【结 构 式】 |
【药物名称】BMS-419437 【化学名称】N-[5-(5-tert-Butyloxazol-2-ylmethylsulfanyl)thiazol-2-yl]-2-[4-[2-hydroxy-1-(hydroxymethyl)ethylaminomethyl]phenyl]acetamide 【CA登记号】333389-24-5, 333389-66-5 (hydrochloride) 【 分 子 式 】C23H30N4O4S2 【 分 子 量 】490.64795 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】Oncolytic Drugs, CDK1 Inhibitors, CDK2/Cyclin E Inhibitors, CDK4 Inhibitors |
合成路线1
Substitution of 1-bromo-3,3-dimethyl-2-butanone (I) with NaN3 affords the azido ketone (II), which is reduced to amino ketone (III) by either catalytic hydrogenation or with triphenylphosphine. Acylation of (III) with chloroacetyl chloride affords amide (IV). Cyclization of the keto amide (IV) in hot POCl3 or in the presence of Burgess' reagent leads to the chloromethyl oxazole (V). Displacement of the chlorine atom of (V) with thiourea provides the S-alkyl isothiourea (VI). Hydrolysis of (VI), followed by condensation with 2-amino-5-bromothiazole (VII) under phase-transfer conditions furnishes thioether (VIII). The amino thiazole (VIII) is then coupled with 4-(bromomethyl)phenylacetic acid (IX), yielding amide (X). Finally, the bromide group of (X) is displaced with 2-amino-1,3-propanediol (XI) to produce the title compound.
【1】 Kim, K.S.; Misra, R.N.; Hunt, J.T.; Kimball, S.D.; Poss, M.A.; Han, W.-C.; Webster, K.R.; Cai, Z.-W.; Rawlins, D.B. (Bristol-Myers Squibb Co.); N-[5-[[[5-Alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases. EP 1240165; WO 0144241 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(I) | 30809 | 1-bromo-3,3-dimethyl-2-butanone | 5469-26-1 | C6H11BrO | 详情 | 详情 |
(II) | 58414 | 1-azido-3,3-dimethyl-2-butanone | 76779-98-1 | C6H11N3O | 详情 | 详情 |
(III) | 58415 | 1-amino-3,3-dimethyl-2-butanone | 82962-91-2 | C6H13NO | 详情 | 详情 |
(IV) | 58416 | 2-chloro-N-(3,3-dimethyl-2-oxobutyl)acetamide | C8H14ClNO2 | 详情 | 详情 | |
(V) | 58417 | 5-(tert-butyl)-2-(chloromethyl)-1,3-oxazole | 224441-73-0 | C8H12ClNO | 详情 | 详情 |
(VI) | 58418 | 2-({[amino(imino)methyl]sulfanyl}methyl)-5-(tert-butyl)-1,3-oxazole | 345629-22-3 | C9H15N3OS | 详情 | 详情 |
(VII) | 58419 | 5-bromo-1,3-thiazol-2-ylamine; 5-bromo-1,3-thiazol-2-amine | C3H3BrN2S | 详情 | 详情 | |
(VIII) | 58420 | 5-({[5-(tert-butyl)-1,3-oxazol-2-yl]methyl}sulfanyl)-1,3-thiazol-2-amine; 5-({[5-(tert-butyl)-1,3-oxazol-2-yl]methyl}sulfanyl)-1,3-thiazol-2-ylamine | 224436-97-9 | C11H15N3OS2 | 详情 | 详情 |
(IX) | 58421 | 2-[4-(bromomethyl)phenyl]acetic acid; 4-(Bromomethyl)phenyl acetic acid; 4-Carboxymethylbenzyl bromide | 13737-36-5 | C9H9BrO2 | 详情 | 详情 |
(X) | 58422 | 2-[4-(bromomethyl)phenyl]-N-[5-({[5-(tert-butyl)-1,3-oxazol-2-yl]methyl}sulfanyl)-1,3-thiazol-2-yl]acetamide | C20H22BrN3O2S2 | 详情 | 详情 | |
(XI) | 23333 | 2-amino-1,3-propanediol; serinol | 534-03-2 | C3H9NO2 | 详情 | 详情 |