|
【结 构 式】 
|
【分子编号】45766 【品名】methyl 5-hydroxy-3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate 【CA登记号】 |
【 分 子 式 】C20H22O3 【 分 子 量 】310.39288 【元素组成】C 77.39% H 7.14% O 15.46% |
合成路线1
该中间体在本合成路线中的序号：(VII)A new large-scaleable synthesis of TAK-779 has been developed: The reduction of 4'-methylbiphenyl-4-carbonitrile (I) with sodium bis(2-methoxyethoxy)aluminum hydride (SBMEA) in THF gives the corresponding aldehyde (II), which is submitted to a Wittig condensation with the phosphonium bromide (III) by means of NaOMe in methanol to yield the pentenoic acid derivative (IV). Reduction of the double bond of (IV) with H2 over Pd/C in THF, followed by cyclization with hot PPA affords the benzocycloheptanone (V), which is treated with refluxing dimethyl carbonate and NaOMe to provide the beta-ketoester (VI). The reduction of (VI) with NaBH4 in THF gives the hydroxyester (VII), which is dehydrated with Ms-Cl and DBU and hydrolyzed with NaOH to yield 8-(4-methylphenyl)benzocyclohept-1-ene-2-carboxylic acid (VIII). Condensation of (VIII) with 4-aminobenzyl alcohol (IX) by means of (COCl)2 and TEA in THF affords the corresponding amide (X), which is treated with SOCl2 in THF to provide the chloromethyl derivative (XI). Finally, this compound is condensed with 4-(dimethylamino)tetrahydropyran (XII) in hot DMF to furnish the target ammonium salt. The tertiary amine (XII) has been obtained by reductive condensation of tetrahydropyran-4-one (XIII) with dimethylamine by means of H2 over Pd/C in THF.
| 【1】 Ikemoto, T.; Hashimoto, H.; Kaarasaki, T.; Tomimatsu, K.; Ito, T.; Nishiguchi, A.; Wakimasu, M.; Mitsudera, H.; Development of a new synthetic route of a non-peptide CCR5 antagonist, TAK-779, for large-scale preparation. Org Process Res Dev 2000, 4, 6, 520. |
| 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) | 45764 | 4'-methyl[1,1'-biphenyl]-4-carbonitrile | C14H11N | 详情 | 详情 | |
| (II) | 18985 | 4'-methyl[1,1'-biphenyl]-4-carbaldehyde | C14H12O | 详情 | 详情 | |
| (III) | 37404 | (3-carboxypropyl)(triphenyl)phosphonium bromide | 17857-14-6 | C22H22BrO2P | 详情 | 详情 |
| (IV) | 45765 | (Z)-5-(4'-methyl[1,1'-biphenyl]-4-yl)-4-pentenoic acid | C18H18O2 | 详情 | 详情 | |
| (V) | 31555 | 3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C18H18O | 详情 | 详情 | |
| (VI) | 33422 | methyl 3-(4-methylphenyl)-5-oxo-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate | C20H20O3 | 详情 | 详情 | |
| (VII) | 45766 | methyl 5-hydroxy-3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-6-carboxylate | C20H22O3 | 详情 | 详情 | |
| (VIII) | 31560 | 2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxylic acid | C19H18O2 | 详情 | 详情 | |
| (IX) | 34430 | (4-aminophenyl)methanol | 623-04-1 | C7H9NO | 详情 | 详情 |
| (X) | 33424 | N-[4-(hydroxymethyl)phenyl]-2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxamide | C26H25NO2 | 详情 | 详情 | |
| (XI) | 33425 | N-[4-(chloromethyl)phenyl]-2-(4-methylphenyl)-6,7-dihydro-5H-benzo[a]cycloheptene-8-carboxamide | C26H24ClNO | 详情 | 详情 | |
| (XII) | 33426 | N,N-dimethyltetrahydro-2H-pyran-4-amine; N,N-dimethyl-N-tetrahydro-2H-pyran-4-ylamine | C7H15NO | 详情 | 详情 | |
| (XIII) | 31563 | tetrahydro-4H-pyran-4-one | 29943-42-8 | C5H8O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)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 |