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【结 构 式】

【分子编号】44276

【品名】3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(methoxyimino)-5-oxopentyl]-N-methylbenzamide

【CA登记号】

【 分 子 式 】C20H18Cl4N2O3

【 分 子 量 】476.1854

【元素组成】C 50.45% H 3.81% Cl 29.78% N 5.88% O 10.08%
与该中间体有关的原料药合成路线共 6 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6

合成路线1

该中间体在本合成路线中的序号：(XIV)

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2

该中间体在本合成路线中的序号：(XIV)

The title compound is obtained by reductive condensation between the chiral intermediate aldehyde (XIV) and piperidine (XXV) in the presence of NaBH(OAc)3 in trifluoroethanol

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
(XIV) 44276 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(methoxyimino)-5-oxopentyl]-N-methylbenzamide C20H18Cl4N2O3 详情 详情
(XXV) 61354 　 C13H23N3O2 详情 详情

合成路线3

该中间体在本合成路线中的序号：(IX)

In a different strategy, the racemic intermediate aldehyde (IX) has been obtained as follows: Swern oxidation of the known racemic alcohol (I) yields aldehyde (II), which is further reductively aminated with methylamine to produce the secondary amine (III). Acylation of amine (III) with 3,5-dichlorobenzoyl chloride (IV) leads to amide (V). Subsequent desilylation of (V) with HF in acetonitrile provides alcohol (VI). The thioketal group of (VI) is then removed by treatment with HgClO4 and CaCO3, yielding ketone (VII). Treatment of (VII) with O-methyl hydroxylamine, followed by separation of the resultant E-/Z- mixture of isomers furnishes the desired O-methyl oxime (VIII). The primary alcohol function of (VIII) is then oxidized under Swern conditions to provide aldehyde (IX)

参考文献 中间体
合成目标
【1】 Ting, P.C.; Lee, J.F.; Shih, N.-Y.; et al.; Identification of a novel 1'-[5-((3,5-dichlorobenzoyl)methylamino)-3-(3,4-dichlorophenyl)-4-(methoxyimino)pentyl]- 2-oxo-(1,4'-bipiperidine) as a dual NK(1)/NK(2) antagonist. Bioog. Med. Chem. Lett. 2002, 12, 16, 2125.
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) 49155 [2-[3-[[tert-butyl(dimethyl)silyl]oxy]-1-(3,4-dichlorophenyl)propyl]-1,3-dithiolan-2-yl]methanol C19H30Cl2O2S2Si 详情 详情
(II) 61355 2-[3-{[tert-butyl(dimethyl)silyl]oxy}-1-(3,4-dichlorophenyl)propyl]-1,3-dithiolane-2-carbaldehyde C19H28Cl2O2S2Si 详情 详情
(III) 61356 N-({2-[3-{[tert-butyl(dimethyl)silyl]oxy}-1-(3,4-dichlorophenyl)propyl]-1,3-dithiolan-2-yl}methyl)-N-methylamine; {2-[3-{[tert-butyl(dimethyl)silyl]oxy}-1-(3,4-dichlorophenyl)propyl]-1,3-dithiolan-2-yl}-N-methylmethanamine C20H33Cl2NOS2Si 详情 详情
(IV) 27769 3,5-dichlorobenzoyl chloride 2905-62-6 C7H3Cl3O 详情 详情
(V) 61357 N-({2-[3-{[tert-butyl(dimethyl)silyl]oxy}-1-(3,4-dichlorophenyl)propyl]-1,3-dithiolan-2-yl}methyl)-3,5-dichloro-N-methylbenzamide C27H35Cl4NO2S2Si 详情 详情
(VI) 61358 3,5-dichloro-N-({2-[1-(3,4-dichlorophenyl)-3-hydroxypropyl]-1,3-dithiolan-2-yl}methyl)-N-methylbenzamide C21H21Cl4NO2S2 详情 详情
(VII) 61359 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-5-hydroxy-2-oxopentyl]-N-methylbenzamide C19H17Cl4NO3 详情 详情
(VIII) 61360 3,5-dichloro-N-[3-(3,4-dichlorophenyl)-5-hydroxy-2-(methoxyimino)pentyl]-N-methylbenzamide C20H20Cl4N2O3 详情 详情
(IX) 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4

该中间体在本合成路线中的序号：(IX)

Reductive condensation between racemic intermediate aldehyde (IX) and racemic piperidine (XIX) leads to a diastereoisomeric mixture of substituted piperidines, from which the target isomer is finally isolated through chiral chromatography

参考文献 中间体
合成目标
【1】 Ting, P.C.; Lee, J.F.; Shih, N.-Y.; et al.; Identification of a novel 1'-[5-((3,5-dichlorobenzoyl)methylamino)-3-(3,4-dichlorophenyl)-4-(methoxyimino)pentyl]- 2-oxo-(1,4'-bipiperidine) as a dual NK(1)/NK(2) antagonist. Bioog. Med. Chem. Lett. 2002, 12, 16, 2125.
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) 44276 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(methoxyimino)-5-oxopentyl]-N-methylbenzamide C20H18Cl4N2O3 详情 详情
(XIX) 61354 　 C13H23N3O2 详情 详情

合成路线5

该中间体在本合成路线中的序号：(XV)

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

合成路线6

该中间体在本合成路线中的序号：(XV)

Acylation of 4-amino-1-benzylpiperidine (XVI) with 5-chlorovaleryl chloride (XVII) yielded chloro amide (XVIII). This was cyclized to the piperidino piperidinone (XIX) by treatment with NaH in THF. Subsequent hydrogenolysis of the N-benzyl group of (XIX) furnished piperidine (XX). Finally, reductive alkylation of piperidine (XX) with aldehyde (XV) in the presence of sodium triacetoxyborohydride gave rise to the title compound.

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
(XV) 44276 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(methoxyimino)-5-oxopentyl]-N-methylbenzamide C20H18Cl4N2O3 详情 详情
(XVI) 34808 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine 50541-93-0 C12H18N2 详情 详情
(XVII) 44277 5-chloropentanoyl chloride 1575-61-7 C5H8Cl2O 详情 详情
(XVIII) 44278 N-(1-benzyl-4-piperidinyl)-5-chloropentanamide C17H25ClN2O 详情 详情
(XIX) 44279 　 C17H24N2O 详情 详情
(XX) 44280 N-(4-Piperidine)-2-piperidinone C10H18N2O 详情 详情
Extended Information