Acid addition salts of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine and (S)-3-(2-methoxy-5-(methylthio)-4-(trifluoromethyl)phenyl)piperidine, specific polymorphs thereof, and methods for producing them.

Abstract

The present invention relates to certain pharma- ceutically acceptable salts of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine and (S)-3-(2-methoxy-5-(methylthio)-4-(trifluoromethyl)phenyl)piperidine and certain polymorphs thereof. More particularly, the present invention relates to a compound of formula (VI) and chemical routes for its preparation.

Description

[Technical Field]

[0001] The present invention relates to (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine and specific pharmaceutically acceptable salts of (S)-3-(2-methoxy-5-(methylthio)-4-(trifluoromethyl)phenyl)piperidine, as well as specific polymorphs thereof having, for example, high crystallinity, high solubility, high stability and good thermal properties. The present invention also relates to novel routes for producing such salts and polymorphs. [Background technology]

[0002] Recent research efforts (see Patent Document 1) have shown that a new class of 3-(2,4,5-trisubstituted phenyl)piperidine, 3-(2,4-disubstituted phenyl)piperidine, or 3-(3,4-disubstituted phenyl)piperidine is 5-HT 2A The fact that these compounds act as agonists and that this class of compounds holds great potential for the treatment of depression, particularly treatment-resistant depression, indicates the need to develop these compounds into active pharmaceutical ingredients (APIs) suitable for use in pharmaceutical manufacturing. Compound properties such as solubility, hygroscopicity, crystallinity, and chemical / physical stability are paramount in drug development to obtain safe and effective drugs. Salt formation is a common method, for example, to improve the solubility, dissolution rate, hygroscopicity, crystallinity, stability, and even toxicity of a drug. Therefore, salt screening in various solvents is necessary to identify appropriate salt forms and their stable polymorphs (i.e., different crystal lattices) in order to develop compounds into APIs for pharmaceutical manufacturing. Polymorphs often exhibit significant differences in solubility, crystallinity, dissolution rate, and stability. Therefore, it is crucial to characterize various salts and specific polymorphic forms to ensure that the polymorphs are stable both during manufacturing and throughout the drug's shelf life. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] PCT / EP2020 / 081357 [Overview of the Initiative] [Problems that the invention aims to solve]

[0004] Therefore, in one aspect, the present invention sets out to solve the problem of providing (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine and specific salts and polymorphs of (S)-3-(2-methoxy-5-(methylthio)-4-(trifluoromethyl)phenyl)piperidine suitable for drug manufacturing.

[0005] Medicinal chemical routes for the synthesis of novel compounds often focus on diversity to provide small-scale, rapid access to various analogues. In contrast, process chemical routes for producing APIs on an industrial scale must consider factors such as scalability, overall yield, safety, environmental hazards, economics, and the overall feasibility of the route.

[0006] Therefore, in another aspect, the present invention solves the problem of providing a scalable and efficient process chemical route for the production of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine and specific salts and polymorphs of (S)-3-(2-methoxy-5-(methylthio)-4-(trifluoromethyl)phenyl)piperidine disclosed herein. [Means for solving the problem]

[0007] Summary of the Invention In the first aspect, the present invention is a) A step of reacting a compound of formula (III) with hydrogen gas (H2) in a solvent in the presence of a transition metal catalyst to obtain a racemic compound of formula (IVa) or (IVb), or a step of reacting a compound of formula (III) with a deprotection reagent in a solvent to obtain a compound of formula (IIIa); [ka] b) If a compound of formula (IVa) is formed in step a), the step of reacting the compound of formula (IVa) with a deprotection agent in a solvent to obtain a racemic compound of formula (IVb), or if a compound of formula (IIIa) is formed in step a), the step of reacting the compound of formula (IIIa) with hydrogen gas (H2) in a solvent in the presence of a transition metal catalyst to obtain a racemic compound of formula (IVb); [ka] c) A step of reacting the compound of formula (IVb) with a chiral acid in a solvent to obtain the compound of formula (V) having at least 70% enantiomer excess (ee), and a step of liberating the salt of formula (V) to obtain the compound of formula (S)-(IVb); [ka] d) A step of reacting the compound of formula (S)-(IVb) with succinic acid, L-tartaric acid, or HCl in a solvent to obtain the crystalline compound of formula (VI); [ka] (wherein Y is selected from S or O, and A is 3-carboxypropanoic acid, (2R,3R)-3-carboxy-2,3-dihydroxypropanoic acid or chloride (Cl - ) will be selected as. The present invention relates to a method for producing a compound of formula (VI) including [the compound].

[0008] In a second aspect, the present invention is a) A step of reacting a compound of formula (III) with hydrogen gas (H2) in a solvent in the presence of a transition metal catalyst and a chiral ligand to obtain a compound of formula (S)-(IVa) or (S)-(IVb) having an enantiomeric excess of at least 70% (%ee), or a step of reacting a compound of formula (III) with a deprotection reagent in a solvent to obtain a compound of formula (IIIa); [ka] b) If a compound of formula (S)-(IVa) is formed in step a), the step of reacting the compound of formula (S)-(IVa) with a deprotection reagent in a solvent to obtain a compound of formula (S)-(IVb) having at least 70% enantiomeric excess (%ee), or if a compound of formula (IIIa) is formed in step a), the step of reacting the compound of formula (IIIa) with hydrogen gas (H2) in a solvent in the presence of a transition metal catalyst and a chiral ligand to obtain a compound of formula (S)-(IVb) having at least 70% enantiomeric excess (%ee); [ka] c) A step of reacting the compound of formula (S)-(IVb) with succinic acid, L-tartaric acid, or HCl in a solvent to obtain the crystalline compound of formula (VI); [ka] (In the formula, A - This includes 3-carboxypropanoic acid, (2R,3R)-3-carboxy-2,3-dihydroxypropanoic acid, or chloride (Cl - ) will be selected as. The present invention relates to a method for producing a compound of formula (VI) including [the compound].

[0009] In a third aspect, the present invention relates to a crystalline compound of formula (VI): [ka] During the ceremony, Y is selected as either O or S. A - This includes 3-carboxypropanoic acid, (2R,3R)-3-carboxy-2,3-dihydroxypropanoic acid, or chloride (Cl -) will be selected as.

[0010] In a fourth aspect, the present invention relates to an intermediate of formula (III) or (IIIa): [ka] During the ceremony, Y is selected from O or S. PG is an amine protecting group.

[0011] In a fifth aspect, the present invention relates to the use of an intermediate of formula (IIIa) for the production of compounds of formula (IVa), (IVb), (IIIa), (S)-(IVa), (S)-(IVb), (V), or (VI), or to the use of an intermediate of formula (IIIa) for the production of compounds of formula (IVb), (S)-(IVb), (V), or (VI). [Brief explanation of the drawing]

[0012] [Figure 1] The XPRD spectrum of polymorph A of the compound of formula (VI), where Y is O and A- is 3-carboxypropanoic acid (i.e., a 1:1 salt formed between (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine and succinic acid), is shown. [Figure 2] The XPRD spectrum of polymorph A of the compound of formula (VI), where Y is O and A- is chloride (Cl-) (i.e., a 1:1 salt formed between (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine and HCl), is shown. [Figure 3] The XPRD spectrum of polymorph B of the compound of formula (VI), where Y is O and A- is (2R,3R)-3-carboxy-2,3-dihydroxypropanoic acid (i.e., a 1:1 salt formed between (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine and L-tartaric acid), is shown. [Modes for carrying out the invention]

[0013] Embodiments of the present invention will be described in more detail below with reference to the accompanying drawings.

[0014] Detailed description of the invention The present invention relates to specific advantageous pharmaceutically acceptable salts of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine and (S)-3-(2-methoxy-5-(methylthio)-4-(trifluoromethyl)phenyl)piperidine, as well as specific polymorphs thereof. The present invention also relates to novel routes for the large-scale production of these salts and polymorphs.

[0015] In particular, the present inventors have identified succinate of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine (i.e., a 1:1 salt formed between (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine and succinic acid), and L-tartrate of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine (i.e., (S)-3-(2,5-dimethoxy-4-(trifluoromethyl) We found that the 1:1 salt formed between (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine and L-tartaric acid, and the HCl salt of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine, exhibit improved properties compared to other salts of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine and (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine as a free base. Therefore, these salts were found to be suitable for API development. In particular, the succinate (1:1) of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine and the HCl salt of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine were found to be promising salt candidates.

[0016] Mode I In the first aspect, the present invention is a) A step of reacting a compound of formula (III) with hydrogen gas (H2) in a solvent in the presence of a transition metal catalyst to obtain a racemic compound of formula (IVa) or (IVb), or a step of reacting a compound of formula (III) with a deprotection reagent in a solvent to obtain a compound of formula (IIIa); [ka] b) If a compound of formula (IVa) is formed in step a), the step of reacting the compound of formula (IVa) with a deprotection agent in a solvent to obtain a racemic compound of formula (IVb), or if a compound of formula (IIIa) is formed in step a), the step of reacting the compound of formula (IIIa) with hydrogen gas (H2) in a solvent in the presence of a transition metal catalyst to obtain a racemic compound of formula (IVb); [ka] c) A step of reacting the compound of formula (IVb) with a chiral acid in a solvent to obtain the compound of formula (V) having at least 70% enantiomer excess (ee), and a step of liberating the salt of formula (V) to obtain the compound of formula (S)-(IVb); [ka] d) A step of reacting the compound of formula (S)-(IVb) with succinic acid, L-tartaric acid, or HCl in a solvent to obtain the crystalline compound of formula (VI); [ka] (In the formula, Y is selected from S or O, and A - This includes 3-carboxypropanoic acid, (2R,3R)-3-carboxy-2,3-dihydroxypropanoic acid, or chloride (Cl - ) will be selected as. The present invention relates to a method for producing a compound of formula (VI) including [the compound].

[0017] In embodiments of the present invention, the method is performed before step a), a1) A step of reacting the compound of formula (I) with the compound of formula (II) in a solvent in the presence of a base and a transition metal catalyst to obtain the compound of formula (III); It also includes. [ka] During the ceremony, Z is selected from the group consisting of boronic acids, trifluoroborates, and boronic acid esters. PG is an amine protecting group, Y is selected from S or O. X is selected from Cl, Br, I, or OTf. [ka]

[0018] Therefore, in a preferred embodiment, the present invention is a1) A step of reacting the compound of formula (I) with the compound of formula (II) in a solvent in the presence of a base and a transition metal catalyst to obtain the compound of formula (III); [ka] During the ceremony, Z is selected from the group consisting of boronic acids, trifluoroborates, and boronic acid esters. PG is an amine protecting group, Y is selected from S or O. X is selected from Cl, Br, I, or OTf. [ka] a) A step of reacting a compound of formula (III) with hydrogen gas (H2) in a solvent in the presence of a transition metal catalyst to obtain a racemic compound of formula (IVa) or (IVb); [Chemical formula] b) When the compound of formula (IVa) is formed in step 1) of the process, reacting the compound of formula (IVa) with a deprotection reagent in a solvent to obtain a compound of formula (IVb); [Chemical formula] c) Reacting the compound of formula (IVb) with a chiral acid in a solvent to obtain a compound of formula (V) having an enantiomeric excess (ee) of at least 70%, and liberating the salt of formula (V) to obtain a compound of formula (S)-(IVb); [Chemical formula] d) Reacting the compound of formula (S)-(IVb) with succinic acid, L-tartaric acid or HCl in a solvent to obtain a crystalline compound of formula (VI); [Chemical formula] (In the formula, A - is selected as 3-carboxypropanoic acid, (2R,3R)-3-carboxy-2,3-dihydroxypropanoic acid or chloride (Cl - ).) Relates to a method for producing a compound of formula (VI) containing

[0019] The hydrogenation and deprotection steps may be reversed such that deprotection is carried out before hydrogenation.

[0020] Thus, in a more preferred embodiment, the present invention a1) Reacting a compound of formula (I) with a compound of formula (II) in a solvent in the presence of a base and a transition metal catalyst to obtain a compound of formula (III); [Chemical formula] During the ceremony, Z is selected from the group consisting of boronic acids, trifluoroborates, and boronic acid esters. PG is an amine protecting group, Y is selected from S or O. X is selected from Cl, Br, I, or OTf. [ka] a) A step of reacting the compound of formula (III) with a deprotection agent in a solvent to obtain the compound of formula (IIIa); [ka] b) A step of reacting the compound of formula (IIIa) with hydrogen gas (H2) in a solvent in the presence of a transition metal catalyst to obtain the racemic compound of formula (IVb); [ka] c) A step of reacting the compound of formula (IVb) with a chiral acid in a solvent to obtain the compound of formula (V) having at least 70% enantiomer excess (ee), and a step of liberating the salt of formula (V) to obtain the compound of formula (S)-(IVb); [ka] d) A step of reacting the compound of formula (S)-(IVb) with succinic acid, L-tartaric acid, or HCl in a solvent to obtain the compound of formula (VI); [ka] (In the formula, Y is selected from S or O, and A -This includes 3-carboxypropanoic acid, (2R,3R)-3-carboxy-2,3-dihydroxypropanoic acid, or chloride (Cl - ) will be selected as. The present invention relates to a method for producing a compound of formula (VI) including [the compound].

[0021] Process a1); Suzuki-Miyaura cross coupling (SMC)

[0022] Step a1) of the method according to the first embodiment is an SMC reaction between the compound of formula (I) and the compound of formula (II) in a solvent, in the presence of a base and a transition metal catalyst. In step a1), other suitable cross-coupling reactions, such as the Negishi coupling, Still coupling, or Hiyama coupling, may be used by substituting organoboron (i.e., the compound of formula (I)) with a suitable organozinc, organostannane, or organosilane. The organozinc, organostannane, or organosilane may be prepared by conventional methods known in the art.

[0023] Compounds of formula (I): Boronic acid (RB(OH)2), trifluoroborate (R-BF3K, i.e., Morander salt), and various boronic acid esters (RB(OR)2), such as pinacol boronic acid, catechol boronic acid, trimethylene glycol boronic acid, MIDA boronic acid, and triisopropyl boronic acid, may be used in the SMC reaction of step a1). In embodiments of the present invention, Z in formula (I) is selected from the group consisting of boronic acid, trifluoroborate, and boronic acid esters. In the most preferred embodiment, Z is selected as pinacol boronic acid. Various protecting groups may be used for the amine in the compound of formula (I). Common amine protecting groups include carbamates, such as 9-fluorenylmethylcarbamate (Fmoc-NR2), t-butylcarbamate (Boc-NR2), and benzylcarbamate (Cbz-NR2); amides, such as acetamide (Ac-NR2) and trifluoroacetamide (CF3CO-NR2); benzylamines, such as benzylamine (Bn-NR2) or 4-methoxybenzylamine (PMB-NR2); triphenylmethylamine (Tr-NR2); benzylideneamine; and sulfonamides, such as p-toluenesulfonamide (Ts-NR2). In embodiments, the protecting group is 9-fluorenylmethylcarbamate (Fmoc-NR2), t-butylcarbamate (Boc-NR2), or benzylcarbamate (Cbz-NR2). In other embodiments, the protecting group is acetamide (Ac-NR2) or trifluoroacetamide (CF3CO-NR2). In yet another embodiment, the protecting group is benzylamine (Bn-NR2) or 4-methoxybenzylamine (PMB-NR2). In yet another embodiment, the protecting group is triphenylmethylamine (Tr-NR2). In yet another embodiment, the protecting group is p-toluenesulfonamide (Ts-NR2). Standard conditions for protection and deprotection can be found, for example, in Greene's Protective Groups in organic synthesis. Preferably, the protecting group (PG) is a carbamate protecting group such as Boc (t-butyloxycarbonyl) or CBz (carboxybenzyl).The Boc protecting group has the advantage of being removable under acidic conditions involving salt formation. This may, in certain embodiments, allow for one-pot deprotection, precipitation, and isolation of the product. The CBz protecting group has the advantage of allowing deprotection and reduction of the alkene (i.e., the piperidine double bond) in the compound of formula (III) to be carried out in a single step without requiring a separate deprotection step (i.e., step a or b). In some embodiments, the SMC reaction may be carried out without using the amine protecting group in the compound of formula (I) (i.e., the compound of formula I where PG=H) so that a deprotection step (i.e., step a or b) is not required. In the most preferred embodiment, the compound of formula (I) is the compound of formula (Ia). The compound of formula (Ia) has been previously described and is commercially available [CAS number 885693-20-9].

[0024] [ka]

[0025] Compound of formula (II): Aryl halides (chloro, bromo, or iodine) or pseudohalides (e.g., sulfonates such as triflate, 4-fluorobenzenesulfonate, sulfurofluoride, mesylate, tosylate, nonaflate, 1H-imidazole-1-sulfonate) may be used in the SMC reaction of step a1). Thus, in embodiments of the present invention, the compound of formula (II) is 1-chloro-2,5-dimethoxy-4-(trifluoromethyl)benzene or (5-chloro-4-methoxy-2-(trifluoromethyl)phenyl)(methyl)sulfan. In another embodiment of the present invention, the compound of formula (II) is 1-iodo-2,5-dimethoxy-4-(trifluoromethyl)benzene or (5-iodo-4-methoxy-2-(trifluoromethyl)phenyl)(methyl)sulfan. In the most preferred embodiments of the present invention, the compound of formula (II) is 1-bromo-2,5-dimethoxy-4-(trifluoromethyl)benzene or (5-bromo-4-methoxy-2-(trifluoromethyl)phenyl)(methyl)sulfane. These compounds have been previously described, for example, in Angew. Chem. Volume 50, Issue 8, February 18, 2011, pages 1896-1900 and are commercially available from various suppliers, or may be prepared in a few steps from commercially available starting materials as shown herein.

[0026] Bases: Numerous bases have been successfully used in SMC reactions. Bases help in the formation of more reactive borate complexes. Typical bases for SMC include carbonate bases, phosphate bases, alkoxide bases, hydroxide bases, or amine bases. In embodiments of the present invention, the base is a carbonate base, for example, Na2CO2. 3、 K2CO 3、 Cs2CO 3、 The base is selected from MgCO3 or CaCO3, a phosphate base such as K3PO4, an alkoxide base such as KOtBu, a hydroxide base such as NaOH or KOH, a carboxylic acid base such as KOAc, or an amine base such as triethylamine. In the most preferred embodiment, the base is K2CO3.

[0027] Typically, the base is added in excess, such as 1.2 to 10 equivalents. In the most preferred embodiment of the present invention, 2 equivalents of base are added.

[0028] Catalysts: Various transition metal catalysts have been successfully used in SMC reactions. Typically, such catalysts depend on the transition metal palladium or nickel. An example of such a palladium catalyst is Pd(dba) 2、 Pd(acac) 2、 Pd(PPh3) 4、 Pd(Cl2)(dppf), Pd(Cl) 2、 Pd(OAc)2 is one example, but it is not limited to these.

[0029] The palladium in the catalyst is in the required oxidation state (i.e., Pd(dba)2). 0 ) may exist in a higher oxidation state (i.e., Pd(OAc)2) +2 ) exists in place, and Pd is situated by the base used, arylboronic acid, or phosphine ligand, for example. 0 It may be reduced to. Various phosphine ligands may be added to the SMC reaction to form an active catalyst. Such phosphine ligands include PPh 3、 PC 3、 P(o-tolyl) 3、 P(iPr) 3、 P(O-Pr-i) 3、 n-BuP(1-Ad) 2、 Examples of phosphine ligands include, but are not limited to, those selected from the list consisting of P(t-Bu)2(p-NMe2-Ph), DavePhos, JophnPhos, SPhos, XPhos, RuPhos, DPPF, DPPE, and DPPP. Similarly, various nickel catalysts may be used. Such catalysts may optionally include Ni(acac) in the presence of the above phosphine ligands. 2、 Ni(COD) 2、 Ni(dppf)Cl 2、A list of NiCl2-based catalysts is provided, but is not limited to, those comprising NiCl2. Further examples of Pd / Ni catalysts and suitable ligands for SMC reactions can be found, for example, in the textbook Suzuki-Miyaura Cross-Coupling Reaction and Potential Applications, 2018 (ISBN: 3038425567, 9783038425564). In the most preferred embodiment, the catalyst is Pd(dppf)Cl2.

[0030] The catalyst packing in the SMC is typically used in the range of 0.15 to 0.001 equivalents, for example, in the range of 0.10 to 0.005 equivalents, preferably in the range of 0.07 to 0.01 equivalents, and more preferably in the range of 0.05 to 0.02 equivalents. In the most preferred embodiment, the catalyst is Pd(dppf)Cl2, and most preferably the catalyst packing is 0.03 equivalents (based on the compound of formula (II)).

[0031] Solvent: Various solvents may be used in the SMC reaction. Typical solvents include, but are not limited to, those selected from the list consisting of ACN, THF, 2-Me-THF, DMF, NMP, toluene, H2O, dioxane, acetone, MeOH, EtOH, iPrOH, and nBuOH. Almost all SMC reactions require at least trace amounts of water. Water may play a role in transmetallation by hydrolyzing the boronic acid ester to the active boronic acid. Water may arise from biphasic conditions in the solvent or base, or from accidental water. In some embodiments of the present invention, mixtures of solvents, such as a dioxane / H2O mixture or a DMF / H2O mixture, may be used. In the most preferred embodiment of the present invention, the solvent is ACN. The inventors have found that the addition of a small amount of aqueous NaBr increases catalytic activity and / or stability. Therefore, in the most preferred embodiment, an aqueous NaBr solution is added to the solvent, preferably ACN as the solvent. Various conditions for the SMC reaction were investigated. The most favorable conditions found were K2CO3 (2.0 eq), Pd (dppf)Cl2 (0.03 eq), and ACN (6V) at 80-85°C.

[0032] Step a) or b); Hydrogenation Hydrogenation may be carried out in either step a) or step b). Therefore, hydrogenation of the compound of formula (III) may be carried out in step a) to obtain a racemic compound of formula (IVa) or (IVb). Alternatively, hydrogenation of the compound of formula (IIIa) may be carried out in step b) to obtain a racemic compound of formula (IVb). In addition to reducing the alkene in the compound of formula (III), hydrogenation may also have an effect on cleaving the protecting group (PG) when a benzyl carbamate such as Cbz is used as the PG. The inventors have found that hydrogenation is faster in the compound of formula (IIIa) compared to the compound of formula (III). Therefore, in the most preferred embodiment, deprotection of formula (III) is carried out in step a), and hydrogenation is carried out in step b).

[0033] Catalyst: A range of catalysts that can be used in the hydrogenation reaction. Such catalysts include, but are not limited to, palladium / activated carbon (Pd / C), PtO2, palladium complexes, rhodium complexes (e.g., Wilkinson catalysts), ruthenium complexes, or iridium complexes. In the most preferred embodiment, the catalyst is Pd / C. Typical catalyst loadings range from 1 to 20% by weight at process scale. In the most preferred embodiment, the catalyst loading is about 10% by weight of Pd / C.

[0034] Solvent: A range of solvents may be used in the hydrogenation reaction. Examples of such solvents include, but are not limited to, toluene, THF, 2-Me-THF, DMF, toluene, H2O, dioxane, MeOH, EtOH, iPrOH, and nBuOH. In the most preferred embodiment, the solvent is toluene.

[0035] Pressure: Hydrogenation may be carried out at various hydrogen pressures. Typically, the pressure is between 1 and 5 bar, depending on the desired reaction time. In some embodiments, hydrogenation is carried out at atmospheric pressure without the need for a pressurized reactor. In the most preferred embodiment, the reaction is carried out at about 3.5 bar (50 psi) to shorten the reaction time.

[0036] Various conditions for the hydrogenation reaction were investigated. The optimal conditions found were Pd / C (10 wt%), H2 (50 psi), and  (6V) at 25-30°C.

[0037] Step a) or step b); Deprotection Deprotection of the protecting group (PG) may be carried out in either step a) or step b). If the compound of formula (IVa) is formed in step a), the amine protecting group (PG), preferably carbamate PG, more preferably Boc PG, is deprotected in step b) to obtain the compound of formula (IVb). Alternatively, deprotection may be carried out on the compound of formula (III) in step a) to obtain the compound of formula (IIIa). Most preferably, deprotection is carried out in step a) to obtain the compound of formula (IIIa). Depending on the selected amine PG, various deprotection conditions may be used. Suitable deprotection conditions for various amine protecting groups can be found, for example, in Greene's Protective Groups in organic synthesis. Preferably, the protecting group is selected from a list consisting of carbamate protecting groups, amide protecting groups, benzylamine protecting groups, and sulfonamide protecting groups. In more preferred embodiments, the protecting group is selected from the list consisting of 9-fluorenylmethylcarbamate (Fmoc-NR2), t-butylcarbamate (Boc-NR2), benzylcarbamate (Cbz-NR2), acetamide (Ac-NR2), trifluoroacetamide (CF3CO-NR2), benzylamine (Bn-NR2), 4-methoxybenzylamine (PMB-NR2), triphenylmethylamine (Tr-NR2), and p-toluenesulfonamide (Ts-NR2). Preferably, if formed in step a), deprotection is carried out by reacting the product of formula (IVa) with an acid in a solvent to remove PG and obtain the compound of formula (IVb). Preferably, if formed in step a), deprotection is carried out by reacting the product of formula (III) with an acid in a solvent to remove PG and obtain the compound of formula (IIIa).

[0038] Deprotection reagents: Examples of deprotection reagents for amine protecting groups may be found, for example, in Greene's Protective Groups in organic synthesis. Preferably, the deprotection reagent is an acid that may be used to deprotect amine protecting groups such as t-butylcarbamate (Boc-NR2). Such acids include, but are not limited to, HCl, HBr, H2SO4, TFA, and TfOH. In the most preferred embodiment, the acid is HCl.

[0039] Solvent: Various solvents may be used in the deprotection reaction. Examples of such solvents include, but are not limited to, H2O, ACN, ƒ, THF, 2-Me-THF, DMF, toluene, dioxane, MeOH, EtOH, iPrOH, and nBuOH. In some embodiments, the solvent may be a mixture of several solvents. In embodiments where hydrogenation is carried out before deprotection, it is preferable to use the same solvent for deprotection (step b) as for hydrogenation (step a) to avoid switching solvents, thereby simplifying the overall process. When the same solvent is used in steps a) and b), the hydrogenation catalyst may be removed by simple filtration followed by deprotection. Therefore, in these embodiments, most preferably, ƒ is used as the solvent in both hydrogenation and deprotection. Most preferably, the solvent is ƒ and the deprotection reagent is HCl. In embodiments where deprotection is carried out before hydrogenation, preferably, in the deprotection step, MeTHF is used, preferably together with HCl as the deprotection reagent, and preferably ƒ is used in hydrogenation.

[0040] When using an acid for deprotection, the compound of formula (IVb) may be obtained by prior art known in the art, such as liberating the protonated piperidine intermediate (i.e., the protonated compound of formula (IVb)) or the protonated 1,2,3,6-tetrahydropyridine (i.e., the protonated compound of formula (IIIa)) obtained under acidic deprotection conditions, and then partitioning the compound between an organic phase (e.g., ethyl acetate) and an aqueous base phase (e.g., a 20% Na2CO3 or saturated NaHCO3 aqueous solution).

[0041] Process c); Chiral partitioning Step c) is chiral resolution to obtain the (S)-enantiomer with a high enantiomer excess (%ee). In embodiments of the present invention, the enantiomer excess is at least 60%ee, e.g., at least 70%ee, e.g., at least 75%ee, e.g., at least 80%ee, e.g., at least 85%ee, preferably at least 90%ee, more preferably at least 95%ee. Most preferably, the enantiomer excess is at least 75% so that the final crystalline salt can be obtained with a high enantiomer excess, preferably without requiring recrystallization. In some embodiments, the enantiomer excess may be further improved by crystallization / recrystallization in a suitable solvent. Chiral resolution can be carried out by derivatizing the racemic compound of formula (IVb) with an optically pure acid that forms a pair of diastereomers that can be separated by conventional techniques such as crystallization. The two diastereomer salts formed have different solubility, which makes it possible to selectively precipitate one diastereomer salt from the other. Alternatively, the enantiomers may be separated, for example, by chiral serial chromatography.

[0042] Chiral acids: Numerous chiral acids are commercially available and inexpensive, making them suitable for use in large-scale (e.g., kg-scale) process chemical pathways. Examples of such chiral acids include chiral amino acids, (1S)-(-)-camfanic acid, L-(+)-mandelic acid, D-(-)-tartaric acid or L-(+)-tartaric acid, and their derivatives.

[0043] In embodiments of the present invention, chiral resolution is performed by reacting a compound of formula (VIb) with a chiral acid selected from (-)-O,O'-di-p-toluyl-L-tartaric acid or (-)-di-p-anisoily-L-tartaric acid, preferably (-)-di-p-anisoily-L-tartaric acid, to form a pair of diastereomers, wherein the diastereomer salt between (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine or (S)-3-(2-methoxy-5-(methylthio)-4-(trifluoromethyl)phenyl)piperidine and the chiral acid has lower solubility than the diastereomer salt formed between (R)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine or (R)-3-(2-methoxy-5-(methylthio)-4-(trifluoromethyl)phenyl)piperidine and the chiral acid. The precipitated diastereomer salt may be separated by conventional filtration.

[0044] Solvent: Various solvents can be used for chiral resolution. Examples of such solvents include, but are not limited to, 2-Me-THF, THF, MeOH, EtOH, ACN, IPA, MTBE, DCM, or acetone. In some embodiments, water may be added as a co-solvent.

[0045] Various conditions were tested for the selective precipitation of the compound of formula (V). The chiral acids (-)-di-p-anisioyl-L-tartaric acid, (+)-dipivaloyl-D-tartaric acid, (-)-O,O'-di-p-toluyl-L-tartaric acid, (1S)-(-)-camfanic acid, (S)-2-acetoxy-2-phenylacetic acid, L-glutamic acid, N-acetyl-L-isoleucine, and D-(-)-tartaric acid were tested with solvents ACN, IPA, THF, and MTBE. Solvents ACN, IPA, and THF were used with water as a cosolvent (15 volumes solvent: 3 volumes H2O). MTBE was used with water as a cosolvent (20 volumes MTBE: 5 volumes H2O). The optimal condition was found to be (-)-di-p-anisioyl-L-tartaric acid (1 equivalent) in a THF / H2O mixture. Table 1 shows some representative examples of the obtained %ee.

[0046] [Table 1]

[0047] As shown in Table 1a, the solubility of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine (-)-di-p-anisioyl-L-tartrate (1:1) and (R)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine (-)-di-p-anisioyl-L-tartrate (1:1) was investigated. The data suggest that DCM is an even better solvent than THF / H2O and may provide an even higher enantiomeric excess. Therefore, in another very preferred embodiment, DCM is used in step c).

[0048] [Table 1a]

[0049] The precipitated enantiorich salt of formula (V) may be liberated into the compounds of formula (S)-(IVb) by conventional techniques known in the art, such as partitioning the compound between an organic phase (e.g., SiO) and an aqueous base phase (e.g., a 20% Na2CO3 or saturated NaHCO3 aqueous solution). The majority of the compounds of formula (S)-(IVb) remain in the organic phase, but the salt remains in the aqueous phase.

[0050] Step d); Preparation of the final salt Step d) involves precipitating the compound of formula (S)-(IVb) with succinic acid, L-tartaric acid, or HCl to obtain the crystalline compound of formula (VI).

[0051] As shown in the experimental section below, the inventors found that the HCl salt (polyform A), L-tartrate (polyform B, 1:1 acid:base salt), and succinate (polyform A, 1:1 acid:base) of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine have generally good properties, such as crystallinity, thermal properties, stability, solubility, and hygroscopicity. In particular, the HCl salt (polyform A) and succinate (polyform A, 1:1 salt) had excellent overall properties.

[0052] Both succinic acid and L-tartaric acid are dibasic acids. Therefore, these acids may form salts with the compound of formula (S)-(IVb) in a 1:1 ratio (acid:base) or a 0.5:1 ratio (acid:base). As shown in Examples 3 and 4, the inventors surprisingly found that excellent properties of succinates and L-tartarates were obtained when salts were formed in a 1:1 ratio (acid:base). These salts yielded a single stable polymorph as anhydrides in the screened solvent, while hemi-L-tartarates and hemi-succinates (acid:base ratio of 0.5:1) yielded dehydrated hydrates with low crystallinity and / or hygroscopicity. Therefore, in a very preferred embodiment, one equivalent of the compound of formula (S)-(IVb) is precipitated with one equivalent of succinic acid or one equivalent of HCl to form a salt in a 1:1 ratio (i.e., the compound of formula (VI)). In the most preferred embodiment of the present invention, one equivalent of the compound of formula (S)-(IVb) is precipitated with one equivalent of succinic acid to form a 1:1 ratio salt (i.e., the compound of formula (VI)). Since all solvents provided the same stable polymorph (polymorph A), it was found that any of the solvents ACN, EtOH, or acetone are suitable for crystallization. Example 5 (Table 10) suggests that a wide range of other solvents may also be used, as the same polymorph was obtained under solvent-mediated equilibrium. In the most preferred embodiment, the solvent is EtOH. The compound of formula (VI) may be isolated by simple filtration.

[0053] Appearance II The inventors have further found that the process route can be carried out without requiring chiral reconciliation (i.e., step c). Therefore, in a second embodiment, the desired (S)-enantiomer may be obtained by enantioselective synthesis using asymmetric hydrogenation to avoid chiral reconciliation. Therefore, in a second embodiment, the method includes including a chiral catalyst in step a) or b) of Embodiment I to carry out the enantioselective reduction (i.e., hydrogenation) of the alkene in the compound of formula (III) or (IIIa). The advantage of asymmetric hydrogenation is that it is an overall shorter API route, which makes the chiral reconciliation (i.e., step c) in Embodiment I) using a chiral derivatizer redundant.

[0054] Therefore, in the second aspect, the present invention is a) A step of reacting a compound of formula (III) with hydrogen gas (H2) in a solvent in the presence of a transition metal catalyst and a chiral ligand to obtain a compound of formula (S)-(IVa) or (S)-(IVb) having an enantiomeric excess of at least 70% (%ee), or a step of reacting a compound of formula (III) with a deprotection reagent in a solvent to obtain a compound of formula (IIIa); [ka] b) If a compound of formula (S)-(IVa) is formed in step a), the compound of formula (S)-(IVa) is reacted with a deprotection reagent in a solvent to obtain a compound of formula (S)-(IVb) having at least 70% enantiomeric excess (%ee), or if a compound of formula (IIIa) is formed in step a), the compound of formula (IIIa) is reacted with hydrogen gas (H2) in a solvent in the presence of a transition metal catalyst and a chiral ligand to obtain a compound of formula (S)-(IVb) having at least 70% enantiomeric excess (%ee); [ka] c) A step of reacting the compound of formula (S)-(IVb) with succinic acid, L-tartaric acid, or HCl in a solvent to obtain the crystalline compound of formula (VI); [ka] (In the formula, A - This includes 3-carboxypropanoic acid, (2R,3R)-3-carboxy-2,3-dihydroxypropanoic acid, or chloride (Cl - ) will be selected as. The present invention relates to a method for producing a compound of formula (VI) including [the compound].

[0055] Step a) or step b); Asymmetric hydrogenation In an embodiment of the second aspect, the compound of formula (IIIa) is hydrogenated in the presence of a chiral catalyst (i.e., step b) to obtain the compound of formula (S)-(IVb) (i.e., the desired (S)-enantiomer) with an enantiomeric excess (ee). In a preferred embodiment of the second aspect, the compound of formula (III) is hydrogenated in the presence of a chiral catalyst (i.e., step a) to obtain the compound of formula (S)-(IVa) or (S)-(IVb) (i.e., the desired (S)-enantiomer) with an enantiomeric excess (ee). Most preferably, asymmetric hydrogenation is performed on the compound of formula (III) (i.e., step a) because the protecting group improves the enantiomeric excess compared to the deprotected compound of formula (IIIa). Preferably, the enantiomeric excess in asymmetric hydrogenation is at least 60%ee, e.g., at least 70%ee, e.g., at least 75%ee, preferably at least 80%ee, e.g., at least 85%ee, more preferably at least 90%ee, e.g., at least 92%ee, even more preferably at least 94%ee, e.g., at least 96%ee, even more preferably at least 97%ee, e.g., at least 98%ee, and most preferably, the enantiomeric excess is >99%ee. The obtained enantiomeric excess may be verified by methods commonly used in the art, such as chiral HPLC. Most preferably, asymmetric hydrogenation provides the (S)-enantiomer with a high enantiomeric excess such that chiral resolution is not required. If only a moderate enantiomeric excess is achieved in asymmetric hydrogenation (e.g., at least 70%ee), the enantiomeric excess can be further increased in the final precipitation step to obtain the compound of formula (VI) with a high enantiomeric excess (e.g., >95%ee). This is due to the fact that the (S)-enantiomer is present in a higher excess than the (R)-enantiomer, and the enantiomers have the same solubility (i.e., the (S)-enantiomer precipitates first). If the final precipitate for forming the compound of formula (VI) does not yield the desired enantiomeric excess, the compound of formula (VI) may be recrystallized once or more times until the desired enantiomeric excess is reached, for example, at least 97%ee, preferably at least 98%ee, and most preferably at least 99%ee.The conditions described for step a) or b) of hydrogenation (i.e., aspect I) are equally applicable to asymmetric hydrogenation, but require the presence of a chiral ligand.

[0056] chiral ligand A range of chiral ligands can be used for asymmetric hydrogenation. Examples of such chiral ligands include BINAP, SYNPHOS, DIOP, DuPhos, Josiphos, BDPP, BIBOP, Mandyphos, or phosphine ligands based on phosphoramidites, such as MONOPHOS. Most preferably, the chiral ligand is (R,R)-i-Pr-DuPhos. Asymmetric reduction avoids the need for chiral resolution with a chiral acid. Therefore, when using asymmetric hydrogenation, step d) (i.e., chiral resolution with a chiral acid) is not required. However, the remaining steps (i.e., step a), SMC coupling, step b or c) deprotection, and step d) preparation of the final salt) may be carried out in the same manner as described herein. Thus, the embodiments described herein for the remaining steps are applicable to embodiments using asymmetric hydrogenation with necessary modifications. The optimal conditions for asymmetric hydrogenation were found to be Rh(NBD)BF4 as the catalyst, (R,R)-i-Pr-DuPhos as the chiral ligand, and EtOH as the solvent, preferably with pre-mixing of the catalyst and chiral ligand. Table 2 shows some representative examples of the obtained %ee.

[0057] [Table 2]

[0058] Step a) or step b); Deprotection The deprotection in step a) or step b) of Embodiment II is carried out in the same manner as the deprotection in step a) or step b) of Embodiment I. Therefore, the description and embodiments of deprotection in Embodiment I apply equally to Embodiment II.

[0059] Step c); Preparation of the final salt Step c) of Embodiment II is the preparation of the final crystalline salt and its specific polymorphs, which is carried out in the same manner as the preparation of the final salt in Embodiment I. Therefore, the description and embodiments of the preparation of the final salt in Embodiment I are equally applicable to Embodiment II.

[0060] In the embodiment of aspect II, the method further includes, before step a), a1) reacting the compound of formula (I) with the compound of formula (II) in a solvent in the presence of a base and a transition metal catalyst to obtain the compound of formula (III). [ka] During the ceremony, Z is selected from the group consisting of boronic acids, trifluoroborates, and boronic acid esters. PG is an amine protecting group, Y is selected from S or O. X is selected from Cl, Br, I, or OTf. [ka]

[0061] Process a1); Suzuki-Miyaura cross coupling (SMC) Step a1) in Embodiment II is identical to step a1) in Embodiment I. Therefore, the description and embodiments of the SMC reaction in Embodiment I apply equally to Embodiment II.

[0062] Therefore, in a very preferred embodiment of Embodiment II, the present invention is a1) A step of reacting the compound of formula (I) with the compound of formula (II) in a solvent in the presence of a base and a transition metal catalyst to obtain the compound of formula (III); [ka] During the ceremony, Z is selected from the group consisting of boronic acids, trifluoroborates, and boronic acid esters. PG is an amine protecting group, Y is selected from S or O. X is selected from Cl, Br, I, or OTf. [ka] a) A step of reacting a compound of formula (III) with hydrogen gas (H2) in the presence of a transition metal catalyst and a chiral ligand to obtain a compound of formula (S)-(IVa) or (S)-(IVb) having an enantiomeric excess of at least 70% (%ee), or a step of reacting a compound of formula (III) with a deprotection reagent in a solvent to obtain a compound of formula (IIIa); [ka] b) If a compound of formula (S)-(IVa) is formed in step a), the step of reacting the compound of formula (S)-(IVa) with a deprotection reagent in a solvent to obtain a compound of formula (S)-(IVb) having at least 70% enantiomeric excess (%ee), or if a compound of formula (IIIa) is formed in step a), the step of reacting the compound of formula (IIIa) with hydrogen gas (H2) in a solvent in the presence of a transition metal catalyst and a chiral ligand to obtain a compound of formula (S)-(IVb) having at least 70% enantiomeric excess (%ee); [ka] c) A step of reacting the compound of formula (S)-(IVb) with succinic acid, L-tartaric acid, or HCl in a solvent to obtain the crystalline compound of formula (VI); [ka] (In the formula, A -This includes 3-carboxypropanoic acid, (2R,3R)-3-carboxy-2,3-dihydroxypropanoic acid, or chloride (Cl - ) will be selected as. The present invention relates to a method for producing a compound of formula (VI) including [the compound].

[0063] Most preferably, asymmetric hydrogenation is carried out on the compound of formula (III) (i.e., the protecting intermediate).

[0064] Preparation of the compound of formula (II) To obtain the compound of formula (II) for use in step a) at a lower cost and in larger quantities, the inventors developed a two-step scalable process chemical route from the less expensive precursor 4-methoxy-3-(trifluoromethyl)phenol (formula IIa) to 1-bromo-2,5-dimethoxy-4-(trifluoromethyl)benzene.

[0065] Therefore, in some embodiments of the present invention, the methods according to the first and second aspects include, prior to step a1), a further step of reacting the compound of formula (IIa) with a halogenating agent in a solvent in the presence of an acid to obtain the compound of formula (IIb), and reacting the compound of formula (IIb) with a methylating agent in a solvent in the presence of a base to obtain the compound of formula (II): [ka]

[0066] Halogenation: Halogenating agents: Various halogenating agents are suitable for locating chlorine, bromine, or iodine atoms in the compound of formula (IIa). Suitable chlorinating agents include, but are not limited to, cyanuric acid chloride, N-chlorosuccinimide, N-chlorophthalimide, 1,3-dichloro-5,5-dimethylhydantoin, sodium dichloroisocyanurate, trichloroisocyanuric acid, N-chlorosaccharin, chloramine B hydrate, o-chloramine T dihydrate, chloramine T trihydrate, dichloramine B, dichloramine T, and benzyltrimethylammonium tetrachloroiodate. Suitable brominating reagents include Br 2、 CBr 4、 Tetrabutylammonium tribromide, trimethylphenylammonium tribromide, benzyltrimethylammonium tribromide, pyridinium bromide perbromide, 4-dimethylaminopyridinium bromide perbromide, 1-butyl-3-methylimidazolium tribromide, 1,8-diazabicyclo[5.4.0]-7-undecene hydrogen bromide, N-bromosuccinimide, N-bromophthalimide, N-bromosaccharin, N-bromoacetamide, 2-bromo-2-cyano-N,N-dimethylacetamide, 1,3-dibromo-5,5-dimethylhydantoin, dibromoisocyanuric acid, monosodium bromoisocyanurate hydrate, PBr 3、 Examples of iodinating agents include, but are not limited to, bromodimethylsulfonium bromide, 5,5-dibromomeldrumic acid, 2,4,4,6-tetrabromo-2,5-cyclohexadienone, and bis(2,4,6-trimethylpyridine)-bromonium hexafluorophosphate. Various iodinating agents include, 2、 HI, CI 4、A list of compounds comprising N-iodosuccinimide, N-iodosaccharin, 1,3-diiodo-5,5-dimethylhydantoin, pyridine monochloride iodine, tetramethylammonium dichloroiodate, benzyltrimethylammonium dichloroiodate, and bis(pyridine)iodonium tetrafluoroborate is available, but is not limited thereto. In preferred embodiments of the present invention, the halogenating agent is a brominating agent, most preferably pyridinium bromide perbromide (PyHBr3).

[0067] Acids: Several acids are suitable for use in the halogenation reactions of compounds of formula (IIa). Such acids include both Lewis acids and Brønsted acids. Suitable acids may include, but are not limited to, those selected from the list consisting of pTsOH, MsOH, HCl, and TfOH.

[0068] Solvents: Several solvents are suitable for the halogenation reaction of the compound of formula (IIa). Examples of such solvents include MTBE, THF, ACN, DMF, 2-MeTHF, alkyl, EtOH, toluene, acetone, or MeOH.

[0069] The inventors investigated various conditions for halogenation. The most preferred conditions found were pyridinium bromide perbromide (PyHBr3, 1 equivalent), TfOH (2.0 equivalents), and DCM (6V) at 0-10°C.

[0070] Alkylation: Alkylating reagents: Various methylating agents are suitable for methylating compounds of formula (IIb). Such reagents include, but are not limited to, methylating agents selected from the list consisting of MeI, methyl fluorosulfonate, methyl methanesulfonate, dimethyl carbonate, and dimethyl sulfate. In the most preferred embodiment of the present invention, the methylating agent is MeI.

[0071] Base: Various bases may be used for methylation of the compound of formula (IIb). For example, Na2CO3、 K2CO 3、 Examples include, but are not limited to, alkaline carbonates such as Cs2CO3, alkaline earth metal bases such as MgCO3 or CaCO3, or hydride bases such as NaH.

[0072] The inventors investigated various conditions for alkylation. The optimal conditions found were MeI (1.1 equivalents), K2CO3 (1.5 equivalents), and acetone (6V) at temperatures of 50-55°C.

[0073] Phenomenon III As shown in Examples 3 and 4, the inventors found that HCl salt (polymorph A), succinate (i.e., polymorph A, acid:base ratio 1:1), and L-tartrate (i.e., polymorph B, acid:base ratio 1:1) exhibited superior overall properties compared to other salts in the salt screening. In particular, these salts produced anhydrous products exhibiting high crystallinity, high melting point, good thermal properties, little to no hygroscopicity, good solubility, and good bulk stability, forming a single stable polymorph in the screened solvent. In contrast, hemisuccinate and hemi-L-tartrate (i.e., acid:base ratio 1:0.5) produced hydrated products that underwent dehydration as determined by differential scanning calorimetry (DSC), were more hygroscopic, and / or formed different polymorphs from those in the tested solvent. Furthermore, succinate (i.e., polymorph A, acid:base ratio 1:1) and HCl salt (polymorph A) showed considerably higher solubility in water than L-tartrate (i.e., polymorph B, acid:base ratio 1:1). Therefore, succinate (i.e., polymorph A, acid:base ratio 1:1, Figure 1) and HCl salt (polymorph A, Figure 2), most preferably succinate (1:1 ratio), were identified as the best salts for developing APIs for drug manufacturing.

[0074] Therefore, in a third aspect, the present invention relates to a crystalline compound of formula (VI): [ka] During the ceremony, Y is selected as either O or S. A is 3-carboxypropanoic acid, (2R,3R)-3-carboxy-2,3-dihydroxypropanoic acid, or chloride (Cl - ) will be selected as.

[0075] In a preferred embodiment, Y is selected as O. In another preferred embodiment, Y is selected as S. In a further preferred embodiment, Y is selected from O or S, and A - is 3-carboxypropanoic acid or Cl - , more preferably selected as 3-carboxypropanoic acid. In another preferred embodiment, Y is selected as S and A - is 3-carboxypropanoic acid or Cl - Most preferably selected from 3-carboxypropanoic acid. In a more preferred embodiment, Y is selected as O and A - is 3-carboxypropanoic acid or Cl - Most preferably selected from 3-carboxypropanoic acid.

[0076] Amorphous and crystalline compounds can be easily distinguished, for example, using a microscope. The best way to distinguish between amorphous and crystalline materials is to measure their XRD patterns. Crystalline materials always show sharp diffraction peaks, while amorphous materials do not. Similarly, different polymorphs of crystalline materials may be identified by their different XRD patterns. The crystallinity of a material can also be confirmed from the limited-field electron diffraction (SAED) pattern using a transmission electron microscope (TEM micrograph).

[0077] In this embodiment, Y is selected as O, and A -The salt was selected as (2R,3R)-3-carboxy-2,3-dihydroxypropanoic acid, and the 2θ peaks were 5.925°, 10.183°, 11.313°, 11.823°, 12.209°, 12.542°, 15.233°, 15.592°, 15.776°, and 16.27°, as shown in Figure 3. 5°, 16.719°, 17.063°, 17.406°, 17.752°, 18.012°, 19.568°, 19.692°, 20.291°, 20.746°, 21.261°, 21.839°, 22.200°, 22.700°, 23.226°, 23.372°, 23.603°, 23. 962°, 24.516°, 24.707°, 25.013°, 25.440°, 25.914°, 26.502°, 27.003°, 27.496°, 27.902°, 28.365°, 28.786°, 29.078°, 29.791°, 30.027°, 30.299°, 30.785°, 3 This polymorph has an XRPD spectrum with the following values: 1.187°, 31.686°, 32.070°, 32.392°, 33.434°, 33.862°, 34.358°, 34.790°, 35.584°, 36.277°, 36.801°, 37.197°, 38.121°, and 39.667°.

[0078] In a very preferred embodiment, Y is selected as O, and A - is chloride (Cl -Selected as ), the salt exhibits 2θ peaks at 7.457°, 9.185°, 10.899°, 11.738°, 12.604°, 14.956°, 17.706°, 18.215°, 18.382°, 19.307°, 19.902°, 20.442°, 20.956°, 21.850°, 22.449°, 23.781°, 24.007°, 24.357°, 24.752°, 25.327°, 25.557°, 26.064°, 27.377°, and 27. It is a polymorph with an XRPD spectrum having 702°, 28.340°, 28.557°, 29.144°, 29.366°, 29.915°, 30.164°, 30.669°, 30.975°, 32.213°, 32.725°, 33.018°, 33.742°, 34.605°, 35.012°, 35.618°, 36.883°, 37.131°, 37.250°, 37.772°, 38.358°, 38.626°, 39.140°, and 39.869°.

[0079] In the most preferred embodiment, Y is selected as O, and A - As shown in Figure 1, the 2θ peaks were selected as 3-carboxypropanoic acid, and the salt was found to have 2θ peaks of 4.077°, 8.108°, 11.991°, 12.156°, 13.893°, 15.876°, 16.218°, 16.412°, 16.596°, 17.849°, 19.507°, 19.786°, 20.031°, 20.297°, 21.122°, 22.011°, 22.635°, 23.000°, 23.268°, 24.065°, and 24.40°. It is a polymorph with an XRPD spectrum having 8°, 25.414°, 25.758°, 26.947°, 27.751°, 28.032°, 28.314°, 29.966°, 30.358°, 30.562°, 30.770°, 31.378°, 32.306°, 32.868°, 33.505°, 34.710°, 35.206°, 36.418°, 36.714°, 37.306°, 38.147°, 38.322°, and 38.745°.

[0080] In this context, it should be understood that the XRPD spectrum (i.e., the given 2θ peak) is obtained using X-ray powder diffractometers and methods disclosed in the General Instruments Methods section.

[0081] Phenomenon IV In a fourth aspect, the present invention relates to an intermediate of formula (III) or (IIIa): [ka] During the ceremony, Y is selected from O or S. PG is an amine protecting group.

[0082] Common amine protecting groups include carbamates, such as 9-fluorenylmethylcarbamate (Fmoc-NR2), t-butylcarbamate (Boc-NR2), and benzylcarbamate (Cbz-NR2); amides, such as acetamide (Ac-NR2) and trifluoroacetamide (CF3CO-NR2); benzylamines, such as benzylamine (Bn-NR2) or 4-methoxybenzylamine (PMB-NR2); triphenylmethylamine (Tr-NR2); and sulfonamides, such as p-toluenesulfonamide (Ts-NR2). Therefore, in embodiments of the present invention, the protecting group PG is selected from a list consisting of carbamates, amides, benzylamines, or sulfonamides. In preferred embodiments, the PG is selected from the list consisting of 9-fluorenylmethylcarbamate (Fmoc-NR2), t-butylcarbamate (Boc-NR2), benzylcarbamate (Cbz-NR2), acetamide (Ac-NR2), trifluoroacetamide (CF3CO-NR2), benzylamine (Bn-NR2), 4-methoxybenzylamine (PMB-NR2), triphenylmethylamine (Tr-NR2), and p-toluenesulfonamide (Ts-NR2).

[0083] More preferably, the protecting group (PG) is a carbamate protecting group such as Boc (t-butyloxycarbonyl) or CBz (carboxybenzyl). The Boc protecting group has the advantage that it may be removed under acidic conditions involving salt formation. This may, in certain embodiments, allow for one-pot deprotection, precipitation, and isolation of the product. For example, the CBz protecting group has the advantage that cleavage of the protecting group and reduction of the alkene (i.e., the piperidine double bond) in the compound of formula (III) may be carried out in a single step, without requiring a separate deprotection step (i.e., step c). Those skilled in the art are well aware of suitable protecting groups for amines, the protection conditions used to set them, and the conditions for their deprotection (i.e., cleavage), which can be found, for example, in Greene's Protective Groups in organic synthesis. Therefore, the protecting group may be changed to other suitable amine protecting groups not explicitly mentioned herein.

[0084] In a preferred embodiment, PG is a carbamate protecting group. In a very preferred embodiment, the carbamate is selected from Boc or Cbz. In the most preferred embodiment, the carbamate protecting group is a Boc group. Most preferably, Y is O.

[0085] Mode V In a fifth aspect, the present invention relates to the use of an intermediate of formula (III) for the production of compounds of formula (IVa), (IVb), (IIIa), (S)-(IVa), (S)-(IVb), (V), or (VI), or to the use of an intermediate of formula (IIIa) for the production of compounds of formula (IVb), (S)-(IVb), (V), or (VI): [ka]

[0086] Suitable amine PGs can be found, for example, in Greene's Protective Groups in Organic Synthesis or the list described in Embodiment IV, which are equally applicable to Embodiment V. In preferred embodiments, the PG is a carbamate protecting group. In very preferred embodiments, the carbamate protecting group is selected from Boc or Cbz. In most preferred embodiments, the carbamate protecting group is a Boc group. Most preferably, Y is O. [Examples]

[0087] experiment General equipment methods

number

[0088] Example 1 - Synthesis of the compound of formula (VI) The following reaction scheme 1 shows the overall route developed for the synthesis of the compound of formula (VI). [ka]

[0089] Reaction Scheme 1 Synthesis of 2-bromo-4-methoxy-5-(trifluoromethyl)phenol (2): [ka]

[0090] 1. Set up a 2L jacketed flask equipped with an overhead stirrer. 2. Fill R1 with 1 (100g, 1.0±0.05 times) under N2. 3. Fill R1 with DCM (750~850g, 7.5~8.5 times, 6V) under N2. 4. Adjust R1 to 0~10℃. 5. Add TfOH (156.2g, 1.56~1.60 times, 2.0 equivalents) to R1 over 1 hour at 0~10℃. 6. Add PyHBr3 (166.5g, 1.66~1.68 times, 1.0 equivalent) to R1 over 0~10 o Add C over 1 hour. 7. Stir R1 at 0-10°C for 16-20 hours. 8. Add PyHBr3 (8g, 0.05-0.20 times, 0.05 equivalent) to R1 at 0-10°C. 9. Stir R1 at 0-10°C for 6-12 hours. 10. Add 20% Na2SO3 (550-650g, 5.5-6.5 times, 6V) at 0-10 o Add C over 1 hour. 11. Adjust R1 to 15-25°C. 12. Stir R1 at 15-25°C for 1-2 hours. 13. Let R1 stand for 1-2 hours. 14. Separate the lower layer and remove the upper layer. 15. Add 7% NaHCO3 (950-1150g, 8.5-11.5 times, 10V) and stir for 15-25 o Adjust pH to 7-9 with C. 16. Stir R1 at 15-25°C for 1-2 hours. 17. Let R1 stand for 1-2 hours. 18. Separate the lower layer and remove the upper layer. 19. Pack DCM (600-700g, 6.0-7.0 times dilution, 5V) at 15-25°C. 20. Let R1 stand for 1-2 hours. 21. Separate the lower layer and remove the upper layer. 22. Pack saturated NaCl (550-650g, 5.5-6.5 times dilution, 6V) at 15-25°C. 23. Stir R1 at 15-25°C for 1-2 hours. 23. Let R1 stand for 1-2 hours. 24. Separate the lower layer and remove the upper layer. 25. Concentrate R1 1-3 times under vacuum at less than 40°C. 26. Fill R1 with acetone (468g, 4.5-5.0 times dilution, 6V). 26. Concentrate R1 1-3 times under vacuum at less than 40°C. 27. Fill R1 with acetone (468g, 4.5-5.0 times dilution, 6V). Compound 2 is obtained as a solution in acetone. Laboratory yield: approximately 90%. 1H NMR:400MHz, CDCl3δ7.20(s,1H),7.10(s,1H),3.87(s,3H)

[0091] Synthesis of 1-bromo-2,5-dimethoxy-4-(trifluoromethyl)benzene (3): [ka]

[0092] 1. Set up a 2L jacketed flask equipped with an overhead stirrer. 2. Fill R1 with acetone solution (100g, 1.0x dilution (0.98~1.02x), 1.0 equivalent). 3. Fill R1 with K2CO3 (76.5g, 0.77x dilution (0.72~0.80x), 1.52 equivalents). 4. Fill R1 with MeI (62.45g, 0.62x dilution (0.59~0.65x), 1.20 equivalents). 5. Adjust R1 to 30°C (25~35°C) under N2 flow. 6. Stir R1 at 30°C (25~35°C) for 18 hours (16~20 hours). 7. Fill R1 with MeI (7.9g, 0.08x dilution (0.06~0.10x), 0.15 equivalents). 8. Stir R1 at 30°C (25-35°C) for 8 hours (6-10 hours). 9. Filter the suspension and transfer the liquid to R2. 10. Rinse the wet cake with acetone (158g, 1.58 times (1.50-1.66 times), 2V (1.90-2.10V)). 11. Rinse the wet cake with acetone (158g, 1.58 times (1.50-1.66 times), 2V (1.90-2.10V)). IPC: Residual MeI in K2CO3 cake: ≤100ppm. 12. Concentrate R2 to 3-4V under vacuum at less than 45°C. 13. Adjust R2 to 30-35°C. 14. Fill R1 with process water (600g, 5.9-6.1 times) under N2 at 30-35°C for 40 minutes. 15. Stir R2 at 30-35°C for 1-2 hours. 16. Adjust R2 to 10-15°C over 1 hour. 17. Stir R2 at 10-15°C for 12-16 hours. 18. Filter the mixture. 19. Wash the cake (140g, 1.3-1.5 times) with a solution (acetone / H2O = 1 / 2, V / V). 20. Dry the wet cake at 50-55°C for 16-24 hours. Compound 3 is obtained as a solid. Laboratory yield: approximately 85%. 1 HNMR: 400MHz, CDCl3δ7.23 (s, 1H), 7.09 (s, 1H), 3.97 (s, 3H), 3.88 (s, 3H).

[0093] Synthesis of tert-butyl 5-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate(4): [ka]

[0094] 1. Set up a 2L jacketed flask equipped with an overhead stirrer. 2. Fill R1 with 3 (100g, 1.0±0.02 times) under N2. 3. Fill R1 with 3b (116~120g, 1.19~1.21 times) under N2. 4. Fill R1 with ACN (450~550g, 4.5~5.5 times, 6V). 5. Fill with NaBr aqueous solution (27~30g, 0.27~0.30 times, 0.2V). 6. Fill R1 with K2CO3 (95~98g, 0.95~1.00 times). 7. Purge R1 three times with N2. 8. Fill R1 with Pd(dppf)Cl2.CH2Cl2 (8.4~8.6g, 0.084~0.086 times). 9. Fill R1 with ACN (50-100g, 0.5-1.0 times). 10. Purge R1 three times with N2. 11. Fill R1 with 75-85 o Adjust to C. 12. Stir R1 at 75-85°C for 16-24 hours. 13. Stir R1 at 45-55°C. o Adjust to C. 14. Adjust R1 to 20-40°C. 15. Fill R1 with Pd(dppf)Cl2.CH2Cl2 (1-3g, 0.01-0.03 times). 15. Purge R1 three times with N2. 16. Adjust R1 to 75-85°C. 17. Stir R1 at 75-85°C for 6-10 hours. 18. Adjust R1 to 45-55 o Adjust to C. 19. Filter the mixture at 45-55°C. 20. Rinse the cake with ACN (150-200g, 1.5-2.0 times dilution, 2V). 21. Rinse the cake with ACN (150-200g, 1.5-2.0 times dilution, 2V). 22. Pack the organic phase into R1. 23. Add process water (800-1200g, 8.0-12.0 times dilution, 8V) over 3 hours at 45-55°C. 24. Adjust R1 to 0-10°C over 2 hours. 25. Stir R1 at 0-10°C for 4-8 hours. 26. Filter the cake and wash with ACN:H2O=1:3 (V / V) (100-200g, 1.0-2.0 times dilution, 2V). 27. Pack the wet cake into R1. 28. Fill with ACN (300-400g, 3.0-4.0 times, 4V). 29. Set R1 to 45-55 oAdjust to C. 30. Add process water (400-500g, 4.0-5.0 times dilution, 4V) over 3 hours at 45-55°C. 31. Adjust R1 to 0-10°C over 2 hours. 32. Stir the mixture at 0-10°C for 1-2 hours. 33. Filter the cake and wash with ACN:H2O=1:3 (V / V) (100-200g, 1.0-2.0 times dilution, 2V). 34. Fill R1 with the wet cake. 35. Fill R1 with sorbate (900-1000g, 9.0-10.0 times dilution). 36. Fill R1 with silicathiol (10-15g, 0.1-0.15 times dilution). 37. Fill R1 with sorbate (300-400g, 3.0-4.0 times dilution). 38. R1 45-55 o Adjust to C. 39. Stir R1 at 45-55°C for 12-18 hours. 40. Adjust R1 to 15-25°C. 41. Stir R1 at 15-25°C for 1-3 hours. 42. Filter the cake and wash with HCl (90-150g, 0.9-1.5 times dilution, 1V). 43. Decolorize the organic layer in R1 using CUNO (CUNO apparatus; supplier: 3M; model: Zeta Carbon; Zeta Plus activated carbon, supplier: 3M; grade: R55SP; carbon content: 1.4g; total weight: 3g; size: 47*6mm) at 25-35°C for 10-16 hours. 44. Wash CUNO with HCl (200-400g, 2.0-4.0 times dilution, 3V) for 2-4 hours. 45. Wash CUNO with HCl (200-400g, 2.0-4.0x dilution, 3V) for 2-4 hours. 46. Wash CUNO with HCl (200-400g, 2.0-4.0x dilution, 3V) for 3-6 hours. 47. Concentrate R1 2-3 times under vacuum at less than 40°C. 48. Fill R1 with HCl (600-700g, 6.0-7.0x dilution). Laboratory yield: approximately 80%. Compound 4 is obtained as an off-white solid, which is 1 Confirmed by 1H-NMR 1 H-NMR:400MHz, CDCl3δ7.07(s,1H),6.85(s,1H),5.95(m,1H),4.22(m,2H),δ3. 89(s,3H),3.82(s,3H),3.61-3.58(t,J=5.6Hz,3H),2.33(m,2H),1.50(s,9H).

[0095] Synthesis of 3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine (6): [ka]

[0096] 1. Set up a 2L jacketed flask equipped with an overhead stirrer. 2. Fill R1 with 4 acetate solution (net: 100g, 1.0x, 1.0 equivalent) under N2. 3. Fill R1 with acetate (890g, 8.9x, 10V) under N2. 4. Fill R1 with wet Pd / C (10.0g, 0.1x) under N2. 5. Purge R1 three times with H2 at 0.5-1 MPa. 6. Adjust R1 to 0.5-1 MPa under H2 flow. 7. Adjust R1 to 25-35°C. 8. Stir R1 at 25-35°C for 20-24 hours. 9. Fill R1 with wet Pd / C (2.5g, 0.025x) under N2. 10. Purge R1 three times with H2 at 0.5-1 MPa. 11. Adjust R1 to 0.5-1 MPa with H2 flow. 12. Adjust R1 to 25-35°C. 13. Stir R1 at 25-35°C for 20-24 hours. 14. Filter the mixture through a diatomaceous earth (0.5-2.0 times) pad. 15. Wash the pad with ELISA (160-240 g, 1.6-2.4 times). 16. Combine the ELISA solutions and transfer to R2. 17. Concentrate the organic phase to 7-9V at below 50°C. Compound 5 is obtained as a solid. 1¹H-NMR.δ 7.04(s,1H), 6.85(s,1H), 4.17~4.14(d,J=12.0Hz,1H), 3.86(s,3H), 3.83(s,3H), 3.13~3.10(m,1H), 2.79(s,1H), 1.96~1.94(d,J=9.20Hz,1H), 1.75(s,1H), 1.69~1.61(m,3H), 1.47(s,9H). 18. Adjust R2 to 10~15℃. 19. Add concentrated HCl (135g, 1.30~1.40 times, 5.0 equivalents) to R2 over 1 hour at 10~15℃. 20. Adjust R2 to 25~30℃. 21. Stir R2 at 25-35°C for 16-20 hours. 22. Adjust R2 to 10-15°C. 23. Add concentrated HCl (26g, 0.2-0.3 dilution, 1.0 equivalent) to R2 over 1 hour at 10-15°C. 24. Stir R2 at 25-35°C for 8-10 hours. 25. Add 2N NaOH aqueous solution (650-900g, 6.5-9.0 dilution) to R2 and adjust the pH to 8-9 at 10-30°C. 26. Stir R2 at 15-25°C for 1-2 hours. 27. Let R2 stand for 1-2 hours. 28. Separate the aqueous phase. 29. Transfer the aqueous phase to R2. 30. Pack R2 with ELISA (160-240g, 1.6-2.4 dilution). 31. Stir R2 at 15-25°C for 1-2 hours. 32. Let R2 stand for 1-2 hours. 33. Separate the aqueous phase. 34. Combine with the organic phase. 35. Wash the combined organic phase with 10% NaCl aqueous solution (500-700g, 5.0-7.0 times dilution). 36. Stir R2 at 15-25°C for 1-2 hours. 37. Let R2 stand for 1-2 hours. 38. Separate the aqueous phase. 39. Concentrate the organic phase to 5-6V at below 50°C. Laboratory yield: approximately 88% in 2 steps. Compound 6 (130g, crude) is obtained as an off-white solid, and this 1 Confirmation is performed by 1H NMR. 1 H NMR:400MHz,MeOD δ7.14(s,1H),7.04(s,1H),3.89(s,3H),3.86(s,3H),3.34-3.32(m,2H),3 .25-3.22(m,2H)2.88-2.81(m,2H),1.97-1.94(m,2H),1.85-1.79(m,2H).

[0097] Synthesis of 3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine (8): [ka]

[0098] 1. Set up a 3L jacketed flask equipped with an overhead stirrer. 2. Fill R1 with 6 (100g, 1.0±0.02 times) under N2. 3. Fill R1 with THF (850~950g, 8.5~9.5 times, 10V). 4. Fill with process water (90~110g, 2.8~3.2 times, 1V). 5. Adjust R1 to 25~35℃. 5. Fill R1 with (2R,3R)-2,3-bis[(4-methoxybenzoyl)oxy]butanediic acid (144~146g, 1.44~1.46 times). 6. Adjust R1 to 45~55 o Adjust to C. Stir R1 at 45-55°C for 10-16 hours. 7. Adjust R1 to 30-40°C. 8. Concentrate R1 to 2-4V at 40°C under vacuum. 9. Pack with DCM (900-1000g, 9.0-10.0 times, 7V). 10. Concentrate R1 to 2-4V at 40°C under vacuum. 11. Pack with DCM (900-1000g, 9.0-10.0 times, 7V). 12. Stir R1 at 35-45°C for 3-6 hours. 13. Adjust R1 to 20-30°C. 14. Stir R1 at 20-30°C for 10-16 hours. 15. Filter the mixture. IPC: ee% of 7 in wet cake (as di-anisioyl tartrate) ≥ 98.0%. 16. Fill R1 with wet cake. 17. Fill R1 with DCM (1300-1400g, 13.0-14.0 times, 10V). 18. Adjust R1 to 35-45°C. 19. Stir R1 at 35-45°C for 1-3 hours. 20. Adjust R1 to 20-30°C. 21. Stir R1 at 20-30°C for 3-6 hours. 22. Filter the mixture. 23. IPC: ee% of 7 in wet cake (as di-anisioyl tartrate) ≥ 98.0%. 7 (as di-anisioyl tartrate) 1 1H NMR: 400MHz, MeOD δ 8.09-8.06 (m, 4H), 7.15 (s, 1H), 7.02-6.97 (m, 5H), 5.88 (s, 2H), 3.88-3.84 (m, 12H), 3.34-3.32 (m, 3H), 3.09-3.03 (t, J=12.0Hz, 1H), 2.97 (m, 1H), 2.00 (m, 1H), 1.91-1.87 (m, 3H). 24. Fill R1 with wet cake. 25. Fill R1 with ₹ (450-500g, 4.5-5.0x dilution, 5V). 26. Fill R1 with 20% Na2CO3 (450-500g, 4.5-5.0V, 5V) aqueous phase. 27. Stir R1 at 20-30°C for 2-4 hours. 28. Let R1 stand for 1-2 hours. 29. Separate the upper layer and remove the lower layer. 30. Fill R1 with 20% Na2CO3 (450-500g, 4.5-5.0V, 5V) aqueous phase. 31. Stir R1 at 20-30°C for 1-3 hours. 32. Let R1 stand for 1-2 hours. 33. Separate the upper layer and remove the lower layer. 34. Concentrate R1 to 2-3V under vacuum at 40°C. Laboratory yield of 7: 35-40%. 1 H-NMR: 400MHz, MeOD δ7.14(s,1H),6.99(s,1H),3.86-3.84(d,6H),3.21(m,1H),3.08-3.05(m,2H),2.65-2.58(m,2H),1.90-1.64(m,4H). 35. Fill R1 with EtOH (450-500g, 4.5-5.0 times dilution, 5V). 36. Concentrate R1 to 2-3V under vacuum at 40°C. 37. Fill R1 with EtOH (50-300g, 0.5-3.0 times dilution, 2V). 38. Fill R1 with succinic acid (15-25g, 0.15-0.25 times dilution). 39. Concentrate R1 to 45-55 o Adjust to C. 40. Stir R1 at 45-55°C for 3-6 hours. 41. Adjust R1 to 20-30°C over 3 hours. 42. Stir R1 at 20-30°C for 16-20 hours. 43. Filter the mixture. 44. Dry the wet cake at 35-45°C for 18-24 hours. Laboratory yield of 8: approximately 70%. 1 H-NMR: 400MHz, MeOD δ7.16(s,1H),7.08(s,1H),3.89(d,6H),3.46-3.43(m,3H),3.15-3.02(m,2H),2.53(s,4H),2.08-1.89(m,4H).

[0099] If Y is S, the same procedure as above may be used to synthesize the compound of formula (VI) by using the compound of formula (II) shown below, where X is Cl, Br, or I. [ka]

[0100] The compound of formula (II), where Y is S, may also be prepared from commercially available 4-fluoro-3-(trifluoromethyl)phenol as shown in the following reaction scheme. The brominating agent may, if necessary, be substituted with a chlorinating agent or iodizing agent disclosed herein to obtain (5-chloro-4-methoxy-2-(trifluoromethyl)phenyl)(methyl)sulfan or (5-iodo-4-methoxy-2-(trifluoromethyl)phenyl)(methyl)sulfan, respectively. [ka]

[0101] Example 1A - Synthesis of the compound of formula (VI) The following reaction scheme 1A shows an alternative route for the synthesis of the compound of formula (VI), in which deprotection is carried out before hydrogenation. [ka]

[0102] Reaction Scheme 1A Synthesis of 2-bromo-4-methoxy-5-(trifluoromethyl)phenol (2): [ka]

[0103] 1. Set up a 2L jacketed flask equipped with an overhead stirrer. 2. Fill R1 with 1 (100g, 1.0±0.05 times) under N2. 3. Fill R1 with DCM (750~850g, 7.5~8.5 times, 6V) under N2. 4. Adjust R1 to 0~10℃. 5. Add PyHBr3 (166.5g, 1.66~1.68 times, 1.0 equivalent) to R1 at 0~10℃. o Add with C. 6. Add TfOH (156.2g, 1.56-1.60 times, 2.0 equivalents) to R1 over 2 hours at 0-10°C. 7. Stir R1 at 0-10°C for 16-20 hours. 8. Add PyHBr3 (8g, 0.05-0.20 times, 0.05 equivalents) to R1 over 0-10 o Add C. 9. Stir R1 at 0-10°C for 6-12 hours. 10. Add 20% Na2SO3 (550-700g, 5.5-7.0 times dilution, 6V) at 0-10°C. o Add C over 4 hours. 11. Adjust R1 to 15-25°C. 12. Stir R1 at 15-25°C for 1-2 hours. 13. Let R1 stand for 1-2 hours. 14. Separate the lower layer and remove the upper layer. 15. Add 7% NaHCO3 (950-1150g, 8.5-11.5 times, 10V) and stir for 15-25 o Adjust pH to 7-9 with C. 16. Stir R1 at 15-25°C for 1-2 hours. 17. Let R1 stand for 1-2 hours. 18. Separate the lower layer and remove the upper layer. 19. Pack DCM (600-700g, 6.0-7.0 times dilution, 5V) at 15-25°C. 20. Let R1 stand for 1-2 hours. 21. Separate the lower layer and remove the upper layer. 22. Pack saturated NaCl (550-650g, 5.5-6.5 times dilution, 6V) at 15-25°C. 23. Stir R1 at 15-25°C for 1-2 hours. 23. Let R1 stand for 1-2 hours. 24. Separate the lower layer and remove the upper layer. 25. Concentrate R1 1-3 times under vacuum at less than 40°C. 26. Fill R1 with acetone (468g, 4.5-5.0 times dilution, 6V). 26. Concentrate R1 1-3 times under vacuum at less than 40°C. 27. Fill R1 with acetone (468g, 4.5-5.0 times dilution, 6V). Compound 2 is obtained as a solution in acetone. Laboratory yield: approximately 90%.1 ¹H NMR: 400MHz, CDCl3δ 7.26 (s,1H), 7.14 (s,1H), 5.94 (Broad's s,1H), 3.87 (s,3H)

[0104] Synthesis of 1-bromo-2,5-dimethoxy-4-(trifluoromethyl)benzene (3): [ka]

[0105] 1. Set up a 2L jacketed flask equipped with an overhead stirrer. 2. Fill R1 with acetone solution (100g, 1.0x dilution (0.98~1.02x), 1.0 equivalent). 3. Fill R1 with K2CO3 (76.5g, 0.77x dilution (0.72~0.80x), 1.5 equivalents). 4. Fill R1 with MeI (62.45g, 0.62x dilution (0.59~0.65x), 1.20 equivalents). 5. Adjust R1 to 30°C (25~35°C) under N2 flow. 6. Stir R1 at 30°C (25~35°C) for 18 hours (16~20 hours). 7. Fill R1 with MeI (7.9g, 0.08 times (0.06~0.10 times), 0.15 equivalents). 8. Stir R1 at 30°C (25~35°C) for 8 hours (6~10 hours). 9. Filter the suspension and transfer the liquid to R2. 10. Rinse the wet cake with acetone (158g, 1.58 times (1.50~1.66 times), 2V (1.90~2.10V)). 11. Adjust R2 to 25~35°C. 12. Fill R1 with process water (1600g, 15.0~18.0 times) under N2 at 25~35°C for 40 minutes. 13. Stir R2 at 25~35°C for 1~2 hours. 14. Adjust R2 to 5~15°C over 1 hour. 15. Stir R2 at 5-15°C for 12-16 hours. 16. Filter the mixture. 17. Wash the cake (150g, 1.0-2.0 times) with solution (acetone / H2O = 1 / 2, V / V). 18. Dry the wet cake at 45-55°C for 16-24 hours. Compound 3 is obtained as a solid. Laboratory yield: approximately 85%. 1HNMR: 400 MHz, CDCl3 δ 7.24 (s, 1H), 7.10 (s, 1H), 3.89 (s, 3H), 3.88 (s, 3H).

[0106] Synthesis of tert-butyl 5-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (4):

Chemical formula

[0107] 1. Install a 2 L jacketed flask equipped with an overhead stirrer. 2. Charge 3 (100 g, 1.0 ± 0.02 times) into R1 under N2. 3. Charge 3b (116 - 120 g, 1.19 - 1.21 times) into R1 under N2. 4. Charge ACN (450 - 550 g, 4.5 - 5.5 times, 6V) into R1. 5. Charge an aqueous NaBr solution (27 - 30 g, 0.27 - 0.30 times, 0.2V). 6. Charge K2CO3 (95 - 98 g, 0.95 - 1.00 times) into R1. 7. Purge R1 with N2 three times. 8. Charge Pd(dppf)Cl2·CH2Cl2 (8.4 - 8.6 g, 0.084 - 0.086 times) into R1. 9. Charge ACN (50 - 100 g, 0.5 - 1.0 times) into R1. 10. Purge R1 with N2 three times. 11. Adjust R1 to 75 - 85 o °C. 12. Stir R1 at 75 - 85 °C for 16 - 24 hours. 13. Adjust R1 to 45 - 55 o °C. 14. Adjust R1 to 20 - 40 °C. 15. Charge Pd(dppf)Cl2·CH2Cl2 (1 - 3 g, 0.01 - 0.03 times) into R1. Purge R1 with N2 three times. 16. Adjust R1 to 75 - 85 °C. 17. Stir R at 75 - 85 °C for 6 - 10 hours. 18. Adjust R1 to 45 - 55 o °C. 19. Filter the mixture at 45 - 55 °C. 20. Wash the cake with ACN (150 - 200 g, 1.5 - 2.0 times, 2V). 21. Charge the organic phase into R1. 22. Charge silica thiol (10 - 15 g, 0.1 - 0.15 times) into R1. 23. Adjust R to 45 - 55 oAdjust to C. 24. Stir R1 at 45 - 55 °C for 12 - 18 hours. 25. Filter the cake and wash it with ACN (100 - 200 g, 1.0 - 2.0 times, 2V). 26. Fill the organic phase into R1. 27. Add process water (1000 - 1500 g, 10.0 - 15.0 times, 11V) at 45 - 55 °C over 3 hours. 28. Adjust R1 to 0 - 10 °C over 2 hours. 29. Stir R1 at 0 - 10 °C for 4 - 8 hours. 26. Filter the cake and wash it with ACN:H2O = 1:3 (V / V) (100 - 200 g, 1.0 - 2.0 times, 2V). 27. Dry the wet cake at 35 - 45 °C for 10 - 16 hours. Laboratory yield: about 80%. Compound 4 is obtained as an off - white solid, which 1 is confirmed by 1H - NMR. 1 1H - NMR: 400 MHz, CDCl3 δ 7.07 (s, 1H), 6.85 (s, 1H), 5.94 (m, 1H), 4.22 (m, 2H), δ 3.89 (s, 3H), 3.83 (s, 3H), 3.61 - 3.58 (t, J = 5.6 Hz, 3H), 2.33 (m, 2H), 1.54 (s, 9H).

[0108] Synthesis of 3-(2,5 - dimethoxy - 4-(trifluoromethyl)phenyl)piperidine (6):

Chemical Structure

[0109] 1. Set up a 2L jacketed flask equipped with an overhead stirrer. 2. Fill R1 with 4 (net: 100g, 1.0x, 1.0 equivalent) under N2. 3. Fill R1 with 2-MeTHF (860g, 8.0-9.0x, 10V) under N2. 4. Add concentrated HCl (135g, 1.30-1.40x, 5.0 equivalent) to R1 over 1 hour at 5-15°C. 5. Adjust R1 to 25-35°C. 6. Stir R1 at 25-35°C for 16-20 hours. 7. Adjust R1 to 5-15°C. 8. Add concentrated HCl (26g, 0.2-0.3x, 1.0 equivalent) to R1 over 1 hour at 5-15°C. 9. Stir R1 at 25-35°C for 8-10 hours. 10. Adjust R1 to 0-10°C. 11. Add 3N NaOH aqueous solution (800-1500g, 8.0-15.0 dilution) to R1 and adjust the pH to 10-13 at 0-25°C. 12. Stir R1 at 15-25°C for 1-3 hours. 13. Let R1 stand for 1-2 hours. 14. Separate the aqueous phase. 15. Add 3N NaOH aqueous solution (500-700g, 5.0-7.0 dilution) to R1 at 0-25°C. 16. Stir R1 at 15-25°C for 1-3 hours. 17. Let R1 stand for 1-2 hours. 18. Separate the aqueous phase. 19. Pack 20% NaCl aqueous solution (500-700g, 5.0-7.0V) into R1 at 15-25°C. 20. Stir R1 at 15-25°C for 1-3 hours. 21. Let R1 stand for 1-2 hours. 22. Separate the aqueous phase. 23. Concentrate the organic phase to 2-3V under vacuum at below 40°C. 24. Pack R1 with siRNA (630g, 6.0-7.0x dilution). 25. Concentrate the organic phase to 2-3V under vacuum at below 40°C. 26. Pack R1 with siRNA (630g, 6.0-7.0x dilution). Compound 5 is obtained as a solution in siRNA. 27. Pack R2 with wet Pd / C (8.0g, 0.07-0.09x dilution) under N2. 28. Pack R2 with the organic phase. 29. Purge R2 three times with N2 at 0.5-1 MPa. 30. Purge R2 three times with H2 at 0.5-1 MPa. 31. Adjust R2 to 0.5-1 MPa under H2 flow. 32. Adjust R2 to 25-35°C. 33. Stir R2 at 25-35°C for 20-24 hours. 34. Fill R2 with moist Pd / C (2.5g, 0.025 times) under N2. 35. Purge R2 three times with N2 at 0.5-1 MPa.36. Purge R2 three times with H2 at 0.5 - 1 MPa. 37. Adjust R2 to 0.5 - 1 MPa under a H2 flow. 38. Adjust R2 to 25 - 35 °C. 39. Stir R2 at 25 - 35 °C for 10 - 16 hours. 40. Filter the mixture through a diatomaceous earth (0.5 - 2.0 times) pad. 41. Wash the pad with EtOAc (200 - 300 g, 2.0 - 3.0 times). 42. Combine the EtOAc solutions. Laboratory yield: approximately 88% in 2 steps. Compound 6 (130 g, crude) was obtained as an off - white solid, which was 1 confirmed by 1H NMR. 1 1H NMR: 400 MHz, MeOD δ7.11(s,1H),7.02(s,1H),3.86(s,3H),3.84(s,3H),3.34 - 3.32(m,1H),3.22 - 3.20(m,2H)2.86 - 2.77(m,2H),1.94 - 1.91(m,2H),1.83 - 1.77(m,2H).

[0110] Synthesis of 3-(2,5 - dimethoxy - 4-(trifluoromethyl)phenyl)piperidine (8):

Chemical formula

[0111] 1. Install a 3 L jacketed flask equipped with an overhead stirrer. 2. Charge a solution of 6 in EtOAc (100 g, 1.0 ± 0.02 times) into R1 under N2. 3. Concentrate R In vacuo to 2 - 3 times at a temperature below 40 °C. 4. Charge THF (850 - 950 g, 8.5 - 9.5 times, 10V) into R1. 5. Charge process water (90 - 110 g, 0.9 - 1.1 times, 1V). 6. Adjust R1 to 25 - 35 °C. 6. Charge (2R,3R)-2,3 - bis[(4 - methoxybenzoyl)oxy]butanedioic acid (144 - 146 g, 1.44 - 1.46 times) into R1. 7. Adjust R1 to 45 - 55 oAdjust to C. 8. Stir R1 at 45-55°C for 10-16 hours. 9. Adjust R1 to 30-40°C. 10. Concentrate R1 to 2-4V at 40°C under vacuum. 11. Fill with DCM (900-1000g, 9.0-10.0 times, 7V). 12. Concentrate R1 to 2-4V at 40°C under vacuum. 13. Fill with DCM (900-1000g, 9.0-10.0 times, 7V). 14. Stir R1 at 35-45°C for 4-8 hours. 15. Adjust R1 to 20-30°C. 16. Stir R1 at 20-30°C for 4-8 hours. 17. Filter the mixture. IPC: ee% of 7 in the wet cake (as di-anisioyl tartrate) ≥ 98.0%. 18. Fill R1 with the wet cake. 19. Fill R1 with DCM (1300-1400g, 13.0-14.0 times, 10V). 20. Adjust R1 to 30-45°C. 21. Stir R1 at 30-45°C for 4-6 hours. 22. Filter the mixture. 23. IPC: ee% of 7 in the wet cake (as di-anisioyl tartrate) ≥ 98.0%. 7 (as di-anisioyl tartrate) 1 1H NMR: 400MHz, MeOD δ 8.10-8.06 (m, 4H), 7.15 (s, 1H), 7.02-6.97 (m, 5H), 5.88 (s, 2H), 3.88-3.85 (m, 12H), 3.33-3.32 (m, 3H), 3.09-3.03 (t, J=12.0Hz, 1H), 2.98-2.97 (m, 1H), 2.00 (m, 1H), 1.91-1.87 (m, 3H). 24. Fill R1 with wet cake. 25. Fill R1 with ₹ (450-500g, 4.5-5.0 times, 5V). 26. Fill R1 with 20% Na2CO3 (550-700g, 5.5-7.5V, 5V) aqueous solution. 27. Stir R1 at 20-30°C for 2-4 hours. 28. Let R1 stand for 1-2 hours. 29. Separate the upper layer and remove the lower layer. 30. Fill R1 with the aqueous phase. 31. Fill R1 with ELISA (450-500g, 4.5-5.0V, 5V). 32. Stir R1 at 20-30°C for 1-2 hours. 33. Let R1 stand for 1-2 hours. 34. Separate the upper layer and remove the lower layer. 35. Combine the organic phases. 36. Concentrate R1 to 5-6V under vacuum at 40°C. 37. Fill R1 with process water (400-600g, 4.0-6.0 times dilution). 38. Stir R1 at 20-30°C for 1-2 hours. 39. Let R1 settle for 1-3 hours. 40. Separate the upper layer and remove the lower layer. 41. Fill R1 with process water (400-600g, 4.0-6.0 times dilution). 42. Stir R1 at 20-30°C for 1-3 hours. 39. Let R1 stand for 1-2 hours. 43. Separate the upper layer and remove the lower layer. 44. Concentrate R1 to 2-3V under vacuum at 40°C. 45. Fill with EtOH (450-500g, 4.5-5.0 times dilution). 46. Concentrate R1 to 2-3V under vacuum at 40°C. 47. Fill with EtOH (450-500g, 4.5-5.0 times dilution). Laboratory yield of 7 in EtOH solution: 35-40%. 1 H-NMR: 400MHz, MeOD δ7.14(s,1H),6.99(s,1H),3.87(s,3H),3.83(s,3H),3.22(m,1H),3.08-3.05(m,2H),2.65-2.59(m,2H),1.90-1.64(m,4H). 48. Fill R1 with EtOH solution from step 7. 49. Fill R1 with succinic acid (15-25g, 0.15-0.25 times dilution). 39. Fill R1 to 45-55o Adjust to C. 40. Stir R1 at 45 - 55°C for 3 - 6 hours. 41. Adjust R1 to 20 - 30°C over 3 hours. 42. Stir R1 at 20 - 30°C for 16 - 20 hours. 43. Filter the mixture. 44. Dry the wet cake at 35 - 45°C for 18 - 24 hours. Laboratory yield of 8: about 70%. 1 H-NMR: 400 MHz, MeOD δ 7.17 (s, 1H), 7.08 (s, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.46 - 3.44 (m, 3H), 3.34 - 3.32 (m, 1H), 3.16 - 3.03 (m, 2H), 2.53 (s, 4H), 2.00 - 1.90 (m, 4H).

[0112] Example 2 - Synthesis of the compound of formula (VI) The compound of formula (VI) may also be prepared as shown in the following reaction scheme when Y is S. Chiral resolution may be carried out using any of the chiral acids disclosed herein, preferably the chiral acids shown in Table 1.

Chemical formula

[0113] Example 3: Salt screening Fifteen acids were selected as salt - forming agents with (S)-3-(2,5 - dimethoxy - 4-(trifluoromethyl)phenyl)piperidine (see Table 3). Approximately 45 mg was added to an appropriate solvent, and various equivalents of the acid were added while stirring at 50°C for about 2 hours and then at 25°C for at least 32 hours. Ethanol, acetone, and ACN were used as screening solvents. If no precipitate was obtained or only a small amount of solid was obtained, the solution was placed at 5°C for crystallization.

[0114] The resulting suspension was taken out and centrifuged. The obtained solid was analyzed by XRPD. The salt screening results are summarized in Table 4. Salts with high or medium crystallinity were further characterized (see Table 5).

[0115]

Table 3

[0116]

Table 4

[0117] Example 4: Evaluation of the Characteristics of the Crystal Hits According to the salt screening results (see Table 4), a total of 19 potential salt hits were identified. All potential salt hits were further investigated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), 1 1H-NMR, ion chromatography (IC), Karl Fischer titration (KF), and polarized light microscopy (PLM) to confirm the identity of the salt hits and evaluate the physicochemical properties of the salt hits as shown in Table 5 below.

[0118]

Table 5

[0119] Among the salts tested in Table 5, hydrochloride (polymorph A), L-tartrate (polymorph B), and succinate (polymorph A) functioned overall better than other salts and showed good physicochemical properties including high crystallinity, high melting point, proper stoichiometry, and good counterion safety. Therefore, these three salts were selected as candidates.

[0120] Preparation of HCl salt (polymorph A). 1600 mg of free base (polymorph B) was weighed into a 20 mL glass vial, and 4.2 mL of ethanol was added to the vial while stirring at 50°C for about 5 minutes. (Clear solution) 2. 1.79 mL (approximately 1.05 equivalents) of HCl solution (a mixture of 0.2 mL of HCl and 1.8 mL of ethanol) was slowly added to the solution (clear solution). 3. Approximately 22.7 mg of seed crystal was added to the solution, and stirring continued at 50°C for about 2 hours (suspension). 4. The mixture was allowed to cool naturally to 25°C, then stirred at 25°C for about 4 days, and then stirred at 5°C for about 5 hours. 5. The solid was recovered by centrifugal filtration and dried at 50°C for about 16 hours. 6. 461 mg of hydrochloride salt (polymorph A) was obtained as an off-white solid in 74% yield. 1 H NMR:400MHz,MeOD δ7.15(s,1H),7.08(s,1H),3.88(s,3H),3.86(s,3H),3.50-3.42(m,3H),3 .40-3.30(m,1H),3.10-3.06(m,1H),2.10-2.06(m,1H),1.98-1.91(m,3H).

[0121] Preparation of L-tartrate (Polymorph B). 1600 mg of free base (Polymorph B) and 338 mg of L-tartaric acid (approximately 1.05 equivalents) were weighed into a 20 mL glass vial. Then, 2 mL of ethanol was added to the vial while stirring at 50°C (dilute suspension). After stirring for about 3 minutes, a solid precipitate formed. 2.4 mL of ethanol was added to the solution (suspension), and approximately 36.8 mg of seed crystals were added to the solution. The mixture was stirred at 50°C for about 2 hours (suspension). 3. The mixture was allowed to cool naturally to 25°C, then stirred at 25°C for about 4 days, and then stirred at 5°C for about 5 hours. 4. The solid was recovered by centrifugal filtration and dried at 50°C for about 16 hours. 5. 780 mg of L-tartrate (Polymorph B) was obtained as an off-white solid in 80% yield. 1 H NMR:400MHz,DMSO δ7.17(s,1H),7.16(s,1H),3.86-3.83(m,8H),3.31-3.28(m,1H),3.23-3.20( m,1H),3.10-3.06(m,1H),2.85(m,1H),1.90-1.81(m,1H),1.79-1.74(m,3H).

[0122] Preparation of succinate (polymorph A). 1600 mg of free base (polymorph B) and 268 mg of succinic acid (approximately 1.05 equivalents) were weighed into a 20 mL glass vial. Then, 2 mL of ethanol was added to the vial while stirring at 50°C (dilute suspension). After stirring for about 3 minutes, a solid precipitate formed. 2.0 mL of ethanol was added to the solution (suspension). 2. Approximately 23.7 mg of seed crystals were added to the suspension. Then, 1.2 mL of ethanol was added, and the mixture was stirred at 50°C for about 2 hours (suspension). 3. The mixture was allowed to cool naturally to 25°C, then stirred at 25°C for about 4 days, and then stirred at 5°C for about 5 hours. 4. The solid was recovered by centrifugal filtration and dried at 50°C for about 16 hours. 5. 625 mg of succinate (polymorph A) was obtained as an off-white solid in 70% yield. 1 H NMR:400MHz,MeOD δ7.16(s,1H),7.08(s,1H),3.89(d,6H),3.46-3.43(m,3H),3.15-3.02(m,2H),2.53(s,4H),2.08-1.89(m,4H)

[0123] Salt candidate evaluation (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine hydrochloride (polymorph A), L-tartrate (polymorph B), and succinate (polymorph A) were scaled up and thoroughly evaluated in comparison to the free base (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine (polymorph B). The scale-up batches were the same polymorph as those of the screening samples. As shown in Tables 6-10, the three salt candidates were evaluated in terms of physicochemical properties, stability, solubility, hygroscopicity, and polymorphic behavior in comparison to the free form polymorph B (i.e., 3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine).

[0124] [Table 6]

[0125] Crystallinity and thermal properties: The free base (polymorph B) is a monohydrate containing approximately 8% water (1.3 molar equivalents) according to Karl Fischer. It has high crystallinity. DSC is T onset At 53.4°C, it shows a dehydration peak with an enthalpy of approximately 180 J / g, followed by Tonset showing a melting peak at 80.0°C with an enthalpy of approximately 68 J / g. TGA shows a mass loss rate of approximately 8% at approximately 100°C. The residual solvent is 1 It was not detected by 1H-NMR. The hydrochloride salt (polymorph A) is an anhydride. It is highly crystalline. The stoichiometric ratio to free hydrochloric acid is 1:0.99 by IC. DSC was measured at 233.2°C. onset It shows a melting peak. Decomposition occurred during melting. TGA shows a mass loss rate of approximately 0.3% at approximately 160°C. No residual solvent was detected. L-tartrate polymorph B is an anhydride. It is highly crystalline. The stoichiometric ratio to free L-tartaric acid is: 1 The ratio is 1:1.00 based on H-NMR. DSC was measured at 203.1°C. onset It shows a melting peak. Decomposition occurred during melting. TGA shows a mass loss rate of approximately 0.4% at approximately 170°C. No residual solvent was detected. Succinate polymorph A is an anhydride. It is highly crystalline. The stoichiometric ratio to free succinic acid is: 1 The ratio is 1:1.01 based on H-NMR. DSC was measured at 166.4°C. onset A melting peak was observed. Decomposition occurred during melting. TGA showed a mass loss rate of approximately 0.2% at approximately 135°C. No residual solvent was detected.

[0126] stability As shown in Table 7 below, the bulk stability of the free base (polymorph B) and the three salt candidates was investigated over a week in open containers at 25°C / 92%RH, 40°C / 75%RH, and 60°C in sealed containers.

[0127] [Table 7]

[0128] Reprogramming purity: Free base (polymorph B), hydrochloride (polymorph A), L-tartrate (polymorph B), and succinate (polymorph A) have high chemical purity of 98.7%, 99.8%, 99.5%, and 99.9%, respectively. Salt formation demonstrated a purification effect.

[0129] Bulk stability: Hydrochloride (polymorph A), L-tartrate (polymorph B), and succinate (polymorph A) are chemically and physically stable under stress conditions. The free form (polymorph B) is chemically stable under these conditions but physically unstable at 60°C. This was converted to the free base (polymorph A). Candidate salts cannot be identified based solely on this parameter.

[0130] solubility The solubility of the free base (polymorph B) and the three salt candidates was tested at 37°C for 2 hours and 24 hours in four pH buffers (pH 1.2 HCl buffer, pH 4.5 acetate buffer, pH 6.8 phosphate buffer, and water) and three biocompatible media (SGF, FaSSIF-V1, and FeSSIF-V1), as shown in Table 8 below. Solubility was tested down to 2 mg / mL.

[0131] [Table 8]

[0132] The free base and the three salt candidates showed generally good solubility. Their solubility was >2 mg / mL in most pH buffers and bio-related fluids, with the exception of pH 6.8 phosphate buffer. In this buffer, solubility was ranked as L-tartrate (polymorph B) > succinate (polymorph A) > HCl salt.

[0133] [Table 9]

[0134] The three salt candidates showed generally good solubility in water, as shown in Table 9.

[0135] In water, solubility was ranked as follows: HCl salt (polymorph A) > succinate (polymorph A) > L-tartrate (polymorph B). L-tartrate and succinate (1:1) have the advantage of providing increased buffering capacity compared to salts formed from monoprotic acids such as HCl salts. Therefore, based on the solubility data, succinate (polymorph A) appears to be the most promising salt candidate.

[0136] Hygroscopic As shown in Table 10, the hygroscopic properties of the free base (polymorph B) and the three salt candidates were evaluated by dynamic water vapor adsorption (DVS) tests at 25°C.

[0137] [Table 10]

[0138] Free base (polymorph B) is stable at 40%RH to 95%RH. However, free base (polymorph B) undergoes dehydration when the relative humidity is below 40%, and after dehydration, it is converted to the potential anhydrous (polymorph A). The dehydrated product is stable at 0%RH to 70%RH. If RH > 70%, the dehydrated product absorbs water and recovers its water content at 90%RH. As a result, the anhydrous (polymorph A) reverts to free base (polymorph B). Hydrochloride (polymorph A) is non-hygroscopic. Hydrochloride (polymorph A) absorbs approximately 0.17% water at 25°C and 40%RH to 95%RH. No morphological change after DVS test. L-tartrate (polymorph B) is slightly hygroscopic. L-tartrate (polymorph B) absorbs approximately 1.5% water at 25°C and 40%RH to 95%RH. No morphological changes were observed after DVS testing. Succinate (polymorph A) is non-hygroscopic. Succinate (polymorph A) absorbs approximately 0.21% water at 25°C and 40% RH to 95% RH. No morphological changes were observed after DVS testing. Therefore, HCl salt (polymorph A) and succinate (polymorph A) appear to be the most promising salt candidates based on their hygroscopicity.

[0139] Morphic properties Free base (polymorph B) consists of plate-like crystals with a particle size in the range of approximately 10 to 100 μm. Hydrochloride (polymorph A) consists of aggregated small crystals with a particle size in the range of approximately 2 to 30 μm. L-tartrate (polymorph B) consists of aggregated small crystals with a particle size in the range of approximately 2 to 20 μm. Succinate (polymorph A) consists of rod-shaped crystals with a particle size in the range of approximately 5 to 50 μm.

[0140] polymorphism Salt screening identified two polymorphs (polymorph A and polymorph B) of the L-tartrate and one polymorph (polymorph A) of the succinate. One polymorph (polymorph A) of the hydrochloride was also identified. Therefore, based on the number of polymorphs identified, the succinate and HCl salts appear to be the most promising salt candidates based on the formation of a single polymorph from the screened solvent.

[0141] conclusion In particular, free bases have several drawbacks to their technical developmentability, including a very low melting point and physical instability under stress conditions. The three salt candidates adequately addressed these developmentability issues of free bases. The three salt candidates have high crystallinity and high melting points. The three salt candidates are chemically and physically stable and are non-hygroscopic or slightly hygroscopic. All three salts exhibit good solubility in pH buffers and bio-related fluids. It was also found that salt formation provides a purification effect. Based on these, all three salts have better developmentability than free bases. In terms of overall properties, succinate and HCl salts were the most promising salt candidates. Succinate may offer some additional advantages over HCl salts in terms of formulation due to the additional free carboxylic acid, which may increase buffering capacity in aqueous solutions.

[0142] Example 5: Screening for other polymorphs of the monosuccinate of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine.

[0143] Equilibrium with the solvent Solvent-mediated equilibrium is an accepted form for generating new polymorphs. Based on approximate solubility results, approximately 50 mg of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine succinate (polymorph A) was equilibrated in a solvent using a stirring rod on a magnetic stirring plate at a speed of 400 rpm for 2 weeks at 25°C, 1 week at 50°C, or 10 cycles of a 5°C-50°C temperature cycle at a heating / cooling rate of 0.1°C / min. The resulting suspension was filtered through a 0.45 μm nylon membrane filter by centrifugation at 14,000 rpm. The solid portion (wet cake) was investigated by XRPD.

[0144] [Table 11]

[0145] Crystallization at room temperature by slow or fast evaporation Based on approximate solubility results, approximately 30 mg of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine succinate (polymorph A) was dissolved in the solvents shown in Table 12.

[0146] The obtained solution was filtered through a 0.45 μm nylon membrane. The resulting clear solution was slowly evaporated under ambient conditions (approximately 25°C, 50% RH), and then rapidly evaporated at room temperature under a flow of dry nitrogen. The solid residue was investigated by XRPD.

[0147] [Table 12]

[0148] Crystallization from high-temperature saturated solutions by slow cooling or rapid cooling. Based on approximate solubility results, approximately 50 mg of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine succinate (polymorph A) was dissolved at 50°C in the minimum amount of selected solvent shown in Table 13. The resulting solution was filtered through a 0.45 μm nylon membrane. The resulting clear solution was cooled to 5°C at 0.1°C / min (slow cooling), or the resulting clear solution was placed in an ice bath at 0°C and stirred (rapid cooling). The precipitate was recovered by centrifugal filtration through a 0.45 μm nylon membrane filter at 5°C and 14,000 rpm. The solid portion (wet cake) was investigated by XRPD.

[0149] [Table 13]

[0150] Crystallization by addition of poor solvent Based on approximate solubility results, approximately 50 mg of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine succinate (polymorph A) was dissolved in a minimum amount of a selected good solvent at ambient temperature (approximately 25°C). Two to four times the volume of poor solvent was slowly added to the resulting clear solution until a large amount of solid precipitated. The precipitate was collected by centrifugal filtration at 14,000 rpm using a 0.45 μm nylon membrane filter. The solid portion (wet cake) was investigated by XRPD.

[0151] [Table 14]

[0152] Compression simulation experiment Approximately 100 mg of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine succinate (polymorph A) was compressed for 5 minutes at 2 MPa, 5 MPa, and 10 MPa using a hydraulic press. Potential changes in polymorphic form and crystallinity were evaluated by XRPD as shown in Table 15.

[0153] [Table 15]

[0154] Dry grinding simulation experiment Approximately 50 mg of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine succinate (polymorph A) was manually ground for 5 minutes using a mortar and pestle. Potential changes in polymorphism and crystallinity were evaluated by XRPD. No changes in polymorphism or crystallinity were observed.

[0155] Wet granulation simulation experiment Water or ethanol was added dropwise to approximately 50 mg of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine succinate (Polymorph A) until the sample was thoroughly wet. The wet sample was gently ground using a mortar and pestle. The granulated sample was dried under ambient conditions for 10 minutes. Potential changes in polymorphism and crystallinity were evaluated by XRPD. No changes in polymorphism or crystallinity were observed.

[0156] conclusion The results indicate that polymorph A is the only identified polymorph of the mono-succinate of (S)-3-(2,5-dimethoxy-4-(trifluoromethyl)phenyl)piperidine. The data demonstrate that the polymorph is highly stable and very unlikely to spontaneously convert to other polymorphic forms during storage or formulation. Polymorph A possesses high crystallinity, good chemical and physical stability, non-hygroscopicity, and good resistance to the formulation process. Therefore, polymorph A is the optimal polymorph for development.

Claims

1. a) In a solvent, in the presence of a transition metal catalyst, the compound of formula (III) is dissolved in hydrogen gas (H ２ A step of reacting with a compound of formula (IVa) or (IVb) to obtain a racemic compound of formula (III), or a step of reacting a compound of formula (III) with a deprotection agent in a solvent to obtain a compound of formula (IIIa); 【Chemistry 1】 b) If a compound of formula (IVa) is formed in step a), the compound of formula (IVa) is reacted with a deprotection reagent in a solvent to obtain a racemic compound of formula (IVb), or if a compound of formula (IIIa) is formed in step a), the compound of formula (IIIa) is reacted with hydrogen gas (H) in a solvent in the presence of a transition metal catalyst. ２ A step of reacting with ) to obtain a racemic compound of formula (IVb); 【Chemistry 2】 c) A step of reacting the compound of formula (IVb) with a chiral acid in a solvent to obtain the compound of formula (V) having at least 70% enantiomeric excess (ee), and liberating the salt of formula (V) to obtain the compound of formula (S)-(IVb); 【Transformation 3】 d) A step of reacting compounds of formula (S) to (IVb) with succinic acid, L-tartaric acid, or HCl in a solvent to obtain a crystalline compound of formula (VI); 【Chemistry 4】 (In the formula, Y is selected from S or O; A － This includes 3-carboxypropanoic acid, (2R,3R)-3-carboxy-2,3-dihydroxypropanoic acid, or chloride (Cl － ) will be selected as. A method for producing a compound of formula (VI) including [the specified compound].

2. The method according to claim 1, wherein the chiral acid in step c) is selected from (-)-O,O'-di-p-toluyl-L-tartaric acid or (-)-di-p-anisoily-L-tartaric acid.

3. a) In a solvent, in the presence of a transition metal catalyst and a chiral ligand, the compound of formula (III) is dissolved in hydrogen gas (H ２ A step of reacting with a compound of formula (S)-(IVa) or (S)-(IVb) having an enantiomeric excess of at least 70% (%ee), or a step of reacting a compound of formula (III) with a deprotection reagent in a solvent to obtain a compound of formula (IIIa); 【Transformation 5】 b) If a compound of formula (S)-(IVa) is formed in step a), the compound of formula (S)-(IVa) is reacted with a deprotection reagent in a solvent to obtain a compound of formula (S)-(IVb) having at least 70% enantiomeric excess (%ee), or if a compound of formula (IIIa) is formed in step a), the compound of formula (IIIa) is reacted with hydrogen gas (H) in a solvent in the presence of a transition metal catalyst and a chiral ligand. ２ A step of reacting with ) to obtain a compound of formula (S)-(IVb) having at least 70% enantiomer excess (%ee); 【Transformation 6】 c) A step of reacting the compound of formula (S)-(IVb) with succinic acid, L-tartaric acid, or HCl in a solvent to obtain the crystalline compound of formula (VI); 【Transformation 7】 (In the formula, Y is selected from S or O; A － This includes 3-carboxypropanoic acid, (2R,3R)-3-carboxy-2,3-dihydroxypropanoic acid, or chloride (Cl － ) will be selected as. A method for producing a compound of formula (VI) including [the specified compound].

4. The method according to claim 3, wherein the chiral ligand is (R,R)-i-Pr-DuPhos.

5. Before step a), a1) A step of reacting the compound of formula (I) with the compound of formula (II) in a solvent in the presence of a base and a transition metal catalyst to obtain the compound of formula (III); The method according to any one of claims 1 to 4, further comprising: 【Transformation 8】 During the ceremony, Z is selected from the group consisting of boronic acids, trifluoroborates, and boronic acid esters. PG is an amine protecting group, Y is selected from S or O, X is selected from Cl, Br, I, or OTf. 【Chemistry 9】

6. The method according to any one of claims 1 to 4, wherein PG is a carbamate protecting group, an amide protecting group, a benzylamine protecting group, a triphenylmethylamine protecting group, or a sulfonamide protecting group.

7. The method according to any one of claims 1 to 4, wherein the deprotection reagent is an acid.

8. Crystalline compound of formula (VI): 【Chemistry 10】 During the ceremony, A － is 3-carboxypropanoic acid, and the crystalline compound is a polymorph having an XRPD spectrum having 2θ peaks at 4.077°, 8.108°, 11.991°, 12.156°, 13.893°, 15.876°, 16.218°, 16.412, 16.596°, 17.849°, 19.507°, 19.786°, 20.031°, 20.297°, 21.122°, 22.011°, 22.635°, 23.000°, 23.268°, 24.065°, 24.408°, 25.414°, 25.758°, 26.947°, 27.751°, 28.032°, 28.314°, 29.966°, 30.358°, 30.562°, 30.770°, 31.378°, 32.306°, 32.868°, 33.505°, 34.710°, 35.206°, 36.418°, 36.714°, 37.306°, 38.147°, 38.322°, 38.745° as shown in FIG. 1, or A － (2R,3R)-3-carboxy-2,3-dihydroxypropanoic acid is present in the crystalline compound, as shown in Figure 3, with 2θ peaks at 5.925°, 10.183°, 11.313°, 11.823°, 12.209°, 12.542°, 15.233°, 15.592°, 15.776°, and 16.27°. 5°, 16.719°, 17.063°, 17.406°, 17.752°, 18.012°, 19.568°, 19.692°, 20.291°, 20.746°, 21.261°, 21.839°, 22.200°, 22.700°, 23.226°, 23.372°, 23.603°, 23.9 62°, 24.516°, 24.707°, 25.013°, 25.440°, 25.914°, 26.502°, 27.003°, 27.496°, 27.902°, 28.365°, 28.786°, 29.078°, 29.791°, 30.027°, 30.299°, 30.785°, 31. It is a polymorph having an XRPD spectrum with 187°, 31.686°, 32.070°, 32.392°, 33.434°, 33.862°, 34.358°, 34.790°, 35.584°, 36.277°, 36.801°, 37.197°, 38.121° and 39.667°, or A － is chloride (Cl － As shown in Figure 2, the crystalline compound is selected as follows: 2θ peaks 7.457°, 9.185°, 10.899°, 11.738°, 12.604°, 14.956°, 17.706°, 18.215°, 18.382°, 19.307°, 19.902°, 20.442°, 20.956°, 21.850°, 22.449°, 23.781°, 24.007°, 24.357°, 24.752°, 25.327°, 25.557°, 26.064°, 27.377°, It is a polymorph with an XRPD spectrum having 27.702°, 28.340°, 28.557°, 29.144°, 29.366°, 29.915°, 30.164°, 30.669°, 30.975°, 32.213°, 32.725°, 33.018°, 33.742°, 34.605°, 35.012°, 35.618°, 36.883°, 37.131°, 37.250°, 37.772°, 38.358°, 38.626°, 39.140°, and 39.869°.

9. A － The compound is 3-carboxypropanoic acid, and as shown in Figure 1, the crystalline compound has 2θ peaks at 4.077°, 8.108°, 11.991°, 12.156°, 13.893°, 15.876°, 16.218°, 16.412°, 16.596°, 17.849°, 19.507°, 19.786°, 20.031°, 20.297°, 21.122°, 22.011°, 22.635°, 23.000°, 23.268°, 24.065°, 24.408°, and 25. The crystalline compound according to claim 8, which is a polymorph having an XRPD spectrum having 414°, 25.758°, 26.947°, 27.751°, 28.032°, 28.314°, 29.966°, 30.358°, 30.562°, 30.770°, 31.378°, 32.306°, 32.868°, 33.505°, 34.710°, 35.206°, 36.418°, 36.714°, 37.306°, 38.147°, 38.322°, and 38.745°.

10. Intermediate compounds of formula (III) or (IIIa): 【Chemistry 12】 During the ceremony, Y is selected from O or S. PG is a carbamate protecting group, an amide protecting group, a benzylamine protecting group, a triphenylmethylamine protecting group, or a sulfonamide protecting group. The carbamate protecting group is selected from 9-fluorenylmethylcarbamate (Fmoc-NR2), t-butylcarbamate (Boc-NR2), or benzylcarbamate (Cbz-NR2). The amide protecting group is selected from acetamide (Ac-NR2) or trifluoroacetamide (CF3CO-NR2), The benzylamine protecting group is selected from benzylamine (Bn-NR2) or 4-methoxybenzylamine (PMB-NR2). The aforementioned triphenylmethylamine protecting group is triphenylmethylamine (Tr-NR2), The sulfonamide protecting group is p-toluenesulfonamide (Ts-NR2).

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