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【结 构 式】 
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【分子编号】17992 【品名】m-Cyanoacetophenone; 3-acetylbenzonitrile 【CA登记号】6136-68-1 |
【 分 子 式 】C9H7NO 【 分 子 量 】145.16072 【元素组成】C 74.47% H 4.86% N 9.65% O 11.02% |
合成路线1
该中间体在本合成路线中的序号：(I)Condensation of 3-acetylbenzonitrile (I) with N,N-dimethylformamide dimethylacetal (II) at 90 C provided enaminoketone (III). Reaction of (III) with hydrazine acetate in methanol generated pyrazole (IV), and then, reduction of nitrile group with Raney Nickel in aqueous formic acid gave aldehyde (V). Condensation of this aldehyde with benzylamine (VI) in refluxing toluene, followed by reduction of the intermediate imine (VII) with ethanolic NaBH4 yielded secondary amine (VIII). Finally, the target urea was obtained by condensation of amine (VIII) with phenyl N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]carbamate in the presence of triethylamine.
| 【1】 Tanaka, A.; et al.; Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 2. Identification and structure-activity relationships of a novel series of N-alkyl-N-(heteroaryl-substituted benzyl)-N'-arylureas. J Med Chem 1998, 41, 12, 2390-2410. |
| 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) | 17992 | m-Cyanoacetophenone; 3-acetylbenzonitrile | 6136-68-1 | C9H7NO | 详情 | 详情 |
| (III) | 17994 | 3-[(E)-3-(dimethylamino)-2-propenoyl]benzonitrile | C12H12N2O | 详情 | 详情 | |
| (IV) | 17995 | 3-(1H-pyrazol-5-yl)benzonitrile | C10H7N3 | 详情 | 详情 | |
| (V) | 17996 | 3-(1H-pyrazol-5-yl)benzaldehyde | C10H8N2O | 详情 | 详情 | |
| (VII) | 17998 | N-benzyl-N-[(E)-[3-(1H-pyrazol-5-yl)phenyl]methylidene]amine; phenyl-N-[(E)-[3-(1H-pyrazol-5-yl)phenyl]methylidene]methanamine | C17H15N3 | 详情 | 详情 | |
| (VIII) | 17999 | N-benzyl[3-(1H-pyrazol-5-yl)phenyl]methanamine; N-benzyl-N-[3-(1H-pyrazol-5-yl)benzyl]amine | C17H17N3 | 详情 | 详情 | |
| (IX) | 18000 | phenyl 6-methyl-2,4-bis(methylsulfanyl)-3-pyridinylcarbamate | C15H16N2O2S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)3-Acetylbenzonitrile (I) was protected as the ethylene ketal (II) employing ethylene glycol and boron trifluoride etherate. Reduction of the cyano group of (II) with LiAlH4 gave amine (III), and further ketal hydrolysis provided 3-acetylbenzylamine (IV). This was acetylated using acetyl chloride and Et3N to yield the intermediate amide (V). Alternatively, intermediate (V) was obtained by addition of methylmagnesium bromide to N-(3-cyanobenzyl)acetamide (VI). Bromination of (V) in dioxan furnished the bromoacetophenone (VII). This was cyclized to the aminothiazole (IX) by treatment with thiourea (VIII) in refluxing ethanol. Condensation of (IX) with benzoyl isothiocyanate (X) provided the benzoyl thiourea (XI). After selective hydrolysis of the benzoyl group of (XI) with NaOH in MeOH-H2O at 60 C, the resulting thiourea (XII) was methylated with iodomethane yielding S-methylisothiourea (XIII). Finally, displacement of the methylthio group with 2-methoxyetylamine (XIV) furnished the title guanidinothiazole.
| 【1】 Katsura, Y.; Tomishi, T.; Inoue, Y.; Takasugi, H. (Fujisawa Pharmaceutical Co., Ltd.); Guanidino thiazoles and their use as H2-receptor antagonist. EP 0545376; JP 1994321921; US 5532258 . |
| 【2】 Inoue, Y.; Morinaga, C.; Ishikawa, H.; Takasugi, H.; Tomishi, T.; Matsumoto, Y.; Katsura, Y.; Sakane, K.; Anti-Helicobacter pylori agents.4. 2-(Substituted guanidino)-4-phenylthiazoles and some structurally rigid derivatives. J Med Chem 2000, 43, 17, 3315. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 | |
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| 33623 | bromo(methyl)magnesium | 75-16-1 | CH3BrMg | 详情 | 详情 | |
| (I) | 17992 | m-Cyanoacetophenone; 3-acetylbenzonitrile | 6136-68-1 | C9H7NO | 详情 | 详情 |
| (II) | 34665 | 3-(2-methyl-1,3-dioxolan-2-yl)benzonitrile | C11H11NO2 | 详情 | 详情 | |
| (III) | 34673 | 3-(2-methyl-1,3-dioxolan-2-yl)benzylamine; [3-(2-methyl-1,3-dioxolan-2-yl)phenyl]methanamine | C11H15NO2 | 详情 | 详情 | |
| (IV) | 34666 | 1-[3-(aminomethyl)phenyl]-1-ethanone | C9H11NO | 详情 | 详情 | |
| (V) | 34674 | N-(3-acetylbenzyl)acetamide | C11H13NO2 | 详情 | 详情 | |
| (VI) | 34667 | N-(3-cyanobenzyl)acetamide | C10H10N2O | 详情 | 详情 | |
| (VII) | 34668 | N-[3-(2-bromoacetyl)benzyl]acetamide | C11H12BrNO2 | 详情 | 详情 | |
| (VIII) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (IX) | 34669 | N-[3-(2-amino-1,3-thiazol-4-yl)benzyl]acetamide | C12H13N3OS | 详情 | 详情 | |
| (X) | 23530 | benzoyl isothiocyanate | 532-55-8 | C8H5NOS | 详情 | 详情 |
| (XI) | 34670 | N-[3-(2-[[(benzoylamino)carbothioyl]amino]-1,3-thiazol-4-yl)benzyl]acetamide | C20H18N4O2S2 | 详情 | 详情 | |
| (XII) | 34671 | N-(3-[2-[(aminocarbothioyl)amino]-1,3-thiazol-4-yl]benzyl)acetamide | C13H14N4OS2 | 详情 | 详情 | |
| (XIII) | 34672 | 4-[3-[(acetamido)methyl]phenyl]-2-[[(E)-amino(methylsulfanyl)methylidene]amino]-1,3-thiazole | C14H16N4OS2 | 详情 | 详情 | |
| (XIV) | 34675 | 2-methoxyethylamine; 2-methoxy-1-ethanamine | 109-85-3 | C3H9NO | 详情 | 详情 |