RU2820241C2 - Chemical method - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a compound of formula (1) or a salt thereof. Method comprises a step of reacting a compound of formula (2) or a salt thereof and a compound of formula (3) with an alkali metal salt or an alkali salt in the presence of a catalyst based on a complex with a metal to obtain a compound of formula (4) or a salt thereof. Alkali metal salt is K₂CO₃ and catalyst based on complex with metal is (dtbpf)PdCl₂. Then one performs a step of reacting a compound of formula (4) or a salt thereof with a compound of formula (5) to obtain a compound of formula (6) or a salt thereof, and a step of compounding formula (6) with HCl to obtain a compound of formula (1) or a salt thereof. Invention also relates to a embodiment of said method.

EFFECT: disclosed method enables to obtain a compound of formula (1) with higher output and higher purity with fewer by-products and with lower catalyst load.

2 cl, 4 ex

Description

Field of technology to which the invention relates

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

Prerequisites for creating an invention

The compound which is N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-5-yl)pyridin-3-carboxamide, also called herein by a compound of formula (1),

(1),

is an inhibitor of the tyrosine kinase BCR-ABL (chimeric protein of the cluster region of Abelson's point break). WO 2013/171639 A1 discloses compounds of formula (1) useful for the treatment of diseases that respond to inhibition of the enzymatic activity of Abelson protein tyrosine kinase (ABL1), Abelson gene-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 .

The compound of formula (1), the preparation of the compound of formula (1) and pharmaceutical compositions of the compound of formula (1) are originally described in WO 2013/171639 A1 as example 9.

However, there remains a need to provide improved methods for preparing the compound of formula (1) that are more cost-effective, safer and more suitable for full-scale industrial production.

Description of the invention

The present invention is directed to improved synthesis of the compound of formula (1) and its purification using less noxious chemicals and/or reaction conditions, generating less waste, and providing a reproducible process that is easier to implement on an industrial scale. The present invention is also directed to more efficient means of producing a compound of formula (1) in higher yield and purity, which produces fewer by-products, and which requires lower catalyst loading compared to processes disclosed in the prior art.

In this regard, the present invention is presented in the following aspects.

According to a first aspect of the present invention, there is provided a process for preparing a compound of formula (1),

(1),

or a salt, solvate, stereoisomer, complex, co-crystal, ester or oxazoline derivative thereof,

comprising the step of carrying out the reaction of a compound of formula (2),

(2),

or a salt, solvate, stereoisomer, complex, co-crystal, ester or oxazoline derivative thereof;

and compounds of formula (3),

(3),

or pinacol 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-boronic acid ester with an alkali metal salt or an alkali salt in the presence of a metal complex catalyst to produce a compound of formula (1) or its salt, solvate, stereoisomer, complex, co-crystal, ester or oxazoline derivative, preferably to give the compound of formula (1) in its free carboxylic acid form.

In this method, according to the first aspect, the metal complex catalyst may be a metal precursor and a ligand or a preformed metal complex catalyst containing metal M and a ligand.

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

The metal precursor may be selected from M(OAc) ₂ , M ₂ (dba) ₃ , [M(C ₃ H ₅ )Cl] ₂ (allyl metal chloride dimer), M(TFA) ₂ , M(MeCN) ₂ Cl ₂ , MCl ₂ , [(cinnamyl)MCl] ₂ , [MCl] ₂ (metal chloride) and M(acac) ₂ . Preferably, the metal-based precursor is [MCl] ₂ (metal chloride).

The ligand may be selected from Cy ₃ P, (2-MeOPh) ₃ P, P(tBu) ₂ -n-PrSO ₂ H, 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.

The preformed metal complex catalyst may consist of the metal _ligands listed above or may be selected from [(o-tol) _3P ] _2PdCl2 , [t- _Bu3PPdBr ] ₂ /Pd-113, (dtbpf)PdCl ₂ /Pd-118, PEPPSI, PdCl ₂ (PPh ₃ ) ₂ , Pd(tBu ₂ PhP) ₂ , Pd(dppf)Cl ₂ CH ₂ Cl ₂ , [(t-Bu) ₃ P]Pd (0), CataCXium C, Pd(tBu ₂ PhP) ₂ (Pd-122), Pd(dppf)Cl ₂ CH ₂ Cl ₂ (Pd-106), (2-MeOPh) ₃ P/ Pd ₂ (dba) ₃ and PdCl ₂ (Amphos) ₂ /Pd-132. Preferably, the preformed metal complex catalyst is selected from (dtbpf)PdCl ₂ (Pd-118), Pd(tBu ₂ PhP) ₂ (Pd-122), Pd(dppf)Cl ₂ CH ₂ Cl ₂ (Pd-106 ) and (2-MeOPh) ₃ P/Pd ₂ (dba) ₃ .

The alkali metal salt or alkali salt may be selected from Na ₂ CO ₃ , Cs ₂ CO ₃ , K ₃ PO ₄ , KF and K ₂ CO ₃ . Preferably the alkali salt is K ₂ CO ₃ .

WO 2013/171639 A1, example 9, describes a similar method in step 9.5, according to which a preformed catalyst based on a metal complex Pd(PPh ₃ ) ₂ Cl ₂ and an alkali salt K ₃ PO ₄ in toluene is used to obtain an intermediate a compound which is 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 materials and required additional amounts of the compound of formula (3) and K ₃ PO ₄ to complete the reaction, making it therefore unsuitable for large scale preparing a compound of formula (1).

The reaction provided herein provides high conversion [greater than 98% conversion of the compound of formula (1)] and high purity [greater than 96% purity measured as an in-process control (IPC)]. The compound of formula (1) is obtained in high yield (more than 80%).

The advantage of this method compared to methods from the prior art is that it reduces the amount of by-products formed and the catalyst loading required for a more complete conversion of the starting materials. Therefore, the method of the present invention is suitable for scale-up for industrial production purposes.

According to a second aspect of the present invention, there is provided a method according to the first aspect, further comprising the step of reacting a compound of formula (4),

(4),

or a salt, solvate, stereoisomer, complex, co-crystal, ester or oxazoline derivative thereof, preferably the compound of formula (4) is in its free methyl ester form; with a compound of formula (5),

(5),

to obtain a compound of formula (6),

(6),

or a salt, solvate, stereoisomer, complex, co-crystal, ester or oxazoline derivative thereof, preferably the compound of formula (6) is in its free carboxylic acid form.

WO 2013/171639 A1, example 9, describes a similar method in an alternative step 9.1, which consists of 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 HOBt·H ₂ O and EDCI·HCl in THF. However, it was found that 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinic the acid is difficult to crystallize, extract, and ensure its constant release from the reaction. The synthesis also resulted in difficult-to-eliminate impurities that negatively affected yield.

The advantage of the method disclosed herein over the prior art method is that it avoids the problems associated with 6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1- (tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinic acid, and provides a constant yield of the compound of formula (6). Therefore, the method of the present invention is suitable for scale-up for industrial production purposes.

Examples

Example 1. Stage D2+D3 -> D4

Basic procedure

A mixture of (R)-methyl 5-bromo-6-(3-hydroxypyrrolidin-1-yl)nicotinate (45.6 kg, D2), 1-1-(tetrahydro-2H-pyran-2-yl) was added to a dry vessel. -1H-pyrazole-5-boronic acid, pinacol ester (50.5 kg, D3), and K ₂ CO ₃ (41.8 kg) in toluene (282 ml). The suspension was stirred and water was added. PdCl ₂ (dtbpf) (500 g) was added and the suspension was stirred at approximately 50°C until complete conversion was achieved. After completion of the reaction, QuadraSil MP was added to the reaction mixture. Solid residues were removed by filtration through an activated carbon filter and the filter cake was washed with toluene, drinking water and toluene again. 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 using [Na ₂ SO ₄ ] and evaporated in situ to give methyl-6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H -pyran-2-yl)-1H-pyrazol-5-yl)nicotinate (D4). The D4 yield was estimated to be approximately 54 kg D4/kg D2 (~95%).

Example 2. Stage D4+D5 -> D6

To an empty vessel, sodium hydroxide solution (15.8 kg) and water were 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 approximately 25°C. The two-phase mixture was separated and the organic phase was washed twice with water. The organic phase was concentrated by distillation followed by the addition of fresh methyltetrahydrofuran (2 x 148 kg) to obtain a concentrated solution of 4-(chlorodifluoromethoxy)aniline in methyltetrahydrofuran.

In a 10-20% solution, 660 kg of methyl-6-((R)-3-hydroxypyrrolidin-1-yl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl )nicotinate (D4) in toluene, methyltetrahydrofuran (239 kg) was added and the solution was concentrated by distillation. To this concentrated solution was added 148 kg of a concentrated solution of D5 in methyltetrahydrofuran. A 20% solution of potassium tert-butoxide (258 kg) in tetrahydrofuran (169 kg) was dosed into the resulting mixture at approximately 25°C. After completion of the reaction, aqueous sodium chloride (602 kg) was added and the two-phase mixture was separated. The organic phase was extracted with aqueous sodium chloride (602 kg). The organic layer was filtered through an activated carbon filter. The solvent was changed by distillation from methyltetrahydrofuran to isopropanol. 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) followed by n-heptane (1274 kg). D6 was collected by filtration, washed with a mixture of n-heptane and isopropanol and dried in vacuum. The yield of D6 was estimated to be approximately 79-87% D6, depending on the amount of D3 loaded.

Example 3. Stage D6 -> A1

Into 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). The clear solution was then stirred for 1 hour at 22°C (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 adding 30% NaOH. The solution was filtered through an activated carbon filter and then the pH was adjusted to 3.0-3.5 by adding a further 30% sodium hydroxide, followed by the addition of seed N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidine-1 -yl)-5-(1H-pyrazol-5-yl)nicotinamide (0.027 kg, A1). Final pH adjustment to 7.5-9.0 was accomplished by adding approx. 1% sodium hydroxide solution, causing the product to precipitate. The suspension was cooled to 10°C and stirred, after which 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 approximately 76%.

Example 4. A1 -> A1a

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) was heated ) and 37% hydrochloric acid (7 kg) to approximately 50°C and the resulting solution was filtered. First portion of TBME tert-butyl methyl ether (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) was added to the filtrate at approximately 50°C. A second portion of TBME (271 kg) was added and the suspension was cooled to approximately 0°C and stirred to ensure completion of crystallization. A1a was collected by filtration, washed with a mixture of TBME (78 kg) and methanol (9 kg) and dried in vacuum. The yield of A1a was estimated to be approximately 96%.

Claims (30)

1. Method for preparing the compound of formula (1) (1) or its salts, comprising the step of carrying out the reaction of a compound of formula (2) (2) or its salts and compounds of formula (3) (3) with an alkali metal salt or an alkali salt in the presence of a metal complex catalyst to obtain a compound of formula (4) or a salt thereof, wherein the alkali metal salt is K ₂ CO ₃ and the metal complex catalyst is (dtbpf)PdCl ₂ ; step of carrying out the reaction of a compound of formula (4) (4) or a salt thereof with a compound of formula (5) to obtain a compound of formula (6) (6) or its salts; And the step of combining a compound of formula (6) with HCl to obtain a compound of formula (1) or a salt thereof. 2. Method for preparing the compound of formula (1) (1), comprising the step of carrying out the reaction of a compound of formula (2) (2) or its salts and compounds of formula (3) (3) with an alkali metal salt or an alkali salt in the presence of a metal complex catalyst to obtain a compound of formula (4) or a salt thereof, wherein the alkali metal salt is K ₂ CO ₃ and the metal complex catalyst is (dtbpf)PdCl ₂ ; step of carrying out the reaction of a compound of formula (4) (4) or a salt thereof with a compound of formula (5) to obtain a compound of formula (6) (6).