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KR-102964142-B1 - Method for preparing 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide

KR102964142B1KR 102964142 B1KR102964142 B1KR 102964142B1KR-102964142-B1

Abstract

The present invention relates to a method for producing 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (Compound I) in large quantities exceeding 1 kg. The method provides a final product with good yield and at least 95% purity, and provides a controllable and safe reaction.

Inventors

  • 천 샹양

Assignees

  • 베이징 이노케어 파마 테크 씨오., 엘티디.

Dates

Publication Date
20260512
Application Date
20200224
Priority Date
20190225

Claims (7)

  1. A method for preparing 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (Compound I), comprising the following steps: (a) a step of obtaining INB by heating a mixture of INA, SMC and the first palladium-containing catalyst at 60-140°C, [During the meal, PG (protecting group) is tert-butyloxycarbonyl]; (b) a step of obtaining INC by hydrogenating INB under H2 in the presence of a second palladium-containing catalyst; (c) a step of deprotecting INC by adding HCl gas and obtaining IND-HCl salt in solid form; and (d) a step of reacting the IND-HCl salt with acryloyl chloride or 3-chloropropanoyl chloride under basic conditions to obtain 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide; .
  2. In claim 1, 2,6-dichloronicotinamide in a basic solvent or solvent mixture A manufacturing method further comprising the step of preparing INA by heating a mixture of (SMA), SMB, and a palladium-containing catalyst at 60-140°C for 8-12 hours: .
  3. A method for manufacturing according to claim 2, further comprising the step of reacting 2,6-dichloronicotinic acid with oxalyl chloride (COCl) 2 , and then reacting it with aqueous ammonia in an organic solvent to obtain SMA.
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Description

Method for preparing 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide The present invention relates to a method for preparing 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide. 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (Compound I) is a substituted nicotinamide inhibitor of Bruton's tyrosine kinase (BTK). Compound I is useful for treating cancer, inflammation, and autoimmune diseases (WO2015/028662). WO2015/028662 discloses a method for preparing about 50 g of Compound I. In particular, there is a need for an efficient and purity-controlled method to produce Compound I on a large scale exceeding 1 kg. The present invention relates to a method for producing 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide (Compound I) with high purity and good yield. The method is suitable for large-scale production (greater than 1 kg, preferably greater than 2 kg, greater than 4 kg, or greater than 10 kg). The method provides a purity of Compound I of ≥ 90%, or ≥ 95%, or ≥ 98%, or ≥ 99%. In Embodiment 1 A, Compound I is prepared from 6-chloro-2-(4-phenoxyphenyl)nicotinamide (INA), and the method uses tert-butyloxycarbonyl (t-Boc) as a protecting group. The method comprises the following steps: (a) a step of obtaining INB by heating a mixture of INA, SMC and the first palladium-containing catalyst at 60-140°C, [In the formula, PG is the protecting group of tert-butyloxycarbonyl]; (b) a step of obtaining INC by hydrogenating INB under H2 in the presence of a second palladium-containing catalyst; (c) a step of deprotecting INC with a solution containing HCl to obtain an IND-HCl salt in solid form; (d) a step of reacting the IND-HCl salt with acryloyl chloride or 3-chloropropanoyl chloride under basic conditions to obtain 6-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)nicotinamide. In step (a), 6-chloro-2-(4-phenoxyphenyl)nicotinamide (INA), tert -butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (SMC) and a suitable palladium-containing catalyst are reacted in a nitrogen-under reactor in a mixture of basic aqueous organic solvents with a low oxygen content (< 2%) to obtain crude tert -butyl 5-carbamoyl-6-(4-phenoxyphenyl)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate (INB). The reaction mixture is at 60-140°C, preferably 60-100°C, more preferably 75-85°C. The reaction time is typically 1-4 hours. The Pd loading (molar ratio of Pd catalyst to reactant INA) is 0.5-5%. Higher Pd loading increases the reaction rate but also increases costs and impurities. Unpurified INB can be further purified to at least 90% purity without column chromatography, for example, by recrystallization and/or pulverization in tetrahydrofuran and ethyl acetate. Suitable palladium-containing catalysts used in the present application include organic palladium compounds such as tris(dibenzylideneacetone)dipalladium(0) (Pd 2 (dba) 3 ), tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh 3 ) 2Cl 2 ), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl 2 ), and inorganic palladium compounds including various ligands, such as Ph 3P , Ph 2Cy , and Cy 3P -HBF 4 . In step (b), the organic solution of INB is hydrogenated in a hydrogenated reactor with a suitable palladium-containing catalyst to obtain crude tert- butyl 4-(5-carbamoyl-6-(4-phenoxyphenyl)pyridine-2-yl)piperidine-1-carboxylate (INC). The reaction temperature is 15-50°C, preferably 20-45°C. The reaction time is typically 2-10 hours. The palladium-containing catalyst may be Pd/C or Pd(OH) 2 /C, preferably Pd(OH) 2 /C (more process-friendly). In step (c), HCl gas or a solution of HCl is added to an organic solution containing INC and stirred at 10-40°C for 4-9 hours, so that the protecting group (t-Boc) is removed and the 2-(4-phenoxyphenyl)-6-(piperidin-4-yl)nicotinamide (IND)-HCl salt is formed in solid form. The IND-HCl precipitates from the reaction medium and can be easily collected by filtration or centrifugation (suitable for large-scale production). In one embodiment, HCl gas is bubbled into a solution of INC. In another embodiment, an organic solution of HCl (e.g., HCl in ethanol or ethyl acetate) is added to an organic solution of INC (e.g., INC in dichloromethane or ethanol), or an organic solution of INC is added to an organic solution of HCl. The IND-HCl solid can be powdered in ethyl acetate to a purity of at least 90%, preferably at least 95%. In step (d), the IND-HCl salt is reacted with acryloyl chloride in a basic solution (pH 8-14 , e.g., bicarbonate solution HCO3- , carbonate solution CO3-2 , phosphate solution PO4-3 , and hydroxyl solution OH- ) at a low temperature ( 0-8 °C or 2-6° C ) to reduce impurity formation and obtain compound I. The solvent of the solution may be an organic solvent (e.g., THF or dichloromethane) in the presence or absence of water. The reaction time is typically 1-5 hours or 1-3 hours. Altern