Method for producing 6-(cyclopropanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-D3)pyridazine-3-carboxamide

Abstract

We provide therapeutic drugs for autoimmune and autoinflammatory diseases such as psoriasis. [Solution] The present invention relates to an improved method for producing 6-(cyclopropanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide of compound I. TIFF2026067880000101.tif58150

Description

Technical Field

[0001] (Cross - reference to related applications) This application claims the benefit of U.S. Provisional Patent Application No. 62 / 478,789, filed Mar. 30, 2017, and incorporates by reference in its entirety the disclosure thereof herein.

[0002] (Field of the Invention) The present invention generally relates to a method for producing 6 - (cyclopropanecarboxamido) - 4 - ((2 - methoxy - 3-(1 - methyl - 1H - 1,2,4 - triazol - 3 - yl)phenyl)amino) - N - (methyl - d3)pyridazine - 3 - carboxamide, a Tyk2 inhibitor, which is in clinical trials for the treatment of autoimmune and autoinflammatory diseases such as psoriasis, and to novel intermediates used in the method.

Background Art

[0003] Formula I:

Chemical Formula

[0004] Compound I, compositions containing Compound I, and methods of using Compound I are disclosed in U.S. Patent No. 9,505,748 B2, which is assigned to the assignee, and the entire disclosure thereof is incorporated herein by reference.

Summary of the Invention

[0005] In a first aspect, the present invention is a method for producing Compound I of the formula:

Chemical Formula

Chem.

[0006] In a second aspect, the present invention relates to a method for producing compound I of the formula:

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0007] In a third embodiment of the present invention, formula: [ka] A method for producing compound 7, a) Formula: [ka] [In the formula: X3 is Cl, Br, I, or F] Compound 4a, shown in formula:, is reacted with N-methyl-N-formylhydrazine and a suitable base to form the compound: [ka] [In the formula, X3 is defined as above.] The compound 5a shown is obtained; b) Next, treat it with nitric acid, formula: [ka] [In the formula, X3 is defined as above.] The compound 6a shown is obtained; c) The present invention provides a method comprising subsequently reducing it to obtain compound 7.

[0008] In a fourth embodiment of the present invention, formula: [ka] A method for producing the compound, a) Formula: [ka] Compound 4 was reacted with N-methyl-N-formylhydrazine and potassium tert-butoxide to produce the following compound: [ka] Compound 5 is obtained; b) Next, it is reacted with nitric acid and concentrated sulfuric acid, and the formula is: [ka] Compound 6 is obtained; c) The present invention provides a method comprising subsequently reacting it with hydrogen gas in the presence of Pd / C, sodium bicarbonate or sodium carbonate and methanol to obtain compound 7.

[0009] In a fifth embodiment of the present invention, formula: [ka] A general method for producing compound 13, a) Formula: [ka] The d4-methanol is reacted with an activator to produce the formula: [ka] [In the formula, X4 is independently a halide or a sulfonate.] The compound 11a shown is obtained; b) Next, react it with sodium diformylamide, formula: [ka] Compound 12 is obtained; c) Next, hydrolyze it to the formula: [ka] The present invention provides a method for obtaining compound 13.

[0010] Compound 13 can be isolated as a free base or as an HCl or HBr salt.

[0011] In a sixth embodiment of the present invention, formula: [ka] A method for producing compound 13, a) Formula: [ka] D4-methanol is reacted with tosyl chloride and aqueous sodium hydroxide to produce the following formula: [ka] Compound 11 is obtained; b) Next, react it with sodium diformylamide, formula: [ka] Compound 12 is obtained; c) Next, it is subjected to hydrolysis in methanol in the presence of hydrogen chloride, resulting in formula: [ka] The present invention provides a method comprising obtaining compound 13 as its hydrochloride salt.

[0012] In a seventh embodiment of the present invention, novel intermediates identified above as compounds 5, 6, 8, 9, and 12 are provided.

[0013] In the eighth aspect of the present invention, compounds 3, 5, 8, and 9 of the formula are in the form of salts or hydrates, in particular, [ka] [ka] [ka] [ka] It will be offered as such.

[0014] Another aspect of the present invention is to provide compound I, which is produced by the method of claim 1.

[0015] The final aspect of the present invention provides a method for treating autoimmune and inflammatory diseases such as psoriasis, comprising administering a therapeutically effective amount of compound I to a mammalian species in need, preferably a human, wherein compound I is produced using the steps of a novel method of the present invention.

[0016] The method of the present invention has several important advantages compared to the conventional synthesis of compound I. In particular, the reaction pathway is shorter, yields are higher, and the process is improved, resulting in a dramatic improvement in processing capacity, cycle time, and overall yield. In addition, the method consistently provides compound I in a high-quality state for use as a drug substance.

[0017] To convert compound 8(a) to compound 9(a), the methods of the first and second embodiments are carried out in the presence of a palladium catalyst. Preferred palladium catalysts are not limited to, but include, Pd(OAc)2, PdCl2(MeCN)2, Pd2(dba)3, Pd(dba)2, [(allyl)PdCl]2, and [(clotyl)PdCl]2.

[0018] The methods of the first and second embodiments are also carried out in the presence of a ligand. Preferred ligands are not limited to, but include, SL-J009-1, SL-J009-2, SL-J002-1, SL-J002-2, DPEphos, Xantphos, DPPF, DCyPF, BINAP, or derivatives thereof.

[0019] The methods of the first and second embodiments are also carried out in the presence of a base. Preferred bases include, but are not limited to, K2CO3, K3PO4, Cs2CO3, DBU, DBN, TMG, or combinations thereof, particularly DBU / K2CO3. [Modes for carrying out the invention]

[0020] The following schemes illustrate improved synthesis steps of the present invention. These schemes are illustrative and are not intended to limit any possible art techniques that may be used to produce the compounds disclosed herein.

[0021] The general preparation of compound I is described below, as shown in Scheme 1. Compound 1a is reacted with an activating agent to obtain 4,6-diactivated pyridazine compound 2a. Ester hydrolysis occurs in the presence of a base to produce compound 3a in the form of a carboxylic acid or a salt thereof. Compound 3a may be selectively substituted at the C4 position with compound 7 under neutral conditions in the absence of any additives, via contact with a suitable acid, base or metal salt, to produce compound 8a. Compound 8a can be isolated in its free form, or optionally isolated as a salt with a suitable base. Compound 8a will undergo a coupling step with compound 10 in the presence of a metal, a suitable ligand and a base to form compound 9a. Finally, the coupling of compound 9a with compound 13 occurs in the presence of an activating agent and any base to produce compound I. Scheme 1 [ka]

[0022] The preparation of compound I is described as shown in Scheme 2 below. Diethyl 1,3-acetonedicarboxylate is successively treated with 4-acetamidobenzenesulfonyl azide, a Hünig base, tributylphosphine, water, and acetic acid to produce ethyl 4,6-dihydroxypyridazine-3-carboxylate (compound 1). Chlorolysis with phosphorus oxychloride yields the corresponding dichloride (compound 2), which is hydrolyzed in aqueous acetonitrile in the presence of lithium bromide and a Hünig base to obtain lithium carboxylate (compound 3). A nucleophilic aromatic substitution reaction with compound 7 occurs at the C4 position of compound 3 in the presence of zinc acetate, leading to the formation of compound 8 as a zinc salt. Subsequent coupling with compound 10 is catalyzed by palladium acetate and Josiphos ligand to produce compound 9. Finally, compound 9 undergoes amidation with compound 13 in the presence of EDC, HOBt, and NMI to produce compound I. Scheme 2 [ka]

[0023] Another method of the present invention is disclosed in Scheme 3 below. The general preparation of compound 7 is described. Compound 5a is produced by ring condensation of compound 4a with N-methyl-N-formylhydrazine, which is then nitrated to produce compound 6a. Subsequently, it is reduced to produce the corresponding compound 7. Scheme 3 [ka]

[0024] The preparation of compound 7 is described as shown in Scheme 4 below. Compound 4 is reacted with N-methyl-N-formylhydrazine in the presence of potassium t-butoxide to obtain compound 5. Compound 5 is treated with nitric acid and concentrated sulfuric acid to produce compound 6, which is then reacted with hydrogen gas in the presence of Pd / C and sodium carbonate or sodium bicarbonate to obtain compound 7. Scheme 4 [ka]

[0025] Another method of the present invention is disclosed in Scheme 5 below. A general preparation of compound 13 is described. Compound 11a is obtained by reacting D4-methanol with a suitable activating agent, and this is substituted by treatment with sodium diformylamide to form compound 12. This is then subjected to hydrolysis to produce compound 13. Scheme 5 [ka]

[0026] The preparation of compound 13 is described as shown in Scheme 6 below. D4-methanol is reacted with tosyl chloride in the presence of aqueous sodium hydroxide to obtain compound 11. This compound is reacted with sodium diformamide to obtain compound 12, which is then subjected to hydrolysis in the presence of acidic methanol to obtain compound 13 as its hydrochloride salt. Scheme 6 [ka] [Examples]

[0027] The present invention is now described in more detail by the following embodiments, which represent preferred embodiments of the invention. All temperatures are in degrees Celsius (°C) unless otherwise specified. These embodiments are illustrative rather than restrictive, and it should be understood that other embodiments may fall within the spirit and scope of the invention, as defined by the appended claims.

[0028] For ease of reference, the following abbreviations may be used herein. Abbreviation [Table 1]

[0029] Example 1 [ka]

[0030] Toluene (0.26 kg), sulfolane (3.4 kg), compound 1 (1.0 kg), and POCl3 (2.7 kg) were placed in a glass-lined reactor. The crude product was cooled to 0°C. Triethylamine (0.89 kg) was added, and the resulting crude mixture was heated to 65°C and left to stand until the reaction was complete. The reaction product was cooled to 5°C. Water (7.5 kg) was placed in a separation reactor and cooled to 5°C. The reactants were slowly added to the aqueous solution while maintaining the internal temperature below 5°C. Additional water (0.5 kg) was used to rinse the reactor and aid in transfer. The resulting mixture was stirred at 5°C for 3 hours, and then extracted three times (4 x 4.5 kg) with MTBE. The organic layers were combined and washed sequentially with pH 7 buffer solution (5.0 L / kg, 15 wt% KH2PO4 / K2HPO4) and water (2.5 kg). The crude product was distilled under vacuum until the total volume was approximately 3 L / kg. ACN (2 x 6.3 kg) was added, followed by further distillation to return to approximately 3 L / kg. The crude product was cooled to 20°C, and compound 2 was obtained as a 30-36 wt% solution in 90-95% yield.

[0031] Example 2 [ka]

[0032] ACN (2.7 kg), lithium bromide (1.18 kg), and water (0.65 kg) were placed in a glass-lined reactor at 25°C. A crude solution of compound 2 (limiting reagent) prepared above was then added to DIPEA (1.82 kg). The resulting slurry was stirred at 25°C until the reaction was complete. The product was isolated by filtration. The crude solid was washed with ACN (1.6 kg). The cake was dried under vacuum at 45°C. Compound 3 was isolated at 98 AP and in 83% yield.

[0033] Example 3 [ka]

[0034] Water (6.0 kg, 6.0 L / kg) and compound 7 (1.0 kg) were placed in a glass-lined reactor at 25°C. Anhydrous zinc acetate (1.08 kg, 1.0 equivalent) was added, followed by compound 3 (1.28 kg, 1.20 equivalents). The reactor lines were rinsed with 2-propanol (0.79 kg, 1.0 L / kg) and water (1.50 kg, 1.50 L / kg). The resulting homogeneous solution was heated to 65°C and allowed to stand until the reaction was complete. Water (7.0 kg, 7.0 L / kg) was added, and the crude mixture was cooled to 20°C and allowed to stand for 30 minutes. The product was isolated by filtration. The crude solid was successively washed with water (6.0 kg, 6.0 L / kg), water (6.0 kg, 6.0 L / kg), THF (5.3 kg, 6.0 L / kg), and THF (5.3 kg, 6.0 L / kg). The cake was dried at 70°C under vacuum. Compound 8 was isolated at 98 AP and in 94% yield.

[0035] Example 4 [ka]

[0036] The separation glass-lined reactor was flashed with nitrogen. Toluene (0.87 kg, 1.0 L / kg) and MeCN (0.79 kg, 1.0 L / kg) were added, followed by (2R)-1-[(1R)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(dicyclohexylphosphino)ferrocene (Josiphos SL-009-01) (14.1 g, 1.0 mol%) and palladium acetate (2.9 g, 0.5 mol%). The reactor lines were rinsed with toluene (0.43 kg, 0.5 L / kg). The resulting pre-formulated catalyst solution was kept under nitrogen until further use. At 20°C, toluene (3.46 kg, 4.0 L / kg) and ACN (1.57 kg, 2.0 L / kg) were placed in a glass-lined reactor that had been flash-treated with nitrogen. Compound 8 (1.00 kg) was added, followed by DBU (0.39 kg, 1.00 equivalent). The reactor lines were rinsed with toluene (0.43 kg, 0.5 L / kg). Compound 10 (0.54 kg, 2.5 equivalents) and K2CO3 (325 mesh grade, 0.70 kg, 2.0 equivalents) were added to the reaction mixture, followed by toluene (1.30 kg, 1.5 L / kg) and ACN (0.79 kg, 1.0 L / kg). The pre-form catalyst solution was transferred to the reaction mixture, which was then heated to 75°C and stirred until the reaction was complete. The reaction product was cooled to 20°C. An aqueous solution of acetic acid (50% by volume, 4.0 kg, 4.0 L / kg) was slowly added over 1 hour. Next, glacial acetic acid (10.5 kg, 10.0 L / kg) was added. The resulting homogeneous solution was washed twice with heptane (2 x 3.42 kg, 2 x 5.0 L / kg). The aqueous layer at the bottom was collected and transferred to a clean reactor. Water (5.0 kg, 5.0 L / kg) was added, followed by a seed of compound 9 (0.01 kg, 1.0 wt%). The slurry was left at 20°C for 2 hours. Further water (2.0 kg, 2.0 L / kg) was added, and the slurry was left for a further 6 hours. The product was isolated by filtration. The crude cake was washed with aqueous ACN (50% by volume, 4.5 kg, 5.0 L / kg), followed by ACN (3.9 kg, 5.0 L / kg). The cake was dried under vacuum at 65°C. Compound 9 was isolated at 98.5 AP and in 84% yield.

[0037] Example 5 [ka]

[0038] NMP (2.06 kg, 2.0 L / kg) and ACN (0.78 kg, 1.0 L / kg) were placed in a glass-lined reactor and stirred at 20°C. N-methylimidazole (0.13 kg, 0.7 equivalents), compound 13 (0.17 kg, 1.2 equivalents), and compound 9 (1.00 kg) were added to the reaction mixture. The mixture was heated to 65°C and allowed to stand until homogenized. HOBt (20% water (wet), 0.17 kg, 0.5 equivalents) was added to the reaction mixture, followed by EDC·HCl (0.54 kg, 1.4 equivalents). The reactor was rinsed with ACN (0.78 kg, 1.0 L / kg), and the resulting mixture was allowed to stand at 65°C until the reaction was complete. The reaction mixture was quenched by adding water (1.0 kg, 1 L / kg), and then diluted with ACN (3.0 kg, 3 L / kg). The reaction mixture was left at 65°C for 1 hour, then cooled to 0°C, and left at 0°C for a further 12 hours. The product was isolated by filtration. The moist cake was washed with 2:1 water:ACN (2.8 kg, 3 L / kg), then with ACN (2.4 kg, 3 L / kg), and dried at 65°C under high vacuum. Compound I was isolated with >99.5% purity and 91% yield. If necessary, the product can be subjected to any recrystallization operation as follows. NMP (6.2 kg, 6.0 L / kg) and compound I (1.0 kg) were placed in a glass-lined reactor. The batch was heated to 70°C to form a pale yellow solution, which was then transferred to a clean container via a polished filter at 70°C. 2-propanol (2.4 kg, 3 L / kg) was added, followed by the addition of compound I seed (0.005 kg, 0.005 kg / kg). After standing for 1 hour, a further 2-propanol (4.8 kg, 6 L / kg) was added over 2 hours (3 L / kg / hour). The slurry was left at 70°C for 1 hour, slowly cooled to 0°C, and left at 0°C for a further 12 hours. The product was isolated by filtration. The moist cake was washed with 2-propanol (2 x 3.1 kg, 2 x 4 L / kg) and then dried at 65°C under high vacuum. Compound I was isolated with a purity of >99.9% and a yield of 83%.

[0039] Example 6 [ka]

[0040] Methanol (1.6 kg / kg, 2.0 L / kg) and methylhydrazine (1 kg) were added to a glass-lined reactor at 0°C. Methyl formate (0.57 kg / kg, 1.1 equivalents) was added dropwise. The crude product was heated to 20°C and left for 6 hours. The crude product was distilled under vacuum until the total volume was approximately 0.5 L / kg. Put / take distillation with 2-MeTHF (5 x 3.6 kg / kg) was performed five times for azeotropic drying. The crude product was cooled to 20°C. N-methyl-N-formylhydrazine was isolated as an 89-90 wt% solution in a yield of 89-91%.

[0041] Example 7 [ka]

[0042] Potassium tert-butoxide (1.5 kg / kg, 2.4 equivalents) and THF (12.2 kg / kg) were added to a glass-lined reactor at 0°C. A mixture of compound 4 (1.0 kg), N-methyl-N-formylhydrazine (1.0 kg / kg, 2.30 equivalents), and THF (5.3 kg / kg, 6.0 L / kg) was slowly added. The reactor lines were rinsed with THF (0.5 kg / kg). The crude reaction product was left at 0°C until the reaction was complete. Water (5.0 kg / kg) was added, and the resulting mixture was left at 0°C for 30 minutes, then heated to 40°C and left for another 30 minutes. The layers were separated, and the aqueous layer was discarded. The organic layer was washed with brine (15% by weight, 5.7 kg / kg) and distilled under vacuum until the total volume was approximately 5 L / kg. For azeotropic drying, four put / take distillations were performed with ethyl acetate (4 x 10 L / kg). The crude product was cooled to 20°C. Sulfuric acid (0.66 Kg / kg, 1.10 equivalents) was added, and the slurry was stirred for 2-3 hours. The product was isolated by filtration. The cake was successively washed with ethyl acetate (2 x 6.5 L / kg) and heptane (8 L / kg) and dried under vacuum at 45°C. Compound 5 was isolated at 99 AP and in 83% yield.

[0043] Example 8 [ka]

[0044] Concentrated sulfuric acid (4.5 kg / kg) and compound 5 (1.0 kg) were placed in a glass-lined reactor at 0-5°C. Nitric acid (68% by weight, 0.35 kg / kg, 1.2 equivalents) was added dropwise. The mixture was stirred at 0-5°C until the reaction was complete. In a separation reactor, water (12 kg / kg) and methanol (6.5 kg / kg, 8.3 L / kg) were thoroughly mixed at 20°C. The nitrated crude product was slowly transferred to the methanol-water mixture. The reactor line was rinsed with methanol (0.5 kg / kg). The crude product was heated to 40-45°C. Aqueous ammonium hydroxide (25 wt%, 7.4 kg / kg) was slowly added. The resulting slurry was cooled to 20°C and stirred for 3 hours. The product was isolated by filtration. The cake was washed with water (2 x 6 L / kg) and dried under vacuum at 45°C. Compound 6 was isolated at 99 AP and in 95% yield.

[0045] Example 9 [ka]

[0046] Methanol (8.0 kg / kg) and compound 6 (1.0 kg) were added to a high-pressure reactor that had been flashed with nitrogen. Sodium bicarbonate (0.6 kg / kg, 2.0 equivalents) and Pd / C (10% loading, 50% water, 0.02 kg / kg) were added while carefully removing oxygen. The reactor was pressurized with hydrogen (41-46 psi), and the reaction mixture was left at 20°C for 6 hours, then heated to 45°C and left until the reaction was complete. The reactor was flashed with nitrogen, and the crude product was filtered to remove Pd / C. Methanol (5 kg / kg) was used to facilitate transfer. The filtrates were combined and distilled under vacuum until the total volume was approximately 2.5 L / kg. Water (10 kg / kg) was added, and the crude product was distilled under vacuum until the total volume was approximately 2.5 L / kg. The crude product was heated to 70°C. Brine (25% by weight, 9.0 kg / kg) was added, and the resulting crude product was stirred at 70°C for 6 hours. After cooling to 0°C, the crude product was left to stand for another 6 hours. The product was isolated by filtration. The cake was washed with brine (pre-cooled to 0°C, 25% by weight, 2.0 kg / kg) and dried at 45°C under vacuum. Compound 7 was isolated at 99 AP and in 88% yield.

[0047] Example 10 [ka]

[0048] Water (16.3 L / Kg) and sodium hydroxide (3.3 Kg, 3.0 equivalents) were added to a glass-lined reactor that had been flash-treated with nitrogen. The mixture was allowed to stand until the sodium hydroxide was completely dissolved. The crude product was cooled to 0°C. D4-methanol (1.0 Kg) and THF (4.5 L / Kg) were added. A solution of TsCl (6.3 Kg, 1.2 equivalents) in THF (6.3 Kg, 7.1 L / Kg) was added over 2 hours. The crude product was stirred at 0°C until the reaction was complete. The batch was heated to 20°C. The layers were separated. The organic layer was collected, diluted with MTBE (4.0 Kg, 5.4 L / Kg), and washed twice with brine (25 wt%, 4.0 Kg, followed by 12 Kg). The organic layer was distilled under vacuum until the total volume was approximately 10 L / Kg. Two put / take distillations were performed with ACN (2 x 10 L / Kg) for azeotropic drying. The crude product was cooled to 20°C. ACN (10.0 Kg, 12.8 L / Kg) and NaN(CHO)2 (3.3 Kg, 1.2 equivalents) were added. The crude product was heated to 65°C and stirred until the reaction was complete. After cooling to 5°C, the mixture was filtered and the crude cake was washed twice with ACN (2 x 2.5 Kg, 2 x 3.2 L / Kg). The filtrates were combined and distilled under vacuum until the total volume was approximately 3 L / Kg. The crude product was cooled to 20°C. Compound 12 was isolated as an oily substance of 80-85% by weight in a yield of 60-70%.

[0049] Example 11 [ka]

[0050] Compound 12 (1.0 kg) and methanol (3.9 kg, 5.0 L / kg) were added to a glass-lined reactor at 20°C. HCl solution in IPA (5-6 N, 4.5 kg, 1.5 equivalents) was added. The resulting mixture was heated to 50°C and stirred until the reaction was complete. THF (10 kg, 11.2 L / kg) was slowly added, and the crude product was cooled to 0°C over 2 hours to obtain a slurry. The product was isolated by filtration. The cake was washed with THF (3.7 kg, 4.1 L / kg) and dried under vacuum at 45°C. Compound 13 was isolated in 80% yield. If necessary, the product can be subjected to any recrystallization procedure as follows: Methanol (5.6 kg, 8.3 L / kg) and compound 13 (1.0 kg) were placed in a glass-lined reactor. DBU (0.1 kg) was slowly added. The crude product was stirred for 1 hour. THF (12.4 kg, 13.9 L / kg) was slowly added, and the resulting slurry was allowed to stand for 2 hours. The product was isolated by filtration. The cake was washed with THF (2.6 kg, 2.9 L / kg) and dried at 45°C under vacuum. Compound 13 was isolated in 60% yield (first yield). The mother liquor was distilled under vacuum until the total volume was approximately 1 L / kg. Two put / take distillations with methanol (2 x 2.8 kg, 2 x 3.6 L / kg) were performed, and the solution was concentrated back to approximately 1 L / kg. The crude product was cooled to 20°C. THF (4.8 kg, 5.4 L / kg) was added, and the resulting slurry was left to stand for 2 hours. The product was isolated by filtration. The cake was washed with THF (1.0 kg) and dried at 45°C under vacuum. Compound 13 was isolated in 25% yield (second yield).

Claims

1. formula: 【Chemistry 1】 A method for producing compound (I), a) Formula: 【Chemistry 2】 [In the formula: R is C １ -C ６ [It is alkyl or aryl.] Compound Ia, shown by , is reacted with an activating agent to produce the following compound: 【Transformation 3】 [In the formula: X １ and X ２ [Is independently a halide or sulfonate; and R is as defined above] A step to obtain compound 2a shown in; b) Compound 2a is then reacted with an aqueous base to form the formula: 【Chemistry 4】 [In the formula: M is H, Li, Na, K, Cs, Ca, Mg or Zn, X １ and X ２ [This is defined as above] A step to obtain compound 3a shown in; c) Compound 3a, formula: 【Transformation 5】 Compound 7 is reacted with a suitable solvent, optionally in the presence of an acid, base, or metal salt, to produce the formula: 【Transformation 6】 [In the formula: M and X] ２ [This is defined as above] A step to obtain compound 8a shown in; d) Compound 8a, formula: 【Transformation 7】 Compound 10 is reacted with a suitable transition metal catalyst, ligand, one or more bases and one or more suitable solvents to produce the formula: 【Transformation 8】 [In the formula: M is as defined above] A step to obtain compound 9a shown in; e) Compound 9a, formula: 【Chemistry 9】 The process of reacting compound 13 or a free base or a salt thereof with one or more suitable activators, one or more suitable solvents, and optionally a base to obtain compound I. Methods that include...

2. formula: 【Chemistry 10】 A method for producing compound I, a) Formula: 【Chemistry 11】 Compound 1 of POCl ３ And optionally, it may be reacted with an amine base, followed optionally by post-treatment with a buffered aqueous solution, formula: 【Chemistry 12】 Steps to obtain compound 2; b) Compound 2 is then reacted with LiBr and DiPEA in water and acetonitrile to form the following compound: 【Chemistry 13】 The step of obtaining compound 3; c) Compound 3, formula: 【Chemistry 14】 Compound 7 was reacted with water and 2-propanol in the presence of zinc acetate to produce the following compound: 【Chemistry 15】 A step to obtain compound 8 or its hydrate or solvate; d) Compound 8, formula: 【Chemistry 16】 Compound 10 is reacted with a palladium-catalyzed C-N coupling reaction using a dual base system containing potassium carbonate and DBU in the presence of a phosphine ligand and a base, and then optionally isolated from aqueous acetic acid, with formula: 【Chemistry 17】 A step to obtain compound 9 or its hydrate or solvate; e) Compound 9 with EDC or other coupling agent, and formula: [Chemistry 18] A method comprising the step of reacting compound 13 with compound I to obtain compound I, which may be further purified by crystallization from NMP / IPA.

3. formula: 【Chemistry 19】 A method for producing compound 7, a) Formula: 【Chemistry 20】 [where: X ３ is Cl, Br, I or F] Compound 4a, shown in formula:, is reacted with N-methyl-N-formylhydrazine and a suitable base to form: 【Chemistry 21】 Compound 5a is obtained; b) Next, treat it with nitric acid, formula: 【Chemistry 22】 Compound 6a is obtained; c) A method comprising subsequently reducing it to obtain compound 7.

4. formula: 【Chemistry 23】 A method for producing the compound, a) Formula: 【Chemistry 24】 Compound 4 was reacted with N-methyl-N-formylhydrazine and potassium tert-butoxide to produce the following compound: 【Chemistry 25】 Compound 5 is obtained; b) Next, react it with nitric acid in the presence of concentrated sulfuric acid, and the formula is: 【Chemistry 26】 We obtain compound 6; c) A method comprising subsequently reacting it with hydrogen gas in the presence of Pd / C, sodium bicarbonate or sodium carbonate and methanol to obtain compound 7.

5. formula: 【Chemistry 27】 A method for producing compound 13 or a salt thereof, a) Formula: 【Chemistry 28】 The d4-methanol is reacted with an activator, and the formula is: 【Chemistry 29】 [In the formula: X ４ [These are independently halides or sulfonates.] A compound 11a represented by the formula is obtained; b) Next, react it with sodium diformylamide, formula: 【Transformation 30】 Compound 12 is obtained; c) Next, hydrolysis is performed to obtain compound 13. A method that includes doing so.

6. formula: 【Chemistry 31】 A method for producing compound 13, a) Formula: 【Chemistry 32】 d4-methanol is reacted with tosyl chloride and aqueous sodium hydroxide to produce the following: 【Transformation 33】 Compound 11 is obtained; b) Next, react it with sodium diformylamide, formula: 【Transformation 34】 Compound 12 is obtained; c) Next, it is subjected to hydrolysis in methanol in the presence of hydrogen chloride, resulting in formula: 【Chemistry 35】 A method comprising obtaining compound 13 as its hydrochloride salt.

7. below: 【Transformation 36】 A compound, salt thereof, or hydrate selected from the group. 【Request Item 8】 【Chemistry 37】 The compound according to claim 7 or its hydrate. 【Request Item 9】 【Chemistry 38】 The compound according to claim 7 or its hydrate. 【Request Item 10】 【Chemistry 39】 The compound according to claim 7.

11. formula: 【Chemistry 40】 A compound of [unclear].

12. Formulated by the method of claim 1: 【Chemistry 41】 Compound I.

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