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【结 构 式】 
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【分子编号】34197 【品名】dimethyl carbonate 【CA登记号】616-38-6 |
【 分 子 式 】C3H6O3 【 分 子 量 】90.07884 【元素组成】C 40% H 6.71% O 53.28% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of 4-(1H-imidazol-1-yl)acetophenone (I) with dimethyl carbonate (III) by means of NaH in THF gives methyl 4-(1H-imidazol-1-yl)-beta-oxobenzenepropanoate (III), which by condensation with ethyl bromoacetate (IV) by means of NaH in THF is converted into ethyl 4-(1H-imidazol-1-yl-beta-(methoxycarbonyl)-gamma-oxobenzenebutanoate (V). Hydrolytic decarboxylation of (VI) in refluxing 6N HCl yields 4-(1H-imidazol-1-yl)-gamma-oxobenzenebutanoic acid (VI), which is finally cyclized with hydrazine in refluxing ethanol.
| 【1】 Sircar, I.; Bristol, J.A.; Substituted 4,5-dihydro-6-(substituted)-phenyl-3(2H)-pyridazinones and 6-(substituted)phenyl-3(2H)-pyridazinones. CA 1190548; DD 208615; EP 0075436 . |
| 【2】 Serradell, M.N.; Castaner, J.; CI-914. Drugs Fut 1984, 9, 4, 256. |
| 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) | 17772 | 4'-(Imidazol-1-yl)acetophenone; 1-[4-(1H-imidazol-1-yl)phenyl]-1-ethanone | 10041-06-2 | C11H10N2O | 详情 | 详情 |
| (II) | 34197 | dimethyl carbonate | 616-38-6 | C3H6O3 | 详情 | 详情 |
| (III) | 34198 | methyl 3-[4-(1H-imidazol-1-yl)phenyl]-3-oxopropanoate | C13H12N2O3 | 详情 | 详情 | |
| (IV) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (V) | 34199 | 4-ethyl 1-methyl 2-[4-(1H-imidazol-1-yl)benzoyl]succinate | C17H18N2O5 | 详情 | 详情 | |
| (VI) | 34200 | 4-[4-(1H-imidazol-1-yl)phenyl]-4-oxobutyric acid | C13H12N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The condensation of 4-fluorobenzaldehyde (I) with ethyl acetoacetate (II) by means of piperidine, followed by a treatment with hot NaOH and esterification with methanol in acid medium, gives 3-(4-fluorophenyl)glutaric acid dimethyl ester (III), which is stereoselectively hydrolyzed with liver esterase in aqueous acetone, yielding the monoester (IV) with a 95% ee. The selective reduction of the ester group of (IV) with LiH and LiBH4 in THF affords the chiral 5-hydroxypentanoic acid (V), which is esterified with dimethyl sulfate in methanol to the corresponding methyl ester (VI). The reaction of (VI) with MsCl and TEA in toluene gives the mesylate (VII), which is cyclized with benzylamine (VIII) and TEA in toluene, affording the chiral piperidone (IX).The reaction of (IX) with dimethyl carbonate (X) and NaH in hot toluene yields the chiral carboxylate (XI), which is reduced at the carboxylate and ketonic groups with LiAlH4 or BH3 in DMSO, providing the chiral piperidine methanol derivative (XII). The reaction of (XII) with MsCl and TEA in toluene yields the mesylate (XIII), which is condensed with the phenol derivative (XIV) by means of NaH in hot DMF, affording the adduct (XV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C.
| 【1】 Yu, M.S.; Lantos, I.; Cacchio, T.; Peng, Z.-Q.; Yu, J.; Asymmetric synthesis of (-)-paroxetine using PLE hydrolysis. Tetrahedron Lett 2000, 41, 30, 5647. |
| 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) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (II) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (III) | 44013 | dimethyl 3-(4-fluorophenyl)pentanedioate | C13H15FO4 | 详情 | 详情 | |
| (IV) | 44014 | (3S)-3-(4-fluorophenyl)-5-methoxy-5-oxopentanoic acid | C12H13FO4 | 详情 | 详情 | |
| (V) | 44015 | lithium (3R)-3-(4-fluorophenyl)-5-hydroxypentanoate | C11H12FLiO3 | 详情 | 详情 | |
| (VI) | 44016 | methyl (3R)-3-(4-fluorophenyl)-5-hydroxypentanoate | C12H15FO3 | 详情 | 详情 | |
| (VII) | 44017 | methyl (3R)-3-(4-fluorophenyl)-5-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]pentanoate | C15H21FO3S | 详情 | 详情 | |
| (VIII) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (IX) | 44018 | (4R)-1-benzyl-4-(4-fluorophenyl)-2-piperidinone | C18H18FNO | 详情 | 详情 | |
| (X) | 34197 | dimethyl carbonate | 616-38-6 | C3H6O3 | 详情 | 详情 |
| (XI) | 44019 | methyl (3S,4R)-1-benzyl-4-(4-fluorophenyl)-2-oxo-3-piperidinecarboxylate | C20H20FNO3 | 详情 | 详情 | |
| (XII) | 44020 | [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methanol | C19H22FNO | 详情 | 详情 | |
| (XIII) | 44021 | (3S,4R)-1-benzyl-4-(4-fluorophenyl)-3-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)piperidine | C22H28FNOS | 详情 | 详情 | |
| (XIV) | 10985 | 1,3-Benzodioxol-5-ol; Sesamol | 533-31-3 | C7H6O3 | 详情 | 详情 |
| (XV) | 44022 | (3S,4R)-3-[(1,3-benzodioxol-5-yloxy)methyl]-1-benzyl-4-(4-fluorophenyl)piperidine; 1,3-benzodioxol-5-yl [(3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidinyl]methyl ether | C26H26FNO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)A new process for the preparation of oxcarbamazepine has been reported: Reaction of 1-phenyl-2,3-dihydro-1H-indol-2-one (I) with NaOH in refluxing THF gives 2-[2-(phenylamino)phenyl]acetic acid (II), which is condensed with dimethyl carbonate (III) by means of butyl lithium in the same solvent to yield 2-[2-[N-(methoxycarbonyl)-N-phenylamino]phenyl]acetic acid (IV). Cyclization of compound (IV) by means of polyphosphoric acid (PPA) at 100 C, followed by treatment of the reaction mixture with hot methanol (65 C) affords 10-methoxy-5H-dibenzo[b,f]azepine-5-carboxylic acid methyl ester (V), which is treated with NaOH in polyethyleneglycol at 100 C to provide 10-methoxy-5H-dibenzo[b,f]azepine (VI). Reaction of (VI) with sodium cyanate in acetic acid gives 10-methoxy-5H-dibenzo[b,f]azepine-5-carboxamide (VII), which is finally treated with H2SO4.
| 【1】 Kaufmann, D.; Lohse, O.; Zaugg, W.; Funfschilling, P.; Beutler, U. (Novartis AG; Novartis-Erfindungen VmbH); Dibenzo [b,f]azepine derivs. and their preparation. WO 0156992 . |
| 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) | 52656 | 1-phenyl-1,3-dihydro-2H-indol-2-one | C14H11NO | 详情 | 详情 | |
| (II) | 52657 | 2-[2-(phenylamino)phenyl]acetic acid | C14H13NO2 | 详情 | 详情 | |
| (III) | 34197 | dimethyl carbonate | 616-38-6 | C3H6O3 | 详情 | 详情 |
| (IV) | 52658 | 2-{2-[[(methyloxy)carbonyl](phenyl)amino]phenyl}acetic acid | C16H15NO4 | 详情 | 详情 | |
| (V) | 52659 | methyl 10-(methyloxy)-5H-dibenzo[b,f]azepine-5-carboxylate | C17H15NO3 | 详情 | 详情 | |
| (VI) | 24333 | 10-methoxy-5H-dibenzo[b,f]azepine;10-Methoxyiminostilbene | 4698-11-7 | C15H13NO | 详情 | 详情 |
| (VII) | 24335 | 10-methoxy-5H-dibenzo[b,f]azepine-5-carboxamide | C16H14N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(V)The triarylcarbinol intermediate (IV) is obtained by two different ways: 1. The reaction of 2-chloro-4-methoxypyridine-3-carboxylic acid (I) with (COCl)2 in dichloromethane gives the acyl chloride (II), which is condensed with 2-methylsulfanylpyrimidin-4-yl lithium salt (III) in THF to yield the triarylcarbinol (IV). 2. The reaction of the lithium salt (III) with 0.4 equiv. of diethyl carbonate (V) in THF gives the symmetric ketone (VI), which is then condensed with the 2-chloro-4-methoxypyridin-3-yl lithium salt (VII) in THF to yield the desired triarylcarbinol intermediate (IV). The cyclization of the triarylcarbinol intermediate (IV) by means of Tes-H and TEA in 1,2-dichloroethane at 100 C gives the desired core structure (VIII), which is oxidized at its sulfanyl groups with MCPBA in chloroform to yield the sulfinyl derivative (IX). The reaction of (IX) with 4-methoxybenzylamine (X) at 85 ?C affords the protected diamine (XI). The demethylation of (XI) by means of EtS-Na in hot DMF provides the pyridinol (XII), which is finally N-deprotected by means of triflic acid to yield the target variolin B (1).
| 【1】 Morris, J.C.; Anderson, R.J.; Total synthesis of variolin B. Tetrahedron Lett 2001, 42, 49, 8697. |
| 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) | 55708 | 2-chloro-4-methoxynicotinic acid | C7H6ClNO3 | 详情 | 详情 | |
| (II) | 55709 | 2-chloro-4-methoxynicotinoyl chloride | C7H5Cl2NO2 | 详情 | 详情 | |
| (III) | 55710 | [2-(methylsulfanyl)-4-pyrimidinyl]lithium | C5H5LiN2S | 详情 | 详情 | |
| (IV) | 55711 | (2-chloro-4-methoxy-3-pyridinyl){bis[2-(methylsulfanyl)-4-pyrimidinyl]}methanol | C17H16ClN5O2S2 | 详情 | 详情 | |
| (V) | 34197 | dimethyl carbonate | 616-38-6 | C3H6O3 | 详情 | 详情 |
| (VI) | 55712 | bis[2-(methylsulfanyl)-4-pyrimidinyl]methanone | C11H10N4OS2 | 详情 | 详情 | |
| (VII) | 55713 | (2-chloro-4-methoxy-3-pyridinyl)lithium | C6H5ClLiNO | 详情 | 详情 | |
| (VIII) | 55714 | 4-methoxy-9-(methylsulfanyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine; methyl 9-(methylsulfanyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-4-yl ether | C17H15N5OS2 | 详情 | 详情 | |
| (IX) | 55715 | 4-[4-methoxy-9-(methylsulfinyl)pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-5-yl]-2-pyrimidinyl methyl sulfoxide; 4-methoxy-9-(methylsulfinyl)-5-[2-(methylsulfinyl)-4-pyrimidinyl]pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine | C17H15N5O3S2 | 详情 | 详情 | |
| (X) | 15098 | 4-Methoxybenzylamine; (4-Methoxyphenyl)methanamine | 2393-23-9 | C8H11NO | 详情 | 详情 |
| (XI) | 55716 | N-(4-methoxybenzyl)-N-(4-{4-methoxy-9-[(4-methoxybenzyl)amino]pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-5-yl}-2-pyrimidinyl)amine; 4-methoxy-N-(4-methoxybenzyl)-5-{2-[(4-methoxybenzyl)amino]-4-pyrimidinyl}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-9-amine | C31H29N7O3 | 详情 | 详情 | |
| (XII) | 55717 | 9-[(4-methoxybenzyl)amino]-5-{2-[(4-methoxybenzyl)amino]-4-pyrimidinyl}pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidin-4-ol | C30H27N7O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)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 |