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【结 构 式】

【分子编号】65782

【品名】tert-Butyl 4-[[5-[[(5-tert-butyloxazol-2-yl)methyl]thio]thiazol-2-yl]carbamoyl]piperidine-1-carboxylate

【CA登记号】345629-23-4

【 分 子 式 】C22H32N4O4S2

【 分 子 量 】480.65264

【元素组成】C 54.98% H 6.71% N 11.66% O 13.31% S 13.34%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XII)

Treatment of 1-bromo-3,3-dimethyl-2-butanone (I) with hexamethylenetetraamine affords the quaternary salt (II), which is then hydrolyzed to amino ketone (III) under acidic conditions (1-3). Alternatively, reaction of butanone (I) with sodium azide in acetone gives the azido derivative (IV), which is reduced with H2 over Pd/C in methanol to yield 1-amino-3,3-dimethyl-2-butanone (III). Acylation of amine (III) with 2-chloroacetyl chloride by means of triethylamine in dichloromethane yields the chloroacetamide (V), which is cyclized in POCl3 at 105 ºC to provide 5-tert-butyl-2-(chloromethyl)oxazole (VI) (1-4). Condensation of chloride (VI) with thiourea gives the S-alkylated thiouronium salt (VII), which is then submitted to alkaline hydrolysis followed by condensation with 2-amino-5-bromothiazole (VIII) under phase-transfer conditions in the presence of tetrabutylammonium sulfate, leading to thioether (IX) (1-3). Acylation of aminothiazole (IX) with 1-Boc-piperidine-4-carboxylic acid (X) —obtained by reaction of piperidine-4-carboxylic acid (XI) with Boc2O and NaOH in dioxane/acetonitrile— by means of EDAC and DMAP in DMF/dichloromethane yields the carboxamide (XII), which is finally deprotected upon treatment with trifluoroacetic acid (1-3) or by means of HCl in hot dioxane/CHCl (4). Scheme 1.

1 Xiao, H.-Y., Misra, R.N. (Bristol-Myers Squibb Co.). N-[5-[[[5-Alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases. CA 2394552, EP1240166, JP 2003516987, WO 2001044242.
2 Xiao, H.-Y., Misra, R.N. (Bristol-Myers Squibb Co.). N-[5-[[[5-Alkyl-2-oxazolyl]methyl]thio]-2-thiazolyl]-carboxamide inhibitors of cyclin dependent kinases. CA 2417254, EP 1303513, JP 2004509857, WO 2002010162.
3 Kim, K.S., Kimball, D., Cai, Z.-W. et al. (Bristol-Myers Squibb Co.). Aminothiazole inhibitors of cyclin dependent kinases. US 6262096.
4 Misra, N.R., Xiao, H., Kim, K.S. et al. N-(Cycloalkylamino)acyl-2-aminothiazole inhibitors of cyclin-dependent kinase 2. N-[5-[[[5-(1,1-Dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4-piperidinecarboxamide (BMS-387032), a highly efficacious and selective antitumor agent. J Med Chem 2004, 47(7): 1719-28.
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) 65780     C12H23BrN4O 详情 详情
(III) 58415 1-amino-3,3-dimethyl-2-butanone 82962-91-2 C6H13NO 详情 详情
(IV) 58414 1-azido-3,3-dimethyl-2-butanone 76779-98-1 C6H11N3O 详情 详情
(V) 58416 2-chloro-N-(3,3-dimethyl-2-oxobutyl)acetamide C8H14ClNO2 详情 详情
(VI) 58417 5-(tert-butyl)-2-(chloromethyl)-1,3-oxazole 224441-73-0 C8H12ClNO 详情 详情
(VII) 58418 2-({[amino(imino)methyl]sulfanyl}methyl)-5-(tert-butyl)-1,3-oxazole 345629-22-3 C9H15N3OS 详情 详情
(VIII) 65781 2-Amino-5-bromothiazole monohydrobromide; 5-Bromothiazol-2-amine monohydrobromide 61296-22-8 C3H3BrN2S.HBr 详情 详情
(IX) 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
(X) 17404 1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid; 1-BOC-piperidine-4-carboxylic acid; N-Boc-isonipecotic acid 84358-13-4 C11H19NO4 详情 详情
(XI) 17402 4-nipecotic acid;piperidine-4-carboxylic acid;p-nipecotic acid; Isonipecotic acid; Hexahydroisonicotinic acid; 4-Piperidinecarboxylic acid 498-94-2 C6H11NO2 详情 详情
(XII) 65782 tert-Butyl 4-[[5-[[(5-tert-butyloxazol-2-yl)methyl]thio]thiazol-2-yl]carbamoyl]piperidine-1-carboxylate 345629-23-4 C22H32N4O4S2 详情 详情
Extended Information