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【结 构 式】

【分子编号】21738

【品名】3,3-dimethylbutanoyl chloride

【CA登记号】7065-46-5

【 分 子 式 】C6H11ClO

【 分 子 量 】134.60544

【元素组成】C 53.54% H 8.24% Cl 26.34% O 11.89%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(X)

The C-7 hydroxyl group of 10-deacetyl baccatin III (VIII) was selectively protected with triethylsilyl chloride and imidazole to yield silyl ether (IX). Subsequent selective acylation of (IX) at C-10 hydroxyl group with acid chloride (X) in the presence of LiN(SiMe3)2 afforded ester (XI). The title taxoid was then obtained by further coupling of (XI) with b-lactam (VII) using LiN(SiMe3)2 in THF at low temperature, followed by desilylation with HF in pyridine

1 Lin, S.; et al.; Syntheses and biological activity of advanced second-generation taxoids. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 315.
2 Ferlini, C.; Scambia, G.; Lin, S.; Bernacki, R.J.; Ojima, I.; Wang, T.; Pera, P.; Slater, J.C.; Syntheses and biological activity of C3'-difluoromethyl taxoids. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 39.
3 Pera, P.; Scambia, G.; Ojima, I.; Lin, S.; Wang, T.; Ferlini, C.; Slater, J.C.; Bernacki, R.J.; Syntheses and biological activity of C-3'-difluoromethyl-taxoids. Bioorg Med Chem Lett 2000, 8, 7, 1619.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VII) 21735 tert-butyl (2R,3R)-2-(difluoromethyl)-4-oxo-3-[(triisopropylsilyl)oxy]-1-azetidinecarboxylate C18H33F2NO4Si 详情 详情
(VIII) 10467 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,9,12,15-tetrahydroxy-10,14,17,17-tetramethyl-11-oxo-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate 32981-86-5 C29H36O10 详情 详情
(IX) 21737 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-1,12,15-trihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C35H50O10Si 详情 详情
(X) 21738 3,3-dimethylbutanoyl chloride 7065-46-5 C6H11ClO 详情 详情
(XI) 21739 (1S,2S,3R,4S,7R,9S,10S,12R,15S)-4-(acetoxy)-12-[(3,3-dimethylbutanoyl)oxy]-1,15-dihydroxy-10,14,17,17-tetramethyl-11-oxo-9-[(triethylsilyl)oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]heptadec-13-en-2-yl benzoate C41H60O11Si 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XIII)

The hydrolysis of N-(4,5-dimethyl-3-isoxazolyl)carbamic acid tert-butyl ester (I) with HCl in dioxane gives the corresponding amine (II), which is condensed with 2-bromophenylsulfonyl chloride (III) by means of DMAP in pyridine to yield the sulfonamide (IV). The alkylation of (I) with 2-methoxyethoxymethyl chloride (V) and NaH in DMF affords the N,N-disubstituted sulfonamide (VI), which is treated with trimethyl borate (VII) and BuLi in THF to provide the boronate (VIII). The condensation of (VIII) with 2-bromo-5-(2-oxazolyl)benzaldehyde (IX) by means of palladium tetrakis(triphenylphosphine) in hot toluene/ethanol gives the biphenyl derivative (X), which is deprotected by means of HCl in refluxing ethanol/water to yield the sulfonamide (XI). The reductive amination of (XI) with methylamine and NaBH(OAc)3 in dichloromethane/HOAc affords the secondary amine (XII), which is finally acylated with 3,3-dimethylbutyryl chloride and TEA in dichloromethane to furnish the target diamide.

1 Barrish, J.C.; Murugesan, N.; Gu, Z.; Morrison, R.A. (Bristol-Myers Squibb Co.); Endothelin antagonists: N-[[2'-[[4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl) [1,1'-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-4'-(2-oxazolyl)[1,1'-biphenyl]-2-. EP 0996618; JP 2002513397; US 6043265; WO 9833780 .
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) 55414 tert-butyl 4,5-dimethyl-3-isoxazolylcarbamate C10H16N2O3 详情 详情
(II) 55415 4,5-dimethyl-3-isoxazolylamine; 4,5-dimethyl-3-isoxazolamine C5H8N2O 详情 详情
(III) 26890 2-bromobenzenesulfonyl chloride 2905-25-1 C6H4BrClO2S 详情 详情
(IV) 55416 2-bromo-N-(4,5-dimethyl-3-isoxazolyl)benzenesulfonamide C11H11BrN2O3S 详情 详情
(V) 40670 2-(chloromethoxy)ethyl methyl ether; 1-(chloromethoxy)-2-methoxyethane; (2-methoxyethoxy)methyl chloride 3970-21-6 C4H9ClO2 详情 详情
(VI) 55417 2-bromo-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxyethoxy)methyl]benzenesulfonamide C15H19BrN2O5S 详情 详情
(VII) 55418 trimethyl borate C3H9BO3 详情 详情
(VIII) 55419 dimethyl 2-({(4,5-dimethyl-3-isoxazolyl)[(2-methoxyethoxy)methyl]amino}sulfonyl)phenylboronate C17H25BN2O7S 详情 详情
(IX) 55420 2-bromo-5-(1,3-oxazol-2-yl)benzaldehyde C10H6BrNO2 详情 详情
(X) 55421 N-(4,5-dimethyl-3-isoxazolyl)-2'-formyl-N-[(2-methoxyethoxy)methyl]-4'-(1,3-oxazol-2-yl)[1,1'-biphenyl]-2-sulfonamide C25H25N3O7S 详情 详情
(XI) 55422 N-(4,5-dimethyl-3-isoxazolyl)-2'-formyl-4'-(1,3-oxazol-2-yl)[1,1'-biphenyl]-2-sulfonamide C21H17N3O5S 详情 详情
(XII) 55423 N-(4,5-dimethyl-3-isoxazolyl)-N-methyl-2'-[(methylamino)methyl]-4'-(1,3-oxazol-2-yl)[1,1'-biphenyl]-2-sulfonamide C23H24N4O4S 详情 详情
(XIII) 21738 3,3-dimethylbutanoyl chloride 7065-46-5 C6H11ClO 详情 详情

合成路线3

该中间体在本合成路线中的序号:(IX)

The esterification of 4(R)-hydroxypyrrolidine-2(S)-carboxylic acid (I) gives the methyl ester (II), which is N-protected to yield 1-Boc-4(R)-hydroxypyrrolidine-2(S)-carboxylic acid methyl ester (III). Compound (III) which is mesylated to afford 1-Boc-4(R)-(mesyloxy)pyrrolidine-2(S)-carboxylic acid methyl ester (IV). The reaction of (IV) with sodium azide affords (V), which is reduced with H2 over Pd/C in ethanol to provide 4(S)-amino-1-Boc-pyrrolidine-2(S)-carboxylic acid methyl ester (VI). The reductocondensation of (VI) with 3-methoxybenzaldehyde (VII) by means of NaBH(OAc)3 provides the secondary amine (VIII), which is acylated with 3,3-dimethylbutyryl chloride (IX) and TEA in dichloromethane to give the amide (X). The deprotection of the pyrrolidine NH of (X) by means of TFA yields the pyrrolidine (XI), which is reductocondensed with piperonal (XII) by means of NaBH3CN to afford the N-substituted pyrrolidine (XIII). The hydrolysis of the ester group of (XIII) with LiOH in methanol/water provides the carboxylic acid (XIV), which is condensed with N-Boc-piperazine (XV) by means of TBTU and DIEA in DMF to give the protected intermediate (XVI). Finally, this compound is deprotected by means of TFA in dichloromethane to furnish the target carboxamide.

1 Baxter, A.D.; Boyd, E.A.; Price, S.; Guicherit, O.M.; Rubin, L. (Curis, Inc.); Mediators of hedgehog signaling pathways, compsns. and uses related thereto. WO 0126644 .
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) 14489 (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylic acid; L-Hydroxyproline 51-35-4 C5H9NO3 详情 详情
(II) 15796 methyl (2S,4R)-4-hydroxytetrahydro-1H-pyrrole-2-carboxylate C6H11NO3 详情 详情
(III) 15780 1-(tert-butyl) 2-methyl (2S,4S)-4-hydroxytetrahydro-1H-pyrrole-1,2-dicarboxylate;(2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate C11H19NO5 详情 详情
(IV) 15781 1-(tert-butyl) 2-methyl (2S,4R)-4-[(methylsulfonyl)oxy]tetrahydro-1H-pyrrole-1,2-dicarboxylate C12H21NO7S 详情 详情
(V) 43411 1-(tert-butyl) 2-methyl (2S,4S)-4-azido-1,2-pyrrolidinedicarboxylate C11H18N4O4 详情 详情
(VI) 55407 1-(tert-butyl) 2-methyl (2S,4S)-4-amino-1,2-pyrrolidinedicarboxylate C11H20N2O4 详情 详情
(VII) 20589 3-methoxybenzaldehyde; m-Anisaldehyde 591-31-1 C8H8O2 详情 详情
(VIII) 55407 1-(tert-butyl) 2-methyl (2S,4S)-4-amino-1,2-pyrrolidinedicarboxylate C11H20N2O4 详情 详情
(IX) 21738 3,3-dimethylbutanoyl chloride 7065-46-5 C6H11ClO 详情 详情
(X) 55409 1-(tert-butyl) 2-methyl (2S,4S)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-1,2-pyrrolidinedicarboxylate C25H38N2O6 详情 详情
(XI) 55410 methyl (2S,4S)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylate C20H30N2O4 详情 详情
(XII) 10127 1,3-Benzodioxole-5-carbaldehyde; Heliotropine 120-57-0 C8H6O3 详情 详情
(XIII) 55411 methyl (2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylate C28H36N2O6 详情 详情
(XIV) 55412 (2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]-2-pyrrolidinecarboxylic acid C27H34N2O6 详情 详情
(XV) 13225 N-tert-Butoxycarbonyl piperazine; tert-butyl 1-piperazinecarboxylate;tert-butyl piperazine-1-carboxylate 143238-38-4 C9H18N2O2 详情 详情
(XVI) 55413 tert-butyl 4-({(2S,4S)-1-(1,3-benzodioxol-5-ylmethyl)-4-[(3,3-dimethylbutanoyl)(3-methoxybenzyl)amino]pyrrolidinyl}carbonyl)-1-piperazinecarboxylate C36H50N4O7 详情 详情
Extended Information