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【结 构 式】 
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【分子编号】27769 【品名】3,5-dichlorobenzoyl chloride 【CA登记号】2905-62-6 |
【 分 子 式 】C7H3Cl3O 【 分 子 量 】209.45832 【元素组成】C 40.14% H 1.44% Cl 50.78% O 7.64% |
合成路线1
该中间体在本合成路线中的序号：(II)By reaction of tropine (I) with 3,5-dichlorobenzoyl chloride (II) at 140 C.
| 【1】 Fozard, J.R.; Gittos, M.W. (Aventis Pharma SA); Treatment og migraine with substituted tropyl benzoate derivatives. EP 0067770; JP 58000978 . |
| 【2】 Pento, J.T.; Castaner, J.; Serradell, M.N.; MDL-72222. Drugs Fut 1985, 10, 10, 820. |
合成路线2
该中间体在本合成路线中的序号：(I)Reduction of 3,5-dichlorobenzoyl chloride (I) with NaBH4 in THF in the presence of N-methyl pyrrolidone (NMP) provides benzyl alcohol derivative (II), which is then treated with tert-butyl dimethylsilyl chloride (TBDMSCl) in DMF in the presence of imidazole and DMAP to furnish protected compound (III). Lithiation of (III) with BuLi (occasionally in the presence of tetramethylethylenediamine) in THF followed by reaction with p-chlorobenzoyl chloride (IV) in THF affords benzophenone derivative (V), which is then deprotected by means of concentrated HCl to yield benzyl alcohol derivative (VI). Conversion of alcohol (VI) into chloride (VII) is then performed by reaction with SOCl2. Next, reaction of (VII) with NaN3 and NaI in refluxing ethanol gives benzylazide derivative (VIII), which is finally converted into the desired product by reaction with cyanoacetamide (IX) and K2CO3 in DMSO.
| 【1】 Bochis, R.J.; Chabala, J.C.; Fisher, M.H. (Merck & Co., Inc.); 5-(Amino or substd.amino)-1,2,3-triazoles. EP 0151529; JP 1985188376; US 4590201 . |
| 【2】 Hube, D. (Merck & Co., Inc.); 5-Amino or substd. amino-1,2,3-triazoles useful as anti-metastasis agents. JP 1991056417; US 5045543 . |
| 【3】 Hupe, D.; Azzolina, B.A.; Argenbright, L.; Behrens, N. (Merck & Co., Inc.); 5-Amino or substd. amino 1,2,3-triazoles useful as antiproliferative agents. EP 0304221; JP 1989068321; US 4847257 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 49483 | N,N,N',N'-Tetramehylenediamine; 1,2-Bis(dimethylamino)ethane | C6H16N2 | 详情 | 详情 | ||
| (I) | 27769 | 3,5-dichlorobenzoyl chloride | 2905-62-6 | C7H3Cl3O | 详情 | 详情 |
| (II) | 24168 | (3,5-dichlorophenyl)methanol | 60211-57-6 | C7H6Cl2O | 详情 | 详情 |
| (III) | 49482 | tert-butyl(dimethyl)silyl 3,5-dichlorobenzyl ether; tert-butyl[(3,5-dichlorobenzyl)oxy]dimethylsilane | C13H20Cl2OSi | 详情 | 详情 | |
| (IV) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 详情 | 详情 |
| (V) | 49484 | [4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone | C20H23Cl3O2Si | 详情 | 详情 | |
| (VI) | 49485 | (4-chlorophenyl)[2,6-dichloro-4-(hydroxymethyl)phenyl]methanone | C14H9Cl3O2 | 详情 | 详情 | |
| (VII) | 49486 | (4-chlorophenyl)[2,6-dichloro-4-(chloromethyl)phenyl]methanone | C14H8Cl4O | 详情 | 详情 | |
| (VIII) | 49487 | [4-(azidomethyl)-2,6-dichlorophenyl](4-chlorophenyl)methanone | C14H8Cl3N3O | 详情 | 详情 | |
| (IX) | 12122 | Cyanoacetamide; 2-Cyanoacetamide | 107-91-5 | C3H4N2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)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4
该中间体在本合成路线中的序号：(IV)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5
该中间体在本合成路线中的序号：(II)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).
| 【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6
该中间体在本合成路线中的序号：(XVII)Reductive condensation between aldehyde (XIV) and the piperidine derivative (V) in the presence of NaBH3CN leads to the N-alkylated piperidine (XV). The N-Boc group of (XV) is cleaved under acidic conditions to afford amine (XVI), which is further acylated by 3,5-dichlorobenzoyl chloride (XVII), providing benzamide (XVIII). The oxime O-allyl group of (XVIII) is then removed by treatment with palladium tetrakis(triphenylphosphine) and triethylammonium formate, yielding oxime (XIX). This is subsequently alkylated with bromoacetonitrile and NaH, affording (XX)
| 【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 |
|---|---|---|---|---|---|---|
| (V) | 44280 | N-(4-Piperidine)-2-piperidinone | C10H18N2O | 详情 | 详情 | |
| (XIV) | 60820 | tert-butyl 2-[(allyloxy)imino]-3-(3,4-dichlorophenyl)-5-oxopentyl(methyl)carbamate | C20H26Cl2N2O4 | 详情 | 详情 | |
| (XV) | 60821 | C30H44Cl2N4O4 | 详情 | 详情 | ||
| (XVI) | 60822 | C25H36Cl2N4O2 | 详情 | 详情 | ||
| (XVII) | 27769 | 3,5-dichlorobenzoyl chloride | 2905-62-6 | C7H3Cl3O | 详情 | 详情 |
| (XVIII) | 60823 | C32H38Cl4N4O3 | 详情 | 详情 | ||
| (XIX) | 60824 | C29H34Cl4N4O3 | 详情 | 详情 | ||
| (XX) | 60825 | C31H35Cl4N5O3 | 详情 | 详情 |