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【结 构 式】 
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【分子编号】22915 【品名】1,1-dimethoxy-N,N-dimethyl-1-ethanamine;N,N-dimethylacetamide dimethylacetal; N-(1,1-dimethoxyethyl)-N,N-dimethylamine 【CA登记号】18871-66-4 |
【 分 子 式 】C6H15NO2 【 分 子 量 】133.19064 【元素组成】C 54.11% H 11.35% N 10.52% O 24.02% |
合成路线1
该中间体在本合成路线中的序号：(IV)This compound can be obtained by two related ways: 1) The hydrogenation of 4-(diisopropylamino)-2-phenyl-2-(2-pyridyl)butyramide (I) with H2 over PtO2 in acidic water gives the corresponding piperidine derivative (II), which is acetylated with acetic anhydride to the acetylpiperidine (III). Finally, this compound is cyclized by means of KOH in DMSO. 2) The cyclization of piperidine derivative (II) whith dimethylacetamide dimethyl ketal (IV) at 80 C also yields the final produc
| 【1】 McLaughlin, K.T.; Chorvat, R.J.; Stamm, M.H.; Adelstein, G.W.; Stickney, J.L.; Rydzewski, R.M.; Prodan, K.A.; Frederick, L.G.; Schniepp, H.C.; Synthesis and structure-activity relationships of a new series of antiarrhythmic agents: 4,4-disubstituted hexahydro-3H-pyrido[1,2-c]pyrimidin-3-ones and related compounds. J Med Chem 1985, 28, 9, 1285. |
| 【2】 Adelstein, G.W.; Chorvat, R.J. (Pharmacia Corp.); Pyridopyrimidinones. EP 0104647; US 4560754 . |
| 【3】 Baxter, A.D.; Boyd, E.A.; Price, S.; Guicherit, O.M.; Porter, J.; Rubin, L.E. (Curis, Inc.); Small organic molecule regulators of cell proliferation. US 6613798; US 6683108; WO 0174344 . |
| 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) | 22912 | 4-(diisopropylamino)-2-phenyl-2-(2-pyridinyl)butanamide | 3737-09-5 | C21H29N3O | 详情 | 详情 |
| (II) | 22913 | 4-(diisopropylamino)-2-phenyl-2-(2-piperidinyl)butanamide | C21H35N3O | 详情 | 详情 | |
| (III) | 22914 | 2-(1-acetyl-2-piperidinyl)-4-(diisopropylamino)-2-phenylbutanamide | C23H37N3O2 | 详情 | 详情 | |
| (IV) | 22915 | 1,1-dimethoxy-N,N-dimethyl-1-ethanamine;N,N-dimethylacetamide dimethylacetal; N-(1,1-dimethoxyethyl)-N,N-dimethylamine | 18871-66-4 | C6H15NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The reaction of 5-cyano-5-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxocyclohexanecarboxylic acid methyl ester (I) with trifluoromethanesulfonic anhydride gives the enol triflate (II), which is desulfonated with triphenylphosphine, palladium acetate and formic acid yielding 5-cyano-5-(3-cyclopentyloxy-4-methoxyphenyl)-1-clohexene-1-carboxylic acid methyl ester (III). The hydrogenation of the double bond of (III) with H2 over Pd/C in methanol affords the cis carboxylic ester (IV), which is hydrolyzed with KOH in in methanol to provide the free carboxylic acid (V). The reaction of (V) with isobutyl chloroformate and then with NH4OH gives the corresponding amide (VI), which is finally cyclized with N,N-dimethylacetamide dimethylacetal (VII) by heating at 110 C to obtain target compound as a racemate.
| 【1】 Board, M.; Newsholme, E.A. (Isis Pharmaceuticals, Inc.); Use of glucokinase inhibitors for the manufacture of a medicament for treating tumours. WO 9503809 . |
| 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) | 16515 | methyl 5-cyano-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-oxocyclohexanecarboxylate | C21H25NO5 | 详情 | 详情 | |
| (II) | 26690 | methyl 5-cyano-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-[[(trifluoromethyl)sulfonyl]oxy]-1-cyclohexene-1-carboxylate | C22H24F3NO7S | 详情 | 详情 | |
| (III) | 26691 | methyl 5-cyano-5-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-cyclohexene-1-carboxylate | C21H25NO4 | 详情 | 详情 | |
| (IV) | 26692 | methyl (1S,3R)-3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylate | C21H27NO4 | 详情 | 详情 | |
| (V) | 26693 | (1S,3R)-3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylic acid | C20H25NO4 | 详情 | 详情 | |
| (VI) | 26694 | (1S,3R)-3-cyano-3-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxamide | C20H26N2O3 | 详情 | 详情 | |
| (VII) | 22915 | 1,1-dimethoxy-N,N-dimethyl-1-ethanamine;N,N-dimethylacetamide dimethylacetal; N-(1,1-dimethoxyethyl)-N,N-dimethylamine | 18871-66-4 | C6H15NO2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Treatment of 2-aminobenzonitrile (V) with N,N-dimethylacetamide dimethylacetal (VI) at 115 °C yields N’-(2-cyanophenyl)-N,N-dimethylacetamidine (VII), which by cyclization with 4-methoxyaniline (VIII) in AcOH/acetonitrile at 118 °C gives N-(4-methoxyphenyl)- 2-methylquinazolin-4-amine (IX). Finally, the secondary amine group in compound (IX) is methylated by means of NaH in DMF .
Intramolecular cyclization of the acetamidine (II) with 4-methoxy-N-methylaniline (IV) in the presence of AlCl3 in NMP at 200 °C (5).
| 【1】 Foucourt, A., Dubouilh-Benard, C., Chosson, E. et al. Microwave-accelerated Dimroth rearrangement for the synthesis of 4-anilino-6-nitroquinazolines. Application to an efficient synthesis of a microtubule destabilizing agent. Tetrahedron 2010, 66(25): 4495. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 69159 | 4-methoxy-N-methylaniline hydrochloride | C8H11NO.HCl | 详情 | 详情 | |
| (V) | 19493 | 2-aminobenzonitrile | 1885-29-6 | C7H6N2 | 详情 | 详情 |
| (VI) | 22915 | 1,1-dimethoxy-N,N-dimethyl-1-ethanamine;N,N-dimethylacetamide dimethylacetal; N-(1,1-dimethoxyethyl)-N,N-dimethylamine | 18871-66-4 | C6H15NO2 | 详情 | 详情 |
| (VIII) | 10478 | p-Anisidine; 4-Methoxyaniline; 4-Methoxyphenylamine | 104-94-9 | C7H9NO | 详情 | 详情 |
| (IX) | 69161 | N-(4-methoxyphenyl)-2-methylquinazolin-4-amine | C16H15N3O | 详情 | 详情 |