Process for preparing of bortezomibThe present invention provides improved processes for the preparation of Bortezomib, tert-butyl[1-({(1S)-3-methyl-1-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-1-oxo-3-phenylpropan-2-yl]carbamate of formula (IV) and N-{(1S)-3-methyl-1-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6- methano-1,3,2-benzodioxaborol-2-yl]butyl} phenylalanine of formula (V). Compound (IV) is prepared by coupling (1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethyl- hexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butan-1-amine of formula (II) or its salt with N-(tert-butoxycarbonyl)-L-phenylalanine of formula (III) in a first solvent in the presence of a first coupling agent and a first base, wherein the coupling process does not comprise solvent exchange. Compound (V) is prepared by deprotecting compound (IV) using an alcoholic solution of an inorganic acid.1., for the preparation of a method for Velcade, described method comprises:A) in the first solvent, (1R)-3-methyl isophthalic acid-[(3aS, 4S, 6S, 7aR)-3a, 5,5-trimethylammonium six hydrogen-4,6-first bridge-1,3,2-benzo dioxy borine-2-base] fourth-1-amine or its salt of formula (II) is madeWith N-(the tertbutyloxycarbonyl)-L-Phe of formula (III)Coupling is carried out under the existence of the first coupling agent and the first alkali, to obtain [1-({ (1S)-3-methyl isophthalic acid-[(3aS of formula (IV), 4S, 6S, 7aS)-3a, 5,5-trimethylammonium six hydrogen-4,6-first bridge-1,3,2-benzo dioxy borine-2-base] butyl } amino)-1-oxo-3-phenyl third-2-base] t-butyl carbamate;B) use the alcoholic solution of mineral acid by [1-({ (1S)-3-methyl isophthalic acid-[(3aS of formula (IV), 4S, 6S, 7aS)-3a, 5,5-trimethylammonium six hydrogen-4,6-first bridge-1,3,2-benzo dioxy borine-2-base] butyl } amino)-1-oxo-3-phenyl third-2-base] t-butyl carbamate goes protection, to obtain N-{ (1S)-the 3-methyl isophthalic acid-[(3aS of formula (V), 4S, 6S, 7aS)-3a, 5,5-trimethylammonium six hydrogen-4,6-first bridge-1,3,2-benzo dioxy borine-2-base] butyl } phenylalanine or its salt;C) in the second solvent, the pyrazine-2-carboxylic acid of compound (V) or its salt and formula (VI) is madeCoupling is carried out under the existence of the second coupling agent and the second alkali, to obtain N-{ (1R)-the 3-methyl isophthalic acid-[(3aS of formula (VII), 4S, 6S, 7aS)-3a, 5,5-trimethylammonium six hydrogen-4,6-first bridge-1,3,2-benzo dioxy borine-2-base] butyl }-N α-(pyrazine-2-base carbonyl)-L-amphetamine acid amides; AndD) compound of formula (VII) is made to go protection, to obtain Velcade or its acid anhydrides.
보르테조밉을 제조하기 위한 방법본 발명은 보르테조밉, 식 (IV)의 터트-부틸[1-({(1S)-3-메틸-1-[(3aS,4S,6S,7aS)-3a,5,5-트리메틸헥사히드로-4,6-메타노-1,3,2-벤조디옥사보롤-2-일]부틸}아미노)-1-옥소-3-페닐프로판-2-일]카르바메이트 및 식 (V)의 N-{(1S)-3-메틸-1-[(3aS,4S,6S,7aS)-3a,5,5-트리메틸헥사히드로-4,6-메타노-1,3,2-벤조디옥사보롤-2-일]부틸} 페닐알라닌을 제조하는 개선된 방법을 제공한다. 화합물 (IV)는 식 (II)의 (1R)-3-메틸-1-[(3aS,4S,6S,7aR)-3a,5,5-트리메틸-헥사히드로-4,6-메타노-1,3,2-벤조디옥사보롤-2-일]부탄-1-아민 또는 그의 염을 제1 커플링제 및 제1 염기의 존재하에 제1 용매 중 식 (III)의 N-(터트-부톡시카르보닐)-L-페닐알라닌과 커플링하여 제조되고, 상기 커플링 방법은 용매 교환을 포함하지 않는다. 화합물 (V)는 무기산의 알콜 용액을 사용하여 화합물 (IV)를 탈보호하여 제조된다.보르테조밉의 제조방법으로서, 상기 방법은 a) 식 (II)의 (1R)-3-메틸-1-[(3aS,4S,6S,7aR)-3a,5,5-트리메틸헥사히드로-4,6-메타노-1,3,2-벤조디옥사보롤-2-일]부탄-1-아민 또는 그의 염을 [이미지]제1 커플링제 및 제1 염기의 존재하에 제1 용매 중 식 (III)의 N-(터트-부톡시카르보닐)-L-페닐알라닌과 커플링하여 [이미지]식 (IV)의 터트-부틸[1-({(1S)-3-메틸-1-[(3aS,4S,6S,7aS)-3a,5,5-트리메틸헥사히드로-4,6-메타노-1,3,2-벤조디옥사보롤-2-일]부틸}아미노)-1-옥소-3-페닐프로판-2-일]카르바메이트를 수득하는 단계; [이미지]b) 식 (IV)의 터트-부틸[1-({(1S)-3-메틸-1-[(3aS,4S,6S,7aS)-3a,5,5-트리메틸헥사히드로-4,6-메타노-1,3,2-벤조디옥사보롤-2-일]부틸}아미노)-1-옥소-3-페닐프로판-2-일]카르바메이트를 무기산의 알콜 용액을 사용하여 탈보호하여 식 (V)의 N-{(1S)-3-메틸-1-[(3aS,4S,6S,7aS)-3a,5,5-트리메틸헥사히드로-4,6-메타노-1,3,2-벤조디옥사보롤-2-일]부틸} 페닐알라닌 또는 그의 염을 수득하는 단계;[이미지]c) 식 (V)의 화합물 또는 그의 염을 제2 커플링제 및 제2 염기의 존재하에 제2 용매 중 식 (VI)의 피라진-2-카르복실산과 커플링하여[이미지]식 (VII)의 N-{(1R)-3-메틸-1-[(3aS,4S,6S,7aS)-3a,5,5-트리메틸헥사히드로-4,6-메타노-1,3,2-벤조디옥사보롤-2-일]부틸}-Nα-(피라진-2-일카르보닐)-L-페닐알라닌아미드를 수득하는 단계 [이미지]; 및d) 식 (VII)의 화합물을 탈보호하여 보르테조밉 또는 그의 무수물을 수득하는 단계를 포함하는 것인 방법.