Synthesis of EGFR regulators

Abstract

This article provides a method for synthesizing compounds that can be used as EGFR modulators. Specifically, this article provides a method for synthesizing compound A:

Description

Background Technology

[0001] This disclosure relates to a method for synthesizing 2-((3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-1,3-dien-2-yl)thio)-N-(quinolin-3-yl)acetamide (compound A) and its salts:

[0002]

[0003] Compound A is an EGFR modulator that can be used to treat or prevent diseases or conditions (e.g., cancer) associated with abnormal EGFR activity.

[0004] EGFR small molecule tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib, and afatinib have been most successful as single agents in treating lung adenocarcinoma with somatic mutations (such as L858R or deletions in exon 19, i.e., E746-A750), which confer sensitivity to these drugs. Unfortunately, responses rarely last longer than a year because almost all patients develop resistance to the therapy. The third-generation irreversible inhibitor osimertinib (AZD9291) is effective in treating both primary and acquired resistance to first- or second-generation TKIs. However, within a year of osimertinib treatment, most patients develop another mutation in the EGFR kinase domain (C797S), the site of drug covalent linkage. Although several approaches targeting osimertinib-resistant EGFR have been reported, there are currently no TKI treatment options for these patients with C797S mutations. Chemotherapy is the only option.

[0005] In light of the foregoing, there is a need for cancer therapeutics that target EGFR in ways other than inhibiting EGFR tyrosine kinase activity. There is also a need for a cancer therapeutic that does not induce resistance after initial use.

[0006] PCT Publication No. WO 2019 / 165358 discloses compound A as an EGFR modifier and provides a method for preparing said compound A, which is incorporated herein by reference in its entirety. However, improved synthetic methods for achieving higher yields and purity of compound A are desired, particularly for the commercial production of compound A. Summary of the Invention

[0007] This article provides a method for synthesizing compound A or its salts or solvates:

[0008]

[0009] The method includes (i) mixing compound I with a halogenating agent or a sulfonating agent to form compound II:

[0010] Wherein R is a methyl or nitrogen-protecting group, and Z is a halogen or sulfonate group. In some cases, R is methyl. In some cases, R is a nitrogen-protecting group. In some cases, R is tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), benzyl, or p-methoxybenzyl (PMB). In some cases, Z is a sulfonate group. In some cases, the sulfonate group is trifluoromethanesulfonate, methanesulfonate, toluenesulfonate, benzenesulfonate, or nitrobenzenesulfonate. In some cases, the sulfonate group is trifluoromethanesulfonate.

[0011] In some cases, compound II is synthesized by mixing compound I with a halogenating agent. In some cases, the halogenating agent is a chlorinating agent. In some cases, the chlorinating agent includes oxalyl chloride, SOCl2, or POCl3.

[0012] In some cases, compound II is synthesized by mixing compound I with a sulfonating agent. In some cases, the sulfonating agent is selected from trifluoromethanesulfonic anhydride, methanesulfonyl chloride, methanesulfonic anhydride, toluenesulfonyl chloride, toluenesulfonic anhydride, nitrobenzenesulfonyl chloride, and perfluoroalkyl sulfonic anhydride. In some cases, the sulfonating agent is trifluoromethanesulfonic anhydride.

[0013] In some cases, compound II is synthesized by mixing compound I with a halogenating agent or a sulfonating agent in an organic solvent. In other cases, compound II is synthesized by mixing compound I with a halogenating agent or a sulfonating agent in a mixture of dichloromethane and ethyl acetate.

[0014] In various embodiments, the method further includes synthesizing compound A by: (ii) (a) mixing compound II with compound III in the presence of a base to form compound A:

[0015] or

[0016] (b)(I) Compound II is mixed with a nucleophilic sulfide to form compound IIA, and then (II) compound IIA is mixed with compound IIIA in the presence of a base to form compound A:

[0017] Where X is a halogen.

[0018] In some cases, X is Br or Cl. In other cases, X is Cl.

[0019] In some cases, the method includes synthesizing compound A by mixing compound II with compound III in the presence of a base to form compound A. In some cases, the base is NaH, NaOH, KOH, sodium methoxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide.

[0020] In some cases, the method includes synthesizing compound A by: (b)(I) mixing compound II with a nucleophilic sulfide reagent to form compound IIA, and then (II) mixing compound IIA with compound IIIA in the presence of a base to form compound A. In some cases, the nucleophilic sulfide reagent includes Li₂S, Na₂S, K₂S, Li₂S x Na2S x K2S x (Where x = 2-5), NaBH4 / S, NaSH, AcSK, thiourea, or their salts or hydrates. In some cases, the nucleophilic sulfide includes Na2S hydrate. In some cases, the nucleophilic sulfide includes Na2S·4H2O.

[0021] In some cases, the method includes synthesizing compound A by mixing compound II with a nucleophilic sulfide reagent in an organic solvent in (b)(I) to form compound IIA. In some cases, the method includes synthesizing compound A by mixing compound II with a nucleophilic sulfide reagent in a mixture of dichloromethane and ethyl acetate in (b)(I) to form compound IIA. In some cases, the method includes synthesizing compound A by mixing compound II with a nucleophilic sulfide reagent in a mixture of dichloromethane and ethyl acetate in (b)(I) to form compound IIA.

[0022] In some cases, the method includes synthesizing compound A by (II) mixing compound IIA with compound IIIA in the presence of a base to form compound A. In some cases, the base is K₂CO₃.

[0023] In some cases, the method includes synthesizing compound A by (II) mixing compound IIA with compound IIIA in an organic solvent in the presence of a base to form compound A. In some cases, the organic solvent is isopropanol.

[0024] In various embodiments, the method further includes synthesizing compound A by: (iii) optionally, when R is a nitrogen-protecting group, removing the nitrogen-protecting group and methylating the resulting deprotected amine to form compound A, wherein R is methyl. In some cases, when the method includes step (iii), R is a nitrogen-protecting group. In some cases, step (iii) is performed between steps (ii)(b)(I) and (ii)(b)(II). In some cases, when R is a nitrogen-protecting group, the method further includes removing the nitrogen-protecting group from compound IIA and methylating the resulting deprotected amine to form compound IIA, wherein R is methyl. In some cases, removing the nitrogen-protecting group includes mixing in the presence of an acid. In some cases, the deprotected amine is methylated by mixing with NaBH(OAc)3, CH2O, and acetic acid.

[0025] Further aspects and advantages will become apparent to those skilled in the art upon review of the following detailed description. The description below includes specific embodiments, and it should be understood that this disclosure is illustrative and not intended to limit the invention to the specific embodiments described herein. Detailed Implementation

[0026] This article provides methods for synthesizing EGFR regulators and their salts. Specifically, methods are provided for synthesizing 2-((3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-1,3-dien-2-yl)thio)-N-(quinolin-3-yl)acetamide (compound A) and its salts:

[0027]

[0028] PCT Publication No. 2019 / 165358 (“358 Application”) discloses compound A as an EGFR modulator and provides a method for preparing said compound A, which is incorporated herein by reference in its entirety.

[0029] Application '358 generally describes a procedure for preparing a compound (such as compound A as shown in Scheme 1 below), adapted from the disclosure of paragraph

[0090] (General Procedure A) of application '358. Application '358 describes adding substituted acetamide 7A-G to anhydrous acetonitrile containing 3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-3-en-2-thione (labeled as compound 6) and heating to 40°C. Then, 2M aqueous potassium carbonate solution is added to the reaction mixture, and the reaction is maintained at 40°C until TLC analysis indicates loss of starting material and new R fPoint (usually 2-6 hours). Following the procedure in Scheme 1, using 2-chloroacetamide 7, substituted 3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-1,3-dien-2-thiol 8A-G is prepared, comprising the use of 7C (2-chloro-N-quinoline-3-yl-acetamide) to prepare compound A (referred to as "8C" in '358 application).

[0030] General Procedure A for Application of Option 1–′358

[0031]

[0032] Reaction conditions: (i) 2M K2CO3 aqueous solution, acetonitrile, 40℃

[0033] Y:C 0-6 Alkylene

[0034] B: C, which can be arbitrarily replaced 6-10 aryl, 5-10 membered heteroaryl, 3-8 membered cycloalkyl or 3-12 membered heterocycloalkyl

[0035] Application '358 further describes a method for synthesizing intermediate compounds (such as compound 6 in scheme 1). Scheme 2, adapted according to paragraph

[0105] (Examples 15-28) of application '358, represents a general method for synthesizing substituted 2-(4-bromophenyl)-3-thionyl-1,4,8-triazaspiro[4.5]dec-1-ene compounds (e.g., compound 6) as described in application '358. Briefly, Lawesson's reagent is added to a solution of tert-butyl 2-(4-bromophenyl)-3-oxo-1,4,8-triazaspiro[4.5]dec-1-ene-8-carboxylate in THF, and the reaction mixture is heated to 60°C until the reaction is complete by TLC. The reaction mixture was concentrated onto silica gel and purified by rapid column chromatography (0-100% EtOAc / hexane) to give tert-butyl 2-(4-bromophenyl)-3-thionyl-1,4,8-triazaspiro[4.5]dec-1-ene-8-carboxylate.

[0036] Synthesis of the substituted 2-(4-bromophenyl)-3-thionyl-1,4,8-triazaspiro[4.5]dec-1-ene compound claimed in Scheme 2–′358

[0037]

[0038] Reaction conditions: (i) Lloyd's reagent, THF

[0039] The method described in application '358 has several drawbacks for large-scale synthesis. Notably, the Laureth reagent used to convert the amide moiety to thioamide is foul-smelling and highly sensitive to moisture, posing potential difficulties in amide-to-thioamide conversion on a scale of hundreds of grams. The process described in application '358 also employs several column chromatography purification steps, which is impractical for synthesis on a scale of hundreds of grams or larger.

[0040] Advantageously, the method described herein avoids the use of Laureth's reagent in the preparation of thioamides and is more practical and yields higher results. The method also avoids the need for purification by column chromatography.

[0041] This article describes a method for synthesizing compound A and its salts:

[0042] The method includes (i) mixing compound I with a halogenating agent or a sulfonating agent to form compound II:

[0043]

[0044] Where R is a methyl or nitrogen protecting group, and Z is a chloride or sulfonate group;

[0045] (ii)

[0046] (a) Compound II and Compound III are mixed in the presence of a base to form Compound A:

[0047]

[0048] or

[0049] (b)(I) Compound II is mixed with a nucleophilic sulfide to form compound IIA, and then (II) compound IIA is mixed with compound IIIA in the presence of a base to form compound A:

[0050]

[0051] Where X is Cl or Br, and

[0052] (iii) Optionally, when R is a nitrogen protecting group, the nitrogen protecting group is removed and the resulting deprotected amine is methylated to form compound A, wherein R is a methyl group, as discussed in detail below.

[0053] As will be understood, the disclosed method involves forming 3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-1,3-diene by adding a thiol group (e.g., 3-chloro)- or 3-sulfonyloxy-1,4,8-triazaspiro[4.5]dec-1,3-diene-2-thioacetamide or by adding chloro- or bromoacetamide to 1,4,8-triazaspiro[4.5]dec-3-ene-2-thionone.

[0054] The general reaction scheme for the methods described herein is provided in the following scheme 3:

[0055] Scheme 3 - General method for synthesizing compound A

[0056]

[0057] Option 3 is not intended to limit the scope. For example, if necessary, step (iii) for removing the nitrogen protecting group of R and replacing the nitrogen protecting group with a methyl group can be performed before or after step (ii)(a) or (ii)(b). In some cases, step (iii) can be performed between steps (ii)(b)(I) and (ii)(b)(II).

[0058] Synthesis of Compound II

[0059] The method disclosed herein may include the synthesis of precursor V:

[0060]

[0061] As used throughout, R is a methyl or nitrogen-protecting group. In some cases, R is a CD3 group (i.e., a deuterated methyl group). Nitrogen-protecting groups are generally known in the art. Non-limiting examples of nitrogen-protecting groups include benzyloxycarbonyl (Cbz) groups, acetyl groups, tert-butoxycarbonyl (Boc) groups, and 9-fluorenemethoxycarbonyl (Fmoc) groups.

[0062] Specifically, α-aminoamide (precursor III) can be reacted with piperidin-4-one (precursor IV) to form substituted 1,4,8-triazaspiro[4.5]dec-2-one (precursor V):

[0063]

[0064] In some embodiments, the formation of precursor V is carried out in an organic solvent. Organic solvents are generally known in the art. Non-limiting examples of organic solvents that can be used throughout the methods described herein include ethyl acetate, acetonitrile, toluene, benzene, xylene, chlorobenzene, fluorobenzene, naphthalene, trifluorotoluene, tetrahydrofuran (THF), tetrahydropyran, dimethylformamide (DMF), tetrahydrofurfuryl alcohol, diethyl ether, dibutyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (2-MeTHF), dimethyl sulfoxide (DMSO), 1,2-dimethoxyethane (1,2-DME), 1,2-dichloroethane (1,2-DCE), 1,4-dioxane, cyclopentylmethyl ether (CPME), chloroform, carbon tetrachloride, dichloromethane (DCM), 2-butanone, methanol, ethanol, propanol, and 2-propanol, or combinations thereof. In some embodiments, the formation of precursor V is carried out in ethanol. In some embodiments, the formation of precursor V is carried out at elevated temperatures. In some embodiments, the precursor V is formed at a temperature between 20°C and 100°C, for example, at least 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, or 100°C and / or at most 60°C, 70°C, 80°C, 90°C, or 100°C, such as 20°C to 80°C, 40°C to 80°C, 50°C to 90°C, 60°C to 80°C, 75°C to 85°C, or 70°C to 80°C. In some embodiments, the precursor V is formed at a temperature of 80°C.

[0065] The method disclosed herein may include the synthesis of compound I:

[0066]

[0067] Specifically, precursor V can be oxidized to form compound I. In some embodiments, compound I is formed via an addition-elimination reaction. In some embodiments, compound I is formed by treating precursor V with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). In some embodiments, compound I is formed by treating precursor V with an α-brominating agent followed by elimination of an equivalent amount of HBr. In some embodiments, compound I is formed by treating precursor V with N-bromosuccinimide (NBS) followed by heating to form compound I. In some embodiments, compound I is formed by treating precursor V with NBS in the presence of UV light to form compound I. In some embodiments, compound I is formed by treating precursor V with NBS in the presence of UV light and by heating to form compound I. In some embodiments, the wavelength of the UV light is 365 nm. In some embodiments, compound I is formed by treating precursor V with NBS in an organic solvent. In some embodiments, compound I is formed by treating precursor V with NBS in DCM. In some embodiments, compound I is formed in the presence of a base. Non-limiting examples of bases include alkylamines, such as monoalkylamines, dialkylamines, or trialkylamines (e.g., monoethylamine, diethylamine, triethylamine, and N,N-diisopropylethylamine (DIPEA)); pyridines, such as trimethylpyridine and 4-dimethylaminopyridine (DMAP); and imidazoles, such as N-methylimidazole; and benzylamine, methylbenzylamine, morpholine, piperidine, methylpyridine, dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tri... -(2-hydroxyethyl)amine, procaine, dibenzylpiperidine, dehydrorosinamine, N,N'-bisdehydrorosinamine, glucosamine, N-methylglucosamine, quinine, quinoline, lysine, arginine, 1,4-diazabicyclo[2.2.2]octane (DABCO), dimethylpyridine, poly(4-vinylpyridine), Na2CO3, K2CO3, Cs2CO3, CaCO3, LiH, NaH, KH, NaOH, LiOH, and KOH. In some cases, the base is a trialkylamine (e.g., triethylamine or N,N-diisopropylethylamine (DIPEA)), dimethylpyridine, trimethylpyridine, Na2CO3, K2CO3, Cs2CO3, CaCO3, LiH, NaH, or KH. In some embodiments, the formation of compound I is carried out at an elevated temperature. In some embodiments, the formation of compound I is carried out at a temperature between 20°C and 50°C, for example, at least 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C and / or at most 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C, such as 20°C to 50°C, 30°C to 50°C, 40°C to 50°C, or 30°C to 40°C. In some embodiments, the formation of compound I is carried out at a temperature between 35°C and 45°C or 35°C to 40°C.In some embodiments, compound I is formed at a temperature of about 40°C.

[0068] The method disclosed herein may include the synthesis of compound II:

[0069]

[0070] As used throughout, Z represents a halogen or sulfonate group. In some cases, Z represents a chloride. In some cases, Z represents a trifluoromethanesulfonate.

[0071] Specifically, compound I can be mixed with a halogenating agent or a sulfonating agent to form compound II. Halogenating agents and sulfonating agents are generally known in the art. In some cases, the halogenating agent is a chlorinating agent. Non-limiting examples of chlorinating agents that can be used throughout the methods described herein include SOCl2, POCl3, Vilsmeier reagent, oxalyl chloride, PCl5, SOBr2, and POBr3. Non-limiting examples of sulfonating agents that can be used throughout the methods described herein include trifluoromethanesulfonic anhydride, methanesulfonyl chloride, methanesulfonic anhydride, toluenesulfonyl chloride, toluenesulfonic anhydride, benzenesulfonyl chloride, benzenesulfonic anhydride, nitrobenzenesulfonyl chloride, and perfluoroalkylsulfonic anhydride. In some embodiments, compound I is mixed with a halogenating agent to form compound II. In some embodiments, compound I is mixed with a chlorinating agent to form compound II. In some embodiments, compound I is mixed with a sulfonating agent to form compound II. In some embodiments, compound I is mixed with trifluoromethanesulfonic anhydride to form compound II.

[0072] In some embodiments, compound II is formed by mixing compound I with a halogenating agent or a sulfonating agent in an organic solvent. In some embodiments, compound II is formed by mixing compound I with a halogenating agent or a sulfonating agent in DCM. In some embodiments, compound II is formed by mixing compound I with a halogenating agent or a sulfonating agent in ethyl acetate. In some embodiments, compound II is formed by mixing compound I with a halogenating agent or a sulfonating agent in a mixture of organic solvents. In some embodiments, compound II is formed by mixing compound I with a halogenating agent or a sulfonating agent in a mixture of DCM and ethyl acetate. In some embodiments, compound II is formed by mixing compound I with a chlorinating agent or a sulfonating agent in an organic solvent. In some embodiments, compound II is formed by mixing compound I with a chlorinating agent or a sulfonating agent in a mixture of organic solvents. In some embodiments, compound II is formed by mixing compound I with a chlorinating agent or a sulfonating agent in a mixture of DCM and ethyl acetate. In some embodiments, DCM and ethyl acetate are present in a volume ratio of 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, or 1:1. In some embodiments, DCM and ethyl acetate are present in a volume ratio of 1.5:1.

[0073] In some embodiments, compound II is formed by mixing compound I with a chlorinating agent or a sulfonating agent in a mixture of DCM and ethyl acetate in the presence of a base. Non-limiting examples of bases include alkylamines such as trialkylamines (e.g., triethylamine or N,N-diisopropylethylamine (DIPEA)); pyridines such as trimethylpyridine and 4-diethylaminopyridine (DMAP); and imidazoles such as N-methylimidazolium; as well as dimethylbenzylamine, N-methylmorpholine, N-methylpiperidine, methylpyridine, N-methyldicyclohexylamine, N,N'-dibenzylethylenediamine, tri-(2-hydroxyethyl)amine, and procaine. The base is composed of dibenzylpiperidine, dehydrorosinamine, N,N'-didehydrorosinamine, N-methylglucosamine, quinine, quinoline, lysine, arginine, 1,4-diazabicyclo[2.2.2]octane (DABCO), N,N-diisopropylethylamine, dimethylpyridine, poly(4-vinylpyridine), Na2CO3, K2CO3, Cs2CO3, LiH, NaH, KH, NaOH, LiOH, and KOH. In some cases, the base is a trialkylamine (e.g., triethylamine or N,N-diisopropylethylamine (DIPEA)), dimethylpyridine, trimethylpyridine, Na2CO3, K2CO3, Cs2CO3, CaCO3, LiH, NaH, or KH. In some cases, the base is a trialkylamine, or more specifically, includes triethylamine or DIPEA. In some embodiments, compound II is formed by mixing compound I with a chlorinating agent or a sulfonating agent in a mixture of DCM and ethyl acetate in the presence of DIPEA. In some embodiments, the base is present with compound I in a molar ratio of 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, or 1:1. In some embodiments, the base is present with compound I in a molar ratio of 1.5:1. In some embodiments, DIPEA is present with compound I in a molar ratio of 1.5:1.

[0074] In some embodiments, compound II is formed by mixing compound I with a chlorinating agent or a sulfonating agent in the presence of di-tert-butyl dicarbonate (Boc2O) and optionally a base as described above. In some embodiments, compound II is formed by mixing compound I with a chlorinating agent or a sulfonating agent in a mixture of DCM and ethyl acetate in the presence of DIPEA and Boc2O. In some embodiments, Boc2O is present with compound I in a molar ratio of 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, or 1:1. In some embodiments, Boc2O is present with compound I in a molar ratio of 1:1.

[0075] In some embodiments, the formation of compound II is carried out at elevated temperatures. In some embodiments, the formation of compound II is carried out at temperatures ranging from 20°C to 50°C, for example, at least 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C and / or at most 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C, such as 20°C to 50°C, 30°C to 50°C, 40°C to 50°C, or 30°C to 40°C. In some embodiments, the formation of compound II is carried out at temperatures ranging from 35°C to 40°C. In some embodiments, the formation of compound II is carried out at a temperature of 40°C.

[0076] In some embodiments, compound I and / or compound II are present in the form of salts. Salts of compound I, compound II, or any other compound described herein (e.g., compound A) can be prepared, for example, by reacting the compound in its free form with a suitable organic or inorganic acid, and optionally isolating the resulting salt. Non-limiting examples of suitable acid salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, sulfonate, camphor sulfonate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthalate, methanesulfonate, gluconate, lactobionate, lauryl sulfonate, and amino acid salts.

[0077] Compound A is synthesized via step (ii)(a).

[0078] The method disclosed herein may include synthesizing compound A by reacting compound II with compound III (via step (ii)(a)) when R is methyl. When R is a nitrogen-protecting group, compound IV is synthesized using the same method. Specifically, the method disclosed herein may include mixing compound II with compound III in the presence of a base to form compound A directly or indirectly via compound IV:

[0079]

[0080] In some embodiments, the base is LiH, NaH, KH, LDA, KHMDS, NaHMDS, LiHMDS, Na2CO3, K2CO3, Cs2CO3, NaOH, LiOH, KOH, sodium methoxide, sodium ethoxide, sodium tert-butoxide, or potassium tert-butoxide. In some embodiments, the base is NaH. In some embodiments, the base and compound III are present in a molar ratio of 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, or 1:1. In some embodiments, the base and compound III are present in a 1:1 molar ratio.

[0081] In some embodiments, compound II and compound III are present in a molar ratio of 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, or 1:1. In some embodiments, compound II and compound III are present in a molar ratio of 1:1.

[0082] In some embodiments, compound A is formed by mixing compound II, compound III, and a base in an organic solvent. In some embodiments, the organic solvent is ethyl acetate, dichloromethane (DCM), acetonitrile, tetrahydrofuran (THF), tetrahydropyran, dimethylformamide (DMF), diethyl ether, dibutyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (2-MeTHF), dimethyl sulfoxide (DMSO), 1,2-dimethoxyethane (1,2-DME), or 1,4-dioxane, or combinations thereof.

[0083] Compound A is synthesized via step (ii)(b).

[0084] The method of this disclosure may include the synthesis of compound A by forming compound IIA and then reacting it with compound IIIA when R is methyl (step (ii)(b)). When R is a nitrogen-protecting group, compound IV is synthesized using the same method. Specifically, the method of this disclosure may include mixing compound II with a nucleophilic sulfide reagent source to form compound IIA, and then mixing compound IIA with compound IIIA in the presence of a base to form compound A directly or indirectly via compound IV.

[0085]

[0086] The method disclosed herein may include the synthesis of compound IIA:

[0087]

[0088] Specifically, compound II can be mixed with a nucleophilic sulfiding agent to form compound IIA. Non-limiting examples of nucleophilic sulfiding agents include Li₂S, Na₂S, K₂S, NaSH, AcSK, thiourea, and Li₂S. x Na2S x K2S x(where x = 2-5) and NaBH4 / S. In some embodiments, compound IIA is formed by treating compound II with Na2S. In some embodiments, compound IIA is formed by treating compound II with Na2S hydrate. In some embodiments, compound IIA is formed by treating compound II with Na2S 4H2O. In some embodiments, mixing compound II with a nucleophilic sulfide occurs in the presence of a phase transfer catalyst. Non-limiting examples of phase transfer catalysts include tetrabutylammonium chloride (TBACl), tetrabutylammonium bromide (TBAB), and tetrabutylammonium iodide (TBAI). In some embodiments, the nucleophilic sulfide is present with compound II in a molar ratio of 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, or 1:1. In some embodiments, the nucleophilic sulfide is present with compound II in a molar ratio of 1.5:1. In some embodiments, compound IIA is formed by mixing a nucleophilic sulfide reagent with compound II in a mixture of organic solvents. In some embodiments, compound IIA is formed by mixing a nucleophilic sulfide reagent with compound II in a mixture of DCM and ethyl acetate. In some embodiments, DCM and ethyl acetate are present in a volume ratio of 2:1, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.5:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, or 1:1. In some embodiments, DCM and ethyl acetate are present in a volume ratio of 1.5:1.

[0089] The method of this disclosure may include synthesizing compound A through step (ii)(b). Specifically, the method of this disclosure may include mixing compound IIA with compound IIIA to form compound A:

[0090]

[0091] As used throughout, X is a halogen. In some embodiments, X is I, Br, or Cl. In some embodiments, X is Br or Cl. In some embodiments, X is Cl.

[0092] Specifically, compound IIA can be mixed with compound IIIA to form compound A.

[0093] In some embodiments, compound A is formed by mixing compound IIA with compound IIIA in the presence of a base. In some embodiments, the base is NaH, Na₂CO₃, K₂CO₃, Cs₂CO₃, NaOH, LiOH, or KOH, or a combination thereof. In some embodiments, the base includes K₂CO₃. In some embodiments, the base is a trialkylamine, pyridine, a pyridine derivative, or a combination thereof. In some embodiments, the base is a trialkylamine. In some embodiments, the trialkylamine is triethylamine or DIPEA. In some embodiments, the base and compound IIA are present in a molar ratio of 5:1, 4:1, 3:1, 2:1, or 1:1. In some embodiments, the base and compound IIA are present in a molar ratio of 2:1.

[0094] In some embodiments, compounds IIA, IIIA, and a base are mixed in an organic solvent. In some embodiments, the organic solvent is ethyl acetate, dichloromethane (DCM), 2-butanone, acetonitrile, tetrahydrofuran (THF), tetrahydropyran, dimethylformamide (DMF), tetrahydrofurfuryl alcohol, diethyl ether, dibutyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (2-MeTHF), dimethyl sulfoxide (DMSO), 1,2-dimethoxyethane (1,2-DME), 1,4-dioxane, methanol, ethanol, propanol, or 2-propanol, or combinations thereof. In some embodiments, the organic solvent includes 2-propanol.

[0095] In some embodiments, the mixing of compound IIA, compound IIIA, and the base is carried out at an elevated temperature. In some embodiments, the temperature is 20°C to 50°C, for example, at least 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C and / or at most 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C, such as 20°C to 50°C, 30°C to 50°C, 40°C to 50°C, or 30°C to 40°C. In some embodiments, the temperature is 40°C to 45°C. In some embodiments, the temperature is 45°C.

[0096] Compound A is synthesized via step (iii).

[0097] The method disclosed herein may include removing the nitrogen protecting group from R and methylating an intermediate amino group to form compound A, wherein R is methyl (e.g., via step (iii)) or forming a compound intermediate wherein R is methyl (compound II or compound IIA). For compound II, compound IIA, or compound IV, this modification of R from a nitrogen protecting group to a methyl group may occur, for example, before or after any step of the disclosed method. In some cases, the disclosed method includes converting compound IV to compound A.

[0098] Removing the nitrogen protecting group may include mixing the compound (e.g., compound II, compound IIA, or compound IV) in the presence of an acid. Non-limiting examples of suitable acids include hydrobromic acid, hydrochloric acid, sulfuric acid, sulfonic acid, phosphoric acid, nitric acid, acetic acid, trifluoroacetic acid, benzoic acid, and p-toluenesulfonic acid. In some embodiments, the acid includes hydrochloric acid. In some embodiments, the acid is present with the compound (compound II, compound IIA, or compound IV) in a molar ratio of 20:1, 15:1, 12:1, 11:1, 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, or 1:1. In some embodiments, the acid is present with the compound (compound II, compound IIA, or compound IV) in a molar ratio of 10:1.

[0099] In some embodiments, the removal of the nitrogen protecting group can be carried out in the presence of an acid and an organic solvent. In some embodiments, the organic solvent is dichloromethane (DCM), chloroform, 1,2-dichloroethane, ethyl acetate, acetonitrile, tetrahydrofuran (THF), tetrahydropyran, dimethylformamide (DMF), tetrahydrofurfuryl alcohol, diethyl ether, dibutyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (2-MeTHF), dimethyl sulfoxide (DMSO), 1,2-dimethoxyethane (1,2-DME), 1,4-dioxane, methanol, ethanol, propanol, or 2-propanol, or combinations thereof. In some embodiments, the organic solvent includes methanol.

[0100] Removal of nitrogen protecting groups can include the catalytic hydrogenation of compounds (e.g., compound II, compound IIA, or compound IV). Non-limiting examples of suitable hydrogenation catalysts include nickel catalysts (e.g., Ni / Al₂O₃), palladium catalysts (e.g., Pd / C), and platinum catalysts (e.g., Pt / C). In some embodiments, the hydrogenation catalyst is Pd / C.

[0101] In some embodiments, the removal of the nitrogen protecting group can be carried out in the presence of hydrogen, a hydrogenation catalyst, and an organic solvent. In some embodiments, the organic solvent is dichloromethane (DCM), chloroform, 1,2-dichloroethane, tetrahydrofuran (THF), tetrahydropyran, tetrahydrofurfuryl alcohol, diethyl ether, dibutyl ether, diisopropyl ether, methyl tert-butyl ether (MTBE), 2-methyltetrahydrofuran (2-MeTHF), 1,2-dimethoxyethane (1,2-DME), 1,4-dioxane, methanol, ethanol, propanol, or 2-propanol, or combinations thereof. In some embodiments, the organic solvent includes methanol.

[0102] In some embodiments, the removal of the nitrogen protecting group is performed at ambient temperature. In some embodiments, the temperature can be 20°C to 30°C, for example, at least 20°C, 25°C, or 30°C and / or at most 20°C, 25°C, or 30°C, such as 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, or 30°C. In some embodiments, the temperature is 20°C to 25°C. In some embodiments, the temperature is 25°C.

[0103] Methylation of deprotected amines can be performed by mixing the deprotected amine with a methylating agent. In some embodiments, the method includes mixing a deprotected amine compound derived from compound II, compound IIA, or compound IV with a methylating agent and a base (if desired). Non-limiting examples of suitable methylating agents include methyl iodide, dimethyl sulfate, methyl toluenesulfonate, methyl bromide (all in the presence of a suitable base), combinations of NaBH3CN, CH2O, and acetic acid, combinations of NaBH4, CH2O, and acetic acid, combinations of NaBH(OAc)3, CH2O, and Et3N, combinations of NaBH(OAc)3, CH2O, and acetic acid, or CH2O and H2 (in the presence of a Ni, Pt, or Pd catalyst). In some embodiments, the methylating agent is a combination of NaBH(OAc)3, CH2O, and acetic acid. In some embodiments, the combination of NaBH(OAc)3, CH2O and acetic acid exists in a molar ratio of 3:2:3 NaBH(OAc)3:CH2O:acetic acid / molar deprotected amine derived from compound II, compound IIA or compound IV.

[0104] In some embodiments, methylation is performed at a low temperature (e.g., below room temperature, 25°C). In some embodiments, the temperature is from 0°C to 20°C, for example, at least 0°C, 5°C, 10°C, 15°C, or 20°C and / or at most 0°C, 5°C, or 10°C, such as 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, or 10°C. In some embodiments, the temperature is from 0°C to 5°C. In some embodiments, the temperature is 5°C.

[0105] It should be understood that although this disclosure has been read in conjunction with its detailed description, the foregoing description and the following examples are intended to illustrate and not limit the scope of this disclosure, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the appended claims.

[0106] Example

[0107] The following examples are provided for illustration and are not intended to limit the scope of this disclosure.

[0108] Example 1: Synthesis of Compound II

[0109] Precursor III (2-amino-2-(4-bromophenyl)acetamide) was prepared according to the following reaction scheme:

[0110]

[0111] Under a nitrogen atmosphere, precursor I (1.75 kg, 7.6 mol, 1.0 equivalent of 2-amino-2-(4-bromophenyl)acetic acid, 1.75 kg, 7.6 mol, 1.0 equivalent) was charged into a 30 L reactor containing methanol (12.3 L, 7 volumes). The reactor was purged three times with nitrogen and the reaction mixture was cooled to 0 °C. SOCl2 (1.36 kg, 11.4 mol, 1.5 equivalent) was added dropwise to the solution at 10–20 °C. The reaction was stirred at 10–20 °C for 0.5 h, then heated to 30–35 °C and stirred for 6 h. At 40 °C, the solution was partially concentrated to 5 L under reduced pressure, MTBE (18 L, 10 v) was added, and the mixture was stirred at 5–10 °C for 1 h. The solution was filtered, and the filter cake was washed with MTBE (3 L, 2 v). The filter cake was dried at 40 °C under reduced pressure to give precursor II with a purity of 98% in 82% yield.

[0112] Precursor II (1.75 kg, 6.2 mol, 1.0 equivalent) was charged into a 20 L reactor containing NH3·H2O (28%, 8.8 L, 5 V). The mixture was stirred at 10–15 °C for 20 h, then filtered, and the filter cake was washed with water (3.5 L, 2 V). The filter cake was dried under reduced pressure at 50 °C to obtain precursor III (2-amino-2-(4-bromophenyl)acetamide) with a purity of 96 Å in 85% separation yield.

[0113] The precursor V (tert-butyl 2-(4-bromophenyl)-3-oxo-1,4,8-triazaspiro[4.5]decane-8-carboxylate) was prepared according to the following reaction scheme:

[0114]

[0115] Precursor III (2-amino-2-(4-bromophenyl)acetamide, 500.0 g, 2.18 mol, 1.0 equivalent), precursor IV (436.7 g, 2.18 mol, 1.0 equivalent), and EtOH (10 L, 20 v) were charged into a 20 L reactor. The reactor was purged three times with N2, and the reaction mixture was then heated to reflux and stirred for 16 h. At 45 °C, under reduced pressure, the mixture was concentrated to approximately 2 v, and then water (7 L, 7 v) was added and stirred at 15–20 °C for 0.5 h. The reaction mixture was filtered, and the filter cake was washed with a 2:7 EtOH / water mixture (v / v, 1 L, 1 volume). The filter cake was dried under reduced pressure at 50 °C to obtain precursor V (2-(4-bromophenyl)-3-oxo-1,4,8-triazaspiro[4.5]decane-8-carboxylate tert-butyl ester) with a separation yield of 76% and a purity of 98% LC.

[0116] Compound I (tert-butyl 2-(4-bromophenyl)-3-oxo-1,4,8-triazaspiro[4.5]dec-1-ene-8-carboxylate) was synthesized according to the following reaction scheme:

[0117]

[0118] Precursor V (1.5 kg, 1.0 equivalent of 2-(4-bromophenyl)-3-oxo-1,4,8-triazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester, 1.5 kg, 1.0 equivalent), Na₂CO₃ (194 g, 0.5 equivalent), and DCM (15 L, 10 v) were charged into a 30 L reactor, which was purged three times with N₂ and cooled to 0 °C. NBS (651.4 g, 1.0 equivalent) was added to the mixture in four portions. The reaction mixture was stirred at 30–35 °C for 20 h. The reaction mixture was irradiated with UV light at 365 nm for 1 h, and then stirred at 30–35 °C for 4 h. 20 wt% Na₂CO₃ aqueous solution (7.5 L, 5 v) and (Boc)₂O (80 g, 0.1 equivalent) were added to this mixture, and the mixture was stirred for 30 min.

[0119] The reaction mixture was treated as follows: the aqueous phase was separated and extracted with DCM (15 L x 2, 10 V x 2). The organic phase was concentrated to dryness under reduced pressure at 35–40 °C. The product was slurried in EtOH (4.5 L, 3 V), the mixture was filtered, and the filter cake was dried under reduced pressure at 35–40 °C to give compound I (2-(4-bromophenyl)-3-oxo-1,4,8-triazaspiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester) with a separation yield of 81% and a purity of 96.4% by HPLC.

[0120] Compound II (2-(4-bromophenyl)-3-(((trifluoromethyl)sulfonyl)oxy)-1,4,8-triazaspiro[4.5]dec-1,3-diene-8-carboxylic acid tert-butyl ester) was synthesized according to the following reaction scheme:

[0121]

[0122] Under N2, compound I (tert-butyl 2-(4-bromophenyl)-3-oxo-1,4,8-triazaspiro[4.5]dec-1-en-8-carboxylate (600 g, 1.0 equivalent), Boc2O (320.8 g, 1.0 equivalent), DCM (9.0 L, 15 v), and EtOAc (6.0 L, 10 v) were charged into a reactor. DIPEA (284.3 g, 1.5 equivalent) was added to this mixture. The mixture was purged three times with N2, and the solution was cooled. The temperature was lowered to -30°C, and a solution of Tf₂O (620.7 g, 1.5 equivalents) in DCM (1.2 L, 2 v) was added to the mixture at -30°C. The mixture was stirred at -30°C for 1 hour to produce compound II (2-(4-bromophenyl)-3-(((trifluoromethyl)sulfonyl)oxy)-1,4,8-triazaspiro[4.5]dec-1,3-diene-8-carboxylic acid tert-butyl ester) with a purity of 90.2A, and its solution was used directly in the next step.

[0123] Example 2: Synthesis of compound A via steps (ii), (b), and (iii)

[0124] Compound IIA (tert-butyl 2-(4-bromophenyl)-3-thionyl-1,4,8-triazaspiro[4.5]dec-1-ene-8-carboxylate) was synthesized according to the following reaction scheme:

[0125]

[0126] Under N2, pure Na2S·4H2O (461.0 g, 2.0 equivalents) was added to a solution of compound II (2-(4-bromophenyl)-3-oxo-1,4,8-triazaspiro[4.5]dec-1-en-8-carboxylic acid tert-butyl ester) prepared as in Example 1 in DCM (9.0 L, 15 v) and EtOAc (6.0 L, 10 v), and the mixture was stirred at -30 °C for 1 hour. Water (10 L, 10 v) was added to this solution from -30 °C to -10 °C, followed by EtOAc (10 L, 10 v). This mixture was stirred from -10 °C to 0 °C for 0.5 hours. The mixture was filtered and dried under reduced pressure at 40 °C to give compound IIA (2-(4-bromophenyl)-3-thionyl-1,4,8-triazaspiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester) with 98% HPLC purity in a corrected yield of 82%.

[0127] The methylated derivative of compound IIA (“compound IIA-Me”, 3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-3-ene-2-thione) was synthesized according to the following reaction scheme:

[0128]

[0129] Under N2 conditions, compound IIA (2-(4-bromophenyl)-3-thionyl-1,4,8-triazaspiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester, 530 g, 1.0 equivalent) and DCM (26.5 L, 50 v) were charged into a 30 L reactor. The solution was cooled to 0 °C and HCl / MeOH (10 M, 1.25 L, 10.0 equivalent) was added. The solution was heated to 20–25 °C and stirred for 3 h. The mixture was filtered, and the filter cake was washed with DCM and then dried under reduced pressure at 40 °C for 6 h to obtain compound IIA-H 3-(4-bromophenyl)-1,4,8-triazaspiro[4.5]dec-3-ene-2-thione as its hydrochloride in a 90% separation yield with 98.1% HPLC purity.

[0130] Under N2, compounds IIA-H (3-(4-bromophenyl)-1,4,8-triazaspiro[4.5]dec-3-ene-2-thionone hydrochloride, 630 g, 1.0 equivalent), CH2O (283.5 g, 2.0 equivalent, 37 wt%), AcOH (315 g, 3.0 equivalent), and THF (9.5 L, 15 v) were charged into a 20 L reactor. The solution was purged three times with N2 and then cooled to 0 °C. NaBH(OAc)3 (1107 g, 3.0 equivalent) was added to this solution in four portions over 1 hour at 0 °C to 5 °C. The solution was purged three times with N2 and stirred at 0 °C for 1.5 hours. A saturated aqueous solution of Na2CO3 (15 L, 25 v) was added to the solution, followed by the addition of EtOAc (6.3 L, 10 v). The mixture was separated, and the organic phase was washed twice with saturated Na2CO3 aqueous solution (6.3 L x 2, 10 v x 2) and then twice with brine (6.3 L x 2, 10 v x 2). The combined organic layers were combined and concentrated under reduced pressure at 40 °C to give compound IIA-Me (3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-3-ene-2-thione) with a separation yield of 86% and a purity of 97.5% by HPLC.

[0131] Compound A (2-((3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-1,3-dien-2-yl)thio)-N-(quinolin-3-yl)acetamide) was synthesized according to the following reaction scheme:

[0132]

[0133] Under a nitrogen atmosphere, compound IIA-Me (3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-3-ene-2-thione, 500 g, 1.0 equivalent), compound IIIA (325.2 g, 1.0 equivalent), and i-PrOH (12.3 L, 15 v) were loaded into a 30 L reactor and purged three times with nitrogen. A K2CO3 aqueous solution (2 M, 1.48 L, 2.0 equivalent) was added to this solution, and the solution was stirred at 40 °C for 4 hours. A THF solution of Me2NH (33 wt%, 1.00 kg) was added to the solution, and the mixture was stirred for 30 minutes. Water (2 L, 4 v) was added to this mixture, and the mixture was cooled to 10 °C and stirred for 1 hour. The mixture was filtered, and the filter cake was washed with i-PrOH (500 mL, 1 v). The filter cake was dried under reduced pressure at 50 °C for 40 h to give compound A (2-((3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-1,3-dien-2-yl)thio)-N-(quinolin-3-yl)acetamide) with 99% LC purity in 90% corrected (qNMR) yield.

[0134] Compound IIIA (2-chloro-N-(quinolin-3-yl)acetamide) was prepared as follows:

[0135] Quinoline-3-amine (285 g, 1.0 equivalent), Na₂CO₃ (283 g, 1.0 equivalent), and DCM (5.7 L, 20 v) were placed in a 10 L flask. The flask was purged three times with N₂ and cooled to -10 °C. After 0.5 h at -10 °C to 0 °C, 2-chloroacetyl chloride (356 g, 1.5 equivalent) was added to the solution, and the solution was stirred at 20–25 °C for 1.5 h. The mixture was filtered, and the filter cake was washed with DCM (300 mL, 1 v). The filter cake was dissolved in EtOAc (1.5 L, 5 v), and the solution was washed with an aqueous solution of Na₂CO₃ (600 mL, 2 v). The organic phase was separated and washed with brine (1.5 L, 5 v x 2), and then dried over Na₂SO₄ (600 g, 2 w). The solution was filtered, and the filter cake was washed with EtOAc (300 mL x 2, 1 v x 2). The filtrate was concentrated under reduced pressure at 45 °C to give compound IIIA (2-chloro-N-(quinolin-3-yl)acetamide) with a purity of 98.3% LC in 90% fraction.

[0136] Example 3: Synthesizing compound A by substituting steps (ii), (b), and (iii)

[0137] The compound I-Me (3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-3-en-2-one) was synthesized according to the following reaction scheme:

[0138]

[0139] The following Example 5 describes the synthesis of compound IH (3-(4-bromophenyl)-1,4,8-triazaspiro[4.5]dec-3-en-2-one).

[0140] Under N2, compounds IH (3-(4-bromophenyl)-1,4,8-triazaspiro[4.5]dec-3-en-2-one, 1.0 g, 1.0 equivalent), CH2O (1.3 g, 5.0 equivalent, 37 w%), AcOH (584 mg, 3.0 equivalent), and THF (10 mL) were placed in a flask and purged three times with N2. NaBH(OAc)3 (2.1 g, 3.0 equivalent) was added to this mixture, the flask was purged three times with N2, and the solution was stirred at 20-25°C for 1.5 hours. A saturated aqueous solution of Na2CO3 (10 mL) was added to this mixture, followed by EtOAc (10 mL). The organic phase was separated and washed twice with a saturated aqueous solution of Na2CO3 (10 mL x 2), and then twice with brine (10 mL x 2). The organic layer was concentrated under reduced pressure at 40 °C to obtain 750 mg of compound I-Me 3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-3-en-2-one with a purity of 99% by separation in a yield of 72%.

[0141]

[0142] Under N2, compound I-Me (3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-3-en-2-one, 200 mg, 1.0 equivalent) and DCM (2 mL) were placed in a flask, and Et3N (157 mg, 2.5 equivalent) was added to this mixture. The flask was purged three times with nitrogen, and the solution was cooled to -10 °C. Tf2O (326 mg, 2.5 equivalent) was added to the solution in DCM (0.4 mL), and the solution was further cooled to -15 °C. The solution was stirred at -15 °C for 0.5 minutes to give compound II-Me, 3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-3-en-2-yl trifluoromethanesulfonate.

[0143] Li₂S (286 mg, 10.0 equivalent) was added to a solution of compound II-Me (3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-3-en-2-yl trifluoromethanesulfonate), and the mixture was stirred at -10 °C for 1 hour. Water (2 mL) was added to the mixture, followed by EtOAc (2 mL). The organic phase was separated and washed three times with water (2 mL). The organic phase was concentrated to dryness under reduced pressure, and the product was slurried with EtOac (1 mL). The slurry was filtered and dried under reduced pressure at 40 °C to give compound IIA-Me (3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-3-en-2-thione) with a corrected yield of 36% and a purity of 91% by HPLC.

[0144] Compound A (2-((3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-1,3-dien-2-yl)thio)-N-(quinolin-3-yl)acetamide) was synthesized according to the following reaction scheme:

[0145]

[0146] Under a nitrogen atmosphere, compound IIA-Me (100 mg, 1.0 equivalent) and DCM (1 mL) were placed in a flask and purged three times with nitrogen. Compound IIIA-Br (78 mg, 1.0 equivalent) and DIPEA (77 mg, 2.0 equivalent) were added to this solution, and the solution was stirred at 20 °C for 5 hours. Water (1 mL) and DCM (1 mL) were added to this mixture, and the organic phase was separated and washed three times with water (1 mL). The mixture was concentrated to dryness under reduced pressure at 40 °C and purified by preparative TLC (eluting with 1:4 (v / v) DCM / MeOH) to give 0.05 g of compound A (2-((3-(4-bromophenyl)-8-methyl-1,4,8-triazaspiro[4.5]dec-1,3-dien-2-yl)thio)-N-(quinolin-3-yl)acetamide) with 99% HPLC purity in a 32% corrected yield.

[0147] Example 4: Synthesis of compound A-Boc via steps (ii), (b), and (iii)

[0148] The compound A-Boc (2-(4-bromophenyl)-3-((2-oxo-2-(quinolin-3-ylamino)ethyl)thio)-1,4,8-triazaspiro[4.5]dec-1,3-diene-8-carboxylic acid tert-butyl ester) was synthesized according to the following reaction scheme:

[0149]

[0150] Under a nitrogen atmosphere, compound IIA (2-(4-bromophenyl)-3-thionyl-1,4,8-triazaspiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester, 200 mg, 1.0 equivalent) and DCM (2 mL) were placed in a flask and purged three times with nitrogen. Compound IIIA-Br (150 mg, 1.2 equivalent) and Et3N (95 mg, 2.0 equivalent) were added to this solution, and the solution was stirred at 20 °C for 1.5 hours. Water (2 mL) and DCM (2 mL) were added to this mixture, and the organic phase was separated and washed three times with water (2 mL). The mixture was concentrated to dryness under reduced pressure at 40 °C to give 250 mg of compound A-Boc (2-(4-bromophenyl)-3-((2-oxo-2-(quinolin-3-ylamino)ethyl)thio)-1,4,8-triazaspiro[4.5]dec-1,3-diene-8-carboxylic acid tert-butyl ester) with a corrected yield of 87% and a purity of 85 A% by HPLC.

[0151] Example 5: Synthesis of compound A-Bn via steps (ii), (b), and (iii)

[0152] The compound IH (3-(4-bromophenyl)-1,4,8-triazaspiro[4.5]dec-3-en-2-one) was synthesized according to the following reaction scheme:

[0153]

[0154] Under N2 conditions, compound I (55 g, 1.0 equivalent of tert-butyl 2-(4-bromophenyl)-3-oxo-1,4,8-triazaspiro[4.5]dec-1-en-8-carboxylic acid tert-butyl ester, DCM (2.7 L)) and the solution were cooled to 0 °C. HCl / MeOH (10 M, 115 mL, 10.0 equivalent) was added to this solution, and the mixture was heated to 20-25 °C and stirred for 12 hours. The mixture was filtered, and the filter cake was washed with DCM (110 mL). The filter cake was dried under reduced pressure at 40 °C for 6 hours to give 45 g of compound I-H3-(4-bromophenyl)-1,4,8-triazaspiro[4.5]dec-3-en-2-one with a HPLC purity of 94% by separation of 97%.

[0155] The compound I-Bn (8-benzyl-3-(4-bromophenyl)-1,4,8-triazaspiro[4.5]dec-3-en-2-one) was synthesized according to the following reaction scheme:

[0156]

[0157] Under N2, compound IH (3-(4-bromophenyl)-1,4,8-triazaspiro[4.5]dec-3-en-2-one, 45 g, 1.0 equivalent), Na2CO3 (16.6 g, 1.2 equivalent), and DMF (1.1 L, 25 v) were placed in a flask and the solution was cooled to -5°C. Benzyl bromide (26.8 g, 1.2 equivalent) was added to this solution, and the mixture was heated to 20°C to 25°C and stirred for 2 hours. Water (450 mL) was added to this mixture, followed by EtOAc (450 mL). The organic phase was separated and washed twice with water (450 mL), then concentrated to dryness under reduced pressure at 40 °C for 6 hours to obtain 48 g of compound I-Bn8-benzyl-3-(4-bromophenyl)-1,4,8-triazaspiro[4.5]dec-3-en-2-one with a purity of 94% by HPLC in a separation yield of 82%.

[0158] The compound IIA-Bn (8-benzyl-3-(4-bromophenyl)-1,4,8-triazaspiro[4.5]dec-3-ene-2-thionone) was synthesized according to the following reaction scheme:

[0159]

[0160] Under N2, compound I-Bn (8-benzyl-3-(4-bromophenyl)-1,4,8-triazaspiro[4.5]dec-3-en-2-one, 500 mg, 1.0 equivalent) and DCM (5 mL) were placed in a flask. Et3N (254 mg, 2.0 equivalent) was added to this solution, and the flask was purged three times with N2. The solution was cooled to 0 °C, and Tf2O (528 mg, 2.0 equivalent) was added to the solution of DCM (1 mL). This mixture was stirred at 0 °C for 1 hour to produce compound II-Bn (8-benzyl-3-(4-bromophenyl)-1,4,8-triazaspiro[4.5]dec-1,3-dien-2-yl trifluoromethanesulfonate), which was used directly in the next step without purification.

[0161] Na₂S (1.96 g, 10.0 equivalent) was added to a solution of compound II-Bn from the previous step, and the mixture was stirred at 0 °C for 1 hour. Water (5 mL) was added to this solution, followed by EtOAc (5 mL). The organic phase was separated and washed three times with water (5 mL), then concentrated to dryness under reduced pressure at 40 °C. The residue was purified by silica gel column chromatography (eluting with 2:1 (v / v) n-heptane / EtOAc) to give 210 mg of compound IIA-Bn 8-benzyl-3-(4-bromophenyl)-1,4,8-triazaspiro[4.5]dec-3-ene-2-thione with a purity of 97A% in 40% yield from compound I-Bn.

[0162] The compound A-Bn(2-((8-benzyl-3-(4-bromophenyl)-1,4,8-triazaspiro[4.5]dec-1,3-dien-2-yl)thio)-N-(quinolin-3-yl)acetamide) was synthesized according to the following reaction scheme:

[0163]

[0164] Under a nitrogen atmosphere, compound IIA-Bn (8-benzyl-3-(4-bromophenyl)-1,4,8-triazaspiro[4.5]dec-3-ene-2-thione, 150 mg, 1.0 equivalent) and DCM (1.5 mL) were placed in a flask and purged three times with nitrogen. Compound IIIA-Br (101 mg, 1.05 equivalent) and Et3N (73 mg, 2.0 equivalent) were added to this solution, and the solution was stirred at 20 °C for 5 hours. Water (1.5 mL) and DCM (1.5 mL) were added to this mixture, and the organic phase was separated and washed three times with water (1.5 mL). The mixture was concentrated to dryness under reduced pressure at 40 °C and purified by column chromatography (eluting with 0-20% MeOH / DCM) to give 0.1 g of compound A-Bn(2-((8-benzyl-3-(4-bromophenyl)-1,4,8-triazaspiro[4.5]dec-1,3-dien-2-yl)thio)-N-(quinolin-3-yl)acetamide) with 99% HPLC purity in a corrected yield of 46%.

Claims

1. A method for synthesizing compound A or its salt: (Compound A) The method includes: (i) Compound I is mixed with a halogenating agent or a sulfonating agent to form compound II: (I) Japanese (II), Where R is a methyl or nitrogen protecting group, and Z is a halogen or trifluoromethanesulfonate group; (ii) (a) Compound II is mixed with Compound III in the presence of a base to form Compound A: (III); or (b) (I) Compound II is mixed with a nucleophilic sulfide to form compound IIA, and then (II) compound IIA is mixed with compound IIIA in the presence of a base to form compound A: (IIA) and (IIIA), Where X is a halogen; as well as (iii) Optionally, when R is a nitrogen-protecting group, the nitrogen-protecting group is removed and the resulting deprotected amine is methylated to form compound A, wherein R is a methyl group. The sulfonating agent is trifluoromethanesulfonic anhydride. The nucleophilic sulfiding agent is Li₂S, Na₂S, K₂S, or Li₂S. x Na2S x K2S x NaBH4 / S, NaSH, AcSK, thiourea, or a salt or hydrate of any of the aforementioned reagents, wherein x = 2-5.

2. The method according to claim 1, wherein R is methyl.

3. The method according to claim 1, wherein R is a nitrogen protecting group.

4. The method according to claim 3, wherein R is tert-butoxycarbonyl, benzyloxycarbonyl, benzyl or p-methoxybenzyl.

5. The method according to claim 4, wherein R is tert-butoxycarbonyl.

6. The method according to any one of claims 1 to 5, wherein Z is a halogen.

7. The method according to any one of claims 1 to 5, wherein Z is chlorine.

8. The method according to any one of claims 1 to 5, wherein the halogenating agent is a chlorinating agent.

9. The method according to claim 8, wherein the chlorinating agent is oxalyl chloride, SOCl2 or POCl3.

10. The method according to any one of claims 1 to 5, wherein Z is a trifluoromethanesulfonate group.

11. The method according to any one of claims 1 to 5, wherein the trifluoromethanesulfonate group is formed by treating compound I with trifluoromethanesulfonic anhydride in a mixture of dichloromethane and ethyl acetate.

12. The method according to any one of claims 1 to 5, wherein X is Br or Cl.

13. The method of claim 12, wherein X is Cl.

14. The method according to any one of claims 1 to 5, comprising step (ii) (a).

15. The method according to claim 14, wherein the base is NaH, NaOH, KOH, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide.

16. The method according to any one of claims 1 to 5, comprising step (ii) (b).

17. The method according to claim 1, wherein the nucleophilic sulfide is a Na₂S hydrate.

18. The method according to claim 17, wherein the nucleophilic sulfide is Na2S•4H2O.

19. The method of claim 16, further comprising mixing compound II with Na2S•4H2O in a mixture of dichloromethane and ethyl acetate.

20. The method of claim 16, further comprising mixing compound IIA with compound IIIA in the presence of K2CO3 to form compound A.

21. The method of claim 20, wherein the step of mixing compound IIA with compound IIIA in the presence of K2CO3 to form compound A is carried out in isopropanol.

22. The method of claim 1, wherein R is a nitrogen protecting group, and the method comprises step (iii).

23. The method of claim 1, wherein R is a nitrogen protecting group, and the method further comprises removing the nitrogen protecting group from compound IIA and methylating the resulting deprotected amine to form compound IIA, wherein R is a methyl group.

24. The method of claim 22 or 23, wherein removing the nitrogen protecting group comprises mixing in the presence of an acid.

25. The method according to claim 22 or 23, wherein the deprotected amine is methylated by mixing with NaBH(OAc)3, CH2O and acetic acid.

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