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【结 构 式】 
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【分子编号】35647 【品名】diethyl 2-bromomalonate 【CA登记号】685-87-0 |
【 分 子 式 】C7H11BrO4 【 分 子 量 】239.06594 【元素组成】C 35.17% H 4.64% Br 33.42% O 26.77% |
合成路线1
该中间体在本合成路线中的序号：(F)The condensation of 2,3-dichloroanisole (I) with isobutyryl chloride (D) by means of AlCl3 in CH2Cl2 gives 2',3'-dichloro-4'-methoxyisobutyrophenone (VII), which is brominated with Br2 in acetic acid yielding 2-bromo-2',3'-dichloro-4'-methoxyisobutyrophenone (VIII). The dehydrobromination of (VIII) with LiBr in DMF affords (IX), which is cyclized with H2SO4 giving 6,7-dichloro-2-methyl-5-methoxy-1-indanone (X). The phenylation of (X) with diphenyliodonium chloride (E) and potassium tert-butoxide in tert-butanol gives 6,7-dichloro-2-methyl-2-phenyl-5-methoxy-1-indanone (XI), which is demethylated with pyridine hydrochloride at 190 C yielding 6,7-dichloro-2-methyl-2-phenyl-5-hydroxy-1-indanone (XII). Finally, (XII) is treated first with ethyl bromoacetate (G) and K2CO3 in DMF, and then with KOH in hot water-methanol. The phenol (XII) can also be treated with chloroacetonitrile (H) and K2CO3 in acetone to give 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxyacetonitrile (XIII), which is finally hydrolyzed with H2SO4 in acetic acid. The phenol (XII) can also be condensed with diethyl bromomalonate (F) by means of NaH in dimethoxyethane giving diethyl 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxymalonate (XIV), which is hydrolyzed with Na2CO3 in refluxing ethanol yielding 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxymalonic acid (XV). Finally, this acid is decarboxylated by heating at 150 C.
| 【1】 Cragoe, E.J. Jr.; Woltersdorf, O.W. Jr. (Merck & Co., Inc.); Substituted indanones. DE 2448454; ES 430900; FR 2247218; GB 1474459 . |
| 【2】 Castaner, J.; Chatterjee, S.S.; MK 196. Drugs Fut 1977, 2, 3, 179. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (H) | 14443 | 2-chloroacetonitrile; chloroacetonitrile | 107-14-2 | C2H2ClN | 详情 | 详情 |
| (D) | 14932 | isobutyryl chloride; 2-methylpropanoyl chloride | 79-30-1 | C4H7ClO | 详情 | 详情 |
| (G) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (F) | 35647 | diethyl 2-bromomalonate | 685-87-0 | C7H11BrO4 | 详情 | 详情 |
| (E) | 40097 | diphenyliodonium chloride | 1483-72-3 | C12H10ClI | 详情 | 详情 |
| (I) | 40081 | 1,2-dichloro-3-methoxybenzene; 2,3-dichlorophenyl methyl ether | 1984-59-4 | C7H6Cl2O | 详情 | 详情 |
| (VII) | 40088 | 1-(2,3-dichloro-4-methoxyphenyl)-2-methyl-1-propanone | C11H12Cl2O2 | 详情 | 详情 | |
| (VIII) | 40089 | 2-bromo-1-(2,3-dichloro-4-methoxyphenyl)-2-methyl-1-propanone | C11H11BrCl2O2 | 详情 | 详情 | |
| (IX) | 40090 | 1-(2,3-dichloro-4-methoxyphenyl)-2-methyl-2-propen-1-one | C11H10Cl2O2 | 详情 | 详情 | |
| (X) | 40091 | 6,7-dichloro-5-methoxy-2-methyl-1-indanone | C11H10Cl2O2 | 详情 | 详情 | |
| (XI) | 40092 | 6,7-dichloro-5-methoxy-2-methyl-2-phenyl-1-indanone | C17H14Cl2O2 | 详情 | 详情 | |
| (XII) | 40093 | 6,7-dichloro-5-hydroxy-2-methyl-2-phenyl-1-indanone | C16H12Cl2O2 | 详情 | 详情 | |
| (XIII) | 40094 | 2-[(6,7-dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]acetonitrile | C18H13Cl2NO2 | 详情 | 详情 | |
| (XIV) | 40095 | diethyl 2-[(6,7-dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]malonate | C23H22Cl2O6 | 详情 | 详情 | |
| (XV) | 40096 | 2-[(6,7-dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]malonic acid | C19H14Cl2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Addition of 4-tolylmagnesium bromide (II) to 2,3-pyridinedicarboxylic acid anhydride (I) afforded ketoacid (III). Subsequent condensation of (III) with diethyl bromomalonate (VII) in the presence of Et3N, followed by DBU-promoted cyclization produced the pyridine lactone (VI). In an alternative procedure, acid (III) was converted to acid chloride (IV) using SOCl2, and then condensed with diethyl hydroxymalonate (V) in the presence of NaH to give (VI). The tertiary alcohol group of (VI) was then dehydrated with HCl in AcOH to give (VIII). Acid chloride (IX), prepared by treatment of (VIII) with SOCl2, was coupled with 3,5-bis(trifluoromethyl)benzylamine (X) to furnish amide (XI). The tetrahydropyranyl-protected aminoalcohol (XIII) was obtained by reduction of nitrile (XII) with LiAlH4. Reaction of (XIII) with lactone (XI), followed by treatment with DBU, produced the 1,7-naphthyridine system (XIV). Acid-catalyzed deprotection of the tetrahydropyranyl group yielded alcohol (XV).
| 【1】 Tanaka, T.; Kawada, M.; Ishichi, Y.; Kamo, I.; Ishimaru, T.; Fujishima, A.; Ikeura, Y.; Natsugari, H.; Doi, T.; Kasahara, F.; Axially chiral 1,7-naphthyridine-6-carboxamide derivatives as orally active tachykinin NK1 receptor antagonists: Synthesis, antagonistic activity, and effects on bladder functions. J Med Chem 1999, 42, 19, 3982. |
| 【2】 Natsugari, H.; Ishimaru, T.; Doi, T.; Ikeura, Y.; Kimura, C. (Takeda Chemical Industries, Ltd.); Cyclic cpds., their production and use as tachykinin receptor antagonists. CA 2172421; EP 0733632; JP 1997263585; JP 1997263587; US 5786352 . |
| 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) | 17247 | furo[3,4-b]pyridine-5,7-dione; 2,3-Pyridinedicarboxylic anhydride | 699-98-9 | C7H3NO3 | 详情 | 详情 |
| (II) | 35657 | bromo(4-methylphenyl)magnesium | 4294-57-9 | C7H7BrMg | 详情 | 详情 |
| (III) | 35643 | 3-(4-methylbenzoyl)-2-pyridinecarboxylic acid | C14H11NO3 | 详情 | 详情 | |
| (IV) | 35644 | 3-(4-methylbenzoyl)-2-pyridinecarbonyl chloride | C14H10ClNO2 | 详情 | 详情 | |
| (V) | 35645 | diethyl tartronate | C7H12O5 | 详情 | 详情 | |
| (VI) | 35646 | diethyl 5-hydroxy-5-(4-methylphenyl)-8-oxo-5,8-dihydro-6H-pyrano[3,4-b]pyridine-6,6-dicarboxylate | C21H21NO7 | 详情 | 详情 | |
| (VII) | 35647 | diethyl 2-bromomalonate | 685-87-0 | C7H11BrO4 | 详情 | 详情 |
| (VIII) | 35648 | 5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carboxylic acid | C16H11NO4 | 详情 | 详情 | |
| (IX) | 35649 | 5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carbonyl chloride | C16H10ClNO3 | 详情 | 详情 | |
| (X) | 35650 | [3,5-bis(trifluoromethyl)phenyl]methanamine; 3,5-bis(trifluoromethyl)benzylamine | 85068-29-7 | C9H7F6N | 详情 | 详情 |
| (XI) | 35651 | N-[3,5-bis(trifluoromethyl)benzyl]-5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carboxamide | C25H16F6N2O3 | 详情 | 详情 | |
| (XII) | 35652 | (3R)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile | C10H17NO2 | 详情 | 详情 | |
| (XIII) | 35653 | (3R)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butylamine; (3R)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)-1-butanamine | C10H21NO2 | 详情 | 详情 | |
| (XIV) | 35654 | N-[3,5-bis(trifluoromethyl)benzyl]-5-(4-methylphenyl)-7-[(3R)-3-methyl-4-(tetrahydro-2H-pyran-2-yloxy)butyl]-8-oxo-7,8-dihydro[1,7]naphthyridine-6-carboxamide | C35H35F6N3O4 | 详情 | 详情 | |
| (XV) | 35655 | N-[3,5-bis(trifluoromethyl)benzyl]-7-[(3R)-4-hydroxy-3-methylbutyl]-5-(4-methylphenyl)-8-oxo-7,8-dihydro[1,7]naphthyridine-6-carboxamide | C30H27F6N3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Lithiation of 5-benzyloxy-2-bromobenzaldehyde dimethyl acetal (I), followed by addition to N,N-dimethyl-3,4,5-trimethoxybenzamide (II), gave rise to benzophenone (III). After acetal hydrolysis using an acidic ion exchange resin, the resulting aldehyde (IV) was oxidized to carboxylic acid (V) by means of sodium chlorite. Condensation of this keto acid (V) with diethyl bromomalonate (VI), followed by acidic treatment, furnished the isocoumarin derivative (VII). Subsequent addition of water to the double bond upon treatment with NaOH in aqueous methanol produced (VIII). This compound was condensed with N-Boc-p-phenylenediamine (IX) in the presence of N-methylmorpholine in hot 1,3-dimethyl-2-imidazolinone to afford the isoquinolinone (X). The methyl ester (XI) was prepared by reaction of carboxylic acid (X) with iodomethane and K2CO3.
| 【1】 Ikeo, T.; Ukita, T.; Omori, K. (Tanabe Seiyaku Co., Ltd.); Isoquinolinone derivs., process for preparing the same, and their use as phosphodiesterase inhibitors. JP 1998298164; WO 9838168 . |
| 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) | 43965 | 4-(benzyloxy)-1-bromo-2-(dimethoxymethyl)benzene; benzyl 4-bromo-3-(dimethoxymethyl)phenyl ether | C16H17BrO3 | 详情 | 详情 | |
| (II) | 43966 | 3,4,5-trimethoxy-N,N-dimethylbenzamide | C12H17NO4 | 详情 | 详情 | |
| (III) | 43967 | [4-(benzyloxy)-2-(dimethoxymethyl)phenyl](3,4,5-trimethoxyphenyl)methanone | C26H28O7 | 详情 | 详情 | |
| (IV) | 43968 | 5-(benzyloxy)-2-(3,4,5-trimethoxybenzoyl)benzaldehyde | C24H22O6 | 详情 | 详情 | |
| (V) | 43969 | 5-(benzyloxy)-2-(3,4,5-trimethoxybenzoyl)benzoic acid | C24H22O7 | 详情 | 详情 | |
| (VI) | 35647 | diethyl 2-bromomalonate | 685-87-0 | C7H11BrO4 | 详情 | 详情 |
| (VII) | 43970 | 7-(benzyloxy)-1-oxo-4-(3,4,5-trimethoxyphenyl)-1H-isochromene-3-carboxylic acid | C26H22O8 | 详情 | 详情 | |
| (VIII) | 43971 | 7-(benzyloxy)-3-hydroxy-1-oxo-4-(3,4,5-trimethoxyphenyl)-3,4-dihydro-1H-isochromene-3-carboxylic acid | C26H24O9 | 详情 | 详情 | |
| (IX) | 43972 | 4-(N-Boc-aminomethyl)aniline;tert-butyl (4-aminophenyl)carbamate;tert-butyl 4-aminophenylcarbamate | C11H16N2O2 | 详情 | 详情 | |
| (X) | 43973 | 7-(benzyloxy)-2-[4-[(tert-butoxycarbonyl)amino]phenyl]-1-oxo-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-3-isoquinolinecarboxylic acid | C37H36N2O9 | 详情 | 详情 | |
| (XI) | 43974 | methyl 7-(benzyloxy)-2-[4-[(tert-butoxycarbonyl)amino]phenyl]-1-oxo-4-(3,4,5-trimethoxyphenyl)-1,2-dihydro-3-isoquinolinecarboxylate | C38H38N2O9 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)5-Nitrosalicylaldehyde (I) was condensed with diethyl bromomalonate (II) to give ethyl 5-nitrobenzofuran-2-carboxylate (III), which was converted into the corresponding primary amide (IV) by reaction with ethanolic ammonia. Dehydration of amide (IV) to the nitrile (V) was effected by treatment with POCl3. After formation of imidate (VI) with HCl/MeOH, cyclization with ethylenediamine produced the imidazoline (VII). The nitro group of (VII) was then reduced to amine (VIII) using Fe and HCl. This was finally converted to the title isothiocyanate by reaction with thiophosgene.
| 【1】 Hudson, A.L.; Nutt, D.J.; Grundt, P.; Coates, P.A.; Husbands, S.M.; Tyacke, R.; Robinson, E.S.J.; Lewis, J.W.; Probes for imidazole binding sites: Synthesis and evaluation of a selective, irreversible I2 ligand. Bioorg Med Chem Lett 2000, 10, 6, 605. |
| 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) | 42307 | 2-hydroxy-5-nitrobenzaldehyde；5-nitrosalicylaldehyde | 97-51-8 | C7H5NO4 | 详情 | 详情 |
| (II) | 35647 | diethyl 2-bromomalonate | 685-87-0 | C7H11BrO4 | 详情 | 详情 |
| (III) | 42308 | ethyl 5-nitro-1-benzofuran-2-carboxylate | 69404-00-8 | C11H9NO5 | 详情 | 详情 |
| (IV) | 42309 | 5-nitro-1-benzofuran-2-carboxamide | C9H6N2O4 | 详情 | 详情 | |
| (V) | 42310 | 5-nitro-1-benzofuran-2-carbonitrile | C9H4N2O3 | 详情 | 详情 | |
| (VI) | 42311 | methyl 5-nitro-1-benzofuran-2-carboximidoate | C10H8N2O4 | 详情 | 详情 | |
| (VII) | 42312 | 2-(5-nitro-1-benzofuran-2-yl)-4,5-dihydro-1H-imidazole | C11H9N3O3 | 详情 | 详情 | |
| (VIII) | 42313 | 2-(4,5-dihydro-1H-imidazol-2-yl)-1-benzofuran-5-amine; 2-(4,5-dihydro-1H-imidazol-2-yl)-1-benzofuran-5-ylamine | C11H11N3O | 详情 | 详情 |