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【结 构 式】 
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【分子编号】40668 【品名】dichloro(methoxy)methane; dichloromethyl methyl ether 【CA登记号】4885-02-3 |
【 分 子 式 】C2H4Cl2O 【 分 子 量 】114.95856 【元素组成】C 20.9% H 3.51% Cl 61.68% O 13.92% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of 2,3-dihydrobenzofuran (I) with dichloromethyl methyl ether (II) by means of TiCl4 in dichloromethane gives 2,3-dihydrobenzofuran-5-carbaldehyde (III), which is condensed with the phosphonate (IV) by means of NaH in THF to yield the propenoic ester (V). The reduction of (V) with H2 over Pd/C in ethanol affords the saturated propionic ester (VI), which is brominated with Br2 in HOAc providing the 7-bromo derivative (VII). Further bromination of (VII) with Br2 and Fe in HOAc gives the 6,7-dibromo derivative (VIII), which is hydrolyzed with NaOH in THF/water to yield the propionic acid derivative (IX). The reaction of (IX) with hot SOCl2 affords the corresponding acyl chloride (X), which is cyclized by means of AlCl3 in dichloroethane to provide 4,5-dibromo-2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (XI). The debromination of (XI) by means of H2 over Pd/C in Ac-OH gives 2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-one (XII), which is condensed with the phosphorane (XIII) by means of NaH in THF to yield 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)acetonitrile (XIV). The selective reduction of the cyano group of (XIV) by means of H2 over Raney cobalt in ethanol/NH3 affords 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)ethylamine (XV), which is condensed with propionyl chloride (XVI) by means of TEA in THF to provide the propionamide (XVII). Finally this compound is enantioselectively reduced with H2 over a chiral Ru catalyst (Ru(OAc)2-(S)-BINAP) in methanol to give rise to the target (S)-enantiomer. Alternatively, the reduction of 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-ylidene)acetonitrile (XIV) with H2 over RaNi in ethanol/NH3 gives 2-(2,6,7,8-tetrahydro-1H-indeno[5,4-b]furan-8-yl)ethylamine (XVIII), which is acylated with propionyl chloride (XVI) and TEA in DMF to yield the racemic propionamide (XIX). Finally this compound is submitted to optical resolution by means of chiral HPLC to afford the target (S)-enantiomer.
| 【1】 Chilman-Blair, K.; Castaner, J.; Silvestre, J.S.; Bayes, M.; TAK-375. Drugs Fut 2003, 28, 10, 950. |
| 【2】 Ohkawa, S.; Uchikawa, O.; Fukatsu, K.; Miyamoto, M. (Takeda Chemical Industries, Ltd.); Tricyclic cpds., their production and use. EP 0885210; JP 1998287665; JP 1999152281; WO 9732871 . |
| 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) | 14499 | 2,3-Dihydrobenzofuran; 2,3-dihydro-1-benzofuran | 496-16-2 | C8H8O | 详情 | 详情 |
| (II) | 40668 | dichloro(methoxy)methane; dichloromethyl methyl ether | 4885-02-3 | C2H4Cl2O | 详情 | 详情 |
| (III) | 52198 | 2,3-Dihydrobenzo[b]furan-5-carboxaldehyde | C9H8O2 | 详情 | 详情 | |
| (IV) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (V) | 57393 | ethyl (E)-3-(2,3-dihydro-1-benzofuran-5-yl)-2-propenoate | C13H14O3 | 详情 | 详情 | |
| (VI) | 57394 | ethyl 3-(2,3-dihydro-1-benzofuran-5-yl)propanoate | C13H16O3 | 详情 | 详情 | |
| (VII) | 57395 | ethyl 3-(7-bromo-2,3-dihydro-1-benzofuran-5-yl)propanoate | C13H15BrO3 | 详情 | 详情 | |
| (VIII) | 57396 | ethyl 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoate | C13H14Br2O3 | 详情 | 详情 | |
| (IX) | 57397 | 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoic acid | C11H10Br2O3 | 详情 | 详情 | |
| (X) | 57398 | 3-(6,7-dibromo-2,3-dihydro-1-benzofuran-5-yl)propanoyl chloride | C11H9Br2ClO2 | 详情 | 详情 | |
| (XI) | 57399 | 4,5-dibromo-1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one | C11H8Br2O2 | 详情 | 详情 | |
| (XII) | 57400 | 1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-one | C11H10O2 | 详情 | 详情 | |
| (XIII) | 10045 | Diethyl cyanomethylphosphonate | 2537-48-6 | C6H12NO3P | 详情 | 详情 |
| (XIV) | 57401 | 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)acetonitrile | C13H11NO | 详情 | 详情 | |
| (XV) | 57402 | 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)-1-ethanamine; 2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethylamine | C13H15NO | 详情 | 详情 | |
| (XVI) | 15967 | propanoyl chloride; propionyl chloride | 79-03-8 | C3H5ClO | 详情 | 详情 |
| (XVII) | 57403 | N-[2-(1,2,6,7-tetrahydro-8H-indeno[5,4-b]furan-8-ylidene)ethyl]propanamide | C16H19NO2 | 详情 | 详情 | |
| (XVIII) | 57404 | 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)-1-ethanamine; 2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethylamine | C13H17NO | 详情 | 详情 | |
| (XIX) | 57405 | N-[2-(1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl)ethyl]propanamide | C16H21NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：Ethyl 6-azaindole-3-carboxylate (I) was formylated using dichloromethyl methyl ether and AlCl3 to provide aldehyde (II). Nitrogen protection in (II) with benzenesulfonyl chloride and NaH gave sulfonyl derivative (III). Subsequent Wittig condensation of (III) with (ethoxycarbonylmethylene)triphenyl phosphorane produced the unsaturated ester (IV). Finally, removal of the benzenesulfonyl protecting group of (IV) was effected by treatment with ethanolic NaOEt.
| 【1】 Le Hyaric, M.; Doisy, X.; Dekhane, M.; et al.; Synthesis and benzodiazepine receptor (omega receptor) affinities of 3-substituted derivatives of pyrrolo[2,3-c]pyridine-5-carboxylate, a novel class of omega1 selective ligands. Bioorg Med Chem 1999, 7, 5, 921. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 14182 | ethyl 2-(triphenyl-lambda(5)-phosphanylidene)acetate; (Carbethoxymethylene)triphenylphosphorane | 1099-45-2 | C22H21O2P | 详情 | 详情 | |
| 14713 | benzenesulfonyl chloride | 98-09-9 | C6H5ClO2S | 详情 | 详情 | |
| 40668 | dichloro(methoxy)methane; dichloromethyl methyl ether | 4885-02-3 | C2H4Cl2O | 详情 | 详情 | |
| (I) | 26182 | ethyl 1H-pyrrolo[2,3-c]pyridine-5-carboxylate | C10H10N2O2 | 详情 | 详情 | |
| (II) | 26183 | ethyl 3-formyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylate | C11H10N2O3 | 详情 | 详情 | |
| (III) | 26184 | ethyl 3-formyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate | C17H14N2O5S | 详情 | 详情 | |
| (IV) | 26185 | ethyl 3-[(E)-3-ethoxy-3-oxo-1-propenyl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate | C21H20N2O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)An alternative route was based on the formylation of (III) with dichloromethyl methyl ether (IX) in the presence of tin chloride. The resultant aldehyde ester (X) was then reduced to diol (VIII) by means of LiBH4. The crude trifluoroacetate ester obtained by treatment of diol (VIII) with trifluoroacetic anhydride was then refluxed with isopropanol to furnish the title isopropyl ether.
| 【1】 Hudkins, R.L.; Gingrich, D.E. (Cephalon, Inc.); Selected fused pyrrolocarbazoles. WO 0217914 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 59387 | ethyl 3-(5-oxo-5,6,7,13-tetrahydro-12H-indeno[2,1-a]pyrrolo[3,4-c]carbazol-12-yl)propanoate | C26H22N2O3 | 详情 | 详情 | |
| (VIII) | 59392 | 9-(hydroxymethyl)-12-(3-hydroxypropyl)-6,7,12,13-tetrahydro-5H-indeno[2,1-a]pyrrolo[3,4-c]carbazol-5-one | C25H22N2O3 | 详情 | 详情 | |
| (IX) | 40668 | dichloro(methoxy)methane; dichloromethyl methyl ether | 4885-02-3 | C2H4Cl2O | 详情 | 详情 |
| (X) | 59393 | ethyl 3-(9-formyl-5-oxo-5,6,7,13-tetrahydro-12H-indeno[2,1-a]pyrrolo[3,4-c]carbazol-12-yl)propanoate | C27H22N2O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)An alternative route was based on the formylation of (III) with dichloromethyl methyl ether (IX) in the presence of tin chloride. The resultant aldehyde ester (X) was then reduced to the already reported diol (VIII) by means of LiBH4. The crude trifluoroacetate ester obtained by treatment of diol (VIII) with trifluoroacetic anhydride was then refluxed with isopropanol to furnish the isopropyl ether (XI). The remaining hydroxyl group was finally esterified by treatment with N,N-dimethylglycine (XII) in the presence of EDC and DMAP.
| 【1】 Hudkins, R.L.; Gingrich, D.E. (Cephalon, Inc.); Selected fused pyrrolocarbazoles. WO 0217914 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (III) | 59387 | ethyl 3-(5-oxo-5,6,7,13-tetrahydro-12H-indeno[2,1-a]pyrrolo[3,4-c]carbazol-12-yl)propanoate | C26H22N2O3 | 详情 | 详情 | |
| (VIII) | 59392 | 9-(hydroxymethyl)-12-(3-hydroxypropyl)-6,7,12,13-tetrahydro-5H-indeno[2,1-a]pyrrolo[3,4-c]carbazol-5-one | C25H22N2O3 | 详情 | 详情 | |
| (IX) | 40668 | dichloro(methoxy)methane; dichloromethyl methyl ether | 4885-02-3 | C2H4Cl2O | 详情 | 详情 |
| (X) | 59393 | ethyl 3-(9-formyl-5-oxo-5,6,7,13-tetrahydro-12H-indeno[2,1-a]pyrrolo[3,4-c]carbazol-12-yl)propanoate | C27H22N2O4 | 详情 | 详情 | |
| (XI) | 59394 | 12-(3-hydroxypropyl)-9-(isopropoxymethyl)-6,7,12,13-tetrahydro-5H-indeno[2,1-a]pyrrolo[3,4-c]carbazol-5-one | C28H28N2O3 | 详情 | 详情 | |
| (XII) | 16765 | 2-(dimethylamino)acetic acid; N,N-Dimethylglycine | 1118-68-9 | C4H9NO2 | 详情 | 详情 |