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【结 构 式】 
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【分子编号】22761 【品名】3,5-dimethoxybenzoic acid 【CA登记号】1132-21-4 |
【 分 子 式 】C9H10O4 【 分 子 量 】182.176 【元素组成】C 59.34% H 5.53% O 35.13% |
合成路线1
该中间体在本合成路线中的序号：(X)In a further procedure, 3,5-dimethoxybenzoic acid (X) was converted to the acetophenone (XI) using methyllithium. Treatment of (XI) with phenyltrimethylammonium tribromide provided the dibromoacetophenone (XII) which, upon reaction with morpholine at 55 C, followed by hydrolysis with aqueous HCl, gave the phenylglyoxal (VIII). Alternatively, (VIII) was prepared directly by treating acetophenone (XI) with DMSO and HBr or by oxidation with SeO2. Condensation of the phenylglyoxal (VIII) with methyl glyoxylate hemiacetal (XIII) and ammonium acetate produced the phenylimidazole (XIV), which was protected as the tetrahydrofuranyl derivative (XVI) with dihydrofuran and catalytic p-TsOH. Reduction of the protected imidazole ester (XVI) with LiBH4 provided alcohol (XVII), and then reaction of (XVII) with trichloroacetonitrile in the presence of DBU furnished the acetimidate (XVIII). Finally, the target compound was obtained by reaction of ascomycin (I) with trichloroacetimidate (XVIII) in the presence of fluoboric acid etherate, followed by hydrolytic deprotection.
| 【1】 Mathre, D.J.; Sohar, P.; Shuman, R.F.; Song, Z. (Merck & Co., Inc.); Process for the preparation of imidazolyl macrolide immunosuppressants. JP 1999512096; US 5777105; WO 9708182 . |
| 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) | 14951 | (1R,9S,12S,13R,14S,17R,21S,23S,24R,25S,27R)-17-ethyl-1,14-dihydroxy-12-[(E)-2-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethenyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetron | C43H69NO12 | 详情 | 详情 | |
| (VIII) | 22759 | 1-(3,5-dimethoxyphenyl)-2,2-dihydroxy-1-ethanone | C10H12O5 | 详情 | 详情 | |
| (X) | 22761 | 3,5-dimethoxybenzoic acid | 1132-21-4 | C9H10O4 | 详情 | 详情 |
| (XI) | 22762 | 1-(3,5-dimethoxyphenyl)-1-ethanone | 39151-19-4 | C10H12O3 | 详情 | 详情 |
| (XII) | 22763 | 2,2-dibromo-1-(3,5-dimethoxyphenyl)-1-ethanone | C10H10Br2O3 | 详情 | 详情 | |
| (XIII) | 22764 | methyl 2-hydroxy-2-methoxyacetate | 19757-97-2 | C4H8O4 | 详情 | 详情 |
| (XIV) | 22765 | methyl 4-(3,5-dimethoxyphenyl)-1H-imidazole-2-carboxylate | C13H14N2O4 | 详情 | 详情 | |
| (XV) | 22766 | 2,3-dihydrofuran | 1191-99-7 | C4H6O | 详情 | 详情 |
| (XVI) | 22767 | methyl 4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazole-2-carboxylate | C17H20N2O5 | 详情 | 详情 | |
| (XVI) | 22768 | [4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methanol | C16H20N2O4 | 详情 | 详情 | |
| (XVIII) | 22769 | [4-(3,5-dimethoxyphenyl)-1-tetrahydro-2-furanyl-1H-imidazol-2-yl]methyl 2,2,2-trichloroethanimidoate | C18H20Cl3N3O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reduction of 3,5-dimethoxybenzoic acid (I) first with Li in liquid NH3 and methanol, and then with LiAlH4 in THF gives 3,5-dimethoxy-1,4-dihydrobenzyl alcohol (II), which is cyclized with phenylhydrazine (III) in refluxing 4% sulfuric acid yielding 2-(hydroxymethyl)-1,2,3,4-tetrahydrocarbazol-4-one (IV). The reaction of (IV) with tosyl chloride in pyridine affords the corresponding tosylate (V), which is finally condensed with 4-(4-fluorobenzoyl)piperidine (VI) in N-methyl-2-pyrrolidone.
| 【1】 Masaguer, C.F.; Formoso, E.; Raviña, E.; Tristán, H.; Loza, M.I.; Rivas, E.; Fontenla, J.A.; Butyrophenone analogues in the carbazole series: Synthesis and determination of affinities at D2 and 5-HT2A receptors. Bioorg Med Chem Lett 1998, 8, 24, 3571. |
| 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) | 22761 | 3,5-dimethoxybenzoic acid | 1132-21-4 | C9H10O4 | 详情 | 详情 |
| (II) | 25566 | (3,5-dimethoxy-2,5-cyclohexadien-1-yl)methanol | C9H14O3 | 详情 | 详情 | |
| (III) | 11818 | Phenyl hydrazine; 1-Phenylhydrazine | 100-63-0 | C6H8N2 | 详情 | 详情 |
| (IV) | 25567 | 2-(hydroxymethyl)-1,2,3,9-tetrahydro-4H-carbazol-4-one | C13H13NO2 | 详情 | 详情 | |
| (V) | 25568 | (4-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)methyl 4-methylbenzenesulfonate | C20H19NO4S | 详情 | 详情 | |
| (VI) | 21497 | (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine | 56346-57-7 | C12H14FNO | 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 condensation of 3,5-dimethoxybenzoic acid (I) with 4-(4-fluorobenzoyl)piperidine (II) by means of DCC and HOBT in DMF gives the piperidide (III), which is reduced with LiAlH4 in THF to yield 1-(3,5-dimethoxybenzyl)-4-(4-fluorobenzoyl)piperidine (IV). The reduction of (IV) with Li in liquid ammonia affords the 1,4-dihydro derivative (V), which is finally cyclized with phenylhydrazine (VI) in refluxing aqueous sulfuric acid to provide the target tetrahydrocarbazolone.
| 【1】 Masaguer, C.F.; Loza, M.I.; Fontenla, J.A.; Brea, J.; Raviña, E.; Tristan, H.; Butyrophenone analogues in the carbazole series as potential atypical antipsychotics: Synthesis and determination of affinities at D2, 5-HT2A, 5-HT2B and 5-HT2C receptors. Eur J Med Chem 2000, 35, 1, 83. |
| 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) | 22761 | 3,5-dimethoxybenzoic acid | 1132-21-4 | C9H10O4 | 详情 | 详情 |
| (II) | 21497 | (4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine | 56346-57-7 | C12H14FNO | 详情 | 详情 |
| (III) | 51415 | (3,5-dimethoxyphenyl)[4-(4-fluorobenzoyl)-1-piperidinyl]methanone | C21H22FNO4 | 详情 | 详情 | |
| (IV) | 51416 | [1-(3,5-dimethoxybenzyl)-4-piperidinyl](4-fluorophenyl)methanone | C21H24FNO3 | 详情 | 详情 | |
| (V) | 51417 | [1-[(3,5-dimethoxy-2,5-cyclohexadien-1-yl)methyl]-4-piperidinyl](4-fluorophenyl)methanone | C21H26FNO3 | 详情 | 详情 | |
| (VI) | 11818 | Phenyl hydrazine; 1-Phenylhydrazine | 100-63-0 | C6H8N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)The reduction of 3,5-dimethoxybenzoic acid (I) first with Li in liquid NH3 and methanol, and then with LiAlH4 in THF gives 3,5-dimethoxy-1,4-dihydrobenzyl alcohol (II), which is cyclized with phenylhydrazine (III) in refluxing 4% sulfuric acid yielding 2-(hydroxymethyl)-1,2,3,4-tetrahydrocarbazol-4-one (IV). The reaction of (IV) with tosyl chloride in pyridine affords the corresponding tosylate (V), which is finally condensed with 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (VI) in N-methyl-2-pyrrolidone.
| 【1】 Masaguer, C.F.; Formoso, E.; Raviña, E.; Tristán, H.; Loza, M.I.; Rivas, E.; Fontenla, J.A.; Butyrophenone analogues in the carbazole series: Synthesis and determination of affinities at D2 and 5-HT2A receptors. Bioorg Med Chem Lett 1998, 8, 24, 3571. |
| 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) | 22761 | 3,5-dimethoxybenzoic acid | 1132-21-4 | C9H10O4 | 详情 | 详情 |
| (II) | 25566 | (3,5-dimethoxy-2,5-cyclohexadien-1-yl)methanol | C9H14O3 | 详情 | 详情 | |
| (III) | 11818 | Phenyl hydrazine; 1-Phenylhydrazine | 100-63-0 | C6H8N2 | 详情 | 详情 |
| (IV) | 25567 | 2-(hydroxymethyl)-1,2,3,9-tetrahydro-4H-carbazol-4-one | C13H13NO2 | 详情 | 详情 | |
| (V) | 25568 | (4-oxo-2,3,4,9-tetrahydro-1H-carbazol-2-yl)methyl 4-methylbenzenesulfonate | C20H19NO4S | 详情 | 详情 | |
| (VI) | 17910 | 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole | C12H13FN2O | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)The condensation of 3,5-dimethoxybenzoic acid (I) with 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (II) by means of DCC and HOBT in DMF gives the piperidide (III), which is reduced with LiAlH4 in THF to yield 1-(3,5-dimethoxybenzyl)-4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (IV). The reduction of (IV) with Li in liquid ammonia affords the 1,4-dihydro derivative (V), which is finally cyclized with phenylhydrazine (VI) in refluxing aqueous sulfuric acid to provide the target tetrahydrocarbazolone.
| 【1】 Masaguer, C.F.; Loza, M.I.; Fontenla, J.A.; Brea, J.; Raviña, E.; Tristan, H.; Butyrophenone analogues in the carbazole series as potential atypical antipsychotics: Synthesis and determination of affinities at D2, 5-HT2A, 5-HT2B and 5-HT2C receptors. Eur J Med Chem 2000, 35, 1, 83. |
| 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) | 22761 | 3,5-dimethoxybenzoic acid | 1132-21-4 | C9H10O4 | 详情 | 详情 |
| (II) | 17910 | 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole | C12H13FN2O | 详情 | 详情 | |
| (III) | 51420 | (3,5-dimethoxyphenyl)[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methanone | C21H21FN2O4 | 详情 | 详情 | |
| (IV) | 51418 | 3-[1-(3,5-dimethoxybenzyl)-4-piperidinyl]-6-fluoro-1,2-benzisoxazole; 3-[[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl]-5-methoxyphenyl methyl ether | C21H23FN2O3 | 详情 | 详情 | |
| (V) | 51419 | 3-[[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]methyl]-5-methoxy-1,4-cyclohexadien-1-yl methyl ether; 3-[1-[(3,5-dimethoxy-2,5-cyclohexadien-1-yl)methyl]-4-piperidinyl]-6-fluoro-1,2-benzisoxazole | C21H25FN2O3 | 详情 | 详情 | |
| (VI) | 11818 | Phenyl hydrazine; 1-Phenylhydrazine | 100-63-0 | C6H8N2 | 详情 | 详情 |