Ifetroban sodium, BMS-180291-02, BMS-180291 sodium salt

苯丙烷酸,2-[[(1S,2R,3S,4R)-3-[4-[(戊氨基)羰基]-2-恶唑yl]-7-氧双环[2.2.1]庚-2-基]甲基]-,钠盐(1:1) 伊非曲班 Chemical Name: (+)-[1(S)-(1alpha,2alpha,3alpha,4alpha)]-3-[2-[3-[4-(N-Pentylcarbamoyl)oxazol-2-yl]-7-oxabicyclo[2.2.1]hept-2-ylmethyl]phenyl]propanoic acid monosodium salt; (+)-[1S-(exo,exo)]-2-[[3-[4-[(n-Pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl]methyl]benzenepropanoic acid monosodium salt
CAS No. 156715-37-6, 143443-90-7 (free acid)
项目整合开发状态: Phase II
项目研究机构: Bristol-Myers Squibb (Originator)
合成路线:BMS-180291 sodium salt was prepared from optically active 7-oxabicyclo[2.2.1]heptane lactol (I):The interphenylene side chain was introduced by deprotonation of (I) with ethylmagnesium bromide (0.95 eq.) followed by treatment with excess aryl Grignard (II) to afford crystalline diol (III).The extraneous benzylic hydroxyl group in (III) was removed by reduction with hydrogen in the presence of Pearlman's catalyst to give alcohol (IV).Transformation of the alpha-side chain silyloxy carbinol of (IV) to a carboxymethyl ester was accomplished by initial protection of the omega-side chain alcohol as the acetate (Ac2O/py) followed by oxidation under Jones conditions and then exposure of the resulting crude acetate-acid to methanolic hydrogen chloride to afford crystalline alcohol-ester (V).Oxidation of (V) under Jones conditions furnished acid-ester (VI).The oxazole side chain was introduced into (VI) via serine-derived amino alcohol (VII).Standard coupling of acid (VI) with (VII) mediated by water-soluble carbodiimide (EDAC) gave amide (VIII).Acyclic side chain intermediate (VIII) was converted into oxazole (X) in three steps by mesylation followed by treatment with triethylamine to furnish cyclized oxazoline (IX).Dehydrogenation of (IX) employing a novel oxidative protocol (1) involving treatment with a mixture of copper (II) bromide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in chloroform/ethyl acetate solvent yielded oxazole (X).Saponification of (X) followed by acidification afforded (BMS-180291) as a white solid which could be purified by recrystallization from acetonitrile.The water-soluble sodium salt (XI) was available as a precipitate from BMS-18091 by treatment with sodium methoxide/methanol in acetone.

合成路线:The interphenylene side chain was introduced by deprotonation of (I) with ethylmagnesium bromide (0.95 eq.) followed by treatment with excess aryl Grignard (II) to afford crystalline diol (III).The extraneous benzylic hydroxyl group in (III) was removed by reduction with hydrogen in the presence of Pearlman's catalyst to give alcohol (IV).Transformation of the alpha-side chain silyloxy carbinol to a carboxy methyl ester was accomplished by initial protection of the omega-side chain alcohol as the acetate (Ac2O/pyr) followed by oxidation under Jones conditions and then exposure of the resulting crude acetate-acid to methanolic hydrogen chloride to afford crystalline alcohol-ester (V).Oxidation of (V) under Jones conditions furnished acid-ester (VI).The oxazole side chain was introduced into (VI) via serine-derived amino alcohol (VII).Standard coupling of acid (VI) with (VII) mediated by water-soluble carbodiimide (EDAC) gave amide (VIII).Acyclic side chain intermediate (VIII) was converted into oxazole (X) in three steps by mesylation followed by treatment with triethylamine to furnish cyclized oxazoline (IX).Dehydrogenation of (IX) employing a novel oxidative protocol involving treatment with a mixture of copper (II) bromide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in chloroform/ethyl acetate solvent yielded oxazole (X).Saponification of (X) followed by acidification afforded (XI) (BMS-180291) as a white solid which could be purified by recrystallization from acetonitrile.The water-soluble sodium salt was available as a precipitate from (XI) by treatment with sodium methoxide/methanol in acetone.