|
【结 构 式】 
|
【分子编号】30809 【品名】1-bromo-3,3-dimethyl-2-butanone 【CA登记号】5469-26-1 |
【 分 子 式 】C6H11BrO 【 分 子 量 】179.05674 【元素组成】C 40.25% H 6.19% Br 44.62% O 8.94% |
合成路线1
该中间体在本合成路线中的序号：(VII)Ketone (III) was prepared by Friedel-Crafts acylation of benzene (II) with 6-chloronicotinyl chloride (I). Horner-Emmons reaction of (III) with diethyl (N-methylcarbamoylmethyl)phosphonate (IV) using potassium hexamethyl-disilazide produced a 3:1 mixture of E (V) and Z olefins (VI). The desired E isomer (V) was isolated by column chromatography and then treated with bromoketone (VII) to afford the betaine (VIII). Finally, the target imidazopyridine was obtained by condensation of (VIII) with cyanamide in the presence of K2CO3.
| 【1】 Alvarez-Builla, J.; Ezquerra, J.; Vega, J.A.; Vaquero, J.J.; Hamdouchi, C.; Heinz, B.A.; Short synthesis and anti-rhinoviral activity of imidazo[1,2-a]pyridines: The effect of acyl groups at 3-position. Bioorg Med Chem Lett 1999, 9, 10, 1391. |
| 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) | 30256 | 6-chloronicotinoyl chloride | 58757-38-3 | C6H3Cl2NO | 详情 | 详情 |
| (II) | 13364 | Benzene | 71-43-2 | C6H6 | 详情 | 详情 |
| (III) | 30257 | (6-chloro-3-pyridinyl)(phenyl)methanone | C12H8ClNO | 详情 | 详情 | |
| (IV) | 30262 | diethyl 2-(methylamino)-2-oxoethylphosphonate | C7H16NO4P | 详情 | 详情 | |
| (V) | 30807 | (E)-3-(6-chloro-3-pyridinyl)-N-methyl-3-phenyl-2-propenamide | C15H13ClN2O | 详情 | 详情 | |
| (VI) | 30808 | (Z)-3-(6-chloro-3-pyridinyl)-N-methyl-3-phenyl-2-propenamide | C15H13ClN2O | 详情 | 详情 | |
| (VII) | 30809 | 1-bromo-3,3-dimethyl-2-butanone | 5469-26-1 | C6H11BrO | 详情 | 详情 |
| (VIII) | 30810 | 1-[2-Chloro-5-[2-(N-metylcarbamoyl)-1-phenylvinyl]pyridinium-1-yl]-3,3-dimethyl-2-oxo-1-butanide | C21H23ClN2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)Isocyanate (XI) was prepared by treatment of tert-butyl 3-aminobenzoate (X) with triphosgene and triethylamine. Coupling of isocyanate (XI) with amine (IX) gave rise to the urea (XII). The lactam N of (XII) was then alkylated with bromomethyl tert-butyl ketone (XIII) in the presence of K2CO3 and tetrabutylammonium bromide to give (XIV). Cleavage of the tert-butyl ester group of (XIV) with trifluoroacetic acid yielded the carboxylic acid (XV), which was finally isolated as the corresponding calcium salt.
| 【1】 Murata, M.; Shinozaki, K.; Yoneta, T.; Miura, N.; Maeda, K. (Zeria Pharmaceutical Co., Ltd.); 1,5-Benzodiazepine derivs.. EP 0945445; US 6239131; WO 9825911 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 49769 | (3R)-3-amino-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one | C15H21N3O | 详情 | 详情 | |
| (X) | 49770 | tert-butyl 3-aminobenzoate | C11H15NO2 | 详情 | 详情 | |
| (XI) | 49771 | tert-butyl 3-isocyanatobenzoate | C12H13NO3 | 详情 | 详情 | |
| (XII) | 49772 | tert-butyl 3-[([[(3R)-1-cyclohexyl-4-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]amino]carbonyl)amino]benzoate | C27H34N4O4 | 详情 | 详情 | |
| (XIII) | 30809 | 1-bromo-3,3-dimethyl-2-butanone | 5469-26-1 | C6H11BrO | 详情 | 详情 |
| (XIV) | 49773 | tert-butyl 3-[([[(3R)-5-cyclohexyl-1-(3,3-dimethyl-2-oxobutyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]amino]carbonyl)amino]benzoate | C33H44N4O5 | 详情 | 详情 | |
| (XV) | 49774 | 3-[([[(3R)-5-cyclohexyl-1-(3,3-dimethyl-2-oxobutyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl]amino]carbonyl)amino]benzoic acid | C29H36N4O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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 |
合成路线4
该中间体在本合成路线中的序号：(I)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 |