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【结 构 式】

【药物名称】SCH-205528

【化学名称】N-[3(R)-(3,4-Dichlorophenyl)-5-[4-(2-oxopiperidin-1-yl)piperidin-1-yl]-2(Z)-(methoxyimino)pentyl]-N-methyl-3,5-dichlorobenzamide

【CA登记号】226915-45-3, 263892-22-4 ((R)-isomer), 226915-78-2 (undefined isomer)

【 分 子 式 】C30H36Cl4N4O3

【 分 子 量 】642.45842

【开发单位】Schering-Plough (Originator)

【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, Drugs for Allergic Rhinitis, RESPIRATORY DRUGS, Treatment of Upper Respiratory Tract Disorders, Tachykinin NK1 Antagonists, Tachykinin NK2 Antagonists

合成路线1合成路线2合成路线3合成路线4

合成路线1

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
【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2

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
【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3

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
【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4

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
【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
Drug NewChemical Entity Original Patent(1)