Methods for preparing tyk2 inhibitors

Abstract

The present invention relates to an improved process for the synthesis of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide, Compound I, which is currently in clinical trials for the treatment of autoimmune and autoinflammatory diseases such as psoriasis. (I)

Description

[0001] This application is a divisional application of Chinese application No. 202310552731.6, entitled "Method for Preparing Tyk2 Inhibitors", filed on March 29, 2018.

[0002] Cross-reference to related applications

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 478,789, filed March 30, 2017, the entire contents of which are incorporated herein by reference. Technical Field

[0004] This invention generally relates to a method for preparing 6-(cyclopropaneamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide (Tyk2 inhibitor), which is currently used in clinical trials for the treatment of autoimmune and autoinflammatory diseases such as psoriasis, and novel intermediates used in this method. Background Technology

[0005] A method for preparing 6-(cyclopropaneamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide of formula I is disclosed:

[0006]

[0007] (I)

[0008] Compound I, compositions comprising Compound I, and methods of using Compound I are disclosed in U.S. Patent No. 9,505,748 B2, which has been assigned to the assignee of this application, the entire contents of which are incorporated herein by reference. Summary of the Invention

[0009] In a first aspect, the present invention provides a method for preparing compound I of the following formula:

[0010]

[0011] (I)

[0012] The method includes the following steps:

[0013] a) Compound 1a of the following formula

[0014]

[0015] Compound 1a

[0016] Where R is a C1-C6 alkyl or aryl group;

[0017] Reaction with an activating agent to provide compound 2a of the following formula,

[0018]

[0019] Compound 2a

[0020] Where X1 and X2 are independently halogens or sulfonates; and R is as defined above.

[0021] b) Compound 2a is then reacted with an aqueous base to provide compound 3a of the following formula.

[0022]

[0023] Compound 3a

[0024] Where M is H, Li, Na, K, Cs, Ca, Mg, or Zn, and X1 and X2 are as defined above.

[0025] c) Combine compound 3a with compound 7 of the following formula

[0026]

[0027] Compound 7

[0028] The reaction is carried out in a suitable solvent and optionally in the presence of an acid, a base or a metal salt to provide compound 8a of the following formula.

[0029]

[0030] Compound 8a

[0031] M and X2 are defined as above.

[0032] d) Compound 8a is mixed with compound 10 of the following formula.

[0033]

[0034] Compound 10

[0035] The reaction proceeds in the presence of a suitable transition metal catalyst, a ligand, one or more bases, and one or more suitable solvents to provide compound 9a of the following formula.

[0036]

[0037] Compound 9a

[0038] Where M is defined above.

[0039] e) Mix compound 9a with compound 13 (free base or its salt) of the following formula.

[0040]

[0041] Compound 13

[0042] The reaction is carried out in the presence of one or more suitable activators, one or more suitable solvents, and optionally a base to provide the final product compound I.

[0043] In a second aspect, the present invention provides a method for preparing compound I of the following formula:

[0044]

[0045] (I)

[0046] The method includes the following steps:

[0047] a) Compound 1 of the following formula

[0048]

[0049] Compound 1

[0050] Reacts with POCl3 and optionally an amine base, followed by optionally buffered aqueous post-treatment to provide compound 2 of the following formula.

[0051]

[0052] Compound 2

[0053] b) Compound 2 was then reacted with LiBr and DiPEA in water and acetonitrile to provide compound 3 of the following formula.

[0054]

[0055] Compound 3

[0056] c) Combine compound 3 with compound 7 of the following formula

[0057]

[0058] Compound 7

[0059] The reaction in water and 2-propanol in the presence of zinc acetate yields compound 8 of the following formula.

[0060]

[0061] Compound 8

[0062] or its hydrate or solvate;

[0063] d) Mix compound 8 with compound 10 of the following formula

[0064]

[0065] Compound 10

[0066] In a palladium-catalyzed CN coupling reaction, a dual-base system consisting of potassium carbonate and DBU is used in the presence of a phosphine ligand and a base, followed optionally by separation from aqueous acetic acid to provide compound 9 of the following formula.

[0067]

[0068] Compound 9

[0069] or its hydrate or solvate;

[0070] e) React compound 9 with EDC or other coupling agent and compound 13 of the following formula.

[0071]

[0072] Compound 13

[0073] To provide the final product compound I, which can be further purified by crystallization from NMP / IPA.

[0074] In a third aspect of the invention, a method for preparing compound 7 of the following formula is provided.

[0075]

[0076] Compound 7

[0077] The method includes

[0078] a) Compound 4a of the following formula

[0079]

[0080] Compound 4a

[0081] Where X3 is Cl, Br, I or F;

[0082] Reaction with N-methyl-N-formylhydrazide and a suitable base to provide compound 5a of the following formula.

[0083]

[0084] Compound 5a

[0085] Where X3 is defined as above.

[0086] b) It is then nitrated to provide compound 6a of the following formula.

[0087]

[0088] Compound 6a

[0089] Where X3 is defined as above.

[0090] c) It is then reduced to provide compound 7.

[0091] In a fourth aspect of the invention, a method for preparing compound 7 of the following formula is provided.

[0092]

[0093] Compound 7

[0094] The method includes

[0095] a) Compound 4 of the following formula

[0096]

[0097] Compound 4

[0098] Reaction with N-methyl-N-formylhydrazide in the presence of potassium tert-butoxide to provide compound 5 of the following formula.

[0099]

[0100] Compound 5

[0101] b) It is then reacted with nitric acid in the presence of concentrated sulfuric acid to provide compound 6 of the following formula.

[0102]

[0103] Compound 6

[0104] c) It is then reacted with hydrogen in the presence of Pd / C, sodium bicarbonate, or sodium carbonate and methanol to provide compound 7.

[0105] In a fifth aspect of the invention, a general method for preparing compound 13 of the following formula is provided.

[0106]

[0107] Compound 13

[0108] The method includes

[0109] a) The following formula contains d4-methanol

[0110]

[0111] Reaction with an activating agent to provide compound 11a of the following formula:

[0112]

[0113] Compound 11a

[0114] Where X4 is independently a halogen or a sulfonate ester.

[0115] b) It is then reacted with sodium dimethamide to provide compound 12 of the following formula.

[0116]

[0117] Compound 12

[0118] c) It is then hydrolyzed to provide compound 13 of the following formula.

[0119]

[0120] Compound 13

[0121] Compound 13 can be isolated as a free base, or as an HCl or HBr salt.

[0122] In a sixth aspect of the invention, a method for preparing compound 13 of the following formula is provided.

[0123]

[0124] Compound 13

[0125] The method includes

[0126] a) The following formula contains d4-methanol

[0127]

[0128] It reacts with p-toluenesulfonyl chloride in the presence of aqueous sodium hydroxide to provide compound 11 of the following formula:

[0129]

[0130] Compound 11

[0131] b) It is then reacted with sodium dimethamide to provide compound 12 of the following formula.

[0132]

[0133] Compound 12

[0134] c) It is then hydrolyzed in methanol in the presence of hydrochloric acid to provide compound 13 (as a hydrochloride salt).

[0135]

[0136] Compound 13.

[0137] In a seventh aspect of the invention, novel intermediates identified above as compounds 5, 6, 8, 9 and 12 are provided.

[0138] In an eighth aspect of the invention, salt or hydrate forms of compounds 3, 5, 8, and 9 of the following formula are provided. In particular,

[0139]

[0140] Compound 3b

[0141]

[0142] Compound 5b or 5c

[0143]

[0144] Compound 8b

[0145]

[0146] Compound 9b

[0147] Another aspect of the present invention provides compound I, which is prepared by the following method:

[0148] A method for preparing compound I of the following formula

[0149]

[0150] (I)

[0151] It includes the following steps

[0152] a) Compound 1a of the following formula

[0153]

[0154] Compound 1a

[0155] Where R is a C1-C6 alkyl or aryl group;

[0156] Reaction with an activating agent to provide compound 2a of the following formula,

[0157]

[0158] Compound 2a

[0159] Where X1 and X2 are independently halogens or sulfonates; and R is as defined above.

[0160] b) Compound 2a is then reacted with an aqueous base to provide compound 3a of the following formula.

[0161]

[0162] Compound 3a

[0163] Where M is H, Li, Na, K, Cs, Ca, Mg, or Zn, and X1 and X2 are as defined above.

[0164] c) Combine compound 3a with compound 7 of the following formula

[0165]

[0166] Compound 7

[0167] The reaction is carried out in a suitable solvent and optionally in the presence of an acid, a base or a metal salt to provide compound 8a of the following formula.

[0168]

[0169] Compound 8a

[0170] M and X2 are defined as above.

[0171] d) Compound 8a is mixed with compound 10 of the following formula.

[0172]

[0173] Compound 10

[0174] The reaction is carried out in the presence of a suitable transition metal catalyst, ligand, one or more bases, and one or more suitable solvents to provide compound 9a of the following formula.

[0175]

[0176] Compound 9a

[0177] Where M is defined above.

[0178] e) Reacting compound 9a with compound 13 of the following formula or its free base or salt in the presence of one or more suitable activators, one or more suitable solvents and optionally a base, to provide compound I.

[0179]

[0180] Compound 13.

[0181] A final aspect of the invention provides a method for treating autoimmune and autoinflammatory diseases such as psoriasis, the method comprising administering a therapeutically effective amount of compound I to a mammalian species, preferably a human, in need of treatment, wherein compound I is prepared using the novel method steps of the invention.

[0182] Compared to existing methods for synthesizing Compound I, the method of this invention offers several important advantages. In particular, yield, cycle time, and overall yield are significantly improved due to the shorter sequence of chemical steps, higher yield, and process improvements. Furthermore, this method consistently delivers high-quality Compound I for use as a pharmaceutical API.

[0183] To convert compound 8(a) into compound 9(a), the methods of the first and second aspects are carried out in the presence of a palladium catalyst. Preferred palladium catalysts include, but are not limited to, Pd(OAc)2, PdCl2(MeCN)2, Pd2(dba)3, Pd(dba)2, [(allyl)PdCl]2, and [(crotonyl)PdCl]2.

[0184] The methods of the first and second aspects are also carried out in the presence of ligands. Preferred ligands include, but are not limited to, phosphine ligands, such as SL-J009-1, SL-J009-2, SL-J002-1, SL-J002-2, DPEphos, Xantphos, DPPF, DCyPF, BINAP, or derivatives thereof.

[0185] The methods of the first and second aspects are also carried out in the presence of an alkali. Preferred alkalis include, but are not limited to, K2CO3, K3PO4, Cs2CO3, DBU, DBN, TMG, or combinations thereof, especially DBU / K2CO3. Detailed Implementation

[0186] The following schemes illustrate the improved synthetic steps of the present invention. These schemes are illustrative and are not intended to limit the possible techniques that those skilled in the art can use to prepare the compounds disclosed in this application.

[0187] The general preparation of compound I is described in Scheme 1 below. Compound 1a is reacted with an activating agent to give 4,6-diactivated pyridazine compound 2a. Ester hydrolysis occurs in the presence of a base to produce compound 3a as a carboxylic acid or its salt. Compound 3a can be selectively substituted at the C4 position with compound 7 by contact with a suitable acid, base, or metal salt, or under neutral conditions in the absence of any additives, to give compound 8a. Compound 8a can be isolated in its free form or optionally as a salt with a suitable base. Compound 8a will undergo a coupling process with compound 10 in the presence of a metal, a suitable ligand, and a base to form compound 9a. Finally, coupling of compound 9a with compound 13 occurs in the presence of an activating agent, and optionally with a base, to produce compound I.

[0188] Option 1

[0189]

[0190] The preparation of compound I is described in Scheme 2 below. Diethyl 1,3-acetone dicarboxylate was treated sequentially with 4-acetamidobenzenesulfonyl azide and Hunig base, tributylphosphine and water, and acetic acid to yield ethyl 4,6-dihydroxypyridazine-3-carboxylate (compound 1). Chlorination with phosphorus trichloride yielded the corresponding dichloride (compound 2), which was hydrolyzed in aqueous acetonitrile in the presence of lithium bromide and Hunig base to give lithium carboxylate (compound 3). In the presence of zinc acetate, aromatic nucleophilic substitution of compound 3 at the C4 position with compound 7 resulted in the formation of compound 8 as a zinc salt. Subsequent coupling with compound 10 was catalyzed by palladium acetate and Josiphos ligand to produce compound 9. Finally, compound 9 was amidated with compound 13 in the presence of EDC, HOBt, and NMI to give compound I.

[0191] Option 2

[0192]

[0193] Option 3

[0194] Another method of the invention is disclosed in embodiment 3 shown below. The general preparation of compound 7 is described. Compound 4a is cyclized with N-methyl-N-formylhydrazide to give compound 5a, which is then nitrated to give compound 6a. Reduction then provides the corresponding compound 7.

[0195]

[0196] The preparation of compound 7 is described in Scheme 4 below. Compound 4 reacts with N-methyl-N-formylhydrazide in the presence of potassium tert-butoxide to give compound 5. Compound 5 is treated with nitric acid and concentrated sulfuric acid to give compound 6, which reacts with hydrogen in the presence of Pd / C and sodium carbonate or sodium bicarbonate to give compound 7.

[0197] Option 4

[0198]

[0199] Scheme 5 shown below discloses another method of the present invention. The general preparation of compound 13 is described. D4-methanol reacts with a suitable activating agent to produce compound 11a, which is substituted upon treatment with sodium diformamide to form compound 12. Subsequent hydrolysis yields compound 13.

[0200] Option 5

[0201]

[0202] The preparation of compound 13 is described in Scheme 6 below. D4-methanol reacts with p-toluenesulfonyl chloride in the presence of aqueous sodium hydroxide to give compound 11. This compound reacts with sodium diformamide to give compound 12, which is hydrolyzed in the presence of acidic methanol to give the hydrochloride salt compound 13.

[0203] Option 6

[0204]

[0205] Example

[0206] The invention will now be further described through the following working examples, which are preferred embodiments of the invention. Unless otherwise stated, all temperatures are in degrees Celsius (°C). These examples are illustrative and not limiting, and it should be understood that other embodiments may exist that fall within the spirit and scope of the invention as defined by the appended claims.

[0207] For ease of reference, the following abbreviations may be used in this article.

[0208] abbreviation

[0209]

[0210]

[0211] Example 1

[0212]

[0213] Toluene (0.26 kg), sulfolane (3.4 kg), compound 1 (1.0 kg), and POCl3 (2.7 kg) were added to 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 aged until the reaction was complete. The reactants were cooled to 5°C.

[0214] In a separating reactor, water (7.5 kg) was added and the mixture was cooled to 5°C. The reactants were slowly added to the aqueous solution, keeping the internal temperature below 5°C. The reactor was rinsed with additional water (0.5 kg) to facilitate transfer. The resulting mixture was stirred at 5°C for 3 hours and then extracted three times with MTBE (3 x 4.5 kg). The combined organic layers were washed sequentially with a buffered aqueous solution of pH 7 (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 reduced to approximately 3 L / kg. ACN (2 x 6.3 kg) was added, and the mixture was distilled again to approximately 3 L / kg. The crude product was cooled to 20°C to give compound 2 as a 30-36 wt% solution in 90-95% yield.

[0215] Example 2

[0216]

[0217] ACN (2.7 kg), lithium bromide (1.18 kg), and water (0.65 kg) were added to a glass-lined reactor at 25°C. A crude solution of compound 2 prepared above (limit reagent) was added, followed by DIPEA (1.82 kg). The resulting slurry was stirred at 25°C until the reaction was complete. The product was separated by filtration. The crude solid was washed with ACN (1.6 kg). The filter cake was dried under vacuum at 45°C. Compound 3 was separated, with an AP of 98 and a yield of 83%.

[0218] Example 3

[0219]

[0220] Water (6.0 kg, 6.0 L / kg) and compound 7 (1.0 kg) were added to a glass-lined reactor at 25°C. Zinc acetate dehydrate (1.08 kg, 1.0 equivalent) was added, followed by compound 3 (1.28 kg, 1.20 equivalent). The reactor line was 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 aged 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 aged for 30 min. The product was separated by filtration. The crude solid was washed sequentially 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 filter cake was dried under vacuum at 70°C. Compound 8 was separated, with an AP of 98 and a yield of 94%.

[0221] Example 4

[0222]

[0223] The separation glass-lined reactor was flushed 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)phosphono]ethyl]-2-(dicyclohexylphosphono)ferrocene (Josiphos SL-009-01) (14.1 g, 1.0 mol%) and palladium acetate (2.9 g, 0.5 mol%). The reactor line was flushed with toluene (0.43 kg, 0.5 L / kg). The resulting pre-formed catalyst solution was maintained under nitrogen until further use.

[0224] At 20°C, toluene (3.46 kg, 4.0 L / kg) and ACN (1.57 kg, 2.0 L / kg) were added to a nitrogen-filled glass-lined reactor. Compound 8 (1.00 kg) was added, followed by DBU (0.39 kg, 1.00 equivalent). The reactor line was flushed with toluene (0.43 kg, 0.5 L / kg). Compound 10 (0.54 kg, 2.5 equivalent) and K₂CO₃ (325 mesh grade, 0.70 kg, 2.0 equivalent) 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-formed catalyst solution was transferred to the reaction mixture, which was then heated to 75°C and stirred until the reaction was complete.

[0225] The crude reaction product was cooled to 20°C. Aqueous acetic acid (50 vol%, 4.0 kg, 4.0 L / kg) was slowly added over 1 h. Then glacial acetic acid (10.5 kg, 10.0 L / kg) was added. The resulting homogeneous solution was washed twice with heptane (2 × 3.42 kg, 2 × 5.0 L / kg). The bottom aqueous layer was collected and transferred to a clean reactor. Water (5.0 kg, 5.0 L / kg) was added, followed by seed crystals of compound 9 (0.01 kg, 1.0 wt%). The slurry was aged at 20°C for 2 h. Additional water (2.0 kg, 2.0 L / kg) was added, and the slurry was further aged for 6 h. The product was separated by filtration. The crude filter cake was washed with aqueous ACN (50 vol%, 4.5 kg, 5.0 L / kg), followed by the addition of ACN (3.9 kg, 5.0 L / kg). The filter cake was dried under vacuum at 65°C. Compound 9 was isolated with an AP of 98.5% and a yield of 84%.

[0226] Example 5

[0227] NMP (2.06 kg, 2.0 L / kg) and ACN (0.78 kg, 1.0 L / kg) were added to 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 aged until homogeneous. HOBt (20% wet) (0.17 kg, 0.5 equivalents) and then EDC HCl (0.54 kg, 1.4 equivalents) were added to the reaction mixture. The reactor was rinsed with ACN (0.78 kg, 1.0 L / kg), and the resulting mixture was aged at 65°C until the reaction was complete. The reaction 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 aged at 65°C for 1 h, then cooled to 0°C and aged at 0°C for another 12 h. The product was separated by filtration. The wet filter cake was washed with 2:1 water:ACN (2.8 kg, 3 L / kg), then with ACN (2.4 kg, 3 L / kg), and then dried at 65°C under complete vacuum. Compound I was separated with a purity >99.5% and a yield of 91%.

[0228] If necessary, the product can be optionally recrystallized as follows.

[0229] NMP (6.2 kg, 6.0 L / Kg) and Compound I (1.0 Kg) were added to a glass-lined reactor. The batch was heated to 70°C to form a pale yellow solution, which was then transferred through a polished filter to a clean container at 70°C. 2-Propanol (2.4 kg, 3 L / Kg) was added, followed by seed crystals of Compound I (0.005 Kg, 0.005 Kg / Kg). After aging for 1 h, additional 2-propanol (4.8 kg, 6 L / Kg) was added over 2 h (3 L / Kg / hr). The slurry was aged at 70°C for 1 h, slowly cooled to 0°C, and aged at 0°C for another 12 h. The product was separated by filtration. The wet filter cake was washed with 2-propanol (2 x 3.1 kg, 2 x 4 L / Kg) and then dried at 65°C under full vacuum. Compound I was separated with a purity >99.9% and a yield of 83%.

[0230] Example 6

[0231]

[0232] 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 aged for another 6 h. The crude product was distilled under vacuum until the total volume was reduced to approximately 0.5 L / kg. For azeotropic drying, five additions / distillations with 2-MeTHF (5 x 3.6 kg / kg) were performed. The crude product was cooled to 20°C. N-methyl-N-formylhydrazine was separated into an 89-90 wt% solution, in 89-91% yield.

[0233] Example 7

[0234]

[0235] 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-formylhydrazide (1.0 kg / kg, 2.30 equivalents), and THF (5.3 kg / kg, 6.0 L / kg) was slowly added. The reactor line was rinsed with THF (0.5 kg / kg). The crude reaction mixture was aged at 0°C until the reaction was complete. Water (5.0 kg / kg) was added, and the reaction mixture was aged at 0°C for 30 min, then heated to 40°C and aged for another 30 min. The layers were separated and the aqueous layer was discarded. The organic layer was washed with brine (15 wt%, 5.7 kg / kg) and then distilled under vacuum until the total volume was reduced to approximately 5 L / kg. For azeotropic drying, four additions / distillations with ethyl acetate (4 x 10 L / kg) were performed. The crude product was cooled to 20°C. Sulfuric acid (0.66 kg / kg, 1.10 equivalent) was added, and the slurry was stirred for 2–3 h. The product was separated by filtration. The filter cake was continuously washed with ethyl acetate (2 × 6.5 L / kg) and heptane (8 L / kg) and dried under vacuum at 45°C. Compound 5 was separated, with an AP of 99 and a yield of 83%. Example 8

[0236]

[0237] Concentrated sulfuric acid (4.5 kg / kg) and compound 5 (1.0 kg) were added to a glass-lined reactor at 0–5°C. Nitric acid (68 wt%, 0.35 kg / kg, 1.2 equivalents) was added dropwise. The mixture was stirred at 0–5°C until the reaction was complete.

[0238] In a separation reactor, water (12 kg / kg) and methanol (6.5 kg / kg, 8.3 L / kg) were mixed thoroughly at 20°C. The crude nitrated 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 h. The product was separated by filtration. The filter cake was washed with water (2 x 6 L / kg) and dried under vacuum at 45°C. Compound 6 was separated with an AP of 99 and a yield of 95%.

[0239] Example 9

[0240]

[0241] Methanol (8.0 kg / kg) and Compound 6 (1.0 kg) were added to a nitrogen-filled high-pressure reactor. Sodium bicarbonate (0.6 kg / kg, 2.0 equivalent) and Pd / C (10% loading, 50% wet, 0.02 kg / kg) were added after careful removal of oxygen. The reactor was pressurized with hydrogen (41–46 psi) and the reaction mixture was aged at 20°C for 6 h, then heated to 45°C and aged until the reaction was complete. The reactor was purged with nitrogen, and the crude product was filtered to remove Pd / C. Methanol (5 kg / kg) was used to assist in the transfer. The combined filtrates were 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 wt%, 9.0 kg / kg) was added, and the crude product was stirred at 70°C for 6 h. After cooling to 0°C, the crude product was further aged for 6 h. The product was separated by filtration. The filter cake was washed with brine (pre-cooled to 0°C, 25 wt%, 2.0 kg / kg) and dried under vacuum at 45°C. Compound 7 was separated with an AP of 99 and a yield of 88%.

[0242] Example 10

[0243]

[0244] Water (16.3 L / Kg) and sodium hydroxide (3.3 Kg, 3.0 equivalent) were added to a nitrogen-filled glass-lined reactor. The mixture was aged 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 equivalent) in THF (6.3 Kg, 7.1 L / Kg) was added over 2 h. The crude product was stirred at 0°C until the reaction was complete. The batch was warmed to 20°C. The layers were separated. The collected organic layer was diluted with MTBE (4.0 Kg, 5.4 L / Kg) and washed twice with brine (25 wt%, 4.0 Kg, then 12 Kg). The organic layer was distilled under vacuum until the total volume was reduced to approximately 10 L / Kg. For azeotropic drying, two additions / distillations with ACN (2 × 10 L / Kg) were performed. Cool the crude product to 20°C. Add ACN (10.0 kg, 12.8 L / kg) and NaN(CHO)₂ (3.3 kg, 1.2 equivalents). Heat the crude product to 65°C and stir until the reaction is complete. After cooling to 5°C, filter the mixture and wash the crude filter cake twice with ACN (2 × 2.5 kg, 2 × 3.2 L / kg). Distill the combined filtrates under vacuum until the total volume is approximately 3 L / kg. Cool the crude product to 20°C. o C. Compound 12 was isolated as an oily substance of 80-85 wt%, with a yield of 60-70%.

[0245] Example 11

[0246]

[0247] Compound 12 (1.0 kg) and methanol (3.9 kg, 5.0 L / kg) were added to a glass-lined reactor at 20°C. A solution of HCl 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 h to provide a slurry. The product was separated by filtration. The filter cake was washed with THF (3.7 kg, 4.1 L / kg) and dried under vacuum at 45°C. Compound 13 was separated, with a yield of 80%.

[0248] If desired, the product can be optionally recrystallized as follows: Add methanol (5.6 kg, 8.3 L / kg) and compound 13 (1.0 kg) to a glass-lined reactor. Slowly add DBU (0.1 kg). Stir the crude product for 1 h. Slowly add THF (12.4 kg, 13.9 L / kg) and age the resulting slurry for 2 h. Separate the product by filtration. Wash the filter cake with THF (2.6 kg, 2.9 L / kg) and dry under vacuum at 45°C. Separate compound 13, yield 60% (first batch). Distill the mother liquor under vacuum until the total volume is about 1 L / kg. Perform two additions / distillations with methanol (2 × 2.8 kg, 2 × 3.6 L / kg) to concentrate the solution back to about 1 L / kg. Cool the crude product to 20°C. Add THF (4.8 kg, 5.4 L / kg) and age the resulting slurry for 2 h. The product was separated by filtration. The filter cake was washed with THF (1.0 kg) and dried under vacuum at 45°C. Compound 13 was separated, yield 25% (second batch).

Claims

1. A method for preparing compound 13 of the following formula or a salt thereof. It includes a) The following formula contains d4-methanol Reaction with an activating agent to provide compound 11a of the following formula: Compound 11a Where X4 is independently a halogen or a sulfonate ester. b) It is then reacted with sodium dimethamide to provide compound 12 of the following formula. Compound 12 c) It is then hydrolyzed to provide compound 13.

2. A method for preparing compound 13 of the following formula Compound 13 It includes a) The following formula contains d4-methanol It reacts with p-toluenesulfonyl chloride in the presence of aqueous sodium hydroxide to provide compound 11 of the following formula: Compound 11 b) It is then reacted with sodium dimethamide to provide compound 12 of the following formula. Compound 12 c) It is then hydrolyzed in methanol in the presence of hydrochloric acid to provide the hydrochloride salt of compound 13 of the following formula. Compound 13.

3. A compound, said compound being selected from... and , And salts of any of the foregoing and hydrates of any of the foregoing.

4. The compound according to claim 3, wherein the compound is Or its salts or hydrates.

5. The compound according to claim 3, wherein the compound is Or its salts or hydrates.

6. The compound according to claim 3, wherein the compound is 。 7. The compound according to claim 3, wherein the compound is 。 8. A hydrate of a compound, wherein the compound is selected from the group consisting of: and .

9. A hydrate of a compound, wherein the compound is selected from the group consisting of: and .

10. A compound, said compound being: Or its H2SO4 salt or HCl salt.

11. Compound I of the following formula It is prepared by a method including the following steps: a) Compound 1a of the following formula Compound 1a Where R is a C1-C6 alkyl or aryl group; Reaction with an activating agent to provide compound 2a of the following formula, Compound 2a Where X1 and X2 are independently halogens or sulfonates; and R is as defined above. b) Compound 2a is then reacted with an aqueous base to provide compound 3a of the following formula. Compound 3a Where M is H, Li, Na, K, Cs, Ca, Mg, or Zn, and X1 and X2 are as defined above. c) Combine compound 3a with compound 7 of the following formula Compound 7 The reaction is carried out in a suitable solvent and in the presence of an acid, a base or a metal salt to provide compound 8a of the following formula. Compound 8a M and X2 are defined as above. d) Compound 8a is mixed with compound 10 of the following formula. Compound 10 The reaction is carried out in the presence of a suitable transition metal catalyst, ligand, one or more bases, and one or more suitable solvents to provide compound 9a of the following formula. Compound 9a Where M is defined above. e) Reacting compound 9a with compound 13 of the following formula or its free base or salt in the presence of one or more suitable activators, one or more suitable solvents and a base to provide compound I. Compound 13.

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