SNS-032, BMS-387032, -Drug Synthesis Database

【结构式】

【药物名称】SNS-032, BMS-387032

【化学名称】N-[5-(5-tert-Butyloxazol-2-ylmethylsulfany)thiazol-2-yl]piperidine-4-carboxamide hemi(L-tartrate)

【CA登记号】345627-92-1, 345627-80-7 (free base), 345627-90-9 (hydrochloride), 345627-91-0 (hydrobromide), 345627-96-5 (sulfate), 345627-98-

【分子式】C₃₈H₅₄N₈O₁₀S₄

【分子量】911.143

【开发单位】Sunesis Pharmaceuticals, Inc.; licensed from Bristol- Myers Squibb for worldwide development and commercialization.

【药理作用】Cyclin-Dependent Kinase Inhibitor, Oncolytic

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【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

合成路线2

Alternatively, oxazole (VI) can be condensed with 2-amino-5-sulfanylthiazole (XIII) in refluxing ethanol to give thioether (IX). The intermediate 2-amino-5-sulfanylthiazole (XIII) can be obtained by reaction of 2-aminothiazole (XIV) with Br2 and KSCN to give the thiocyanato derivative (XV), which is finally reduced with NaBH4 in ethanol (4). Scheme 2.

参考文献中间体

【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
(VI)	58417	5-(tert-butyl)-2-(chloromethyl)-1,3-oxazole	224441-73-0	C₈H₁₂ClNO	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
(XIII)	65783	2-Amino-5-thiazolethiol	69950-00-1	C₃H₄N₂S₂	详情	详情
(XIV)	19795	2-Thiazolamine; 1,3-thiazol-2-amine; 1,3-thiazol-2-ylamine	96-50-4	C₃H₄N₂S	详情	详情
(XV)	64136	2-amino-1,3-thiazole-5-sulfenyl cyanide	23056-10-2	C₄H₃N₃S₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)