Chemical Process

Abstract

The present invention provides a novel chemical process for the synthesis of the compound N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide.

Description

[Technical field]

[0001] The present invention relates to a novel chemical process for the synthesis of the compound N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide. [Background technology]

[0002] In the present specification, the formula (1) [ka] The compound N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridine-3-carboxamide, also referred to as the compound of formula (1), is a BCR-ABL (breakpoint cluster region-Abelson chimeric protein) tyrosine kinase inhibitor. WO 2013 / 171639 A1 provides compounds of formula (1) as being useful for treating diseases that respond to inhibition of the tyrosine kinase enzyme activity of Abelson protein (ABL1), Abelson-related protein (ABL2) and related chimeric proteins, in particular BCR-ABL1. The compound of formula (1) is also known as (R)-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide or asciminib.

[0003] The compound of formula (1), the preparation of the compound of formula (1) and pharmaceutical compositions of the compound of formula (1) were first described as Example 9 in WO 2013 / 171639 A1. Summary of the Invention [Problem to be solved by the invention]

[0004] Nonetheless, there remains a need to provide improved processes for the preparation of compounds of formula (1) that are economically more efficient, safer and better suited to full-size production scale. [Means for solving the problem]

[0005] The present invention relates to an improved synthesis of the compound of formula (1) and its purification, which provides a reproducible process that uses less hazardous chemicals and / or reaction conditions, generates less waste, and is easier to handle on a production scale. The present invention also relates to a more efficient means to produce the compound of formula (1) in higher yields and higher purity, generates fewer by-products, and requires lower catalyst loadings compared to methods disclosed in the prior art. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0006] In this regard, the present invention is provided in the following aspects.

[0007] According to a first aspect of the present invention, a compound represented by formula (1) [ka] or a salt, solvate, stereoisomer, complex, co-crystal, ester or oxazoline thereof, comprising the steps of: [ka] or a salt, solvate, stereoisomer, complex, cocrystal, ester or oxazoline thereof, and a compound of formula (3) [ka] reacting a compound of formula (1) or a salt, solvate, stereoisomer, complex, co-crystal, ester or oxazoline thereof, preferably to obtain the compound of formula (1) in its free carboxylic acid form.

[0008] In the present process, according to a first embodiment, the metal complex catalyst may be a preformed metal complex catalyst comprising a metal precursor and a ligand or a metal M and a ligand.

[0009] The metal M may be selected from Cu (copper) and Pd (palladium). Preferably, the metal M is Pd.

[0010] The metal precursor may be selected from M(OAc)2, M2(dba)3, [M(C3H5)Cl]2 (allyl metal chloride dimer), M(TFA)2, M(MeCN)2Cl2, MCl2, [(cinnamyl)MCl]2, [MCl]2 (metal chloride) and M(acac)2. Preferably, the metal precursor is [MCl]2 (metal chloride).

[0011] The ligand may be selected from Cy3P, (2-MeOPh)3P, P(tBu)2-n-PrSO2H, Q-phos (1,2,3,4,5-pentaphenyl-1'-(di-tert-butylphosphino)ferrocene), CataCXium ABn (di(1-adamantyl)benzylphosphine), CataCXium A (di(1-adamantyl)-n-butylphosphine) and S-Phos (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl). Preferably, the ligand is S-Phos.

[0012] The preformed metal complex catalyst may be composed of the metal as a ligand as defined above or is selected from [(o-tol)3P]2PdCl2, [t-Bu3PPdBr]2 / Pd-113, (dtbpf)PdCl2 / Pd-118, PEPPSI, PdCl2(PPh3)2, Pd(tBu2PhP)2, Pd(dppf)Cl2·CH2Cl2, [(t-Bu)3P]Pd(0), CataCXium C, Pd(tBu2PhP)2(Pd-122), Pd(dppf)Cl2·CH2Cl2(Pd-106), (2-MeOPh)3P / Pd2(dba)3 and PdCl2(Amphos)2 / Pd-132. Preferably, the preformed metal complex catalyst is selected from (dtbpf)PdCl2(Pd-118), Pd(tBu2PhP)2(Pd-122), Pd(dppf)Cl2·CH2Cl2(Pd-106) and (2-MeOPh)3P / Pd2(dba)3.

[0013] Alkali or alkaline salts are Na2CO3, C s The alkali salt may be selected from K2CO3, K3PO4, KF and K2CO3. Preferably, the alkali salt is K2CO3.

[0014] Example 9 of WO 2013 / 171639 A1 describes a similar process in stage 9.5, in which a preformed metal complex catalyst Pd(PPh3)2Cl2 and an alkali salt K3PO4 in toluene are used to obtain the intermediate methyl 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinate. However, when scaled up to 3 kg, the synthesis resulted in incomplete conversion of the starting material, and additional amounts of the compound of formula (3) and K3PO4 were required to complete the reaction, making it unsuitable for large-scale production of the compound of formula (1).

[0015] The reaction provided herein provided high conversion [>98% conversion to the compound of formula (1)] and high purity [>96% purity measured as in-process control (IPC)]. The compound of formula (1) was obtained in high yield (>80%).

[0016] The advantage of the present process over prior art processes is the reduced by-products produced and the catalyst loading required for more complete conversion of the starting materials, and therefore the process of the present invention is suitable for scale-up for commercial production purposes.

[0017] According to a second aspect of the present invention, a compound represented by formula (4) [ka] or a salt, solvate, stereoisomer, complex, co-crystal, ester or oxazoline thereof (preferably, the compound of formula (4) is in its free methyl ester form) with a compound of formula (5) [ka] to react with a compound of formula (6) [ka] or a salt, solvate, stereoisomer, complex, co-crystal, ester or oxazoline thereof (preferably, the compound of formula (6) is in its free carboxylic acid form).

[0018] Example 9 of WO 2013 / 171639 A1 describes a similar process in alternative stage 9.1 by replacing the compound of formula (4) with 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinic acid in NMM and combining with HOBt·H2O and EDCI·HCl in THF. However, 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinic acid was found to be difficult to crystallize, extract and give consistent yields from the reaction. The synthesis also resulted in problematic impurities that were difficult to remove and negatively affected the yield.

[0019] The advantage of the process disclosed herein over the prior art processes is that it avoids the problems seen with 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinic acid and provides a consistent yield of the compound of formula (6). Thus, the process of the present invention is suitable for scale-up for commercial production purposes. EXAMPLES

[0020] Example 1: Step D2+D3→D4 [ka] Basic steps: A mixture of (R)-methyl 5-bromo-6-(3-hydroxypyrrolidin-1-yl)nicotinate (45.6 kg, D2), 1-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid, pinacol ester (50.5 kg, D3) and K2CO3 (41.8 kg) in toluene (282 mL) was added to a dry vessel. The suspension was stirred and water was added. PdCl2(dtbpf) (500 g) was added and the suspension was stirred at about 50° C. until complete conversion was achieved. Once the reaction was complete, QuadraSil MP was added to the reaction mixture. The solid residue was removed by filtration through an activated charcoal filter and the filter residue was washed with toluene, drinking water and again with toluene. The organic and aqueous phases were separated and the aqueous layer was washed with toluene. The combined organic layers were washed with sodium chloride solution, dried with [Na2SO4] and evaporated in situ to provide methyl 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinate (D4). The yield of D4 was estimated to be about 54 kg D4 / kg D2 (about 95%).

[0021] Example 2: Step D4+D5→D6 [ka] To an empty vessel, a solution of sodium hydroxide (15.8 kg) and water was added to a mixture of 31.6 kg of 4-(chlorodifluoromethoxy)aniline HCl (D5) in methyltetrahydrofuran (344 kg) and the reaction mixture was stirred at about 25° C. The biphasic mixture was separated and the organic phase was washed twice with water. The organic phase was concentrated by distillation and then fresh methyltetrahydrofuran (2×148 kg) was added to obtain a concentrated solution of 4-(chlorodifluoromethoxy)aniline in methyltetrahydrofuran.

[0022] To a 10-20% toluene solution of 660 kg of methyl 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinate (D4), methyltetrahydrofuran (239 kg) was added and the solution was concentrated by distillation. To this concentrated solution, 148 kg of a concentrated solution of D5 in methyltetrahydrofuran was added. To the resulting mixture, 20% potassium tert-butoxide (258 kg) in tetrahydrofuran (169 kg) was dosed at about 25 °C. Once the reaction was complete, aqueous sodium chloride solution (602 kg) was added and the biphasic mixture was separated. The organic phase was extracted with aqueous sodium chloride (602 kg). The organic layer was filtered through an activated charcoal filter. The solvent was exchanged from methyltetrahydrofuran to isopropanol by distillation. Seed crystals of N-(4-(chlorodifluoromethoxy)phenyl)-6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (0.16 kg, D6) were added to the solution, followed by n-heptane (1274 kg). D6 was collected by filtration, washed with a mixture of n-heptane and isopropanol, and dried under vacuum. The yield of D6 was estimated to be about 79-87% D6 based on the amount of D3 charged.

[0023] Example 3: Step D6 → A1 [ka] To a suspension of N-(4-(chlorodifluoromethoxy)phenyl)-6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (39.1 kg, D6) in methanol (346 kg) was added 37% HCl solution (9 kg) at 22 °C (pH < 1). This clear solution was then stirred at 22 °C for 1 h (IPC). The mixture was then quenched with 30% NaOH (4 kg) (pH = 10). Water was added to the mixture and the pH was adjusted to 2.5-3.0 by addition of 30% NaOH. The solution was filtered through an activated charcoal filter and then the pH was adjusted to 3.0-3.5 by the addition of an additional 30% sodium hydroxide, followed by seeding with N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide (0.027 kg, A1). A final pH adjustment to pH 7.5-9.0 was performed by the addition of about 1% sodium hydroxide solution, resulting in precipitation of the product. The suspension was cooled to 10° C., stirred, and the product A1 was isolated by filtration, washed with a 4:1 mixture of water / methanol, and dried. The yield of A1 was estimated to be about 76%.

[0024] Example 4: A1→A1a [ka] A mixture of N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide (29.2 kg, A1), methanol (190 kg) and 37% hydrochloric acid (7 kg) was heated to about 50° C. and the resulting solution was filtered. A first portion of t-butyl methyl ether TBME (146 kg) and seed crystals of N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)-5-(1H-pyrazol-5-yl)nicotinamide hydrochloride (0.26 kg, A1a) were added to the filtrate at about 50° C. A second portion of TBME (271 kg) was added and the suspension was cooled to about 0° C. and stirred to complete the crystallization. A1a was collected by filtration, washed with a mixture of TBME (78 kg) and methanol (9 kg) and dried under vacuum. The yield of A1a was estimated to be about 96%.

Claims

[Claim 1] Formula (1) 【Chemistry 1】 or a salt thereof, comprising the steps of: 【Chemistry 2】 or a salt thereof, and a compound of formula (3) 【Chemistry 3】 with an alkali or an alkali salt in the presence of a metal complex catalyst to obtain the compound of formula (1) or a salt thereof, wherein the alkali salt is K 2 CO 3 and the metal complex catalyst is (dtbpf)PdCl 2 ; Formula (4) 【Chemistry 4】 or a salt thereof, 【Chemistry 5】 The process further comprises reacting the compound of formula (I) with a compound of formula (I).

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