1-azido-3,3-dimethyl-2-butanone -Drug Synthesis Database

【结构式】

【分子编号】58414

【品名】1-azido-3,3-dimethyl-2-butanone

【CA登记号】76779-98-1

【分子式】C₆H₁₁N₃O

【分子量】141.17296

【元素组成】C 51.05% H 7.85% N 29.77% O 11.33%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

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

合成目标

【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

该中间体在本合成路线中的序号：(II)

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.

参考文献中间体

合成目标

【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

Extended Information