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【结 构 式】

【分子编号】44273

【品名】3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(hydroxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide

【CA登记号】

【 分 子 式 】C22H22Cl4N2O2

【 分 子 量 】488.23976

【元素组成】C 54.12% H 4.54% Cl 29.05% N 5.74% O 6.55%
与该中间体有关的原料药合成路线共 5 条
合成路线1合成路线2合成路线3合成路线4合成路线5

合成路线1

该中间体在本合成路线中的序号：(XI)

The intermediate chiral aldehyde (XIV) has been obtained as follows: Acylation of sarcosine methyl ester (II) with 3,5-dichlorobenzoyl chloride (I) provides the N-benzoyl aminoester (III). The dilithium derivative of 3,4-dichlorophenylacetic acid (IV) is condensed with ester (III) to furnish, after acidic work-up, the N-benzoyl amino ketone (V). Subsequent alkylation of (V) with 1-bromo-3-methyl-2-butene (VI) affords (VII). Treatment of ketone (VII) with hydroxylamine yields a mixture of E- and Z- oximes, from which the Z-isomer (VIII) is isolated by column chromatography. Resolution of racemic (VIII) is then accomplished by two procedures. Coupling of (VIII) with N-Boc-D-phenylglycine (IX) produces a diastereomeric mixture of O-acyl oximes, from which isomer (X) can be separated by recrystallization. Hydrazinolysis of the N-acyl oxime (X) furnishes the target (R)-enantiomer (XI). Alternatively, oxime (VIII) is acylated by pivaloyl chloride, and subsequently separated into enantiomers by means of chiral chromatography. The desired isomer (XII) is then subjected to hydrazinolysis, yielding (XI)

参考文献 中间体
合成目标
【1】 Carruthers, N.I.; Alaimo, C.A.; Shih, N.-Y.; Lavey, B.J.; Ting, P.C.; Reichard, G.A. (Schering Corp.); Substd. oximes as neurokinin antagonists. EP 1032561; WO 9926924 .
【2】 Carruthers, N.I.; Reichard, G.A.; Shih, N.-Y.; Lavey, B.J.; Alaimo, C.A.; Ting, P.C. (Schering Corp.); Substd. oximes as neurokinin antagonists. US 6063926 .
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) 27769 3,5-dichlorobenzoyl chloride 2905-62-6 C7H3Cl3O 详情 详情
(II) 10430 methyl 2-(methylamino)acetate; methyl N-methylglycinate 5473-12-1 C4H9NO2 详情 详情
(III) 44268 methyl 2-[(3,5-dichlorobenzoyl)(methyl)amino]acetate C11H11Cl2NO3 详情 详情
(IV) 30414 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid 5807-30-7 C8H6Cl2O2 详情 详情
(V) 44269 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-2-oxopropyl]-N-methylbenzamide C17H13Cl4NO2 详情 详情
(VI) 12989 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene 870-63-3 C5H9Br 详情 详情
(VII) 44270 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-6-methyl-2-oxo-5-heptenyl]-N-methylbenzamide C22H21Cl4NO2 详情 详情
(VIII) 44271 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-2-(hydroxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide C22H22Cl4N2O2 详情 详情
(IX) 61344 BOC-D-alpha-phenylglycine 33125-05-2 C13H17NO4 详情 详情
(X) 61345 3,5-dichloro-N-{(Z,6R)-2-[(1R)-1-(3,4-dichlorophenyl)-4-methyl-3-pentenyl]-8-hydroxy-10,10-dimethyl-5-oxo-6-phenyl-4,9-dioxa-3,7-diaza-2-undecen-1-yl}-N-methylbenzamide C35H39Cl4N3O5 详情 详情
(XI) 44273 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(hydroxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide C22H22Cl4N2O2 详情 详情
(XII) 61346 3,5-dichloro-N-((3R)-3-(3,4-dichlorophenyl)-2-{[(2,2-dimethylpropanoyl)oxy]imino}-6-methyl-5-heptenyl)-N-methylbenzamide C27H30Cl4N2O3 详情 详情

合成路线2

该中间体在本合成路线中的序号：(XI)

Alkylation of oxime (XI) with iodomethane in the presence of NaH provides the O-methyl oxime (XIII). Then, ozonolytic cleavage of the dimethylallyl group of (XIII), followed by reductive treatment with dimethylsulfide leads to aldehyde (XIV)

参考文献 中间体
合成目标
【1】 Carruthers, N.I.; Alaimo, C.A.; Shih, N.-Y.; Lavey, B.J.; Ting, P.C.; Reichard, G.A. (Schering Corp.); Substd. oximes as neurokinin antagonists. EP 1032561; WO 9926924 .
【2】 Carruthers, N.I.; Reichard, G.A.; Shih, N.-Y.; Lavey, B.J.; Alaimo, C.A.; Ting, P.C. (Schering Corp.); Substd. oximes as neurokinin antagonists. US 6063926 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 44273 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(hydroxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide C22H22Cl4N2O2 详情 详情
(XIII) 44275 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(methoxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide C23H24Cl4N2O2 详情 详情
(XIV) 44276 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(methoxyimino)-5-oxopentyl]-N-methylbenzamide C20H18Cl4N2O3 详情 详情

合成路线3

该中间体在本合成路线中的序号：(XI)

Acylation of sarcosine methyl ester (I) with 3,5-dichlorobenzoyl chloride (II) produced the corresponding amide (III). Claisen condensation of (III) with the dianion of 3,4-dichlorophenylacetic acid (IV), generated in the presence of lithium hexamethyldisilazide, gave, after acid decarboxylation, ketone (V). The lithium enolate of ketone (V) was then alkylated with 1-bromo-3-methyl-2-butene (VI) to afford (VII). Treatment of ketone (VII) with hydroxylamine produced a geometric mixture of oximes from which the desired (E)-isomer (VIII) was isolated by column chromatography. Resolution of the racemic (VIII) was achieved by coupling with N-Boc-D-phenylglycine (IX) followed by fractional crystallization of the desired diastereoisomer (X). Hydrazinolysis of the oxime ester then furnished the chiral intermediate (XI).

参考文献 中间体
合成目标
【1】 Carruthers, N.I.; Alaimo, C.A.; Shih, N.-Y.; Lavey, B.J.; Ting, P.C.; Reichard, G.A. (Schering Corp.); Substd. oximes as neurokinin antagonists. EP 1032561; WO 9926924 .
【2】 Carruthers, N.I.; Reichard, G.A.; Shih, N.-Y.; Lavey, B.J.; Alaimo, C.A.; Ting, P.C. (Schering Corp.); Substd. oximes as neurokinin antagonists. US 6063926 .
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) 10430 methyl 2-(methylamino)acetate; methyl N-methylglycinate 5473-12-1 C4H9NO2 详情 详情
(II) 27769 3,5-dichlorobenzoyl chloride 2905-62-6 C7H3Cl3O 详情 详情
(III) 44268 methyl 2-[(3,5-dichlorobenzoyl)(methyl)amino]acetate C11H11Cl2NO3 详情 详情
(IV) 30414 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid 5807-30-7 C8H6Cl2O2 详情 详情
(V) 44269 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-2-oxopropyl]-N-methylbenzamide C17H13Cl4NO2 详情 详情
(VI) 12989 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene 870-63-3 C5H9Br 详情 详情
(VII) 44270 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-6-methyl-2-oxo-5-heptenyl]-N-methylbenzamide C22H21Cl4NO2 详情 详情
(VIII) 44271 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-2-(hydroxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide C22H22Cl4N2O2 详情 详情
(IX) 22613 (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethanoic acid 2900-27-8 C13H17NO4 详情 详情
(X) 44272 tert-butyl (1R)-2-([[(Z,2R)-1-[[(3,5-dichlorobenzoyl)(methyl)amino]methyl]-2-(3,4-dichlorophenyl)-5-methyl-4-hexenylidene]amino]oxy)-2-oxo-1-phenylethylcarbamate C35H37Cl4N3O5 详情 详情
(XI) 44273 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(hydroxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide C22H22Cl4N2O2 详情 详情

合成路线4

该中间体在本合成路线中的序号：(XI)

An alternative procedure for the resolution of (VIII) consisted in the O-acylation of oxime group with pivaloyl chloride (XII) to give (XIII), which was resolved into enantiomers by means of chiral HPLC. Hydrazinolysis of the desired (R)-enantiomer provided (XI).

参考文献 中间体
合成目标
【1】 Carruthers, N.I.; Alaimo, C.A.; Shih, N.-Y.; Lavey, B.J.; Ting, P.C.; Reichard, G.A. (Schering Corp.); Substd. oximes as neurokinin antagonists. EP 1032561; WO 9926924 .
【2】 Carruthers, N.I.; Reichard, G.A.; Shih, N.-Y.; Lavey, B.J.; Alaimo, C.A.; Ting, P.C. (Schering Corp.); Substd. oximes as neurokinin antagonists. US 6063926 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(VIII) 44271 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-2-(hydroxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide C22H22Cl4N2O2 详情 详情
(XI) 44273 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(hydroxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide C22H22Cl4N2O2 详情 详情
(XII) 13597 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride 3282-30-2 C5H9ClO 详情 详情
(XIII) 44274 3,5-dichloro-N-(3-(3,4-dichlorophenyl)-2-[[(2,2-dimethylpropanoyl)oxy]imino]-6-methyl-5-heptenyl)-N-methylbenzamide C27H30Cl4N2O3 详情 详情

合成路线5

该中间体在本合成路线中的序号：(XI)

Oxime (XI) was O-methylated with methyl iodide and NaH to afford (XIV). Subsequent ozonolysis of the double bond of (XIV) generated aldehyde (XV).

参考文献 中间体
合成目标
【1】 Carruthers, N.I.; Alaimo, C.A.; Shih, N.-Y.; Lavey, B.J.; Ting, P.C.; Reichard, G.A. (Schering Corp.); Substd. oximes as neurokinin antagonists. EP 1032561; WO 9926924 .
【2】 Carruthers, N.I.; Reichard, G.A.; Shih, N.-Y.; Lavey, B.J.; Alaimo, C.A.; Ting, P.C. (Schering Corp.); Substd. oximes as neurokinin antagonists. US 6063926 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(XI) 44273 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(hydroxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide C22H22Cl4N2O2 详情 详情
(XIV) 44275 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(methoxyimino)-6-methyl-5-heptenyl]-N-methylbenzamide C23H24Cl4N2O2 详情 详情
(XV) 44276 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(methoxyimino)-5-oxopentyl]-N-methylbenzamide C20H18Cl4N2O3 详情 详情
Extended Information