|
【结 构 式】 
|
【分子编号】31561 【品名】2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carbonyl chloride 【CA登记号】 |
【 分 子 式 】C19H17ClO 【 分 子 量 】296.79608 【元素组成】C 76.89% H 5.77% Cl 11.95% O 5.39% |
合成路线1
该中间体在本合成路线中的序号：(IX)Suzuki coupling of 3-bromo-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (I) with 4-methylphenylboronic acid (II) by means of palladium tetrakis(triphenylphosphine) gave (III). Subsequent refluxing of (III) with dimethyl carbonate in the presence of NaOMe afforded ketoester (IV). This was reduced with NaBH4 to give hydroxy ester (V), which was then dehydrated and hydrolyzed to the unsaturated acid (VI) with HCl in diglyme at 100 C. Alternatively, ketone (III) was carboxylated under CO2 atmosphere in the presence of either potassium carbonate or potassium tert-butoxide. The resulting ketoacid (VII) was reduced to hydroxyacid (VIII) with NaBH4, and then dehydrated to (VI) using 80% formic acid at 100 C. Carboxylic acid (VI) was then converted to the corresponding acid chloride (IX) by means of oxalyl chloride in CH2Cl2.
| 【1】 Shiraishi, M.; Aramaki, Y.; Seto, M.; et al.; Discovery of small molecule CCR5 antagonists. 19th Symp Med Chem and 8th Annu Meet Div Med Chem Jpn (Nov 17-19, Tokyo) 1999, Abst 2P-06. |
| 【2】 Kitayoshi, T.; Aramaki, Y.; Oda, T.; Honda, S.; Shiraishi, M. (Takeda Chemical Industries, Ltd.); Anilide deriv., production and use thereof. JP 1999263764; WO 9932468 . |
| 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) | 31554 | 3-bromo-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C11H11BrO | 详情 | 详情 | |
| (II) | 15540 | 4-methylphenylboronic acid; p-Tolylboronic acid | 5720-05-8 | C7H9BO2 | 详情 | 详情 |
| (III) | 31555 | 3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C18H18O | 详情 | 详情 | |
| (IV) | 31556 | ethyl 3-(4-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate | C21H22O3 | 详情 | 详情 | |
| (V) | 31557 | ethyl 5-hydroxy-3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate | C21H24O3 | 详情 | 详情 | |
| (VI) | 31560 | 2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxylic acid | C19H18O2 | 详情 | 详情 | |
| (VII) | 31558 | 3-(4-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylic acid | C19H18O3 | 详情 | 详情 | |
| (VIII) | 31559 | 5-hydroxy-3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylic acid | C19H20O3 | 详情 | 详情 | |
| (IX) | 31561 | 2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carbonyl chloride | C19H17ClO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)Reductive condensation of p-nitrobenzylamine (X) with tetrahydropyran-4-one (XI) in the presence of sodium triacetoxyborohydride gave the tetrahydropyranylamine (XII), and further reductive condensation with formaldehyde afforded the tertiary amine (XIII). Reduction of the nitro group of (XIII) with iron in acetic acid yielded aniline (XIV), which was coupled with acid chloride (IX) to give amide (XV). Quaternization of (XV) with methyl iodide in DMF produced the ammonium iodide (XVI). This was finally converted to the title chloride salt employing an ion exchange resin.
| 【1】 Kitayoshi, T.; Aramaki, Y.; Oda, T.; Honda, S.; Shiraishi, M. (Takeda Chemical Industries, Ltd.); Anilide deriv., production and use thereof. JP 1999263764; WO 9932468 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 31561 | 2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carbonyl chloride | C19H17ClO | 详情 | 详情 | |
| (X) | 31562 | (4-nitrophenyl)methanamine; 4-nitrobenzylamine | C7H8N2O2 | 详情 | 详情 | |
| (XI) | 31563 | tetrahydro-4H-pyran-4-one | 29943-42-8 | C5H8O2 | 详情 | 详情 |
| (XII) | 31564 | N-(4-nitrobenzyl)-N-tetrahydro-2H-pyran-4-ylamine; N-(4-nitrobenzyl)tetrahydro-2H-pyran-4-amine | C12H16N2O3 | 详情 | 详情 | |
| (XIII) | 31565 | N-methyl-N-(4-nitrobenzyl)tetrahydro-2H-pyran-4-amine; N-methyl-N-(4-nitrobenzyl)-N-tetrahydro-2H-pyran-4-ylamine | C13H18N2O3 | 详情 | 详情 | |
| (XIV) | 31566 | N-(4-aminobenzyl)-N-methyltetrahydro-2H-pyran-4-amine; N-(4-aminobenzyl)-N-methyl-N-tetrahydro-2H-pyran-4-ylamine | C13H20N2O | 详情 | 详情 | |
| (XV) | 31567 | 2-(4-methylphenyl)-N-(4-[[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxamide | C32H36N2O2 | 详情 | 详情 | |
| (XVI) | 31568 | N,N-dimethyl-N-[4-([[2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cyclohepten-8-yl]carbonyl]amino)benzyl]tetrahydro-2H-pyran-4-aminium iodide | C33H39IN2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)1. The reaction of benzocycloheptanone (I) with dimethyl carbonate (II) and NaOMe gives the beta ketoester (III), which is reduced with NaBH4 in methanol to yield the hydroxyester (IV). The dehydration of (IV) by means of Ms-Cl and DBU, followed by hydrolysis with NaOH, affords the unsaturated carboxylic acid (V), which by reaction with oxalyl chloride is converted into the acyl chloride (VI). The condensation of (V) with aniline (VII) by means of TEA in DMF provides the amide (VIII), which by reaction with trimethyl phosphate (IX) gives the adduct (X), which rearranges to the ammonium phosphate (XI). Finally, this compound is converted into the target ammonium chloride by treatment with HCl. 2. Alternatively, benzocycloheptanone (I) is condensed with triethyl orthoformate (XII) by means of BF3 /Et2O giving the aldehyde diethyl acetal (XIII), which by reduction with NaBH4 and dehydration with 6N HCl yields the unsaturated aldehyde (XIV). Finally, this compound is oxidized with NaClO2 and H2O2 in toluene/phosphate buffer to afford the already reported unsaturated carboxylic acid (V).
| 【1】 Ikemoto, T.; et al.; Convenient efficient synthesis of TAK-779, a nonpeptide CCR5 antagonist: Development of preparation of various ammonium salts using trialkylphosphite and N-halogenosuccinimide. Tetrahedron 2001, 57, 8, 1525. |
| 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) | 31555 | 3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C18H18O | 详情 | 详情 | |
| (II) | 34197 | dimethyl carbonate | 616-38-6 | C3H6O3 | 详情 | 详情 |
| (III) | 33422 | methyl 3-(4-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate | C20H20O3 | 详情 | 详情 | |
| (IV) | 45766 | methyl 5-hydroxy-3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate | C20H22O3 | 详情 | 详情 | |
| (V) | 31560 | 2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxylic acid | C19H18O2 | 详情 | 详情 | |
| (VI) | 31561 | 2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carbonyl chloride | C19H17ClO | 详情 | 详情 | |
| (VII) | 31566 | N-(4-aminobenzyl)-N-methyltetrahydro-2H-pyran-4-amine; N-(4-aminobenzyl)-N-methyl-N-tetrahydro-2H-pyran-4-ylamine | C13H20N2O | 详情 | 详情 | |
| (VIII) | 31567 | 2-(4-methylphenyl)-N-(4-[[methyl(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxamide | C32H36N2O2 | 详情 | 详情 | |
| (IX) | 55364 | trimethyl phosphate | C3H9O4P | 详情 | 详情 | |
| (X) | 55366 | trimethoxy{methyl[4-({[2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cyclohepten-8-yl]carbonyl}amino)benzyl]tetrahydro-2H-pyran-4-ylammonio}phosphoranolate | C35H45N2O6P | 详情 | 详情 | |
| (XI) | 55365 | N,N-dimethyl-N-[4-({[2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cyclohepten-8-yl]carbonyl}amino)benzyl]tetrahydro-2H-pyran-4-aminium dimethoxy(oxo)phosphoranolate | C35H45N2O6P | 详情 | 详情 | |
| (XII) | 21304 | Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether | 122-51-0 | C7H16O3 | 详情 | 详情 |
| (XIII) | 55367 | 6-(diethoxymethyl)-3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C23H28O3 | 详情 | 详情 | |
| (XIV) | 55368 | 2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carbaldehyde | C19H18O | 详情 | 详情 |