|
【结 构 式】 
|
【药物名称】SCH-206272 【化学名称】N-[3(R)-(3,4-Dichlorophenyl)-5-[4-[3(R)-(N-methylcarbamoylmethyl)-2-oxopiperidin-1-yl]piperidin-1-yl]-2(Z)-(methoxyimino)pentyl]-N-methyl-3,5-dichlorobenzamide 【CA登记号】226915-43-1, 263892-25-7 (diastereomer), 263892-28-0 (undefined stereoch.) 【 分 子 式 】C33H41Cl4N5O4 【 分 子 量 】713.53782 |
【开发单位】Schering-Plough (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, RESPIRATORY DRUGS, Tachykinin NK1 Antagonists, Tachykinin NK2 Antagonists, Tachykinin NK3 Antagonists |
合成路线1
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)
| 【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
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)
| 【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
3-(Carbomethoxy)propionyl chloride (XV) is condensed with the chiral oxazolidine (XVI) to provide (XVII). Titanium-catalyzed Michael addition of acrylonitrile to the N-acyl oxazolidine (XVII) affords nitrile (XVIII), which is reduced to the primary amine (XIX) by catalytic hydrogenation in the presence of PtO2. Reductive alkylation of amine (XIX) with N-Boc-4-piperidone (XX) gives rise to the aminopiperidine (XXI). This is then cyclized to the piperidinyl piperidone (XXII) upon heating in acetonitrile. After alkaline hydrolysis of the methyl ester group of (XXII), coupling of the resultant acid (XXIII) with methylamine gives rise to the corresponding amide (XXIV). The N-Boc protecting group of (XXIV) is then removed by treatment with trifluoroacetic acid to furnish piperidine (XXV)
| 【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 |
|---|---|---|---|---|---|---|
| (A) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (XV) | 18060 | 4-Chloro-4-oxobutyric acid methyl ester; 3-Carbomethosypropionyl chloride; Methyl 4-chloro-4-oxobutanoate | 1490-25-1 | C5H7ClO3 | 详情 | 详情 |
| (XVI) | 25351 | (4R)-4-benzyl-1,3-oxazolidin-2-one; (R)-(+)-4-benzyl-2-oxazolidinone | 102029-44-7 | C10H11NO2 | 详情 | 详情 |
| (XVII) | 61347 | methyl 4-[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxobutanoate | C15H17NO5 | 详情 | 详情 | |
| (XVIII) | 61348 | methyl (3R)-3-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-5-cyanopentanoate | C18H20N2O5 | 详情 | 详情 | |
| (XIX) | 61349 | methyl (3R)-6-amino-3-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}hexanoate | C18H24N2O5 | 详情 | 详情 | |
| (XX) | 18620 | tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone | 79099-07-3 | C10H17NO3 | 详情 | 详情 |
| (XXI) | 61350 | tert-butyl 4-[((4R)-4-{[(4R)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-6-methoxy-6-oxohexyl)amino]-1-piperidinecarboxylate | C28H41N3O7 | 详情 | 详情 | |
| (XXII) | 61351 | C18H30N2O5 | 详情 | 详情 | ||
| (XXIII) | 61352 | C17H28N2O5 | 详情 | 详情 | ||
| (XXIV) | 61353 | C18H31N3O4 | 详情 | 详情 | ||
| (XXV) | 61354 | C13H23N3O2 | 详情 | 详情 |
合成路线4
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
| 【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 . |
合成路线5
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)
| 【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6
Acylation of 4-amino-1-benzylpiperidine (X) with 5-chloropentanoyl chloride (XI) gives the chloro amide (XII), which is further cyclized to the 2-piperidone (XIII) in the presence of NaH. Replacement of the N-benzyl (XIII) for a N-Boc (XIV) protecting group is then accomplished by catalytic hydrogenolysis in the presence of Boc2O (1,2). Alkylation of piperidone (XIV) with allyl bromide (XV) yields the racemic 3-allyl-2-piperidone (XVI), which is subjected to oxidative cleavage with RuO2/NaIO4, producing carboxylic acid (XVII). After coupling of acid (XVII) with methylamine, the resultant N-methyl amide (XVIII) is deprotected by treatment with trifluoroacetic acid to give piperidine (XIX)
| 【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. |
| 【2】 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 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 34809 | N-benzoyl-N'-(1-benzyl-4-piperidinyl)urea | C20H23N3O2 | 详情 | 详情 | |
| (XI) | 44277 | 5-chloropentanoyl chloride | 1575-61-7 | C5H8Cl2O | 详情 | 详情 |
| (XII) | 44278 | N-(1-benzyl-4-piperidinyl)-5-chloropentanamide | C17H25ClN2O | 详情 | 详情 | |
| (XIII) | 44279 | C17H24N2O | 详情 | 详情 | ||
| (XIV) | 61361 | C15H26N2O3 | 详情 | 详情 | ||
| (XVI) | 61362 | C18H30N2O3 | 详情 | 详情 | ||
| (XVII) | 61352 | C17H28N2O5 | 详情 | 详情 | ||
| (XVIII) | 61353 | C18H31N3O4 | 详情 | 详情 | ||
| (XIX) | 61354 | C13H23N3O2 | 详情 | 详情 |
合成路线7
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
| 【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. |