction by heating of ketones with zinc amalgam and an aqueous mineral acid such as hydrochloric acid (see Vedejs, Org. React. 22, 401-422 (1975)). Other reactants that can also achieve such reductions include triisopropyl phosphate, copper in the presence of sulfuric acid, and tin in the presence of hydrochloric acid.

[0037] In a preferred embodiment, the reduction is carried out using boranes or organoborane reducing agents such as borane-THF complexes, borane-dimethyl sulfide complexes, diborane, borane-ammonia complexes, trialkylboranes (e.g., trimethylborane, triethylborane, or tri-isopropylborane), bis(benzyloxy)borane, or 9-borabicyclo[3.3.1]nonane (9-BBN). Suitable solvents include etheric solvents such as tetrahydrofuran (THF), 1,4-dioxane, diethyl ether, diisopropyl ether, and tert-butylmethyl ether.

[0038] The conditions for the deprotection step (c) of Method 1I or 2I will inevitably vary depending on the selection of protecting group B, and may include, for example, acid or base catalysis or catalytic hydrogenation. Therefore, if the protecting agent is an acyl or alloyl group such as an alkanoyl group or an alkoxycarbonyl group (e.g., ethoxycarbonyl), deprotection can be achieved by hydrolysis with a base such as an alkali metal hydroxide such as lithium hydroxide, potassium hydroxide, or sodium hydroxide. Alternatively, acyl protecting agents such as t-butoxycarbonyl groups can be removed by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, or with trifluoroacetic acid. Arylmethoxycarbonyl protecting agents such as benzyloxycarbonyl groups can be achieved by hydrogenation on a catalyst such as platinum or palladium / carbon, or by treatment with a Lewis acid such as boron tris(trifluoroacetate). For further examples of reactants useful in this deprotection process, see “Protective Groups in Organic Synthesis” by Theodora Green (Publisher: John Wiley & Sons).

[0039] In a preferred embodiment, protecting group B is a carbamate protecting group, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, or t-butoxycarbonyl. In this embodiment, step (c) of method 1I or 2I may be carried out using an acidic aqueous solution, preferably such as an aqueous hydrochloric acid solution, or a non-aqueous acidic medium, such as hydrogen chloride in an organic solvent (e.g., methanol, THF, dioxane, diethyl ether, or a mixture thereof), or a strong organic acid (e.g., solvent-free trifluoroacetic acid (TFA) or a suitable organic solvent, such as TFA in dioxane).

[0040] In another embodiment, the carbamate protecting group (e.g., ethoxycarbonyl) can be removed under basic conditions, for example, step (c) of Method 1I or 2I may be carried out using an alkali metal hydroxide (e.g., sodium hydroxide or potassium hydroxide) in an alcoholic solvent (e.g., methanol, ethanol, isopropanol, n-butanol, t-butanol, or a mixture thereof, optionally further containing water).

[0041] In another preferred embodiment, protecting group B is a benzyloxycarbonyl protecting group, and step (c) of method 1I or 2I is carried out, for example, using hydrogen (e.g., Pd / C or platinum oxide) on a palladium or platinum catalyst in an alcoholic solvent (e.g., methanol, ethanol, propanol, butanol, etc.).

[0042] In one embodiment, step (c) of Method 1I or 2I is carried out under acidic conditions to obtain the compound of formula 1I or 2I in the form of an acid addition salt. For example, the reaction can be carried out using hydrochloric acid to obtain the compound of formula 1I or 2I as a hydrochloride salt. In another embodiment, step (c) of Method 1I or 2I is carried out under acidic conditions, and the reaction mixture is subjected to neutralization or basicization with a suitable base to obtain the compound of formula 1I or 2I in the form of a free base. Suitable bases for carrying out this neutralization or basicization include inorganic bases, such as hydroxides, oxides, carbonates and bicarbonates (e.g., alkali metal or alkaline earth metal bases, including NaOH, KOH, LiOH, Ca(OH)2, CaO, MgO, Na2CO3, K2CO3, Li2CO3, NaHCO3, KHCO3, LiHCO3, CaCO3, MgCO3, etc.).

[0043] In one embodiment, Method 1I or 2I provides the compound of Formula 1I or 2I, respectively, as a crystalline free base or a crystalline acid addition salt, e.g., a hydrochloride salt. The inventors have unexpectedly discovered that the use of Method 1I or 2I or one or more of Methods 5.1 to 5.52 results in the production of the compound of Formula 1I or 2I with far lower levels of contamination by transition metal impurities (e.g., copper) compared to prior art methods for the production of these compounds. For example, the use of the present invention may result in the production of the compound of Formula 1I or 2I containing less than about 50 ppm of copper, less than about 10 ppm of copper, or less than about 5 ppm of copper.

[0044] In a particular embodiment of the first aspect, the present invention provides the following: 5.1 Method 1I or 2I, wherein the compound of formula 1I or 2I is one of the compounds of formulas 1.1-1.8 or 2.1-2.8, respectively. 5.2 Method 1I or 2I, wherein substituent A of the compound of formula 1E or 2E is selected from Br, Cl, and I. 5.3 A is Br, method 5.2. 5.4 Compounds of formula 1E, 1F, 1H and 1I or 2E, 2F, 2H and 2I with substituent R is C 1-4 Alkyl (e.g., methyl), according to any of Method 1I, 2I, or 5.1 onwards. 5.5 Method 1I or 2I or any of 5.1 onwards, wherein the substituent R of the compound of formula 1E and 1F or 2E and 2F is H. 5.6 Method 1I or 2I or any of 5.1 onwards, wherein the protecting group B of a compound of formula 1E, 1F and 1H or 2E, 2F and 2H is of formula PZ, where P is selected from CH2, C(O), C(O)O and S(O)2, Z is optionally substituted alkyl, aryl, alkylaryl or -OR', and R' is alkyl, aryl, arylalkyl or heteroarylalkyl. 5.7 Method 5.6, wherein protecting group B is an acyl group (e.g., an alkanoyl or alkoxycarbonyl group), e.g., t-butoxycarbonyl, phenoxycarbonyl, ethoxycarbonyl or methoxycarbonyl or optionally substituted benzyloxycarbonyl (e.g., benzyloxycarbonyl). 5.8 Method 5.7, wherein protecting group B is an ethoxycarbonyl. 5.9 Method 5.6, wherein the protecting group is optionally substituted benzyl group, e.g., benzyl, 4-methoxybenzyl, or 2,4-dimethoxybenzyl. 5.10 Method 1I, 2I, or any of the methods described in 5.1 or later, wherein the transition metal catalyst in step (a) is a copper catalyst. Method 5.10, in which the transition metal catalyst for step (a) is selected from CuI, CuBr, CuCl, Cu(OAc)2, Cu2Cl2, CuBr2, CuSO4, Cu2SO4 and Cu2O. 5.12 The transition metal catalyst for step (a) is selected from CuI, CuBr, and CuCl, method 5.11. 5.13 The transition metal catalyst is CuI, method 5.12. 5.14 Method 1I, 2I, or any of 5.1 onward, wherein the transition metal catalyst in step (a) is present in an amount of 0.01 to 0.50 equivalents, for example, 0.05 to 0.40 equivalents, 0.10 to 0.30 equivalents, 0.15 to 0.25 equivalents, or approximately 0.20 equivalents. Method 1I or 2I or any of 5.1 onward, wherein the base in step (a) is a Brønsted base selected from, for example, amines, alkoxide bases, carbonate bases and phosphate bases and mixtures thereof. Method 5.15, where the base in step (a) is a carbonate base, for example, an alkali or alkaline earth metal carbonate or bicarbonate or a mixture thereof. Method 5.16, in which the base of step (a) is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate or a mixture thereof. Method 5.17, wherein the base of step (a) optionally contains potassium carbonate in an amount of 1.5 to 3 equivalents, for example, 2 to 2.5 equivalents or about 2.2 equivalents. 5.19 Method 1I or 2I or any of 5.1 onward, wherein step (a) does not contain a base (ii), for example, an alkoxide, carbonate, phosphate or other inorganic base. 5.20 Method 1I or 2I or any of 5.1 onward, wherein step (a) comprises an alkali metal iodide selected from, for example, sodium iodide, potassium iodide, and lithium iodide. 5.21 Method 5.20, wherein step (a) includes potassium iodide. 5.22 Method 1I, 2I, or any of 5.1 onward, wherein step (a) includes a monodentate ligand or a bidentate ligand, for example, a ligand selected from a phenol ligand, an amine ligand, or a phosphine ligand. 5.23 Method 5.22, in which the ligand is optionally substituted, selected from 1,2-diamine, optionally substituted, 1,2-amino alcohol, DBU, DBN, or DABCO. 5.24 Method 5.23, where the ligand is DBU. 5.25 Method 1I, 2I, or any of 5.1 onward, wherein the ligand in step (a) is present in an amount of 0.01 to 0.50 equivalents, for example, 0.05 to 0.45 equivalents, 0.10 to 0.40 equivalents, 0.20 to 0.30 equivalents, or approximately 0.25 equivalents. 5.26 Method 1I, 2I, or any of 5.1 onward, wherein the solvent in step (a) is toluene or dioxane. 5.27 Method 1I, 2I, or any of 5.1 onward, wherein the reduction in step (b) is achieved using a reducing agent selected from metal hydrides, boranes, and organoboranes. 5.28 Method 5.27 in which the reducing agent is selected from boranes, e.g., borane (BH3) and borane complexes (e.g., BH3-THF, BH3-Me2S and BH3-NH3). 5.29 Method 5.28, where the reducing agent is a borane-THF complex. 5.30 Method 1I or 2I or any of 5.1 onward, wherein the solvent in step (b) is a mixture of toluene and THF. 5.31 Method 1I, 2I, or any of 5.1 onwards, wherein the reducing agent in step (b) is present in an amount of 1.5 to 5 equivalents, for example, 2 to 4 equivalents, 2.5 to 3.5 equivalents, or about 3 equivalents. 5.32 Method 1I or 2I or any of 5.1 onward, wherein the deprotection step (c) is an acid or base-mediated cleavage reaction, a hydrolysis reaction (e.g., acid or base-catalyzed) or a hydrogenation reaction. 5.33 Method 5.32, where the deprotection step (c) is aqueous hydrolysis, e.g., acidic or basic hydrolysis. 5.34 Method 5.33 in which aqueous hydrolysis comprises an acidic catalyst selected from, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. 5.35 Method 5.33, in which aqueous hydrolysis is performed, including aqueous hydrochloric acid solution. 5.36 Method 5.33 wherein the aqueous hydrolysis comprises a basic catalyst selected from alkali metal or alkaline earth metal hydroxides, such as sodium hydroxide or potassium hydroxide. 5.37 Method 5.32, wherein the deprotection step (c) is acid-mediated cleavage, for example, comprising a strong acid (e.g., hydrochloric acid, trifluoroacetic acid, or methanesulfonic acid) either without a solvent or together with an organic solvent, if desired. 5.38 Method 5.32, wherein the deprotection step (c) is, for example, base-mediated cleavage involving an organic base (e.g., piperidine) in an organic solvent. 5.39 Method 5.32, where the deprotection step (c) is a hydrogenation reaction, for example, catalytic hydrogenation involving a transition metal catalyst (e.g., platinum or palladium) and hydrogen. 5.40 A compound of formula 1I or 2I (e.g., any compound from 1.1-1.8 or 2.1-2.8) is obtained as a solid, e.g., amorphous or crystalline solid, by method 1I or 2I or any of the methods described in 5.1 or later. 5.41 Method 1I or 2I or any of 5.1 onwards, wherein a compound of formula 1I or 2I (e.g., any compound from 1.1 to 1.8 or 2.1 to 2.8) is obtained in a substantially pure form, e.g., with a purity greater than 90 wt%, or e.g., with a purity of 95 wt% to 100 wt%. 5.42 A compound of formula 1I or 2I (for example, any compound from 1.1 to 1.8 or 2.1 to 2.8) is preferably obtained as a crystalline solid in free form (i.e., free base form) by method 1I, 2I, or any of the methods described in 5.1 or later. 5.43 A compound of formula 1I or 2I (e.g., any compound from 1.1-1.8 or 2.1-2.8) is obtained in salt form, e.g., in acid addition salt form, by method 1I or 2I or any of the methods described in 5.1 or later. Method 5.43, wherein a compound of formula 1I or 2I (e.g., any compound of 1.1-1.8 or 2.1-2.8) is obtained as an addition salt selected from, for example, hydrochloride, hydrobromide, hydroiodide, formate, acetate, trifluoroacetate, or methanesulfonate with a base-to-acid molar ratio of 1:1-3:1. Method 5.44, in which a compound of formula 1I or 2I (e.g., any compound of 1.1-1.8 or 2.1-2.8) is obtained as a hydrochloride, e.g., a solid hydrochloride or a crystalline solid hydrochloride (e.g., monohydrochloride, dihydrochloride and / or trihydrochloride). 5.46 Method 1I or 2I or any of 5.1 onwards, wherein the method is carried out without isolation or purification of the intermediate of formula 1F and 1H or 2F and 2H. 5.47 Method 1I, 2I, or any of 5.1 onward, wherein steps (a), (b), and (c) are carried out sequentially in a single reaction vessel or a set of connected reaction vessels. 5.48 Method 1I or 2I or any of 5.1 onwards, wherein a compound of formula 1I or 2I (e.g., any compound of 1.1-1.8 or 2.1-2.8) is obtained in a form having less than 50 ppm of copper, less than 10 ppm of copper, or less than 5 ppm of copper. 5.49 Method 1I or 2I or any of 5.1 onwards, further comprising step (d) of alkylating the piperidine nitrogen of a compound of formula 1I or 2I with a suitable alkylating agent to obtain a compound of formula 1J or 2J in free form or salt form. 5.50 Method 5.49 wherein a compound of formula 1J or 2J is obtained in free base form from step (d), and the method further comprises step (e) converting the compound of formula 1J or 2J in free base form to a salt form, for example, an acid addition salt form (e.g., a tosylate form). 5.51 Method 5.49 or 5.50, wherein the method provides a compound of formula 1J or 2J as described by formulas 3.1-3.15 or 4.1-4.15, respectively. 5.52 Method 1I or 2I or any of 5.1 to 5.51, further comprising any or all of the following steps described in any of the embodiments herein: a. Preparation of the compound of formula 1A by reacting 2-bromophenylhydrazine in free or salt form with 4-piperidinone in hydrate form, free or salt form, optionally in acetic acid solvent. b. (a) Reduction of the compound of formula 1A to the compound of formula 1B, wherein the reduction optionally involves the reaction of the compound of formula 1A with triethylsilane and methanesulfonic acid, and (b) Separation of the stereoisomer of formula 1B by chiral salt splitting or chiral chromatography to obtain the compound of formula 1C or 2C, wherein the chiral salt splitting optionally is carried out in a single splitting step using S-mandelic acid, thereby producing the compound of formula 1C or 2C in free or salt form. c. Preparation of compounds of formula 1D or 2D in free or salt form by protection of the compound of formula 1C or 2C with a protective agent in the presence of a base, d. Preparation of compounds of formula 1E or 2E in free or salt form by N-alkylating a compound of formula 1D or 2D with (a) a nucleophilic alkyl halide and (b) a base.

[0045] In a second aspect, the present invention relates to (a) reacting a compound of formula 1E in free or salt form with (i) a transition metal catalyst selected from the group consisting of groups 8 to 11 of the periodic table, (ii) optionally a base, (iii) optionally an alkali metal iodide (e.g., potassium iodide), and (iv) optionally a monodentate or bidentate ligand to form an intermediate of formula 1F in free or salt form, (b) reducing the amide carbonyl of the compound of formula 1F to obtain an intermediate of formula 1H in free or salt form, and (c) deprotecting the piperidine nitrogen of the compound of formula 1H to obtain a compound of formula 1H in free or salt form. The present invention provides a method for producing a compound of formula 1J in free form or a salt form or any of 3.1 to 3.15, comprising the steps of (d) alkylating the piperidine nitrogen of the compound of formula 1I with a suitable alkylating agent to obtain a compound of formula 1J in free form or a salt form (or any of 3.1 to 3.15), and optionally (e) converting the free form of the compound of formula 1J to a pharmaceutically acceptable salt form of the compound of formula 1J (or any of 3.1 to 3.15), such as an acid addition salt form (e.g., a tosylate form).

[0046] In another embodiment of the second aspect of the present invention, (a) react a compound of formula 2E in free or salt form with (i) a transition metal catalyst selected from the group consisting of groups 8 to 11 of the periodic table, (ii) a base optionally, (iii) an alkali metal iodide optionally (e.g., potassium iodide), and (iv) an optional monodentate or bidentate ligand to form an intermediate of formula 2F in free or salt form, (b) reduce the amide carbonyl of the compound of formula 2F to obtain an intermediate of formula 2H in free or salt form, and (c) deprotect the piperidine nitrogen of the compound of formula 2H to obtain a free or salt form. The present invention provides a method for producing a compound of formula 2J in free form or a salt form or any of 4.1 to 4.15, comprising the steps of (d) alkylating the piperidine nitrogen of the compound of formula 1I with a suitable alkylating agent to obtain a compound of formula 2J in free form or a salt form (or any of 4.1 to 4.15), and optionally converting the compound of formula 2J in free form to a pharmaceutically acceptable salt form of the compound of formula 2J (or any of 4.1 to 4.15), such as an acid addition salt form (e.g., a tosylate form).

[0047] In all respects, steps (a), (b), and (c) of Methods 1J and 2J may be carried out by Methods 1I and 2I, respectively, which include any of Methods 5.1 to 5.52.

[0048] Alkylating agents suitable for step (d) of Method 1J or 2J (or Method 1I or 2I further comprising step (d)) include compounds of general formula QX (wherein Q is selected from 4-(4-fluorophenyl)-4-oxobutyl and 3-(4-fluorophenoxy)propyl, and X is some suitable leaving group). The leaving group is a reactive group known in the art to be readily subjected to nucleophilic substitution reactions. In one embodiment, X is chloro, bromo, iodine, C 1-4 The selection is made from alkylsulfonyloxy (e.g., methanesulfonyloxy) and optionally substituted arylsulfonyloxy (e.g., benzenesulfonyloxy, 4-nitrobenzenesulfonyloxy, 4-halosulfonyloxy, etc.).

[0049] In one embodiment, step (d) of Method 1J or 2J may further include a suitable base. Suitable bases include, but are not limited to, organic bases, such as amine bases (e.g., ammonia, triethylamine, N,N'-diisopropylethylamine or 4-(dimethylamino)pyridine (DMAP), 1,5-diazabicyclo[4.3.0]-non-5-ene (DBN), 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU)), or inorganic bases, such as hydrides (e.g., sodium, lithium, or potassium hydrides), alkoxides (e.g., sodium, potassium, or lithium t-butoxide), aryl oxides (e.g., lithium, sodium, or potassium phenoxide), or carbonates, bicarbonates, phosphates, or hydroxides of alkalis or alkaline earth metals (e.g., carbonates, bicarbonates, hydroxides, or phosphates of sodium, magnesium, calcium, potassium, cesium, or barium). Optionally, step (d) may further comprise an inorganic iodide salt, such as potassium iodide or sodium iodide, preferably potassium iodide. Suitable solvents include polar protic and / or polar aprotic solvents, such as acetonitrile, dioxane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, methanol, ethanol, isopropanol, and mixtures thereof. In a preferred embodiment, step (d) comprises the reaction of a compound of formula 1I or 2I with an alkylating agent 4-chloro-4'-fluoro-butyrophenone and a base selected from triethylamine, diisopropylethylamine, potassium carbonate, and sodium carbonate. When a base is used, the amount of base can be any amount from a catalytic amount (e.g., 0.01 equivalents) to an excess amount (e.g., 10 equivalents or more). In one embodiment, the reaction is carried out with 1.0 to 5.0 equivalents of base, for example, 1.0 to 3.0 or 1.0 to 2.0 equivalents of base.

[0050] The compound of formula 1J or 2J derived from step (d) of Method 1J or 2J may be obtained as a free base or a salt. Suitable salt forms include acid addition salts, e.g., phosphates, sulfates, hydrohalides (e.g., hydrochlorides), and carbonates (e.g., acetates or formates). Either the free base form or the salt form of the compound of formula 1J or 2J may be obtained by isolation or purification by some suitable method, such as crystallization. In one embodiment, the reaction of step (d) is carried out in the presence of an excess of base, which may allow for the isolation of the free base of the compound of formula 1J or 2J from the reaction mixture (e.g., by water / organic solvent extraction and / or chromatography and / or crystallization from a suitable solvent and / or evaporation of the reaction solvent). In one embodiment, the reaction of step (d) is carried out in the absence of base or in the presence of less than 1 equivalent of base (e.g., 0.5 equivalents or less or a catalytic amount). In particular, when carried out in the absence of a base, step (d) may yield an acid addition salt of the compound of formula 1J or 2J, where the acid component of the salt is derived from the alkylating agent. For example, when the compound of formula 1I or 2I is treated with the alkylating agent QX as described above and without the addition of a base, the resulting compound of formula 1J or 2J may be obtained as an acid addition salt corresponding to group X (for example, if X is chloro, the compound of formula 1J or 2J may be obtained in the form of a hydrochloric acid addition salt). In one embodiment, equimolar amounts or only a small excess of base are used in the reaction of step (d), but an excess acid (e.g., hydrochloric acid) is added before or during purification, resulting in the acquisition of an acid addition salt (e.g., hydrochloride) of the compound of formula 1J or 2J.

[0051] In one embodiment, step (d) of Method 1J or 2J yields the compound of formula 1J or 2J in its free form (i.e., free base form), which is isolated and / or purified, and then, optionally, step (e) is carried out to convert the compound of formula 1J or 2J in its free base form to the salt form of the compound of formula 1J or 2J, e.g., a pharmaceutically acceptable salt form (e.g., an acid-added salt). In one embodiment, the compound of formula 1J or 2J in this acid-added salt form is isolated and / or purified. While not bound by theory, it is believed that the initial isolation of the compound of formula 1J or 2J in its free form, followed by the subsequent conversion of this compound to its salt form (e.g., an acid-added salt form), yields a high-purity and / or processable final product (the compound of formula 1J or 2J).

[0052] Step (e) of Method 1J or 2J may involve reacting a compound of formula 1J or 2J in its free base form with a suitable acid in water, an organic solvent, or a mixture thereof to yield, for example, a pharmaceutically acceptable acid addition salt of formula 1J or 2J of the present invention. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, isopropyl acetate, or acetonitrile are preferred. Suitable acids may include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfone, oxalic acid, isethionic acid, etc. When using a monovalent acid (e.g., hydrochloric acid or toluenesulfonic acid), step (e) may yield a monoaddition salt, diaddition salt, or tripaddition salt, or a mixture thereof, depending on the molar equivalents of acid to free base used (e.g., 1:1 free base to acid to 1:3 free base to acid). Therefore, the salt of formula 1J or 2J may be a monotosylate, ditosylate, tripotosylate, or some combination thereof.

[0053] In a further embodiment of the second aspect, step (e) may yield a specific salt, which is isolated and purified, and in a further step (f), it is converted into a different salt. For example, in one embodiment, step (e) may yield a monotosylate of the compound of formula 1J or 2J, which is isolated and / or purified, and optionally characterized by mass spectrometry, nuclear magnetic resonance spectroscopy, infrared spectroscopy and / or X-ray powder diffraction. The monotosylate may then be combined, for example, with a further amount (e.g., 1 equivalent or slightly more than 1 equivalent) of further toluenesulfonic acid to obtain a ditosylate. Such further acid can be added to a pharmaceutical composition of the compound of formula 1J or 2J as part of a formulation, and therefore such step (f) may be carried out in the absence of a solvent (e.g., dry mixing) or in the presence of a solvent (e.g., wet mixing).

[0054] In a specific embodiment of the second aspect, the present invention provides the following: 6.1 Method 1J or 2J, wherein the compound of formula 1I or 2I is one of the compounds of formulas 1.1-1.8 or 2.1-2.8, respectively. 6.2 Method 1J or 2J, wherein substituent A of the compound of formula 1E or 2E is selected from Br, Cl, and I. 6.3 A is Br, method 6.2. 6.4 Compounds of formula 1E, 1F, 1H and 1I or 2E, 2F, 2H and 2I with substituent R is C 1-4 Alkyl (e.g., methyl), according to method 1J, 2J, or any of 6.1 onwards. 6.5 Method 1J or 2J or any of 6.1 onwards, wherein the substituent R of the compound of formula 1E and 1F or 2E and 2F is H. 6.6 Method 1J or 2J or any of 6.1 onwards, wherein the protecting group B of a compound of formula 1E, 1F and 1H or 2E, 2F and 2H is of formula PZ, where P is selected from CH2, C(O), C(O)O and S(O)2, Z is optionally substituted alkyl, aryl, alkylaryl or -OR', and R' is alkyl, aryl, arylalkyl or heteroarylalkyl. 6.7 Method 6.6, wherein protecting group B is an acyl group (e.g., an alkanoyl or alkoxycarbonyl group), e.g., t-butoxycarbonyl, phenoxycarbonyl, ethoxycarbonyl, or methoxycarbonyl, or optionally substituted benzyloxycarbonyl. 6.8 Method 6.7, wherein protecting group B is an ethoxycarbonyl. 6.9 Method 6.6, wherein the protecting group is optionally substituted benzyl group, e.g., benzyl, 4-methoxybenzyl, or 2,4-dimethoxybenzyl. 6.10 Method 1J or 2J or any of 6.1 onwards, wherein the transition metal catalyst in step (a) is a copper catalyst. Method 6.10, wherein the transition metal catalyst for step (a) is selected from CuI, CuBr, CuCl, Cu(OAc)2, Cu2Cl2, CuBr2, CuSO4, Cu2SO4, and Cu2O. Method 6.11, in which the transition metal catalyst of step (a) is selected from CuI, CuBr, and CuCl, and optionally the catalyst is CuI. 6.13 Method 6.12, where the transition metal catalyst is CuI. 6.14 Method 1J, 2J, or any of 6.1 onwards, wherein the transition metal catalyst in step (a) is present in an amount of 0.01 to 0.50 equivalents, for example, 0.05 to 0.40 equivalents, 0.10 to 0.30 equivalents, 0.15 to 0.25 equivalents, or approximately 0.20 equivalents. Method 1J or 2J or any of 6.1 onward, wherein the base in step (a) is a Brønsted base selected from, for example, amine bases, alkoxides, carbonates and phosphates and mixtures thereof. Method 6.15, where the base in step (a) is a carbonate base, for example, an alkali or alkaline earth metal carbonate or bicarbonate or a mixture thereof. Method 6.16, wherein the base of step (a) is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or a mixture thereof. Method 6.17, wherein the base of step (a) optionally contains potassium carbonate in an amount of 1.5 to 3 equivalents, for example, 2 to 2.5 equivalents or about 2.2 equivalents. 6.19 Method 1J or 2J or any of 6.1 onward, wherein step (a) does not contain a base (ii), for example, an alkoxide, carbonate, phosphate or other inorganic base. 6.20 Method 1J or 2J or any of 6.1 onward, wherein step (a) comprises an alkali metal iodide selected from, for example, sodium iodide, potassium iodide, and lithium iodide. Method 6.20, wherein step (a) includes potassium iodide. 6.22 Method 1J or 2J or any of 6.1 onward, wherein step (a) includes a monodentate ligand or a bidentate ligand, selected from, for example, a phenol ligand or an amine ligand. 6.23 Method 6.22, wherein the ligand is optionally substituted, selected from 1,2-diamine, optionally substituted, 1,2-amino alcohol, DBU, DBN, or DABCO. 6.24 Method 6.23, where the ligand is DBU. 6.25 Method 1J or 2J or any of 6.1 onwards, wherein the ligand in step (a) is present in an amount of 0.01 to 0.50 equivalents, for example, 0.05 to 0.45 equivalents, 0.10 to 0.40 equivalents, 0.20 to 0.30 equivalents, or approximately 0.25 equivalents. 6.26 Method 1J, 2J, or any of the following, wherein the solvent in step (a) is toluene or dioxane. 6.27 Method 1J or 2J or any of 6.1 onward, wherein the reduction in step (b) is achieved using a reducing agent selected from metal hydrides, boranes, and organoboranes. 6.28 Method 6.27 in which the reducing agent is selected from boranes, e.g., borane (BH3) and borane complexes (e.g., BH3-THF, BH3-Me2S and BH3-NH3). 6.29 Method 6.28, where the reducing agent is a borane-THF complex. Method 1J or 2J or any of the following, wherein the solvent in step (b) is a mixture of toluene and THF. 6.31 Method 1J, 2J, or any of 6.1 onwards, wherein the reducing agent in step (b) is present in an amount of 1.5 to 5 equivalents, for example, 2 to 4 equivalents, 2.5 to 3.5 equivalents, or approximately 3 equivalents. 6.32 Method 1J or 2J or any of 6.1 onward, wherein the deprotection step (c) is an acid or base-mediated cleavage reaction, a hydrolysis reaction (e.g., acid or base-catalyzed) or a hydrogenation reaction. 6.33 Method 6.32, where the deprotection step (c) is aqueous hydrolysis, e.g., acidic or basic hydrolysis. 6.34 Method 6.33 in which aqueous hydrolysis comprises an acidic catalyst selected from, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. 6.35 Method 6.33, in which aqueous hydrolysis is performed, including aqueous hydrochloric acid solution. 6.36 Method 6.33 wherein the aqueous hydrolysis comprises a basic catalyst selected from alkali metal or alkaline earth metal hydroxides, such as sodium hydroxide or potassium hydroxide. 6.37 Method 6.32, wherein the deprotection step (c) is acid-mediated cleavage, for example, containing a strong acid (e.g., hydrochloric acid, trifluoroacetic acid, or methanesulfonic acid) either without a solvent or together with an organic solvent, if desired. 6.38 Method 6.32, wherein the deprotection step (c) is a base-mediated cleavage, for example, involving an organic base (e.g., piperidine) in an organic solvent. 6.39 Method 6.32, in which the deprotection step (c) is a hydrogenation reaction, for example, catalytic hydrogenation involving a transition metal catalyst (e.g., platinum or palladium) and hydrogen. 6.40 A compound of formula 1I or 2I (e.g., any compound from 1.1-1.8 or 2.1-2.8) is obtained as a solid, e.g., amorphous or crystalline solid, by method 1J or 2J or any of the methods described in 6.1 onwards. 6.41 Method 1J or 2J or any of 6.1 onwards, wherein a compound of formula 1I or 2I (e.g., any compound of 1.1-1.8 or 2.1-2.8) is obtained in a substantially pure form, e.g., with a purity greater than 90 wt%, or e.g., with a purity greater than 95 wt%, or with a purity of 98.5% to 100 wt%. Method 1J, 2J, or any of 6.1 onwards, wherein a compound of formula 1I or 2I (for example, any compound from 1.1 to 1.8 or 2.1 to 2.8) is preferably obtained as a crystalline solid in a free form (i.e., in a free base form). 6.43 A compound of formula 1I or 2I (e.g., any compound from 1.1-1.8 or 2.1-2.8) is obtained in salt form, e.g., in acid addition salt form, by method 1J or 2J or any of the methods described in 6.1 onwards. Method 6.43, wherein a compound of formula 1I or 2I (e.g., any compound of 1.1-1.8 or 2.1-2.8) is obtained as an addition salt selected from, for example, hydrochloride, hydrobromide, hydroiodide, formate, acetate, trifluoroacetate, or methanesulfonate with a base-to-acid molar ratio of 1:1-3:1. Method 6.44, wherein a compound of formula 1I or 2I (e.g., any compound of 1.1-1.8 or 2.1-2.8) is obtained as a hydrochloride, e.g., a solid hydrochloride or a crystalline solid hydrochloride (e.g., monohydrochloride, dihydrochloride and / or trihydrochloride). 6.46 Method 1J or 2J or any of 6.1 onwards, wherein the method is carried out without isolation or purification of the intermediates of formula 1F and 1H or 2F and 2H. 6.47 Method 1J, 2J, or any of 6.1 onward, wherein steps (a), (b), and (c) are carried out sequentially in a single reaction vessel or a set of connected reaction vessels. Method 1J or 2J or any of 6.1 onwards, wherein a compound of formula 1I or 2I (e.g., any compound of 1.1-1.8 or 2.1-2.8) is obtained in a form having less than 50 ppm of copper, less than 10 ppm of copper, or less than 5 ppm of copper. 6.49 Method 1J, 2J, or any of 6.1 onwards, wherein the compound of formula 1J or 2J is a compound of formula 3.1-3.15 or 4.1-4.15, respectively. Method 1J, 2J, or any of 6.1 onward, wherein the appropriate alkylating agent in step (d) is a compound of general formula QX (wherein Q is selected from 4-(4-fluorophenyl)-4-oxobutyl and 3-(4-fluorophenoxy)propyl, and X is some appropriate leaving group (e.g., a functional group known in the art to be readily subjected to nucleophilic substitution reactions)). 6.51 Group X is chloro, bromo, iodine, C 1-4 Method 6.50, selected from alkylsulfonyloxy (e.g., methanesulfonyloxy) and optionally substituted arylsulfonyloxy (e.g., benzenesulfonyloxy, 4-nitrobenzenesulfonyloxy, 4-halosulfonyloxy, etc.). 6.52 The compound of formula 1J or 2J in which group Q is 4-(4-fluorophenyl)-4-oxobutyl, according to method 1J or 2J or any of 6.1 onwards. 6.53 Method 1J or 2J or any of 6.1 onwards, wherein the group Q of the compound of formula 1J or 2J is 3-(4-fluorophenoxy)propyl. 6.54 Method 1J, 2J, or any of the methods described in 6.1 onwards, wherein the alkylating agent is 4-chloro-4'-fluorobutyrophenone or 1-chloro-3-(4-fluorophenoxy)propane. 6.55 Step (d) contains 1 to 3 equivalents of an alkylating agent (e.g., 4-chloro-4'-fluorobutyrophenone), for example, 1 to 2 equivalents or 1.25 to 1.75 equivalents or about 1.5 equivalents, for example, 1.35 to 1.65 equivalents, by method 1J or 2J or any of 6.1 onwards. 6.56 Method 1J or 2J or any of 6.1 onward, wherein step (d) further comprises a suitable base, for example, an organic base (e.g., an amine base) or an inorganic base (e.g., a hydride, alkoxide, aryl oxide, carbonic acid, bicarbonate, phosphoric acid, or hydroxide base). Method 6.56, in which the base of step (d) is selected from triethylamine, diisopropylethylamine, sodium carbonate, and potassium carbonate. Method 6.57, where the base in step (d) is sodium carbonate or potassium carbonate. 6.59 Method 6.58, in which sodium carbonate or potassium carbonate is present in an amount of 1 to 5 equivalents, for example, 2 to 4 equivalents or 2.5 to 3.5 equivalents or about 3 equivalents, for example, 2.7 to 3.3 equivalents. Method 1J, 2J, or any of 6.1 onward, wherein step (d) optionally further comprises 0.75 to 1.5 equivalents, 1 to 1.25 equivalents, or about 1 equivalent, for example, 0.9 to 1.1 equivalents, of an inorganic iodide salt (e.g., potassium iodide or sodium iodide). 6.61 Method 1J or 2J or any of the methods from 6.1 onward, wherein the solvent in step (d) is 3-pentanone. 6.62 Method 1J or 2J or any of 6.1 onwards, wherein the compound of formula 1J or 2J is obtained in free base form from step (d). 6.63 Method 1J or 2J or any of 6.1 onwards, wherein the compound of formula 1J or 2J is obtained from step (d) in salt form, e.g., an acid addition salt (e.g., hydrochloride). 6.64 Method 6.62, wherein a compound of formula 1J or 2J is obtained in free base form from step (d), and the method further comprises step (e) converting the compound of formula 1J or 2J in free base form to a salt form, for example, an acid addition salt form (e.g., a tosylate form, for example, a monotosylate and / or ditosylate form). Method 6.64, wherein step (e) is carried out by reacting the compound of formula 1J or 2J in the free base form from step (d) with a suitable acid in one or more organic solvents, water, or a mixture thereof. Method 6.64 or 6.65, where the acid in step (e) is toluenesulfonic acid. 6.67 Method 6.66, where the amount of toluenesulfonic acid is 0.9 to 3.2 equivalents, 0.9 to 2.2 equivalents, 0.9 to 1.2 equivalents, for example, 0.95 to 1.10 equivalents or 0.95 to 1.05 equivalents or about 1.0 equivalent, for example, 0.89 to 1.1 equivalents. Method 6.66 or 6.67, wherein the solvent in step (e) comprises ethanol, isopropanol, water, methyl tert-butyl ether, or a mixture thereof. 6.69 Method 6.68, wherein the solvent in step (e) substantially comprises isopropanol, for example, at least 70% by volume isopropanol, at least 80% by volume isopropanol, or at least 90% by volume isopropanol. Method 6.70, where the solvent in step (e) is essentially isopropanol and methyl tert-butyl ether, for example, at least 70% by volume, 80% by volume, or 90% by volume of isopropanol and the remainder is essentially methyl tert-butyl ether. 6.71 Method 1J or 2J or any of the methods described in 6.1 or later, which provides a compound of formula 1J or 2J in free base form. 6.72 Method 1J or 2J or any of 6.1 onwards, which provides a compound of formula 1J or 2J in the form of an acid addition salt. 6.73 Method 6.72, in which the acid addition salt form is a tosylate form (e.g., monotosylate, ditosylate, or tritosylate form or a mixture thereof). 6.74 Method 1J or 2J or any of 6.1 onward further comprises crystallization and / or recrystallization of the compound of formula 1J or 2J initially formed in salt form from a suitable solvent after step (e) or, if step (e) is absent, after step (d), to obtain a crystallized or recrystallized compound of formula 1J or 2J in the same salt form (for example, high purity can be achieved by using one or two rounds or more of crystallization). 6.75 Method 6.74, in which a suitable crystallization solvent for any of the one or more crystallizations comprises ethanol, isopropanol, water, methyl tert-butyl ether or a mixture thereof, for example, crystallization first from isopropanol and recrystallization second from isopropanol / water. Method 6.75, wherein a suitable crystallization solvent for any of the 6.76 crystallizations comprises isopropanol and water in a volume ratio of 90:10 to 99:1, for example, 95:5 to 99:1 or 97:3 to 99:1 or about 98:2, if desired. 6.77 Any method according to 6.74 to 6.76, wherein recrystallization includes the addition of a seed crystal (e.g., a seed crystal of the product of this method). 6.78 Method 1J or 2J or any of 6.1 onward, further comprising step (f) converting the initial salt form of the compound of formula 1J or 2J obtained from step (e) to a different salt form of the compound of formula 1J or 2J. 6.79 Method 6.78, where both the novel salt form and the initial salt form are acid addition salts. 6.80 Method 6.79, where the novel salt form is a diacid addition salt or a triacid addition salt, and the initial salt form is a monoacid addition salt of the same salt. 6.81 Method 6.80, in which the novel salt form is a ditosylate or tritosylate form and the initial salt form is a monotosylate form. 6.82 Any method 6.79 to 6.81, wherein step (f) comprises dissolving or suspending the first salt form in a suitable solvent, followed by the addition of 0.9 to 1.5 equivalents, e.g., 0.95 to 1.25 equivalents or 1.0 to 1.15 equivalents of a suitable acid (e.g., toluenesulfonic acid). 6.83 Method 6.82, in which a suitable solvent is selected from ethanol, isopropanol, water, methyl tert-butyl ether, or a mixture thereof. 6.84 The salt initially formed in step (e) is isolated and / or purified and / or characterized before step (f) by any method of 6.78–6.83. 6.85 Method 1J or 2J or any of 6.1 onwards, wherein the method provides a compound of formula 1J or 2J in solid form, for example, solid amorphous form or solid crystalline form. 6.86 Method 1J or 2J or any of 6.1 onwards, which provides a compound of formula 1J or 2J in a stable crystalline salt form, for example, a stable crystalline tosylate form (e.g., monotosylate, ditosylate, or tritosylate form). 6.87 Method 1J or 2J or any of 6.1 onwards, which provides at least 70%, preferably at least 80%, more preferably at least 90%, and most preferably 95% to 100% of cis stereoisomers for all other stereoisomers. 6.88 Method 1J or 2J or any of 6.1 onwards, wherein the method provides a compound of formula 1J or 2J in a substantially enantiomerically pure form, e.g., at least 90% ee, preferably at least 95% ee or at least 97% ee or at least 99% ee or at least 99.5% ee or at least 99.9% ee to 100% ee. 6.89 Method 1J or 2J or any of 6.1 onwards, wherein the method provides the compound of formula 1J or 2J in a substantially pure form, for example, measured by HPLC, for example, in a form of more than 95% purity or in a form of more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.5%, or 99.9% to 100% purity. 6.90 Method 1J or 2J or any of 6.1 onwards, which provides a compound of formula 1J or 2J in a form having less than approximately 50 ppm of copper, less than approximately 10 ppm of copper, or less than approximately 5 ppm of copper. 6.91 Method 1J or 2J or any of 6.1 to 6.90, wherein the method provides a compound of formula 1J or 2J in a mixture of at least 0.001% by weight and less than 1% by weight of at least one compound selected from the compounds of formula 1K or 2K, 1L or 2L, 1M or 2M, 1N or 2N, 1O or 2O, 1P or 2P and 1Q or 2Q. Method 6.91 provides a compound of formula 1J or 2J in a mixture of at least 0.01% by weight and less than 0.5% by weight of at least one compound selected from the compounds of formula 1K or 2K, 1L or 2L, 1M or 2M, 1N or 2N, 1O or 2O, 1P or 2P and 1Q or 2Q. 6.93 Method 6.91, wherein the method provides a compound of formula 1J or 2J in a mixture with at least 0.01% by weight and less than 0.5% by weight of at least two, at least three, or at least four compounds selected from compounds of formula 1K or 2K, 1L or 2L, 1M or 2M, 1N or 2N, 1O or 2O, 1P or 2P, and 1Q or 2Q. 6.94 Method 6.91, wherein the method provides a compound of formula 1J in an amount of at least 0.001% by weight and less than 1% by weight of each of the compounds of formula 1K, 1L, 1M, 1N, 1O, 1P, and 2Q, for example, in a mixture of each of the compounds in an amount of at least 0.01% and less than 0.5% by weight. Method 6.95 provides a compound of formula 2J in a mixture with each of the compounds of formula 2K, 2L, 2M, 2N, 2O, 2P, and 2Q in an amount of at least 0.001% by weight and less than 1% by weight, for example, at least 0.0005% and less than 0.5% by weight of each of the compounds. Method 6.91 provides a mixture of the compound of formula 1J in about 0.01 to 0.80 wt% of the compound of formula 1K and / or about 0.005 to 0.40 wt% of the compound of formula 1L and / or about 0.005 to 0.30 wt% of the compound of formula 1M and / or about 0.01 to 0.60 wt% of the compound of formula 1N and / or about 0.005 to 0.40 wt% of the compound of formula 1O and / or about 0.005 to 0.45 wt% of the compound of formula 1P and / or about 0.0005 to 0.30 wt% of the compound of formula 1Q. Method 6.91 provides a mixture of the compound of formula 2J in about 0.01 to 0.80 wt% of the compound of formula 2K and / or about 0.005 to 0.40 wt% of the compound of formula 2L and / or about 0.005 to 0.30 wt% of the compound of formula 2M and / or about 0.01 to 0.60 wt% of the compound of formula 2N and / or about 0.005 to 0.40 wt% of the compound of formula 2O and / or about 0.005 to 0.45 wt% of the compound of formula 2P and / or about 0.005 to 0.30 wt% of the compound of formula 2Q. 6.98 Any of the methods 6.91 to 6.97 in which a compound of formula 1K or 2K, 1L or 2L, 1M or 2M, 1N or 2N, 1O or 2O, 1P or 2P, and 1Q or 2Q is obtained, wherein group R is methyl and group Q is -(C=O)-. 6.99 Method 1J or 2J or any of 6.1 to 6.98, wherein the method comprises isolation and / or purification of the compound of formula 1J or 2J in monotosylate form, e.g., in solid crystalline monotosylate form, and the method further comprises combining the compound of formula 1J or 2J with at least 1 molar equivalent of toluenesulfonic acid. 6.100 Method 6.99, where the solvent is water and / or an alcoholic solvent (e.g., methanol, ethanol, propanol, butanol) and / or a ketone solvent (e.g., acetone, 2-butanone, 2-pentanone, 3-pentanone, cyclohexanone, cyclopentanone) and / or an ether solvent (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether) and / or a hydrocarbon solvent (e.g., hexane, pentane, cyclohexane, cyclopentane) or any combination thereof. Method 6.99 or 6.100, wherein a monotosylate of a compound of formula 1J or 2J is converted, in whole or in part, to a ditosylate compound of a salt of formula 1J or 2J. 6.102 Method 1J or 2J or any of 6.1 to 6.94, further comprising any or all of the following steps described in any of the embodiments herein: a. Preparation of the compound of formula 1A by reacting 2-bromophenylhydrazine in free or salt form with 4-piperidinone in hydrate form, free or salt form, optionally in acetic acid solvent; b. (a) Reduction of the compound of formula 1A to the compound of formula 1B, wherein the reduction optionally involves the reaction of the compound of formula 1A with triethylsilane and methanesulfonic acid; and (b) Separation of the stereoisomer of formula 1B by chiral salt splitting or chiral chromatography to obtain the compound of formula 1C or 2C, wherein the chiral salt splitting optionally is carried out in a single splitting step using S-mandelic acid; c. Preparation of compounds of formula 1D or 2D in free or salt form by protection of compounds of formula 1C or 2C with a piperidineamine in the presence of a base-protecting agent; d. Preparation of compounds of formula 1E or 2E in free or salt form by N-alkylating a compound of formula 1D or 2D with (a) a nucleophilic alkyl halide and (b) a base.

[0055] In one embodiment, any of methods 1I, 2I, 1J, 2J, or 5.1-5.52 or 6.1-6.102 involves formula 1C or 2C in free or salt form. [ka] The process may further include the step of producing the compound, a) Equation 1A [ka] The compound is given by formula 1B [ka] Reduce to the compound of formula 1A, 1B, 1C and / or 2C, substituent A of the compound of formula 1A, 1B, 1C and / or 2C is selected from Br, Cl and I; and b) Separating the stereoisomers (e.g., enantiomers) of the compound of formula 1B by chiral acid resolution or chiral chromatography to obtain the compound of formula 1C or 2C; optionally, the compound of formula 1C or 2C is cis stereoisomer of at least 70%, preferably at least 80%, more preferably at least 90%, most preferably over 95%, and up to 100% relative to all other stereoisomers; and / or the compound of formula 1C or 2C has an enantiomer excess (ee) of at least 70%, preferably at least 80%, more preferably at least 90%, most preferably over 95%, over 97%, over 99%, or 99.9% to 100% (e.g., 4aS, 9bR enantiomer or aR, 9bS enantiomer). Includes substeps.

[0056] The reduction of the compound of formula 1A to the compound of formula 1B can be achieved by using reducing agents, including but not limited to sodium triacetoxyborohydride or sodium cyanoborohydride, via the use of silanes in the presence of an acid (e.g., acetic acid, methanesulfonic acid, or trifluoroacetic acid); metals (e.g., zinc) and mineral acids (e.g., hydrochloric acid); sodium and liquid ammonia; sodium in ethanol; or borane-amine complexes (e.g., borane-triethylamine in tetrahydrofuran); sodium triacetoxyborohydride; or sodium cyanoborohydride. The conversion of the compound of formula 1A to the compound of formula 1B can also be achieved via catalytic hydrogenation, in which the compound of formula 1A is treated with hydrogen in the presence of a catalyst such as palladium oxide, palladium / carbon, or platinum oxide (see Hudlicky, M., “Reductions in Organic Chemistry”, Ellis Horwood, Ltd., Chichester, UK, 1984). The reduction of the compound of formula 2A to the compound of formula 2B can be achieved by using agents similar to those described for the reduction of the compound of formula 1A to the compound of formula 1B, such as silanes (e.g., triethylsilane) in the presence of an acid (e.g., acetic acid, methanesulfonic acid, or trifluoroacetic acid); metals (e.g., zinc) and mineral acids (e.g., hydrochloric acid); sodium and liquid ammonia; sodium in ethanol; or borane-amine complexes (e.g., borane-triethylamine in tetrahydrofuran); sodium triacetoxyborohydride; or sodium cyanoborohydride. The conversion of the compound of formula 2A to the compound of formula 2B can also be achieved by catalytic hydrogenation, in which the compound of formula 2A is treated with hydrogen in the presence of a catalyst such as palladium oxide, palladium / carbon, or platinum oxide. In a particularly preferred embodiment of the reduction of the compound of formula 1A or 2A, the reduction is achieved by using triethylsilane in the presence of trifluoroacetic acid or triethylsilane in the presence of methanesulfonic acid. In particular, the substitution of methanesulfonic acid with trifluoroacetic acid unexpectedly proved to significantly improve yield, reaction time, and cost-effectiveness.For example, using 4 volumes of methanesulfonic acid instead of 10 volumes of trifluoroacetic acid significantly reduces the need for expensive triethylsilane reagent (7 to 1.3 volumes), shortens the reaction time from 45 hours to 2-5 hours, and simultaneously increases the yield in this step.

[0057] In one embodiment, enantiomer enrichment (or separation) of isomers of a compound of formula 1B for the production of a compound of formula 1C or 2C can be achieved by chiral salt resolution, using chiral acids such as chiral sulfonic acids or mono or dicarboxylic acids or derivatives thereof. Examples of such acids include, but are not limited to, (+ / -) / (R / S) tartaric acid, (+ / -) / (R / S) (mono- or di-acetyl) tartaric acid, (+ / -) / (R / S) (mono- or di-benzoyl) tartaric acid, (+ / -) / (R / S) (mono- or di-pivaloyl) tartaric acid, (+ / -) / (R / S) mandelic acid, (+ / -) / (R / S) acetoxyphenylacetic acid, (+ / -) / (R / S) methoxyphenylacetic acid, (+ / -) / (R / S) hydroxymandelic acid, (+ / -) / (R / S) halomandelic acid (e.g., 4-fluoromandelic acid), (+ / -) / (R / S) lactic acid, and (+ / -) / (R / S) camphorsulfonic acid. Similarly, enantiomer separation of compounds of formula 2B can be achieved by chiral salt resolution using chiral acids such as chiral sulfonic acids, mono- or dicarboxylic acids, or their derivatives. Examples of such acids include, but are not limited to, (+ / -) / (R / S) tartaric acid, (+ / -) / (R / S) (mono- or di-acetyl) tartaric acid, (+ / -) / (R / S) (mono- or di-benzoyl) tartaric acid, (+ / -) / (R / S) (mono- or di-pivaloyl) tartaric acid, (+ / -) / (R / S) mandelic acid, (+ / -) / (R / S) acetoxyphenylacetic acid, (+ / -) / (R / S) methoxyphenylacetic acid, (+ / -) / (R / S) hydroxymandelic acid, (+ / -) / (R / S) halomandelic acid (e.g., 4-fluoromandelic acid), (+ / -) / (R / S) lactic acid, and (+ / -) / (R / S) camphorsulfonic acid. Preferably, the decomposition of compounds of formula 1B or 2B is achieved using mandelic acid. In a particularly preferred embodiment, the acid is (S)-(+)-mandelic acid. The reconciliation can be optimized so that the unwanted enantiomer is removed first. Therefore, in another preferred embodiment, the reconciliation is achieved by adding (R)-(-)-mandelic acid to remove the unwanted enantiomer first, and then adding (S)-(+)-mandelic acid to obtain the desired product.In one embodiment, only a single split is performed using (S)-(+)-mandelic acid. Preferred solvents for splitting include methanol, ethanol, methyl tert-butyl ether (MTBE), and combinations thereof.

[0058] In other embodiments, enantiomer enrichment (or separation) of stereoisomers of the compound of formula 1B can be achieved using chiral chromatography, for example, with an amylostris (3,5-dimethylphenylcarbamate) column sold under the trade name "Chiralpak® AD®". The isomers of formula 1B can be separated and eluted using a mobile phase such as ethanol at a flow rate of 100 to 450 mL / min. In yet another embodiment, the isomers of formula 1B can be separated and eluted using a mobile phase such as methanol or isopropyl alcohol. Fractions of the desired compound, preferably the compound of formula 1C or 2C, can be collected and isolated. In one embodiment, the chiral chromatography includes the use of a Chiralpak® AD® 20 μm, 5 cm inner diameter × 50 cm length column and a 100% ethanol mobile phase at a flow rate of 150 mL / min. In other embodiments, chiral chromatography includes the use of a Chiralpak® AD® column, 20 μm, 11 cm inner diameter × 25 cm length, and a 100% ethanol mobile phase at a flow rate of 400 mL / min.

[0059] It is understood that by separating the isomers of the compound of formula 1B to obtain the compound of formula 1C or 2C, the diastereomer or enantiomer composition of the compound is fixed or substantially fixed, and all subsequent further reactions leading to the compound of formula 1J or 2J do not substantially alter the diastereomer or enantiomer composition of the compound. Therefore, in all aspects and embodiments of the present invention, each of the intermediates of formulas 1D, 1E, 1F, 1H, and 1I is substantially, essentially, or completely a single cis-enantiomer, and the opposite cis-isomer or any trans-isomer can be removed. Similarly, in all aspects and embodiments of the present invention, each of the intermediates of formulas 2D, 2E, 2F, 2H, and 2I is substantially, essentially, or completely a single cis-enantiomer, in particular the 4aS, 9bR enantiomer, and the opposite cis-isomer or any trans-isomer can be removed. Therefore, each of the intermediates of formulas 1D, 2D, 1E, 2E, 1F, 2F, 1H, 2H, 1I, and 2I used herein may be at least 70%, preferably at least 80%, more preferably at least 90%, and most preferably 95% to 100% cis stereoisomers with respect to all other stereoisomers; and / or may have an enantiomer excess (ee) of at least 70%, preferably at least 80%, more preferably at least 90%, and most preferably exceeding 95%, 97%, 98.5%, 99%, or 99.9% to 100%.

[0060] In some embodiments, any of methods 1I, 2I, 1J, 2J, or 5.1-5.52 or 6.1-6.102 may further include a step to produce the compound of formula 1A in free or salt form by reacting 2-bromophenylhydrazine and 4-piperidinone in an acidic solvent (Fischer-indole reaction). In some embodiments, 2-bromophenylhydrazine and / or 4-piperidinone are provided as acid addition salts, e.g., hydrochloride, hydrobromide, acetate, or trifluoroacetate. In some embodiments, 4-piperidinone exists as a hydrate, e.g., monohydrate. In some embodiments, the product is obtained as an acid addition salt, e.g., hydrochloride, hydrobromide, trifluoroacetate, sulfate, or acetate. The reaction can be carried out in any suitable solvent containing the dissolved acid (e.g., HCl, HBr, H2SO4, acetic acid), such as an aqueous or alcoholic solvent (e.g., water, methanol, ethanol, or isopropanol, or any mixture thereof) or a solvent-free acidic solvent (e.g., acetic acid, trifluoroacetic acid). In some embodiments, the yield can be improved by using a solvent in which the product is sparingly soluble. In some embodiments, the yield can be improved by using solvent-free acetic acid as the solvent.

[0061] In one embodiment, any of methods 1I, 2I, 1J, 2J, or 5.1-5.52 or 6.1-6.102 is used for formula 1D or 2D in free or salt form. [ka] [During the ceremony, (i) A is selected from Br, Cl and I, and (ii) B is the protecting group defined herein. A process for producing a compound of formula 1C or 2C, comprising the step of protecting the piperidineamine of the compound of formula 1C or 2C with a base-protecting agent, Here, the protective agent is a general formula [ka] [During the ceremony, (i) Y is a halogen, imidazolyl, benzotriazole, N-(oxy)succinimide, alkoxy, -O-alkylaryl or -O-aryl, (ii) Z is optionally substituted alkyl, aryl, alkylaryl or -OR, where R is alkyl, aryl, arylalkyl or heteroarylalkyl, (iii) P is -CH2-, -C(O)-, -C(O)O-, or S(O)2. It may further include a process that includes a process having the following characteristics.

[0062] Examples of suitable protective agents for reactions with compounds of formula 1C or 2C include, but are not limited to, benzyloxycarbonyl chloride (Cbz-Cl), triphenylmethyl chloride, ethyl chloroformate, t-butoxycarbonyl anhydride (Boc2O), benzyl carbonate, N-succinimidyl or benzoyl halogenated compounds (e.g., benzoyl chloride or bromide), (benzyloxycarbonyl)-benzotriazole, benzyl halogenated compounds (e.g., benzyl chloride or bromide), 1-arene sulfonyl chloride, or toluenesulfonyl chloride. Another example of a protecting group for compounds of formula 1C or 2C is p-methoxybenzyl, which can be prepared using p-methoxybenzyl chloride, p-methoxybenzyl bromide, or p-methoxybenzaldehyde. The protective agents disclosed herein are not intended to be exhaustive. For further examples of amine protective agents, see one of the many general reference books on the subject, for example, “Protective Groups in Organic Synthesis” by Theodora Green (Publisher: John Wiley & Sons), whose disclosure is incorporated herein by reference. The addition of a protective agent to the compound of formula 1C or 2C results in substituent B of the resulting compound 1D or 2D being, therefore, a general formula [ka] [During the ceremony, (i) Z is optionally substituted alkyl, aryl, alkylaryl or -OR, where R is alkyl, aryl, arylalkyl or heteroarylalkyl, (ii) P is -CH2-, -C(O)-, -C(O)O-, or S(O)2. It has.

[0063] The protection step in this embodiment generally requires the addition of a base such as butyllithium or a metal hydride (e.g., potassium hydride), an alkali or alkaline earth metal bicarbonate, carbonate or hydroxide (e.g., potassium or sodium carbonate, sodium bicarbonate or sodium hydroxide), or an organic amine (e.g., triethylamine). Preferably, the protective agent for the compound of formula 1D or 2D is ethyl chloroformate or BOC anhydride. In a particularly preferred embodiment, the protective agent is ethyl chloroformate, and the base is triethylamine or sodium hydroxide.

[0064] In one embodiment, the conversion of a compound of formula 1C or 2C to a compound of formula 1D or 2D involves treatment with ethyl chloroformate and sodium hydroxide in a mixture of water and THF.

[0065] In one embodiment, a method for protecting the piperidine nitrogen of a compound of formula 1C or 2C includes first neutralizing a salt of the compound of formula 1C or 2C, such as a mandelate, with a suitable base, followed by isolating, separating, or purifying the free base of the compound of formula 1C or 2C. Then, a suitable reactant for protecting the piperidine nitrogen of the compound of formula 1C or 2C is added together with a suitable base to obtain a compound of formula 1D or 2D. The base used for neutralization may be the same as or different from the base used in the protection reaction. In another embodiment, a salt of the compound of formula 1C or 2C (e.g., a mandelate) is reacted with a suitable protective agent in the presence of an excess base to obtain a compound of formula 1D or 2D in a single step. Thus, in these embodiments, the formation of the free base and the acylation reaction are carried out simultaneously. Preferably, the base is sodium hydroxide.

[0066] In one embodiment, any of methods 1I, 2I, 1J, 2J, or 5.1-5.52 or 6.1-6.102 is used for formula 1E or 2E in free form or salt form. [ka] [During the ceremony, (i) A is selected from Br, Cl and I, (ii) R is H and C 1-4 Selected from alkyl (e.g., methyl), and (iii) B is the protecting group defined herein. A process for producing a compound of formula 1D or 2D, wherein (a) general formula [ka] [During the ceremony, (i) A = Cl, F, Br or I, and (ii) R is H or C 1-4 It is alkyl. The process may include a step of N-alkylation with a nucleophilic alkyl halide and (b) a base.

[0067] Examples of nucleophilic alkyl halides suitable for alkylating compounds of formulas 1D and 2D include 2-chloroacetamide, 2-bromoacetamide, and NC. 1-4 Alkyl 2-chloroacetamides (e.g., N-methyl 2-chloroacetamide) and NC 1-4This includes, but is not limited to, alkyl 2-bromoacetamides (e.g., N-methyl 2-bromoacetamide). Examples of bases useful for alkylation include, but are not limited to, organic bases such as amine bases (e.g., ammonia, triethylamine, N,N'-diisopropylethylamine or 4-(dimethylamino)pyridine (DMAP), 1,5-diazabicyclo[4.3.0]-non-5-ene (DBN), 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU)); or inorganic bases such as hydrides (e.g., sodium, lithium, or potassium hydrides), alkoxide bases (e.g., sodium, potassium, or lithium t-butoxide and K(OAr), Na(OAr)), or carbonates, bicarbonates, phosphates, or hydroxides of alkalis or alkaline earth metals (e.g., carbonates, bicarbonates, hydroxides, or phosphates of sodium, magnesium, calcium, potassium, cesium, or barium). If desired, such N-alkylation reactions can be achieved in the presence of an iodide source, such as potassium iodide or sodium iodide, preferably potassium iodide. In certain embodiments, alkylation may be carried out using 2-chloroacetamide or N-methyl2-chloroacetamide in dimethylacetamide solvent, in the presence of N,N'-diisopropylethylamine and potassium iodide. Suitable solvents also include acetonitrile, dioxane, dimethylformamide, and dimethylacetamide.

[0068] In other embodiments, the present invention provides active pharmaceutical compositions (active pharmaceutical components, i.e., APIs) comprising a compound of formula 1J or 2J in substantially pure form. In further embodiments of this aspect, the present invention provides the following: 7.1 An active pharmaceutical composition (active pharmaceutical component) comprising a compound of formula 1J or 2J in a pharmaceutically acceptable salt form, wherein the composition comprises at least 97% by weight of the compound (measured as a salt form). 7.2 Composition 7.1, wherein the compound is a compound of formula 1J, where R is methyl and Q is 3-(4-fluorophenyl)-4-oxobutyl. 7.3 A composition in which the compound is substantially enantiomerically pure, for example, at least 97%ee or at least 98%ee or at least 98.5%ee or at least 99%ee to 100%ee. 7.4 Composition 7.2 or 7.3, wherein the composition contains at least 98%, at least 98.5%, or at least 99.0% by weight (measured as salt form) of the compound. 7.5 Any composition from 7.2 to 7.4 in which the compound is in tosylate or hydrochloride form (e.g., mono, di, or tritosylate form or mono, di, or trihydrochloride form). 7.6 Composition 7.5 in which the compound is in monotosylate form (i.e., the composition contains at least 97% by weight of the compound in monotosylate form). 7.7 A composition in which the compound is in monotosylate form and the composition contains at least 98%, at least 98.5%, or at least 99.0% by weight (measured as monotosylate) of the compound. 7.6 7.8 Any of compositions 7.1 to 7.7 in which the compound is in crystalline salt form. 7.9 Any of compositions 7.1 to 7.7, comprising each of the compounds of formula 1A, 1B, 1C, 1D, 2D, 1E, 2E, 1F, 2F, 1H, 2H, 1I, or 2I in an amount not exceeding 0.50% by weight, for example, each not exceeding 0.40% by weight or each not exceeding 0.30% by weight. 7.10 Any of compositions 7.1 to 7.8, wherein the composition contains a compound of formula 1I or 2I (for example, in which R is methyl) in an amount not exceeding 0.25% by weight. 7.11 Any composition from 7.1 to 7.10, which contains copper not exceeding 50 ppm, for example, not exceeding 40 ppm, not exceeding 25 ppm, or not exceeding 10 ppm. 7.12 Any composition from 7.1 to 7.11, wherein the composition contains at least 0.001% by weight of at least one compound selected from compounds of formula 1K or 2K, 1L or 2L, 1M or 2M, 1N or 2N, 1O or 2O, 1P or 2P, and 1Q or 2Q in less than 1% by weight. 7.13 Any composition according to 7.1 to 7.11, wherein the composition comprises at least 0.005% by weight of a compound of formula 1J or 2J, mixed with less than 0.5% by weight of at least one compound selected from the compounds of formula 1K or 2K, 1L or 2L, 1M or 2M, 1N or 2N, 1O or 2O, 1P or 2P, and 1Q or 2Q. 7.14 Any composition according to 7.1 to 7.11, wherein the composition comprises at least 0.005% by weight of a compound of formula 1J or 2J, mixed with less than 0.5% by weight of at least two, at least three, or at least four compounds selected from the compounds of formula 1K or 2K, 1L or 2L, 1M or 2M, 1N or 2N, 1O or 2O, 1P or 2P, and 1Q or 2Q. 7.15 Any composition from 7.1 to 7.11, wherein the composition contains at least 0.001% by weight of the compound of formula 1J, mixed with less than 1% by weight of each of the compounds of formula 1K, 1L, 1M, 1N, 1O, 1P, and 2Q, for example, at least 0.01% and less than 0.5% by weight of each of the said compounds. 7.16 Any of compositions 7.1 to 7.11, wherein the composition contains at least 0.001% by weight of the compound of formula 2J, mixed with less than 1% by weight of each of the compounds of formula 2K, 2L, 2M, 2N, 2O, 2P, and 2Q, for example, at least 0.01% and less than 0.5% by weight of each of the said compounds. 7.17 Any composition according to 7.1 to 7.11, wherein the composition comprises a compound of formula 1J mixed with about 0.01 to 0.80% by weight of a compound of formula 1K and / or about 0.005 to 0.40% by weight of a compound of formula 1L and / or about 0.005 to 0.30% by weight of a compound of formula 1M and / or about 0.01 to 0.60% by weight of a compound of formula 1N and / or about 0.005 to 0.40% by weight of a compound of formula 1O and / or about 0.005 to 0.45% by weight of a compound of formula 1P and / or about 0.005 to 0.30% by weight of a compound of formula 1Q. 7.18 Any composition according to 7.1 to 7.11, wherein the composition comprises a compound of formula 2J mixed with about 0.01 to 0.80% by weight of a compound of formula 2K and / or about 0.005 to 0.40% by weight of a compound of formula 2L and / or about 0.005 to 0.30% by weight of a compound of formula 2M and / or about 0.01 to 0.60% by weight of a compound of formula 2N and / or about 0.005 to 0.40% by weight of a compound of formula 2O and / or about 0.005 to 0.45% by weight of a compound of formula 2P and / or about 0.005 to 0.30% by weight of a compound of formula 2Q. 7.19 Any of the compositions from 7.12 to 7.19, in which the compounds of formula 1K or 2K, 1L or 2L, 1M or 2M, 1N or 2N, 1O or 2O, 1P or 2P, and 1Q or 2Q, the group R is methyl and the group Q is -(C=O)-. 7.20 The compound of formula 1J or 2J is a compound prepared by any of methods 1J, 2J or 6.1-6.102 or methods 1K, 2K or 8.1-8.49, or any of compositions 7.1-7.19.

[0069] In other embodiments, the present invention provides a pharmaceutical composition comprising an active pharmaceutical composition (active pharmaceutical component) from any of compositions 7.1 to 7.20 mixed with one or more pharmaceutically acceptable additives, diluents, or solvents. In some embodiments, the pharmaceutical composition is selected from tablets, capsules, caplets, powders, wafers, gels, or sterile injectable solutions. In some embodiments, the pharmaceutical composition is an orally disintegrating tablet. In some embodiments, the pharmaceutical composition is a long-acting injectable composition for intramuscular or subcutaneous administration, for example. In some embodiments, the pharmaceutical composition contains 1 to 60 mg of a compound of formula 1J or 2J, measured by weight of equivalent free base (e.g., 20 to 60 mg or 20 to 40 mg or 40 to 60 mg for oral dosage forms; e.g., 1 to 30 mg or 5 to 20 mg or 5 to 15 mg or 1 to 10 mg for orally soluble dosage forms).

[0070] In certain embodiments, the pharmaceutical composition contains 40-42 mg of the compound of formula 1J or 2J, measured by weight of equivalent free base. For example, the pharmaceutical composition contains 60 mg of the compound of formula 1J or 2J, where R is methyl, Q is 4-(4-fluorophenyl)-4-oxobuchi, and the compound is in the form of a monotosylate addition salt.

[0071] In other embodiments, the present invention provides pharmaceutical compositions comprising a compound of formula 1J or 2J or any of 3.1-3.15 or 4.1-4.15, wherein the compound is mixed with toluenesulfonic acid and at least one additive, diluent, or solvent. For example, in one embodiment, the pharmaceutical composition comprises a compound of formula 1J or 2J in the form of a toluenesulfonic acid addition salt mixed with toluenesulfonic acid. In one embodiment, toluenesulfonic acid is present in an amount of at least 1 molar equivalent, e.g., about 1 molar equivalent or 1-1.15 molar equivalents, 1-1.5 molar equivalents, or 1-2 molar equivalents relative to the amount of the compound of formula 1J or 2J present in the composition. The composition may be in solid oral dosage forms, such as tablets, capsules, or orally disintegrating tablets. The compound of formula 1J or 2J is preferably a compound in which R is methyl and Q is 4-(4-fluorophenyl)-4-oxobutyl.

[0072] Examples of suitable additives, diluents, and solvents for pharmaceutical compositions include, but are not limited to, cellulose acetate, cellulose phthalate acetate, methacrylic acid / methyl acrylate copolymer, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose succinate (HPMC-AS), hydroxypropyl methylcellulose phthalate (HPMC-P), polyvinyl acetate, polyvinylpyrrolidone, polyvinylpyrrolidone / vinyl acetate copolymer, polyethylene glycol / polyvinyl acetate / polyvinyl caprolactam copolymer, tocopherol, butylated hydroxytoluene (BHT), propyl gallate (OPG), ascorbic acid, butylated hydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), carotenoids, glutathione, sodium metabisulfite, sodium ethylenediaminetetraacetic acid, cysteine, methionine, sesamol, citric acid, and surfactants (e.g., anionic, cationic, zwitterionic, or neutral surfactants). Generally, suitable additives fall into the following categories: (a) Diluents / extensions (e.g., cellulose or microcrystalline cellulose (e.g., silicified microcrystalline cellulose), mannitol, lactose monohydrate, calcium diphosphate, or isomalt), (b) Binders (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, copovidone), (c) Disintegrants (e.g., sodium starch glycolate, crospovidone, or croscarmellose sodium), (d) Lubricants (e.g., magnesium stearate) (e) a silicon dioxide or glyceryl monostearate, (f) a foaming agent, (g) a polymer, (h) a plasticizer, (i) a desiccant or hygroscopic agent, (j) a humectant (e.g., polyol), (k) a wetting agent, (l) an antioxidant (e.g., BHT, citric acid, propyl gallate, ascorbic acid or sodium metabisulfite), (m) a thickening agent (e.g., a gelling agent), (n) a surfactant, (o) a buffer, (p) a sweetener or flavoring agent, and (q) a pigment or coloring agent may be selected.

[0073] As used herein, “active pharmaceutical composition” refers to an active pharmaceutical ingredient (API) intended to be incorporated into a pharmaceutical composition for administration to a human or animal subject. That is, an API consists only of an active pharmaceutical compound (e.g., a compound of formula 1J or 2J) and any incidental impurities resulting from its synthesis. In contrast, “pharmaceutical composition” includes an API mixed with at least one additive, diluent, or solvent. Suitable additives, diluents, and solvents are known in the art and include, but are not limited to, binders, disintegrants, polymers, sugars, fillers, sweeteners, adhesives, buffers, release regulators, protective coatings (e.g., gastric coatings), colorants, flavorings, and liquid carriers (including water, ethanol, glycerol, sorbitol, propylene glycol, etc.).

[0074] In other embodiments, the present invention provides a method (Method 1K) for producing a compound of formula 1J or any of 3.1 to 3.15 (if appropriate), wherein the compound of formula 1J is in a pharmaceutically acceptable salt form, and the method comprises (a) converting the compound of formula 1J in free or salt form to a pharmaceutically acceptable salt form (e.g., a different salt form), such as an acid-added salt form (e.g., a tosylate form) of the compound of formula 1J (or any of 3.1 to 3.15). Therefore, for example, step (a) may include converting a compound of formula 1J in a pharmaceutically unacceptable salt form to a pharmaceutically acceptable salt form of the compound of formula 1J. Alternatively, step (a) may include converting a less preferred pharmaceutically acceptable salt form (e.g., hydrochloride) of the compound of formula 1J to a more preferred pharmaceutically acceptable salt form (e.g., tosylate). In one embodiment, step (a) may include the conversion of a compound of formula 1J in monotosylate form to a compound of formula 1J in ditosylate form.

[0075] In other embodiments, the present invention provides a method (Method 2K) for producing a compound of formula 2J or any of 4.1 to 4.15 (if appropriate), comprising the step of (a) converting the compound of formula 2J in free or salt form to a compound of formula 2J (or any of 4.1 to 4.15) in an acid-added salt form, e.g., a tosylate form. Therefore, for example, step (a) may include the conversion of a compound of formula 2J in an unacceptable salt form to a compound of formula 2J in an acceptable salt form. Alternatively, step (a) may include the conversion of a compound of formula 2J in a less preferred pharmaceutically acceptable salt form (e.g., hydrochloride) to a more preferred pharmaceutically acceptable salt form (e.g., tosylate). In one embodiment, step (a) may include the conversion of a compound of formula 2J in monotosylate form to a compound of formula 2J in ditosylate form.

[0076] In all cases, step (a) of methods 1K and 2K may be carried out in accordance with the above description relating to step (e) or step (f) of methods 1J and 2J, respectively. For example, when step (a) of method 1K or 2K involves the conversion of a compound of formula 1J or 2J in free base form to a compound of formula 1J or 2J in salt form, the method may be carried out in accordance with the above description relating to step (e) of method 1J or 2J, respectively. When step (a) of method 1K or 2K involves the conversion of a compound of formula 1J or 2J in salt form to a compound of formula 1J or 2J in a different salt form, the method may be carried out in accordance with the above description relating to step (f) of method 1J or 2J, respectively.

[0077] In further embodiments of Methods 1K and 2K, the present invention provides the following: 8.1 Method 1K or 2K, wherein the method is initiated with a compound of formula 1J or 2J in its free base form, and the method comprises step (a) of converting the compound of formula 1J or 2J in its free base form to a pharmaceutically acceptable salt form of the compound of formula 1J or 2J, e.g., an acid addition salt form (e.g., a tosylate form, e.g., monotosylate and / or ditosylate form). Method 8.1, wherein step (a) is carried out by the reaction of the first free base form of the compound of formula 1J or 2J with one or more organic solvents, water, or mixtures thereof, of a suitable acid. 8.3 Method 1K or 2K, wherein the Method begins with a compound of formula 1J or 2J in a salt form, e.g., an acid addition salt form, and the Method comprises step (a) of converting the compound of formula 1J or 2J in a salt form to a pharmaceutically acceptable salt form of the compound of formula 1J or 2J, e.g., a different salt form, e.g., a different acid addition salt form (e.g., a tosylate form, e.g., monotosylate and / or ditosylate form). Method 8.3, wherein step (a) is carried out by the reaction of the first salt form of the compound of formula 1J or 2J with one or more organic solvents or water or mixtures thereof of a suitable acid. 8.5 Method 8.2 or 8.4, where the appropriate acid for step (a) is toluenesulfonic acid. 8.6 Method 8.5, where the amount of toluenesulfonic acid is 0.9 to 3.2 equivalents, 0.9 to 2.2 equivalents, 0.9 to 1.2 equivalents, for example, 0.95 to 1.10 equivalents or 0.95 to 1.05 equivalents or about 1.0 equivalent, for example, 0.89 to 1.1 equivalents. Method 1K or 2K or any of 8.1 onwards, wherein the solvent in step (a) comprises methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, t-butanol, water, methyl tert-butyl ether, dioxane, diethyl ether, diisopropyl ether, or a mixture thereof. 8.8 Method 8.7, wherein the solvent in step (a) substantially comprises isopropanol, for example, at least 70% by volume isopropanol, at least 80% by volume isopropanol, or at least 90% by volume isopropanol. Method 8.8, wherein the solvent of step (a) is essentially isopropanol and methyl tert-butyl ether, for example, at least 70% by volume, 80% by volume, or 90% by volume of isopropanol and the remainder is essentially methyl tert-butyl ether. 8.10 Method 1K or 2K or any of 8.1 onward, which provides a compound of formula 1J or 2J in a pharmaceutically acceptable acid addition salt form. 8.11 Method 8.10, in which the acid addition salt form is a tosylate form (e.g., monotosylate, ditosylate, or tritosylate form or a mixture thereof). 8.12 Any method of 8.3 to 8.12, wherein the initial salt form of the compound of formula 1J or 2J is a toluenesulfonic acid addition salt form (e.g., monotosylate), and the salt form of the compound of formula 1J or 2J after step (a) is a different toluenesulfonic acid addition salt form (e.g., ditosylate). 8.13 Any method of 8.3 to 8.12, wherein the initial salt form of the compound of formula 1J or 2J is a hydrochloric acid addition salt form (e.g., mono-HCl or di-HCl), and the salt form of the compound of formula 1J or 2J after step (a) is a toluenesulfonic acid addition salt form (e.g., monotosylate or ditosylate). 8.14 Method 1K or 2K or any of 8.1 onward, further comprising step (b) after step (a) crystallization and / or recrystallization (from step (a)) of the compound of formula 1J or 2J initially formed in salt form from a suitable solvent, in order to obtain a crystallized or recrystallized compound of formula 1J or 2J in the same salt form (for example, high purity can be achieved by using one or two rounds or more of crystallization). 8.15 A suitable crystallization solvent for any of the one or more crystallizations includes ethanol, isopropanol, water, methyl tert-butyl ether, or a mixture thereof. For example, crystallization first from isopropanol and recrystallization a second time from isopropanol / water, method 8.14. Method 8.15, wherein a suitable crystallization solvent for any of the 1 or more crystallizations comprises isopropanol and water in a volume ratio of 90:10 to 99:1, for example, 95:5 to 99:1 or 97:3 to 99:1 or about 98:2, if desired. 8.17 Any method of 8.14 to 8.16, wherein recrystallization includes the addition of a seed crystal (e.g., a seed crystal of the product of this method). 8.18 Method 1K or 2K or any of 8.1 onward, wherein the method begins with a compound of formula 1J or 2J in salt form, the method further comprises a step of converting the initial salt form of the compound of formula 1J or 2J to a free base form before step (a) as described above, and then converting the free base form to a salt form by step (a) as described above. 8.19 Method 8.18, wherein the preceding step involves treating the first salt form of the compound of formula 1J or 2J with a suitable base in a suitable solvent. 8.20 Method 8.19, where the suitable base is an inorganic base such as an alkali metal or alkaline earth metal hydroxide, oxide, carbonate, or bicarbonate. 8.21 Method 8.20, in which the base is selected from NaOH, KOH, LiOH, Ca(OH)2, Mg(OH)2, CaO, MgO, Na2CO3, K2CO3, Li2CO3, NaHCO3, KHCO3, LiHCO3, CaCO3, and MgCO3. 8.22 Method 8.19, 8.20, or 8.21, in which a suitable solvent is selected from water, methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, t-butanol, THF, dioxane, methyl t-butyl ether, or any combination thereof. 8.23 Any method of 8.18 to 8.22, wherein the first salt form is an acid addition salt form, e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, methanesulfonate, or toluenesulfonate (e.g., monotosylate or ditosylate). 8.24 Any method of 8.18 to 8.22, wherein the salt form of the compound of formula 1J or 2J after step (a) is a toluenesulfonic acid addition salt form (e.g., monotosylate or ditosylate). 8.25 Method 1K or 2K or any of 8.1 onward, wherein the method begins with a compound of formula 1J or 2J in free base form, the method further includes a step of converting the compound of formula 1J or 2J in free base form to an intermediate salt form before step (a) as described above, and then converting the intermediate salt form to the final salt form by step (a) as described above. 8.26 If the first salt form is an acid addition salt form, e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, methanesulfonate, or toluenesulfonate (e.g., monotosylate), then method 8.25. 8.27 Method 8.25 or 8.26, wherein the preceding steps are carried out by reacting the initial free base form of the compound of formula 1J or 2J with a suitable acid in one or more organic solvents, water, or a mixture thereof to obtain an intermediate salt form. 8.28 Method 8.22, 8.23, or 8.24, wherein the solvent in the preceding step comprises water, methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, t-butanol, THF, dioxane, methyl t-butyl ether, or any combination thereof. 8.29 If the appropriate acid is toluenesulfonic acid, use method 8.27 or 8.28. 8.30 Any method of 8.25 to 8.29, wherein the salt form of the compound of formula 1J or 2J after step (a) is a toluenesulfonic acid addition salt form (e.g., monotosylate or ditosylate). 8.31 Method 1K or 2K or any of 8.1 onwards, wherein the method provides a compound of formula 1J or 2J in solid form, for example, solid amorphous or solid crystalline form. 8.32 Method 1K or 2K or any of 8.1 onwards, which provides a compound of formula 1J or 2J in a stable crystalline salt form, for example, a stable crystalline tosylate form (e.g., monotosylate, ditosylate, or tritosylate form). 8.33 Method 1K or 2K or any of 8.1 onwards, which begins with a stable, crystalline salt form of the compound of formula 1J or 2J. Method 8.34 is initiated with a compound of formula 1J or 2J in a stable, crystalline toluenesulfonic acid addition salt form (e.g., monotosylate, ditosylate, or tritosylate form), method 8.33. 8.35 Method 1K or 2K or any of 8.1 onwards, wherein the method provides at least 70%, preferably at least 80%, more preferably at least 90%, and most preferably between 95% and 100% cis stereoisomers for all other stereoisomers. 8.36 Method 1K or 2K or any of 8.1 onwards, wherein the method provides a compound of formula 1J or 2J in a substantially enantiomerically pure form, for example, at least 90% ee, preferably at least 95% ee or at least 97% ee or at least 99% ee or at least 99.5% ee or at least 99.9% ee to 100% ee. 8.37 Method 1K or 2K or any of 8.1 onwards, which provides a compound of formula 1J or 2J in a substantially pure form, for example, measured by HPLC to a pure form of more than 95%, or more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.5%, or more than 99.9%, or up to 100% purity. 8.38 Method 1K or 2K or any of 8.1 onwards, which provides a compound of formula 1J or 2J in a form having less than approximately 50 ppm of copper, less than approximately 10 ppm of copper, or less than approximately 5 ppm of copper. 8.39 Method 1K or 2K or any of 8.1 to 8.38, wherein the method provides a compound of formula 1J or 2J in a mixture of at least 0.001% by weight and less than 1% by weight of at least one compound selected from the compounds of formula 1K or 2K, 1L or 2L, 1M or 2M, 1N or 2N, 1O or 2O, 1P or 2P and 1Q or 2Q. Method 8.40 Method 8.39 provides a mixture of a compound of formula 1J or 2J in an amount of at least 0.01% by weight and less than 0.5% by weight of at least one compound selected from the compounds of formula 1K or 2K, 1L or 2L, 1M or 2M, 1N or 2N, 1O or 2O, 1P or 2P and 1Q or 2Q. 8.41 Method 8.39, wherein the method provides a compound of formula 1J or 2J in a mixture with at least 0.01% by weight and less than 0.5% by weight of at least two, at least three, or at least four compounds selected from compounds of formula 1K or 2K, 1L or 2L, 1M or 2M, 1N or 2N, 1O or 2O, 1P or 2P, and 1Q or 2Q. 8.42 Method 8.39, wherein the method provides a compound of formula 1J in an amount of at least 0.001% by weight and less than 1% by weight of each of the compounds of formula 1K, 1L, 1M, 1N, 1O, 1P, and 2Q, for example, in an amount of at least 0.01% and less than 0.5% by weight of each of the compounds. 8.43 Method 8.39, wherein the method provides a compound of formula 2J in a mixture with each of the compounds of formula 2K, 2L, 2M, 2N, 2O, 2P, and 2Q in an amount of at least 0.001% by weight and less than 1% by weight, for example, at least 0.0005% and less than 0.5% by weight of each of the compounds. Method 8.44 Method 8.39 provides a mixture of the compound of formula 1J with about 0.01 to 0.80 wt% of the compound of formula 1K and / or about 0.005 to 0.40 wt% of the compound of formula 1L and / or about 0.005 to 0.30 wt% of the compound of formula 1M and / or about 0.01 to 0.60 wt% of the compound of formula 1N and / or about 0.005 to 0.40 wt% of the compound of formula 1O and / or about 0.005 to 0.45 wt% of the compound of formula 1P and / or about 0.0005 to 0.30 wt% of the compound of formula 1Q. Method 8.45 provides a mixture of the compound of formula 2J with about 0.01 to 0.80 wt% of the compound of formula 2K and / or about 0.005 to 0.40 wt% of the compound of formula 2L and / or about 0.005 to 0.30 wt% of the compound of formula 2M and / or about 0.01 to 0.60 wt% of the compound of formula 2N and / or about 0.005 to 0.40 wt% of the compound of formula 2O and / or about 0.005 to 0.45 wt% of the compound of formula 2P and / or about 0.005 to 0.30 wt% of the compound of formula 2Q. 8.46 Any of the methods 8.39 to 8.45 in which a compound of formula 1K or 2K, 1L or 2L, 1M or 2M, 1N or 2N, 1O or 2O, 1P or 2P, and 1Q or 2Q is obtained, wherein group R is methyl and group Q is -(C=O)-. 8.47 Method 1K or 2K or any of 8.1 onwards, wherein the method comprises isolation and / or purification of the compound of formula 1J or 2J in monotosylate form, e.g., in solid crystalline monotosylate form, and the method further comprises combining the compound of formula 1J or 2J with at least 1 molar equivalent of toluenesulfonic acid. 8.48 Method 8.47, where the solvent is water and / or an alcoholic solvent (e.g., methanol, ethanol, propanol, butanol) and / or a ketone solvent (e.g., acetone, 2-butanone, 2-pentanone, 3-pentanone, cyclohexanone, cyclopentanone) and / or an ether solvent (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether) and / or a hydrocarbon solvent (e.g., hexane, pentane, cyclohexane, cyclopentane) or any combination thereof. Method 8.47 or 8.48, wherein a monotosylate of a compound of formula 1J or 2J is converted, in whole or in part, to a ditosylate compound of a salt of formula 1J or 2J.

[0078] The compounds described herein and their pharmaceutically acceptable salts may be prepared using the methods described and illustrated herein, as well as by similar methods and methods known in the field of chemistry. In the description of the synthesis methods described herein, it is understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental time, and workup method, are selected to be standard conditions for the reaction, readily recognizable to those skilled in the art. Therefore, in some cases, any reaction may need to be carried out at a higher temperature or for a longer or shorter time than described herein. It is understood to those skilled in the field of organic synthesis that the functional groups present in various parts of the molecule must be compatible with the intended reactants and reactions. If not commercially available, the starting materials for these methods may be prepared by methods selected from techniques similar to or analogous to the synthesis of known compounds. All references herein are incorporated herein by reference in whole.

[0079] Unless a term is specifically defined for a particular embodiment, the terms used herein are generally defined as follows:

[0080] The term "pharmaceutically acceptable salt" refers to a derivative of a compound disclosed herein, which is a modified parent compound formed by the formation of an acid or base addition salt of that parent compound. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. A pharmaceutically acceptable salt is, for example, a conventional non-toxic salt or quaternary ammonium salt of a parent compound formed from a non-toxic inorganic or organic acid. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, as well as salts prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, and isethionic acid.

[0081] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture thereof; generally, non-aqueous media such as ether, ethyl acetate, isopropyl acetate, ethanol, isopropanol, or acetonitrile are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, which is incorporated herein by reference. The compounds of the present invention have more than one basic nitrogen atom. For example, compounds of formula 1J and 2J each have three basic nitrogen atoms (two N-arylpiperazine nitrogen and one aliphatic piperidine nitrogen). It is known that piperidine nitrogen is more basic than two piperazine nitrogens. It is also understood that any one, two, or all of these nitrogen atoms can form acid addition salts with the acidic hydrogen of monoprotic, diprolotonic, or triprotonic Brønsted acids, depending on the free base-to-acid molar ratio provided in the reaction. Consequently, when terms such as “acid addition salt” are used herein, such terms refer to any possible such salts and combinations thereof. For example, the term “tosylate form” of a compound of formula 1J or 2J may refer to a monotosylate, ditosylate, or tritosylate of the compound or any mixture thereof. Similarly, the term “hydrochloride form” of a compound of formula 1I or 2I may refer to a monohydrochloride, dihydrochloride, or trihydrochloride of the compound or any mixture thereof. This applies to all other acid addition salt forms disclosed herein.

[0082] The term "alkyl" is intended to include both branched and linear saturated aliphatic hydrocarbon groups having a specific number of carbon atoms; for example, "C1-C4 alkyl" refers to alkyl groups having 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0083] As used herein, "halo," "halogen," or "halide" refers to fluoro, chloro, bromo, and iodine. Therefore, "alkyl halide" refers to a halogen group bonded to an alkyl group as defined above, such as methyl iodide or iodobutane.

[0084] The term "cycloalkyl" is intended to include monocyclic or polycyclic ring systems containing at least one aliphatic ring. Therefore, "cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and the like. When a cycloalkyl is a polycyclic system, such a system may include an aliphatic ring fused to an aromatic, non-aromatic, heteroaromatic, or heteronon-aromatic ring. Examples of these include octahydro-1H-indene, 2,3-dihydro-1H-indene, and 5,6,7,8-tetrahydroquinoline.

[0085] The term "heterocycloalkyl" as used herein refers to a monocyclic or polycyclic system containing at least one aliphatic ring that includes at least one heteroatom selected from the group consisting of O, N, and S. Therefore, heterocycloalkyls may include piperidinyl, piperazinyl, 2-pyrrolidonyl, 1,2,3,4-tetrahydroquinolinyl, 2H,6H-1,5,2-dithiadinyl, 2H-pyrrolyl, or 1,2,3,4-tetrahydro-1,8-naphthyridine.

[0086] As used herein, the term "aryl" refers to a stable 5- to 7-membered monocyclic or polycyclic or 7- to 14-membered polycyclic ring system containing at least one aromatic ring (i.e., a planar ring containing 4n + 2 pi electrons, where n is an integer). Therefore, the term "aryl" includes phenyl, naphthyl, and their derivatives. The term "aryl" is also intended to include polycyclic ring systems (e.g., 2,3-dihydro-1H-indene) containing at least one aromatic ring fused to one or more aromatic, non-aromatic, or heteroaromatic rings.

[0087] As used herein, the terms “heterocyclic,” “heterocyclic ring,” or “heteroaryl” are intended to mean a stable 5- to 7-membered monocyclic or polycyclic or 7- to 14-membered polycyclic ring containing at least one aromatic ring containing at least one heteroatom independently selected from the group consisting of N, O, and S. Therefore, “heterocyclic,” “heterocyclic ring,” or “heteroaryl” may include monoheteroaromatic or heteroaromatic rings fused to other heteroaromatic rings or nonheteroaromatic or nonaromatic rings. Heterocyclic rings may be bonded to side chains with any heteroatom or carbon atom, resulting in a stable structure. Heterocyclic rings described herein may be substituted with carbon or nitrogen atoms, provided that the resulting compound is stable. Examples of heterocyclic or heteroaryl groups include, but are not limited to, 1H-indazole, thiazolyl, furyl, pyridyl, quinolinyl, pyrrolyl, indole, or 5,6,7,8-tetrahydroquinoline.

[0088] The term "substitution" used here means that any one or more hydrogen atoms on a specified atom are replaced by a group of choice from a specified group, provided that the substitution does not exceed the normal valence of the specified atom and the substitution results in a stable compound. Therefore, optionally substituted alkyls are alkyl groups as defined above, in which one or more hydrogens are replaced by a select group from a specified group, including but not limited to halogens, hydroxyl, amino, sulfhydryl, alkyl, alkenyl, alkynyl, haloalkyl (e.g., CH2Cl, CF3, CH3CH2Br), amide, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, alkoxy, carboxy, carbonyl, silyl, alkylamino, alkylamide, nitro, cyano, halo, -S(O)-alkyl, -S(O)2-alkyl, R-cycloalkyl, R-heterocycloalkyl, RC(O)-, RC(O)-OR', RO-, -N(R)(R') (wherein R and R' are independently H, alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heteroarylalkyl, or heterocycloalkyl).

[0089] The term "splitting" is a technical term referring to the reaction of components of a racemic mixture with a chiral organic acid or base to form a diastereomer salt, and the separation of said salt into its enantiomer by any means, including, for example, crystallization techniques. The term "chiral salt splitting" refers to the separation of a racemic mixture into its enantiomer via the use of a chiral acid.

[0090] The term "chromatography" is well-known in this field and refers to the technique of separating components of a mixture by interacting them with a stationary phase and then eluting the mixture of components with a mobile phase such as ethanol, methanol, acetonitrile, water, or a mixture thereof. The term "chiral chromatography" refers to chromatography in which the stationary phase is chiral.

[0091] The term "chiral acid" refers to any optically active acid that can form diastereomer salts with compounds of formula 1B or 2B. The terms "mono- or di-carboxylic acid" or "sulfonic acid" refer to any compound containing one or two carboxyl functional groups and / or sulfonic acid groups, respectively. Examples of such acids include, but are not limited to, (+ / -) / (R / S) tartaric acid, (+ / -) / (R / S) (mono- or di-acetyl) tartaric acid, (+ / -) / (R / S) (mono- or di-benzoyl) tartaric acid, (+ / -) / (R / S) (mono- or di-pivaloyl) tartaric acid, (+ / -) / (R / S) mandelic acid, (+ / -) / (R / S) acetoxyphenylacetic acid, (+ / -) / (R / S) methoxyphenylacetic acid, (+ / -) / (R / S) hydroxymandelic acid, (+ / -) / (R / S) halomandelic acid (e.g., 4-fluoromandelic acid), (+ / -) / (R / S) lactic acid, and (+ / -) / (R / S) camphorsulfonic acid.

[0092] The term "protecting agent" refers to any compound that reacts with an atom to which protection is desired in order to block or sequester a functional group. They are commonly used to transiently modify potentially reactive functional groups to protect against unwanted chemical transformations. Desired protecting agents are those that are compatible with or stable under the reaction conditions and readily cleave after protection is no longer desired.

[0093] The terms “protecting group” and “protective group” refer to removable chemical groups used to protect or block reactive functional moieties during synthetic transformations. The term “protecting agent” refers to a reactant used to attach a protecting group to the functional moiety to be protected. For example, the protecting agent ethyl chloroformate is used to attach the protecting group ethoxycarbonyl, and the protecting agent BOC-anhydride is used to attach the protecting group t-butoxycarbonyl. Protecting groups as defined herein include those of the general formula -PZ (wherein Z is optionally substituted alkyl, aryl, alkylaryl, alkoxycarbonyl, or -OR, where R is alkyl, aryl, arylalkyl, or heteroarylalkyl, and P is -CH2-, -C(O)-, -C(O)O-, or S(O)2). Examples of protecting groups include benzyloxycarbonyl (Cbz), triphenylmethyl, alkyloxy and aryloxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, phenoxycarbonyl), benzyl N-succinimidylcarbonyl, benzoyl, substituted benzoyl, substituted benzyloxycarbonyl, benzyl, substituted benzyl, and alkyl and arylsulfonyl (e.g., methanesulfonyl, benzenesulfonyl, toluenesulfonyl). Further suitable protective agents and protecting groups can be found, for example, in “Protective Groups in Organic Synthesis” by Theodora Green (publisher: John Wiley & Sons, Fourth Edition, 2007), the disclosure of which is incorporated herein by reference in its entirety.

[0094] The term "deprotection" refers to the act of removing or cleaving a protecting group. The conditions for deprotecting the above-mentioned protecting group will inevitably vary depending on the choice of protecting group and may include acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, or trifluoroacetic acid or Lewis acid, e.g., boron tris(trifluoroacetate)) or base (alkali metal hydroxide, e.g., lithium hydroxide, potassium hydroxide, or sodium hydroxide) catalytic or catalytic hydrogenation conditions (e.g., hydrogen and palladium / carbon).

[0095] The term "catalyst" as used herein refers to any substance or agent that influences, induces, increases, affects, or promotes the reactivity or reaction of a compound without being consumed by itself. The term "transition metal catalyst" refers to any metal having valence electrons in its d orbitals, for example, a metal selected from one of groups 3 through 12 of the periodic table. Catalysts useful in the methods of the present invention include atoms, ions, salts, or complexes of transition metals from groups 8 through 11 of the periodic table. "Groups 3 through 12 of the periodic table" refers to the groups of the periodic table as numbered by the IUPAC system. Therefore, the transition metals of groups 8 through 11 include iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, palladium, platinum, copper, silver, and gold. Examples of such catalysts include, but are not limited to, CuI, CuCl, CuBr, CuBr2, Cu(II) acetate, Cu2Cl2, Cu2O, CuSO4, Cu2SO4, Cu, Pd / C, PdCl2, Pd(OAc)2, (CH3CN)2PdCl2, Pd[P(C6H5)3]4, bis(dibenzylideneacetone)palladium[Pd(dba)2], tris(dibenzylideneacetone)dipalladium[Pd2(dba)3], Ni(acetylacetonate)2, NiCl2[P(C6H5)]2, and Ni(1,5-cyclooctadiene)2. The catalyst is generally, but not necessarily, used in a quasi-stoichiometric amount relative to the reactants. Preferably, 0.5 to 20 mol%, most preferably 10 mol%, of the transition metal catalyst is used relative to the reactants.

[0096] The term "base" as used herein refers to organic or inorganic bases such as amine bases (e.g., ammonia, triethylamine, N,N'-diisopropylethylamine or 4-(dimethylamino)pyridine (DMAP); 1,5-diazabicyclo[4.3.0]-non-5-ene (DBN), 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU)); hydrides (e.g., sodium, lithium, or potassium hydrides); alkoxides (e.g., sodium, potassium, or lithium t-butoxide and K(OAr), Na(OAr)); or carbonates, bicarbonates, phosphates, or hydroxides of alkalis or alkaline earth metals (e.g., carbonates, bicarbonates, hydroxides, or phosphates of sodium, magnesium, calcium, potassium, cesium, or barium).

[0097] The term "Brønsted base" is a term recognized in this art and refers to an uncharged or charged atom or molecule that is a proton acceptor, such as an oxide, amine, alkoxide, or carbonate. Examples of Brønsted bases include, but are not limited to, K3PO4, K2CO3, Na2CO3, Tl2CO3, Cs2CO3, K(OtBu), Li(OtBu), Na(OtBu), K(OPh), and Na(OPh) or mixtures thereof.

[0098] The term "Lewis base" is recognized in this field as referring to a chemical moiety capable of donating an electron pair under certain reaction conditions. Examples of Lewis bases include, but are not limited to, uncharged compounds such as alcohols, thiols, olefins, and amines (e.g., ammonia, triethylamine), as well as charged moieties such as alkoxides, thiolates, carbanions, and various other organic anions.

[0099] The term "acid" here refers to Lewis acids or Brønsted acids. A Lewis acid is a technical term referring to a chemical moiety that can accept an electron pair (e.g., boron trifluoride). A Brønsted acid refers to any chemical moiety that can donate a proton (e.g., acetic acid, trifluoroacetic acid, methanesulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and other organic acids known in this field).

[0100] The term "ligand" refers to any atom, molecule, or ion that can donate or share one or more electrons with another central atom, generally a metal, through coordination and / or covalent bonding. A "monodentate ligand" is a ligand that has one bonding site with a central atom (e.g., pyridine or ammonia). A "bidentate ligand" is a ligand that has two bonding sites (e.g., N,N'-dimethylethylenediamine, N,N,N',N'-tetramethylethylenediamine, or 1,10-phenanthroline).Examples of useful ligands for group 8-11 transition metals include 2-phenylphenol, 2,6-dimethylphenol, 2-isopropylphenol, 1-naphthol, 8-hydroxyquinoline, 8-aminoquinoline, DBU, DBN, DABCO, 2-(dimethylamino)ethanol, N,N-diethylsalicylamide, 2-(dimethylamino)glycine, N,N,N',N'-tetramethyl-1,2-diaminoethane, 4,7-diphenyl-1,10-phenanthroline, and 4,7-dimethyl-1,10-phenantholine. Loline, 5-methyl-1,10-phenanthroline, 5-chloro-1,10-phenanthroline, 5-nitro-1,10-phenanthroline, 4-(dimethylamino)pyridine, 2-(aminomethyl)pyridine, (methylimide)diacetic acid, cis-1,2-diaminocyclohexane, trans-1,2-diaminocyclohexane, mixture of cis- and trans-1,2-diaminocyclohexane, cis-N,N'-dimethyl-1,2-diaminocyclohexane, trans-N,N'-dimethyl-1 ,2-diaminocyclohexane, mixtures of cis- and trans-N,N'-dimethyl-1,2-diaminocyclohexane, cis-N-tolyl-1,2-diaminocyclohexane, trans-N-tolyl-1,2-diaminocyclohexane, mixtures of cis- and trans-N-tolyl-1,2-diaminocyclohexane, ethanolamine, 1,2-diaminoethane, N,N'-dimethyl-1,2-diaminoethane, N,N-dimethyl-2-hydroxybenzamide, N,N-diethyl-2-hydroxybenzamide The ligands include, but are not limited to, droxybenzamide, fluoro-N,N-diethyl-2-hydroxybenzamide, chloro-N,N'-diethyl-2-hydroxybenzamide, (2-hydroxyphenyl)(pyrrolidine-1-yl)methanone, biphenyl-2-ol, 2-pyridylphenol, 1,2-benzenediamine, ammonia, N,N-dimethylformamide, dimethyl sulfoxide, 1-methyl-2-pyrrolidinone, or mixtures thereof, as well as the aforementioned biphenyl and binaphthyl ligands. In some embodiments, the amount of ligand used may be stoichiometric or in excess. In other embodiments, the ligand may be used as a reaction solvent.Therefore, reactants such as N,N-dimethylformamide, dimethyl sulfoxide, 1-methyl-2-pyrrolidinone, or other liquid amines can serve as solvents and ligands for the reaction.

[0101] The term "N,N'-dimethylethylenediamine" is interchangeable with "N,N'-dimethyl-1,2-diaminoethane".

[0102] The term "nucleophilic alkyl halide" refers to any compound that possesses both an alkyl halide functional group (electrophile) and a nucleophilic functional group. The terms "nucleophilic" or "nucleophile" are well understood in this field and refer to the chemical part that has a reactive electron pair.

[0103] The term "reduction" or "to reduce" refers to the conversion of a functional group in a molecule from a high oxidation state to a low oxidation state. The term "reducing agent" or "reducing agent" refers to any compound or complex known in this art to be effective in converting a functional group in a molecule from a high oxidation state to a low oxidation state. Examples of reduction include both the reduction of a carbon-carbon double bond to a carbon-carbon single bond and the reduction of a carbonyl group (C=O) to methylene (CH2). Reduction can be achieved by direct electron, hydride, or hydrogen-atom transfer. Typical reducing agents useful in methods 1C and 2C include catalysts (e.g., Raney nickel, palladium / carbon, nickel boride, platinum metal or its oxides, rhodium, ruthenium, and zinc oxide, pentacyanocobalt(II)Co(CN)5) 3-The catalytic hydrogenation is carried out in the presence of metal hydrides (e.g., lithium aluminum hydride, sodium borohydride, sodium cyanobolohydride) and hydrogen. Catalytic hydrogenation is generally carried out at room temperature and atmospheric pressure, but higher temperatures and / or higher pressures may be required for more resistant double bonds. Other reducing agents useful for converting double bonds to single bonds include silanes and acids, sodium cyanobolohydrides and acids, zinc and acids; sodium and liquid ammonia, sodium in ethanol, and borane-triethylamine. Typical reducing agents useful for the reduction of carbonyl to methylene, as in methods 1H and 2H, include, but are not limited to, metal hydrides (e.g., diisobutylaluminum hydride (DIBAL), sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al), or sodium cyanobolohydride), boranes (e.g., BH3-THF), or organoboranes (e.g., bis(benzyloxy)borane). Alternatively, such transformations can also be achieved by catalytic hydrogenation using hydrogen in the presence of a catalyst (e.g., nickel, palladium / carbon, nickel boride, platinum metal, platinum oxide, palladium oxide, rhodium oxide, ruthenium oxide, or zinc oxide), Wolff-Kishner reduction by heating ketones and hydrazine hydrate in the presence of a base such as sodium hydroxide or potassium hydroxide (see Todd, Org. React. 4, 378-422 (1948)), or Clemsen reduction by heating ketones with zinc amalgam and an aqueous mineral acid such as hydrochloric acid (see Vedejs, Org. React. 22, 401-422 (1975)). Other reactants that can also achieve such reductions include triisopropyl phosphate, copper in the presence of sulfuric acid, and tin in the presence of hydrochloric acid. For further examples of reducing agents, see “Advanced Organic Chemistry: Reactions, Mechanisms, and Structure” by Jerry March, pp. 771-790, John Wiley & Sons, Inc. (Fourth Edition).

[0104] The term "alkylation" refers to the introduction of an alkyl group into an organic compound by substitution or addition. Therefore, the term "N-alkylation" refers to the introduction of an alkyl group into the nitrogen atom of an organic compound.

[0105] Methods for producing the compounds described herein and for carrying out some steps of the methods described herein are known to those skilled in the art, for example, as can be seen in U.S. Patents 8,309,722; 8,779,139; 9,315,504; 9,751,883; 8,648,077; 9,199,995; and 9,586,960; the contents of each of these are incorporated herein by reference as a whole. [Examples]

[0106] Example 1: 6-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride. [ka] 1-(2-bromophenyl)hydrazine hydrochloride and 4-piperidinone monohydrate hydrochloride are combined in acetic acid in a ratio of approximately 1:1.1 molars. The resulting slurry is heated under reflux (e.g., for 6 hours) until the residual amount of hydrazine starting material is less than 1% by HPLC analysis. The reaction mixture is then cooled to room temperature, filtered, the cake is washed with acetone, and dried to a solid state for use in the next step.

[0107] Example 2: [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole [ka] Reduction (Option 1): [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole can be prepared by mixing 6-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride with trifluoroacetic acid (630 ml, 8.48 mmol, 10 vols) and triethylsilane (172 ml). The mixture is stirred at room temperature under nitrogen for 19 hours. Excess trifluoroacetic acid and triethylsilane are removed under reduced pressure. Hexane (550 ml) is added to the remaining oil and stirred at room temperature for 1 hour, then the hexane is discarded. Another 250 ml of hexane is added and stirred for 1 hour, then the hexane is discarded. 2N aqueous sodium hydroxide solution is added to the remaining oil until the pH reaches 10, then the solution is extracted with dichloromethane. Combine the organic layers, wash with salt water, and dry (Na2SO4).

[0108] Reduction (Option 2): Alternatively, charge methanesulfonic acid (400 mL) into a 3 L 3-neck RBF equipped with a magnetic stirrer, N2 inlet, and drying tube. Gradually add 6-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (100 g). Heat the reaction mixture to 40°C-45°C, then add triethylsilane (TES) (55.5 mL, 1 equivalent) dropwise over 1 hour to control the exothermic reaction. Maintain the temperature at 40°C-45°C. Once the addition is complete, stir the mixture at 40°C-45°C for 1.5 hours. You may then add another TES (13.9 mL, 0.25 equivalent) over approximately 10 minutes, and then stir the mixture at 40°C-45°C for 30 minutes. Further, 13.9 mL (0.25 equivalents) of TES may be added over approximately 10 minutes, and the mixture may be stirred overnight at room temperature. Further, 5.5 mL (0.1 equivalents) of TES may be added, and the mixture may be stirred at room temperature for 90 minutes. After cooling to <10°C, the reaction is stopped by adding water (600 mL) dropwise at a rate that maintains the temperature at <40°C (strong exothermic reaction is observed). Add dichloromethane (1000 mL) and adjust the pH of the mixture to approximately 12 with a 50% w / v NaOH aqueous solution. Filter the mixture through a Celite layer. Separate the layers and extract the aqueous layer with dichloromethane (100 mL). Wash the combined organic layers with water (100 mL), dry over magnesium sulfate (120 g), filter, and concentrate under reduced pressure. Treat the residue with heptane. After filtration, the obtained solid was dried under reduced pressure at 30°C to obtain 73.1 g of product (yield: 83%, HPLC purity: 97.1%).

[0109] Separation (Option 1): Enantiomer separation of [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole can be achieved by dissolving racemic cis-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (8 g, 31.6 mmol) in methanol (160 mL) at 50°C (oil bath) and gradually adding (R)-(-)-mandelic acid (4.8 g, 31.6 mmol). The resulting clear solution is stirred at 50°C for several minutes, and then ether (80 mL) is added dropwise. The resulting solution is cooled to room temperature, and the white precipitate (R-mandelate, 3.7 g) is filtered off. HPLC analysis shows >99% ee. The filtrate is concentrated and 1N The sample is treated with sodium hydroxide (100 mL) and extracted twice with dichloromethane (2 × 50 mL). The dichloromethane layers are combined, washed with brine (2 × 200 mL), and dried over sodium sulfate. The dichloromethane solution is concentrated to an oily consistency (5.59 g) and redissolved in methanol (90 mL) at 50°C. (S)-(+)-mandelic acid (3.53 g, 23.2 mmol) is added gradually. The resulting clear solution is stirred at 50°C for several minutes, and ether (45 mL) is added dropwise. The resulting solution is cooled to room temperature, and the white precipitate (S-mandelate, 4.19 g) is filtered off. HPLC analysis shows >99% ee. R-mandelate: [α] D 25 = -98.1, S-Mandelaat: [α] D 25 = +102, solvent: DMSO. Alternatively, the resolution may be carried out in a mixture of methanol and t-butyl methyl ether (MTBE) or separately in ethanol.

[0110] Separation (Option 2): Alternatively, [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole can be separated by dissolving racemic cis-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (9.61 g, 38.0 mmol) in methanol (190 mL) at 50°C, and gradually adding (S)-(+)-mandelic acid (5.78 g, 38.0 mmol). The resulting clear solution is stirred at 50°C for several minutes, and ether (95 mL) is added dropwise. The resulting solution is cooled to room temperature. The white precipitate (S-mandelate, 4.1 g) is filtered off. HPLC analysis shows >99% ee.

[0111] As a variation of the above method, [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole can be separated by dissolving racemic cis-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole in a 2 wt% aqueous ethanol solution at 45°C, then refluxing the mixture to obtain a clear solution. A 2 wt% aqueous / ethanol solution of (S)-(+)-mandelic acid (0.5~0.58 equivalents) is slowly added to the starting material solution at a rate that maintains a temperature of 65~80°C. After refluxing for another hour, the mixture is cooled to 70°C, and optionally, purified [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole is added as a seed crystal to stimulate crystallization. The reaction becomes slurry-like as it is cooled further to approximately 20°C over 2-3 hours. The product cake is finally isolated by filtration, washed with ethanol, and then dried under reduced pressure at 35-50°C.

[0112] Separation (Option 3): Enantiomer separation of [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole can be achieved by dissolving racemic cis-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (1710 g "as is", theoretically 1570 g, 6.21 mol) in methanol (24 L) while heating to 40-50°C (under nitrogen). To this mixture, (R)-(-)-mandelic acid (944 g, 6.2 mol) is added all at once. The heating mantle is turned off and MTBE (13 L) is added to the mixture. The resulting solution is cooled to room temperature while stirring and aged for 30-40 hours at 15-25°C with stirring. The product was isolated by filtration as a white to grayish-white precipitate and air-dried overnight at ambient temperature. This yielded 580 gm (23%) of R-mandelate. Chiral HPLC analysis showed >99% ee.

[0113] The filtrate is concentrated, diluted with water (25 L), stirred, and treated with 50% NaOH (800 ml) until the pH is measured with pH test paper and reduced to approximately 14. The free base is extracted with dichloromethane (2 × 17 L and 1 × 6 L). The DCM layers are combined, dried (Na2SO4), and concentrated to obtain solid free base (approximately 1150 g). The free base is dissolved in methanol (17 L) while being heated to 40-50°C under N2, and (S)-(+)-mandelic acid (692 g, 4.55 mol) is added. The heating mantle is turned off, and MTBE (8.5 L) is added to the solution all at once. The resulting solution is cooled to room temperature while stirring and aged for 30-40 hours. The product is isolated by filtration as a white to grayish-white precipitate and air-dried overnight at ambient temperature. This yields 828 gm (33%) of S-mandelate. Chiral HPLC analysis shows the presence of a fast-moving enantiomer (>99%ee) and two other impurities at approximately 1% each (which elute immediately before the unwanted enantiomer). R-Mandelaat:[α] D 25 = -98.1, S-Mandelaat: [α] D 25= +102, Solvent: DMSO (approximately 10 mg in 3 ml DMSO). Chiral HPLC conditions: Chiralpak AD-H, 250 × 4.6 mm, 30% IPA in hexane containing 0.1% diethylamine, flow rate 0.8 ml / min, UV detection 254 nm. The sample was prepared by ultrasonic treatment of the salt in IPA.

[0114] Separation (Option 4): Instead of chiral resolution, enantiomer separation of [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole can also be achieved by preparative chromatography using a Chiralpak® AD® column, 20 μm, 5 cm inner diameter × 50 cm length. 26.4 g, 23.0 g, and 14.8 g of racemic 6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole are dissolved separately in 100% ethanol with stirring (and optionally with slight heating), and then filtered through a 0.4 μm filter. The feeds are injected separately in 25 mL volumes and eluted with 100% ethanol at a flow rate of 150 mL / min at 25°C. Alternatively, dissolve 420 g of racemic 6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole in the same manner, filter, and inject 55 mL of the solution into a Chiralpak® AD® column, 20 μm, 11 cm inner diameter × 25 cm length, at a flow rate of 400 mL / min. Detect the product at a UV wavelength of 330 nm. Collect the product and evaporate the solvent in a rotary evaporator at 40°C and under reduced pressure of 50–70 mbar. Analyze the product by chiral HPLC analysis using an AD-H 4.6 mm ID × 250 mm column with a column temperature of 30°C, a 100% ethanol mobile phase at a flow rate of 0.7 mL / min, and detection at 200 nm, 230 nm, 250 nm, 280 nm, or 325 nm. The product is also analyzed by achiral HPLC using an Eclipse, 5 μm XDB-C8, 4.6 mm ID × 250 mm column, at a column temperature of 30°C and a flow rate of 1 mL / min with a 75:25 methanol / 0.1% diethylamine aqueous solution and detection at 250 nm, 200 nm, 230 nm, 280 nm, or 325 nm. The isolated product has >98% ee.

[0115] Example 3: (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate [ka] (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate can be prepared by first using a 50% aqueous sodium hydroxide solution and extracting the product with MTBE to obtain [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (36.0 g, 0.142 mol)) as a free base. Next, the conversion to (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate can be carried out by cooling a suspension of [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (36.0 g, 0.142 mol)) in THF (300 ml) and triethylamine (24 ml) in an ice-water bath. Ethyl chloroformate (13.5 ml, 0.142 mol) is added dropwise from a syringe pump over 1 hour. The ice-water bath is removed and the reaction mixture is stirred at room temperature for a further 1 hour. The reaction mixture is passed through a Celite pad to remove the solvent and obtain (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate). 1 H NMR (CDCl3, 300 MHz):1.20-1.35 (m,3H), 1.73-1.85 (m, 1H), 1.85-1.99 (m, 1H), 3.22-3.52 (m, 3H), 3.52-3.66 (m, 1H), 3.66-3.95 (Br, 1H), 3.95-4.21 (m, 4H), 6.60 (t, J=7.7 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H)

[0116] Instead of using the free base of [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (compound of formula 1C), the reaction can also be carried out by starting with the (S)-mandelate of [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole. A 100 mL round-bottom flask is fitted with a magnetic stirring bar, a pressure-equalizing dropping funnel, and an N2 inlet at the top of the dropping funnel. The flask is charged with S-mandelate starting material (5 g, 12.35 mmol), Na2CO3 (2.88 g, 27.17 mmol), and 25 mL of THF. To the yellow reaction mixture, add 5 mL of ethyl chloroformate (1.64 g, 15.11 mmol) in a THF solution dropwise over approximately 70 minutes at 25°C (heating block temperature). Stir the reaction batch at 25°C for a further 10 minutes, then confirm by HPLC. Less than 2% of the starting material is observed by HPLC, and the desired product is shown at approximately 98%. Add 12.5 mL of EtOH to the reaction, and concentrate the reaction under reduced pressure to remove approximately 30 mL of solvent (mostly THF). Then add 37.5 mL of H2O to the reaction, and the resulting mixture shows a pH > 9 on pH test paper. Stir the yellow mixture at room temperature for approximately 1 hour, then filter. Rinse the solid with 25 mL of H2O. After drying in a vacuum oven at 58°C for approximately 16 hours, 3.9442 g of yellow solid is obtained (98% yield). 1 ¹H NMR analysis confirms that (s)-mandelic acid is not present. HPLC analysis of the product shows the desired product with >99% purity. LC-MS shows a peak with M / e = 326 (M+1).

[0117] Example 4: [4aS,9bR]-ethyl 5-(2-amino-2-oxoethyl)-6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate [ka] (4aS,9bR)-ethyl 5-(2-amino-2-oxoethyl)-6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate can be prepared by heating an acetonitrile (80 mL) suspension of (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate (5.648 g, 17.4 mmol), 2-chloroacetamide (7.32 g, 78.2 mmol), potassium iodide (19.2 g, 77.7 mol), and diisopropylethylamine (19 mL, 115 mmol) for 27 hours under reflux. Remove the solvent under reduced pressure, add water (200 mL) to the residue, and stir for 1 hour. The resulting white solid is filtered, washed with ethanol, and dried.

[0118] Example 5: (4aS,9bR)-ethyl6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate [ka] 1,000 equivalents of ethyl(4aS,9bR)-6-bromo-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate are charged into a reactor at 20°C with 0.50 volumes of dimethylacetamide solvent. 1,500 equivalents of N-methylchloroacetamide are added in 0.30 volumes of dimethylacetamide solution, followed by 1,000 equivalents of potassium iodide and 1,700 equivalents of diisopropylethylamine. The resulting suspension is heated at 102°C for 15-18 hours. After cooling to 45°C, 5.00 volumes of water are added. After further cooling and stirring, the product is isolated as a solid filter cake, washed with water, and dried under reduced pressure.

[0119] Example 6: (6bR,10aS)-ethyl 2,3,6b,9,10,10a-hexahydro-2-oxo-1H-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline-8-carboxylate [ka] A dioxane (20 mL) suspension containing [4aS,9bR]-ethyl 5-(2-amino-2-oxoethyl)-6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate (254 mg, 1.34 mmol), cuprous iodide (254 mg, 1.34 mol), potassium carbonate (3.96 g, 28.7 mmol), and N,N'-dimethylethylenediamine (0.31 mL, 2.87 mmol) was heated under reflux for 4.5 hours. Cuprous iodide (250 mg, 1.32 mmol) and N,N'-dimethylethylenediamine (0.33 mL, 3.05 mmol) were then added. The resulting mixture was heated under reflux for a further 3 hours, and then heated at 73°C for approximately 66 hours. The reaction mixture is concentrated and passed through a short alumina column using a 100:3:3 dichloromethane:triethylamine:methanol mixture. The solvent from the resulting column is evaporated until solid and redissolved in dichloromethane. The dichloromethane solution is washed with brine, dried over sodium sulfate, and concentrated to a solid (3.7 g, 95%, 83% purity by HPLC).

[0120] Example 7: (6bR,10aS)-ethyl 2,3,6b,9,10,10a-hexahydro-3-methyl-2-oxo-1H-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline-8-carboxylate [ka] (6bR,10aS)-ethyl 3,6b,9,10,10a-hexahydro-3-methyl-2-oxo-1H-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline-8-carboxylate can also be prepared by a one-pot method starting from the compound of formula 1D. A 2-liter four-neck round-bottom flask is fitted with a mechanical stirrer, reflux condenser, N2 inlet, Teflon-coated K-type temperature probe with controller, and heating mantle. Charge a flask with (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate (250 g, 769 mmol), N-methylchloroacetamide (124 g, 1153 mmol, 1.5 equivalents), potassium iodide (191.5 g, 1160 mmol, 1.5 equivalents), diisopropylethylamine (266 mL, 1531 mmol, 2.0 equivalents), and dioxane (625 mL). Heat the reaction mixture to reflux temperature of approximately 103°C (approximately 48 hours) until the amount of starting substrate observed by HPLC is less than 3%. Further addition of N-methylchloroacetamide and diisopropylethylamine may be necessary. Next, the reaction mixture is cooled to approximately 80°C, and at this temperature, copper iodide (29.2 g, 153.8 mmol, 0.2 equivalents), potassium carbonate (232.5 g, 1682 mmol, 2.2 equivalents), dimethylethylenediamine (49.6 mL, 461 mmol, 0.6 equivalents), and dioxane (375 mL) are added. Then, the reaction mixture is reheated to reflux temperature and monitored by HPLC. Reflux occurs at approximately 103°C. Monitor the reaction by HPLC.

[0121] When complete, the reaction mixture is cooled to approximately 40°C and poured into a flash-grade silica gel plug (625g, 2.5g / g). It is then eluted with 6.25L of ethyl acetate (under reduced pressure). The eluent is concentrated to obtain a solid residue (320gm), which is then dissolved in hot ethanol (800ml). This mixture is cooled to ambient temperature and stirred overnight. The next day, it is cooled to 0-5°C, aged for 1 hour, and filtered. The cake is washed with cold ethanol (150ml) and air-dried to obtain 170g (70%) of the product as a white solid, which has a purity of >99% according to HPLC. HPLC 10:90-90:10 CH3CN:H2O for 15 minutes. Maintained at 90:10 for 2 minutes, 0.025% TFA buffer, 1.5 mL / min, 220 nm UV, on a 4.6 mm × 250 mm Phenomenex Jupiter C18 column. The product was found to be 75A% pure by LC / MS with total ion chromatography. 1 H-NMR (300MHz, CDCl3) 1.28(t, J=6.9Hz, 3H), 1.86-1.96(m, 2H), 2.72(br, 1H), 3.09-3.48(m, 7H), 3.86-4.21(m, 5H), 6.75(dd, J=1.2, 7.8Hz, 1H), 6.82(t, J=7.8Hz, 1H), 6.90(dd, J=1.2, 7.2Hz, 1H)

[0122] Example 8: (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline-8-carboxylate [ka] (6bR,10aS)-ethyl 2,3,6b,9,10,10a-hexahydro-3-methyl-1H-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline-8-carboxylate can be obtained by adding BH3·THF (1M in THF, 143mL, 143 mmol) dropwise to a 50 ml THF suspension of (6bR,10aS)-ethyl 2,3,6b,9,10,10a-hexahydro-3-methyl-2-oxo-1H-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline-8-carboxylate (18.0 g, approximately 57 mmol) at room temperature for 15 minutes. The resulting mixture is heated under reflux for 3 hours. The reaction mixture is cooled in an ice-water bath, and 150 ml of 6N HCl is added dropwise. After removing THF under reduced pressure, 2N NaOH is added to pH=9, followed by extraction with 500 ml of DCM. The DCM layer is washed with brine and dried over Na2SO4. By evaporation of the solvent, crude (6bR,10aS)-ethyl 2,3,6b,9,10,10a-hexahydro-3-methyl-1H-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]-quinoxaline-8-carboxylate is obtained.

[0123] Alternatively, (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline can be prepared as follows: In a 5 L, three-necked round-bottom flask equipped with an overhead stirrer, an N2 inlet, and a K-type Teflon-coated temperature probe, (6bR,10aS)-ethyl 2,3,6b,9,10,10a-hexahydro-3-methyl-2-oxo-1H-pyrido[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline-8-carboxylate (218 g, 691.3 mmol) is charged using THF (approximately 50 mL). The reaction vessel is purged three times by vacuum / N2, and then a 1M solution of the BH3-THF complex in THF (1962 mL, 1962 mmol, 2.8 equivalents) is slowly added from a dropping funnel. The resulting clear solution is then heated to 60°C. The resulting batch is then stirred at 60°C for about 17 hours, and HPLC shows 89.0% of the desired product and about 3.0% of unreacted substrate. The batch is stirred at 60°C for a further 3 hours, and then cooled to about 10°C in an ice bath. MeOH (327 mL, 8073 mmol, 11.7 equivalents) is slowly added to the batch from a dropping funnel while maintaining the internal temperature below 25°C. The resulting batch is stirred in an ice bath for about 30 minutes, and then concentrated under reduced pressure to obtain a yellow paste. The crude paste is then partitioned into siRNA (2180 mL) and H2O (2180 mL). The separated organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure to obtain 227.6 g of a yellow liquid. HPLC analysis of the liquid showed 89% of the desired product, 2.6% impurities with an RRt of 0.62, and 2.5% of the starting material. 1 H NMR (CDCl3, 300 MHz) δ 1.28 (t, J=7.0Hz, 3H), 1.79-1.95 (m, 2H), 2.74-2.92 (m, 5H), 3.02-3.22 (m, 2H), 3.22-3.38 (m, 3H), 3.54-3.64 (m, 1H), 3.78-4.24 (m, 4H), 6.41(d, J=7.8Hz, 1H), 6.54 (d, J=7.2Hz, 1H), 6.66 (t, J=7.7Hz, 1H); 13C- NMR (CDCl3, 75 MHz) δ 14.9, 24.7, 37.7, 39.9, 41.4, 44.4, 45.8, 50.7, 61.4, 65.0, 109.3, 113.3, 120.6, 128.8, 135.1, 138.2, 155.6

[0124] Example 9: (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline [ka] Ethyl (6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline-8-carboxylate (approx. 18.5g, 57mmol), KOH (12.7g, 226mmol), and n-butanol are placed in a 300ml pressure bottle and heated in an oil bath at 120°C for 3 hours. The n-butanol is removed under reduced pressure, 300ml of water is added, and then the mixture is extracted with DCM. The DCM layers are combined, washed with brine, and dried (Na2SO4). By evaporation of the solvent, (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline is obtained.

[0125] Example 10: (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline hydrochloride [ka] This example represents a one-pot three-step transformation involving cyclization of the compound of formula 1E to obtain the compound of formula 1F, reduction of the amide of the compound of formula 1F to obtain the compound of formula 1H, and deprotection of the compound of formula 1H to obtain the compound of formula 1I (wherein R is methyl and B is ethoxycarbonyl).

[0126] Charge 1.00 equivalents of ethyl(4aS,9bR)-6-bromo-5-(2-(methylamino)-2-oxoethyl)-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate into the reactor with 1.90 volumes of toluene, followed by the addition of 2.20 equivalents of potassium carbonate. Distill the reaction mixture at 110°C in an azeotropic distiller until the distillate becomes clear. Adjust the temperature to 50°C, then add 0.20 equivalents of copper(I) iodide and 0.25 equivalents of DBU. Heat the reaction mixture and stir at 95°C for 3-4 hours. Once the alkylation reaction is complete, as determined by HPLC, adjust the temperature to 35°C and add 3.00 equivalents of 1.0 M borane-THF complex THF solution. Stir the reaction mixture at 10°C-40°C for 3-4 hours. Once the reduction reaction is complete, as determined by HPLC, the reaction mixture is cooled to 5°C, and the excess reactant is slowly inactivated by adding 1.0 volume of methanol. The reaction mixture is stirred for a further 1 hour, then filtered through Celite and washed with THF. The solvent is removed by distillation, and the intermediate product, ethyl(6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline-8(7H)-carboxylate, is isolated by aqueous extraction between a 5% sodium hydroxide solution and ethyl acetate. The organic phases are combined, washed with brine, and then filtered through Florisil. A 20-33% aqueous hydrochloric acid solution is added to lower the pH to below 1, and the two-phase mixture is vigorously stirred for 15 minutes. The layers are separated, the organic layer is discarded, and the aqueous layer is distilled under reduced pressure to remove the solvent. Add a 33% hydrochloric acid aqueous solution to the residue and reflux the reaction for 15-17 hours. Once the decarboxylation reaction is complete, cool the reaction to 5°C, dilute with 5 volumes of MTBE, and basicize to pH 12 with a 30% sodium hydroxide aqueous solution. After stirring for 30 minutes, extract the aqueous layer with MTBE, combine with the organic phase, and then filter through Celite. Remove the solvent under reduced pressure and dissolve the residue in 3 volumes of isopropanol. Add a 33% hydrochloric acid aqueous solution to adjust the pH to 4.5-6.5. After stirring for at least 1 hour, isolate the product by filtration at 2°C followed by vacuum drying. The yield is 65-85% over several trials.

[0127] A series of implementations are carried out to evaluate the range of implementation conditions that produce the product of Example 10 in an acceptable yield and purity. It is found that the reaction can be successfully carried out starting with 1.0 equivalent of a toluene solution of the starting material and 2.20 equivalents of potassium carbonate, using 0.18–0.22 equivalents of copper iodide, 0.23–0.27 equivalents of DBU, and 2.7–3.3 equivalents of the borane-THF complex.

[0128] Example 11: 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline-8-(7H)-yl)-1-(4-fluorophenyl)-1-butanone free base [ka] (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline (approx. 11.8 g, approx. 50 mmol), 4-chloro-4'-fluorobutyrophenone (15.0 g, 74.8 mmol), triethylamine (30 mL, 214 mmol), and potassium iodide (12.6 g, 76 mmol) are suspended in dioxane (65 ml) and toluene (65 ml) and heated under reflux for 7 hours. After filtration and evaporation of the solvent, 200 ml of DCM is added. The DCM solution is washed with brine, dried (Na2SO4), and concentrated to approximately 55 ml. The concentrated solution is added dropwise to 600 ml of 0.5 N HCl ether solution. The solid was filtered off, washed with ether, and then dissolved in water. The resulting aqueous solution was basicized with 2N NaOH and extracted with DCM. The DCM layers were combined, washed with brine (2 × 200 mL), and dried (Na₂SO₄). By evaporation of the solvent and chromatography of the residue on silica gel, 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline-8-(7H)-yl)-1-(4-fluorophenyl)-1-butanone.

[0129] Instead of using dioxane, the reaction can be carried out in 3-pentanone. In a 5 L, three-necked, round-bottom flask equipped with a mechanical stirrer, N2 inlet, reflux condenser and temperature probe, 230 g of (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido-[3’,4’:4,5]-pyrrolo[1,2,3-de]quinoxaline (1 mol), 249.78 g of KI (1.5 mol, 1.5 equivalents), 194.12 g of i Pr2NEt (1.5 mol, 1.5 equivalents), 301.76 g of 4-chloro-4’-fluorobutyrophenone (1.5 mol, 1.5 equivalents) and 2300 mL of 3-pentanone are charged. Then, the resulting mixture is heated at 95 °C (internal temperature) for 17 hours, and then the completion of the reaction is confirmed by HPLC. Then, the batch is cooled to about 10 °C in an ice bath, and then 5% NaOH solution (2300 mL) is added. Then, the separated aqueous layer is extracted with EtOAc (2300 mL). The combined organic layers are filtered through a silica gel pad (115 g) pre-packed with EtOAc. Then, EtOAc (2300 mL) is passed through the silica gel. The combined filtrate is concentrated under reduced pressure to obtain a dark brown liquid. Then, EtOAc (2300 mL) and 1.5 N HCl solution (2300 mL) are added to the liquid. The batch is stirred at RT for about 20 minutes and the layers are separated. The separated organic layer is extracted with 1.5 N HCl solution (1150 mL) and the layers are separated. The combined aqueous layers are cooled to about 10 °C in an ice bath and EtOAc (2300 mL) is added. Then, 25% NaOH solution (1000 mL) is added dropwise to the stirred mixture while maintaining the internal temperature below 25 °C. The resulting mixture is stirred in an ice bath for about 20 minutes and the layers are separated. The aqueous layer shows a pH of 11 - 12 on pH test paper. The aqueous layer is back-extracted with EtOAc (1150 mL) and the layers are separated. The combined organic layers are washed with brine (1150 mL), dried over Na2SO4 (230 g), filtered and concentrated under reduced pressure to obtain 368.8 g of a dark brown liquid. The crude free base is stored under N2 in a cold dark room.

[0130] Example 12: 4-((6bR,10aS)-3-Methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3’,4’:4,5]-pyrrolo[1,2,3-de]quinoxalin-8-(7H)-yl)-1-(4-fluorophenyl)-1-butanone hydrochloride To a 250 mL three-necked round-bottom flask equipped with a mechanical stirrer, a nitrogen inlet, and a thermocouple, add a solution of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3’,4’:4,5]-pyrrolo[1,2,3-de]quinoxalin-8-(7H)-yl)-1-(4-fluorophenyl)-1-butanone (10 g) in isopropyl acetate (100 mL). Add 18 wt% HCl / isopropyl acetate solution (1.8 mL) to adjust the pH to about pH 1. Stir the reaction mixture at 0 - 5 °C under nitrogen for 1.5 hours. Filter the suspension and wash the solid with isopropyl acetate (25 mL) to obtain the solid 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3’,4’:4,5]-pyrrolo[1,2,3-de]quinoxalin-8-(7H)-yl)-1-(4-fluorophenyl)-1-butanone hydrochloride and a clear filtrate. Dry the solid in a vacuum oven at 45 °C to obtain 10.77 g (95% purity by HPLC).

[0131] Example 13: 4-((6bR,10aS)-3-Methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido-[3’,4’:4,5]-pyrrolo[1,2,3-de]quinoxaline free base

Chemical formula

[0132] In a 22 L three-neck round-bottom flask equipped with a mechanical stirrer, nitrogen inlet, thermocouple, Dean-Stark trap, and condenser, add (4aS,9bR)-ethyl 6-bromo-5-(2-(methylamino)-2-oxoethyl)-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate (1.45 kg), potassium carbonate powder 325 mesh (1.11 kg), and toluene (2.9 L). Heat the resulting suspension under reflux (110-112°C) and stir for 30-60 minutes. Cool the reaction mixture to 45-55°C, then add copper(I) iodide (139.4 g) and DBU (139.3 g), and stir the reaction mixture at the same temperature for 1 hour. Next, the reactants are heated again to reflux temperature and maintained for 2.5 to 5 hours while monitoring the reaction progress with HPLC. The reaction continues until the amount of starting material is 3.5% or less, as measured by HPLC.

[0133] While cooling to maintain a temperature of 15-25°C, add the borane-THF complex solution (1 M in THF, 11 L) dropwise using a funnel. Stir the reaction mixture at the same temperature for 12-24 hours, monitoring the reaction progress by HPLC. Continue the reaction until the amide intermediate is reduced to less than 1% by HPLC. Then, transfer the reaction mixture to a 50 L three-neck round-bottom flask equipped with a mechanical stirrer, nitrogen inlet, and thermocouple. Slowly stop the reaction by cooling the reaction mixture to 0-10°C and adding methanol (1.45 L) at a rate that controls foaming and maintains the desired temperature. After the addition is complete, stir the reaction mixture at 0-20°C for 1 hour, then filter through a 0.5-inch thick layer of Celite, followed by rinsing with THF (3 × 2.2 L).

[0134] The combined filtrates are concentrated under reduced pressure (30-50°C and 60-80 mm Hg) to obtain an amber-colored oily substance and a fine brown solid. The residue is resuspended in ethyl acetate (4.35 L), filtered through a 0.5-inch thick layer of Celite, and then rinsed with ethyl acetate (2 × 1.45 L). The combined filtrates are washed with a 5 wt% sodium hydroxide aqueous solution (2.18 L) and then washed with brine (1.45 L).

[0135] Place Florisil (0.435 kg) and ethyl acetate (1 L) in a 22 L three-neck round-bottom flask, stir for 30 minutes, then add the washed filtrate. Stir the resulting suspension for 14-24 hours at 15-25°C. Add water (2.2 L) and stir the mixture for a further 2-4 hours. Filter the suspension and wash the filter cake with ethyl acetate (2 × 1.45 L).

[0136] Charge a 22L three-neck round-bottom flask equipped with a mechanical stirrer, nitrogen inlet, and thermocouple with water (2.9L) and concentrated hydrochloric acid aqueous solution (1.45L). Cool the solution to 0-10°C, then add the ethyl acetate filtrate at a rate that maintains a temperature below 20°C. After stirring for 15 minutes, separate the layers and concentrate the organic layer to remove the solvent. Add the concentrate to a 22L three-neck round-bottom flask equipped with a mechanical stirrer, nitrogen inlet, and thermocouple, and add concentrated hydrochloric acid aqueous solution (1.45L). Stir the solution at ambient temperature for 15 minutes, then heat under reflux (99-104°C) for 24-40 hours. Monitor the reaction progress by HPLC.

[0137] Once complete, the reaction mixture is cooled to ambient temperature. Water (2.9 L) and isopropyl acetate (2.9 L) are added. The layers are separated, the organic layer is discarded, and isopropyl acetate (4.35 L) is added to the aqueous layer. The aqueous layer is cooled to 0-15°C, and 50 wt% sodium hydroxide aqueous solution is added at a rate that maintains a temperature below 20°C. After the addition is complete, the reaction mixture is stirred at 0-20°C for 10-20 minutes, and then the layers are separated. The aqueous layer is extracted with isopropyl acetate (1.5 L), the two organic layers are combined, washed once with brine (1.45 L), and then dried over sodium sulfate. The filtrate is then stirred with Florisil (363 g) for 2-4 hours, filtered, and the filter cake is washed with isopropyl acetate (2 × 2.9 L). The organic solution is concentrated under reduced pressure, and the product is recrystallized from n-heptane. HPLC is performed to obtain 642 g (76%) of light brown crystalline solid with 99% purity.

[0138] Example 14: 4-((6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline hydrochloride In a 2 L three-neck round-bottom flask equipped with a mechanical stirrer, thermocouple, and nitrogen inlet, charge (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline (80 g) (free base) and 2-propanol (360 mL, 4.5 vol). Stir the mixture for 10-30 minutes to obtain a dark amber solution. Add water (80 mL, 0.3488 mol). Stir the mixture at room temperature for 5-15 minutes. Adjust the pH of the mixture to 6-8 (using pH test paper) by adding concentrated HCl dropwise from a dropping funnel. A concentrated suspension will form during the addition. Once the desired pH is reached, stir the mixture at room temperature for a further 30-60 minutes, then cool to 0-5°C. Dilute the suspension with 2-propanol (40 mL, 0.5 vol) to allow stirring. After filtration, wash the filter cake twice with a cold mixture of water (4 mL, 0.05 vol) and 2-propanol (76 mL, 0.95 vol) (0-5°C), followed by sequential washing with cold 2-propanol (0-5°C) (80 mL, 1 vol), cold (0-5°C) MTBE (80 mL, 1 vol), and MTBE (80 mL, 1 vol). Dry the solid under reduced pressure at 40-45°C to obtain 68.9 g of the product as crystalline monohydrochloride (HPLC purity: 99.18%).

[0139] The monohydrochloride salt of the obtained 4-((6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline hydrochloride was analyzed by X-ray powder diffraction (XRPD).

[0140] XRPD pattern, 4-((6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline monohydrochloride: [Table 1]

[0141] XRPD pattern, 4-((6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline free base: [Table 2]

[0142] Example 15: 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido-[3',4':4,5]-pyrrolo[1,2,3-de]quinoxaline-8-(7H)-yl)-1-(4-fluorophenyl)-1-butanone tosylate Mix water, (6bR,10aS)-3-methyl-2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de]quinoxaline hydrochloride (1.0 equivalent), and isopropyl acetate, and cool to 0°C to 30°C. Add the dilute NaOH solution while maintaining the temperature between 0°C and below 30°C, and stir the mixture for at least 30 minutes while maintaining the pH above 12. Then separate the phases and back-extract the lower aqueous phase once with isopropyl acetate. Separate the layers again, combine the organic extracts, and wash with a 10% sodium chloride solution. Remove the isopropyl acetate by distillation under reduced pressure.

[0143] Next, 3-pentanone is added, and vacuum distillation is performed to remove any remaining isopropyl acetate. 3-pentanone is added again, and the temperature is maintained at 20°C ± 10°C. 4-chloro-4'-fluorobutyrophenone (1.35–1.65 equivalents) is added. Sodium carbonate (2.7–3.3 equivalents) and potassium iodide (0.9–1.1 equivalents) are added. The reaction mixture is purged with nitrogen, and then slowly heated to approximately 73°C, and maintained at that temperature for at least 16 hours until the reaction is complete by HPLC. Once the reaction is complete, the reaction mixture is cooled to 30°C. Water is then added, and the mixture is stirred for at least 30 minutes. The layers are then separated, and the lower aqueous phase is discarded. The organic layer is cooled to 5°C and washed with 10% HCl solution (maintaining the temperature below 20°C and the pH below 1). The layers are then separated, the aqueous layer is transferred to a clean container, and the organic layer is discarded. Add ethyl acetate and stir the mixture for 15 minutes, then separate the layers and discard the organic layer.

[0144] Add ethyl acetate to the aqueous layer and cool the mixture to 3°C. Then slowly add the 30% NaOH solution while maintaining a temperature below 20°C. Adjust the pH of the mixture to at least 10. After mixing, separate the phases and transfer the lower aqueous phase to a clean container. Add ethyl acetate to the aqueous layer, mix, separate the layers, and discard the aqueous layer. Combine the remaining organic layers and wash with a 20% sodium chloride solution. Then discard the aqueous layer. Remove the solvent from the organic layers by vacuum distillation and dissolve the residue in MTBE. Treat the organic layers with activated carbon in ethyl acetate for at least 60 minutes at 20°C. Remove the activated carbon by filtration and remove the MTBE by distilling the mixture under reduced pressure. Add isopropyl alcohol and distill the mixture under reduced pressure to remove any remaining MTBE. Add the isopropyl alcohol back to the reactor and add the isopropyl alcohol solution of p-toluenesulfonic acid (0.89-1.11 equivalents) while maintaining the temperature at 33°C. If desired, seed crystals of the desired tosylate product may be added to stimulate crystallization. The product is isolated by centrifugation. The cake is washed with isopropanol, followed by MTBE. The crude product is dried under reduced pressure at 45°C. The crude product is added to the reactor with isopropanol and water. The mixture is heated to reflux and stirred under reflux for at least 10 minutes to ensure complete dissolution of the solid. The solution is then filtered and cooled to 65°C, to which seed crystals of the product are optionally added and / or further cooled to 55°C, then cooled to 0-10°C, and granulated at this temperature for at least 60 minutes. The final product is isolated, washed with isopropanol and MTBE, and the cake is dried under reduced pressure at 45°C. The material is then ground to achieve the desired particle size. In various batches, the yield was found to be 65%-85% through multiple steps.

Claims

1. Formula 1I in free form or salt form 【Chemistry 1】 [During the ceremony, R is H or C １－４ It is an alkyl group (for example, methyl). This is a method for producing the compound, (a) Formula 1E in free form or salt form 【Chemistry 2】 [In the formula, (i) A is selected from Br, Cl and I, and (ii) R is H and C １－４ (iii) B is a protecting group. The compound is reacted with (i) a transition metal catalyst selected from groups 8 to 11 of the periodic table, (ii) a base if desired, (iii) an alkali metal iodide (e.g., potassium iodide) if desired, and (iv) a monodentate or bidentate ligand to obtain the free or salt form of formula 1F 【Transformation 3】 [In the formula, (i)R is H and C １－４ (ii) B is a protecting group, selected from alkyl groups (e.g., methyl). Obtaining an intermediate, (b) Reduce the amide carbonyl of the compound of formula 1F to obtain the free or salt form of formula 1H 【Chemistry 4】 [In the formula, (i)R is H and C １－４ (ii) B is a protecting group, selected from alkyl groups (e.g., methyl). We obtain an intermediate, and (c) Deprotect the piperidine nitrogen of the compound of formula 1H to obtain the free form or salt form of formula 1I 【Transformation 5】 [In the formula, (i)R is H and C １－４ Selected from alkyl (e.g., methyl). Obtain the compound A method that includes a process.

2. Formula 1J in free form or salt form 【Transformation 6】 [During the ceremony, R is H or C １－４ It is alkyl (for example, methyl), and Q is selected from 4-(4-fluorophenyl)-4-oxobutyl and 3-(4-fluorophenoxy)propyl. A method for producing the compound, (a) Formula 1E in free form or salt form 【Transformation 7】 [In the formula, (i) A is selected from Br, Cl and I, and (ii) R is H and C １－４ (iii) B is a protecting group. The compound is reacted with (i) a transition metal catalyst selected from groups 8 to 11 of the periodic table, (ii) a base if desired, (iii) an alkali metal iodide (e.g., potassium iodide) if desired, and (iv) a monodentate or bidentate ligand to obtain the free or salt form of formula 1F 【Transformation 8】 [In the formula, (i)R is H and C １－４ (ii) B is a protecting group, selected from alkyl groups (e.g., methyl). Obtaining an intermediate, (b) Reduce the amide carbonyl of the compound of formula 1F to obtain the free or salt form of formula 1H 【Chemistry 9】 [wherein, (i) R is selected from H and C １－４ alkyl (such as methyl), and (ii) B is a protecting group.] We obtain an intermediate, and (c) Deprotect the piperidine nitrogen of the compound of formula 1H to obtain the free form or salt form of formula 1I 【Chemistry 10】 [In the formula, (i)R is H and C １－４ Selected from alkyl (e.g., methyl). Obtaining the compound, (d) The piperidine nitrogen of the compound of formula 1I is alkylated with a suitable alkylating agent to obtain the compound of formula 1J in free form or salt form, and if desired (e) Convert the free form of the compound of formula 1J into a pharmaceutically acceptable salt form of the compound of formula 1J, such as an acid addition salt form (e.g., tosylate form). A method that includes a process.

3. The method according to claim 1 or 2, wherein A is Br.

4. The substituent R of the compounds of formula 1E, 1F, 1H, and 1I is C １－４ The method according to any one of claims 1 to 3, wherein the alkyl (for example, methyl) is used.

5. The protecting group B of the compounds of formulas 1E, 1F, and 1H is the group of formula P-Z, where P is CH ２ , C(O), C(O)O and S(O) ２ The method according to any one of claims 1 to 4, wherein Z is selected from and optionally substituted alkyl, aryl, alkylaryl or -OR', and R' is alkyl, aryl, arylalkyl or heteroarylalkyl.

6. The method according to claim 5, wherein protecting group B is an acyl group (e.g., an alkanoyl or alkoxycarbonyl group), for example, t-butoxycarbonyl, phenoxycarbonyl, ethoxycarbonyl, or methoxycarbonyl, or optionally a substituted benzyloxycarbonyl.

7. The method according to claim 6, wherein protecting group B is an ethoxycarbonyl.

8. The method according to any one of claims 1 to 7, wherein the transition metal catalyst in step (a) is a copper catalyst.

9. The transition metal catalyst in step (a) is CuI, CuBr, CuCl, Cu(OAc) ２ ,Cd ２ Cl ２ CuBr ２ , CdSO ４ ,Cd ２ SO ４ and Cu ２ The method according to claim 8, selected from O.

10. The method according to claim 9, wherein the transition metal catalyst is CuI.

11. The method according to any one of claims 1 to 10, wherein the base in step (a) is a Brønsted base selected from, for example, amine bases, alkoxides, carbonates and phosphates and mixtures thereof.

12. The method according to any one of claims 1 to 11, wherein step (a) comprises, for example, an alkali metal iodide selected from sodium iodide, potassium iodide, and lithium iodide.

13. The method according to any one of claims 1 to 12, wherein step (a) includes a monodentate ligand or a bidentate ligand, selected from, for example, a phenol ligand or an amine ligand.

14. The method according to claim 13, wherein the ligand is selected from optionally substituted 1,2-diamines, optionally substituted 1,2-amino alcohols, DBU, DBN, or DABCO.

15. The method according to claim 14, wherein the ligand is DBU.

16. The method according to any one of claims 1 to 15, wherein the reduction in step (b) is achieved using a reducing agent selected from metal hydrides, boranes, and organoboranes.

17. The method according to claim 16, wherein the reducing agent is a borane-THF complex.

18. The method according to any one of claims 1 to 17, wherein the deprotection step (c) is aqueous hydrolysis, for example, acidic or basic hydrolysis.

19. The method according to claim 18, wherein the aqueous hydrolysis includes an aqueous hydrochloric acid solution.

20. The method according to any one of claims 1 to 19, wherein the compound of formula 1I is obtained as a solid, for example, amorphous or crystalline solid.

21. The method according to claim 20, wherein the compound of formula 1I is obtained as a hydrochloride salt, for example, a solid hydrochloride salt or a crystalline solid hydrochloride salt.

22. The method according to any one of claims 1 to 21, wherein the method is carried out without isolating or purifying the intermediates of formula 1F and 1H.

23. The method according to any one of claims 1 to 22, wherein steps (a), (b), and (c) are carried out sequentially in a single reaction vessel or in a set of connected reaction vessels.

24. The method according to any one of claims 1 to 23, wherein the compound of formula 1I is obtained in a form having less than 50 ppm of copper, less than 10 ppm of copper, or less than 5 ppm of copper.

25. The method according to any one of claims 2 to 24, wherein the appropriate alkylating agent in step (d) is a compound of general formula Q-X (wherein Q is selected from 4-(4-fluorophenyl)-4-oxobutyl and 3-(4-fluorophenoxy)propyl, and X is some appropriate leaving group (e.g., a functional group known in the art to be readily subjected to nucleophilic substitution reactions)).

26. The method according to any one of claims 2 to 24, wherein group Q of the compound of formula 1J is 4-(4-fluorophenyl)-4-oxobutyl and group R of the compound of formula 1J is methyl.

27. The method according to any one of claims 2 to 26, wherein the compound of formula 1J is obtained in free base form from step (d).

28. The method according to any one of claims 2 to 27, wherein a compound of formula 1J is obtained in free base form from step (d), and the method further comprises step (e) of converting the compound of formula 1J in free base form to a salt form, for example, an acid addition salt form (for example, a tosylate form, for example, a monotosylate and / or ditosylate form) of the compound of formula 1J.

29. The method according to claim 28, wherein the acid addition salt form is a tosylate form (for example, monotosylate, ditosylate, or tritosylate form or a mixture thereof).

30. The method according to any one of claims 2 to 29, wherein the method provides a compound of formula 1J in a substantially enantiomerically pure form, for example, at least 90% e.e., preferably at least 95% e.e., or at least 98% e.e., or at least 99% e.e.

31. The method according to any one of claims 2 to 30, wherein the method provides the compound of formula 1J in a substantially pure form, for example, by measurement by HPLC, in a form that is, for example, more than 95% pure or more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.5%, or more than 99.9% pure.

32. The method according to any one of claims 2 to 31, wherein the method provides a compound of formula 1J or 2J in a form having less than about 50 ppm of copper, less than about 10 ppm of copper, or less than about 5 ppm of copper.

33. Pharmaceutically acceptable salt form: Formula 1J 【Chemistry 11】 [During the ceremony, R is H or C １－４ It is alkyl (for example, methyl), and Q is selected from 4-(4-fluorophenyl)-4-oxobutyl and 3-(4-fluorophenoxy)propyl. A method for producing the compound, (a) A method comprising converting a compound of formula 1J in free form or salt form (wherein R and Q are as defined above) to a pharmaceutically acceptable salt form of the compound of formula 1J, such as an acid addition salt form (e.g., tosylate form).

34. The method according to claim 33, wherein the method is initiated with a compound of formula 1J or 2J in free base form, and the method comprises step (a) of converting the compound of formula 1J or 2J in free base form to a pharmaceutically acceptable salt form of the compound of formula 1J or 2J, for example, an acid addition salt form (e.g., a tosylate form, e.g., monotosylate and / or ditosylate form).

35. The method according to claim 33, wherein the method is initiated with a compound of formula 1J or 2J in a salt form, for example, an acid addition salt form, and the method comprises step (a) of converting the compound of formula 1J or 2J in a salt form to a pharmaceutically acceptable salt form of the compound of formula 1J or 2J which is a different salt form, for example, a different acid addition salt form (for example, a tosylate form, for example, a monotosylate and / or ditosylate form).

36. Free form or salt form, for example, acid addition salt form of formula 1I 【Chemistry 12】 [During the ceremony, R is H or C １－４ It is an alkyl group (for example, methyl). A compound that exists in solid form.

37. The compound according to claim 36, wherein the compound is in the form of an acid addition salt.

38. The compound according to claim 37, wherein the acid addition salt form is a hydrohalide salt form (for example, a hydrochloride salt, hydrobromide salt, hydroiodide salt, or hydrofluoride salt, with a base-to-acid molar ratio of 1:1 to 3:1).

39. Pharmaceutically acceptable salt form: Formula 1J 【Chemistry 13】 [During the ceremony, R is H or C １－４ It is alkyl (for example, methyl), and Q is selected from 4-(4-fluorophenyl)-4-oxobutyl and 3-(4-fluorophenoxy)propyl. An active pharmaceutical composition (active pharmaceutical component) comprising the compound, wherein the composition comprises at least 97% by weight of the compound (measured in salt form).

40. Formula 1J in free form or salt form 【Chemistry 14】 [During the ceremony, R is H or C １－４ It is alkyl (for example, methyl), and Q is selected from 4-(4-fluorophenyl)-4-oxobutyl and 3-(4-fluorophenoxy)propyl. A pharmaceutical composition comprising the compound of the above compound mixed with toluenesulfonic acid and at least one additive, diluent, or solvent.

41. The composition according to claim 40, wherein R is methyl, Q is 4-(4-fluorophenyl)-4-oxobutyl, and the compound of formula 1J is in tosylate form.

42. A compound selected from the following group: 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】

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