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【结 构 式】 
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【分子编号】27189 【品名】trimethyl[2-(trimethylsilyl)ethynyl]silane 【CA登记号】14630-40-1 |
【 分 子 式 】C8H18Si2 【 分 子 量 】170.40192 【元素组成】C 56.39% H 10.65% Si 32.96% |
合成路线1
该中间体在本合成路线中的序号：(II)The reaction of cyclopropanecarbonyl chloride (I) with bis(trimethylsilyl)acetylene (II) gives 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-one (III), which is reduced with NaBH4 and CeCl3 in methanol to the corresponding propynol (IV). The condensation of (IV) with 3-hydroxy-4,5-dimethoxybenzaldehyde (V) by means of triphenylphosphine and dimethyl azodicarboxylate in toluene yields the expected propynyl ether (VI), which is cyclized in N,N-diethylaniline at 200 C affording 2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carbaldehyde (VII). The condensation of (VII) with 3-anilinopropionitrile (VIII) by means of potassium tert-butoxide in DMSO gives the acrylonitrile (IX), which is finally cyclized with guanidine (X) by means of potassium tert-butoxide in ethanol. (1)
| 【1】 Sorbera, L.A.; Castañer, J.; Rabasseda, X.; Iclaprim. Drugs Fut 2004, 29, 3, 220. |
| 【2】 Masciadri, R. (F. Hoffmann-La Roche AG); Diaminopyrimidines, pharmaceutical compsns. containing them and their use as antibacterial. EP 0866791; JP 2000501399; US 5773446; WO 9720839 . |
| 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) | 14061 | Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride | 4023-34-1 | C4H5ClO | 详情 | 详情 |
| (II) | 27189 | trimethyl[2-(trimethylsilyl)ethynyl]silane | 14630-40-1 | C8H18Si2 | 详情 | 详情 |
| (III) | 27190 | 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-one | C9H14OSi | 详情 | 详情 | |
| (IV) | 27191 | 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-ol | C9H16OSi | 详情 | 详情 | |
| (V) | 27192 | 3-hydroxy-4,5-dimethoxybenzaldehyde | C9H10O4 | 详情 | 详情 | |
| (VI) | 27193 | 3-[[1-cyclopropyl-3-(trimethylsilyl)-2-propynyl]oxy]-4,5-dimethoxybenzaldehyde | C18H24O4Si | 详情 | 详情 | |
| (VII) | 27194 | 2-cyclopropyl-7,8-dimethoxy-2H-chromene-5-carbaldehyde | C15H16O4 | 详情 | 详情 | |
| (VIII) | 27195 | 3-anilinopropanenitrile | 1075-76-9 | C9H10N2 | 详情 | 详情 |
| (IX) | 27196 | 3-(2-cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl)-2-[(phenylimino)methyl]propanenitrile | C24H24N2O3 | 详情 | 详情 | |
| (X) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)The reaction of cyclopropanecarbonyl chloride (I) with bis(trimethylsilyl)acetylene (II) gives 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-one (III), which is reduced with NaBH4 and CeCl3 in methanol to the corresponding propynol (IV). The condensation of propynol (IV) with 3-hydroxy-4,5-dimethoxybenzoic acid methyl ester (XI) by means of triphenylphosphine and dimethyl azodicarboxylate in toluene yields the expected propynyl ether (XII), which is cyclized in N,N-diethylaniline at 200 C affording 2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carboxylic acid methyl ester (XIII). Finally, this compound is reduced with NaAlH2(OCH2CH2)2 and morpholine in toluene to give the previously described 2-cyclopropyl-7,8-dimethoxy-2H-1-benzopyran-5-carbaldehyde (VII). The condensation of (VII) with 3-anilinopropionitrile (VIII) by means of potassium tert-butoxide in DMSO gives the acrylonitrile (IX), which is finally cyclized with guanidine (X) by means of potassium tert-butoxide in ethanol.
| 【1】 Masciadri, R. (F. Hoffmann-La Roche AG); Diaminopyrimidines, pharmaceutical compsns. containing them and their use as antibacterial. EP 0866791; JP 2000501399; US 5773446; WO 9720839 . |
| 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) | 14061 | Cyclopropanecarbonyl chloride; Cyclopropanecarboxylic acid chloride | 4023-34-1 | C4H5ClO | 详情 | 详情 |
| (II) | 27189 | trimethyl[2-(trimethylsilyl)ethynyl]silane | 14630-40-1 | C8H18Si2 | 详情 | 详情 |
| (III) | 27190 | 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-one | C9H14OSi | 详情 | 详情 | |
| (IV) | 27191 | 1-cyclopropyl-3-(trimethylsilyl)-2-propyn-1-ol | C9H16OSi | 详情 | 详情 | |
| (VII) | 27194 | 2-cyclopropyl-7,8-dimethoxy-2H-chromene-5-carbaldehyde | C15H16O4 | 详情 | 详情 | |
| (VIII) | 27195 | 3-anilinopropanenitrile | 1075-76-9 | C9H10N2 | 详情 | 详情 |
| (IX) | 27196 | 3-(2-cyclopropyl-7,8-dimethoxy-2H-chromen-5-yl)-2-[(phenylimino)methyl]propanenitrile | C24H24N2O3 | 详情 | 详情 | |
| (X) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (XI) | 27197 | methyl 3-hydroxy-4,5-dimethoxybenzoate | C10H12O5 | 详情 | 详情 | |
| (XII) | 27198 | methyl 3-[[1-cyclopropyl-3-(trimethylsilyl)-2-propynyl]oxy]-4,5-dimethoxybenzoate | C19H26O5Si | 详情 | 详情 | |
| (XIII) | 27199 | methyl 2-cyclopropyl-7,8-dimethoxy-2H-chromene-5-carboxylate | C16H18O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)The nitration of 2-(3,4-dichlorophenyl)acetic acid (I) with HNO3 and H2SO4 gives 2-(4,5-dichloro-2-nitrophenyl)acetic acid (II), which is treated with refluxing SOCl2 to yield the corresponding acyl chloride (III). The condensation of (III) with bis(trimethylsilyl)acetylene (IV) by means of AlCl3 in dichloromethane affords 1-(2-nitro-4,5-dichlorophenyl)-4-(trimethylsilyl)-3-butyn-2-one (V), which is submitted to a reductive cyclization by means of Fe/AcOH to provide 5,6-dichloro-2-ethynyl-1H-indole (VI) after desilylation with NaOH in methanol. The reaction of (VI) with (Bu3Sn)BuCuCNLi2 gives 5,6-dichloro-2-[2(E)-(tributylstannyl)vinyl]-1H-indole (VII), which is condensed with methyl 3-bromo-2-methoxy-2-propenoate (VIII) by means of Pd(PPh3)4 in hot THF to yield the pentadienoic ester (IX). The hydrolysis of (IX) with LiOH in MeOH affords the corresponding carboxylic acid (X), which is finally condensed with the amine (XI) by means of EDC and HOBT in dichloromethane to provide the target amide.
| 【1】 Conde, J.J.; McGuire, M.; Wallace, M.; Towards the synthesis of osteoclast inhibitor SB-242784. Tetrahedron Lett 2003, 44, 15, 3081. |
| 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) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (II) | 63912 | 2-(4,5-dichloro-2-nitrophenyl)acetic acid | C8H5Cl2NO4 | 详情 | 详情 | |
| (III) | 63913 | 2-(4,5-dichloro-2-nitrophenyl)acetyl chloride | C8H4Cl3NO3 | 详情 | 详情 | |
| (IV) | 27189 | trimethyl[2-(trimethylsilyl)ethynyl]silane | 14630-40-1 | C8H18Si2 | 详情 | 详情 |
| (V) | 63914 | 1-(4,5-dichloro-2-nitrophenyl)-4-(trimethylsilyl)-3-butyn-2-one | C13H13Cl2NO3Si | 详情 | 详情 | |
| (VI) | 63915 | 5,6-dichloro-2-ethynyl-1H-indole | C10H5Cl2N | 详情 | 详情 | |
| (VII) | 63916 | 5,6-dichloro-2-[(E)-2-(tributylstannyl)ethenyl]-1H-indole | C22H33Cl2NSn | 详情 | 详情 | |
| (VIII) | 23638 | C5H7BrO3 | 详情 | 详情 | ||
| (IX) | 19103 | methyl (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoate | C15H13Cl2NO3 | 详情 | 详情 | |
| (X) | 19104 | (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoic acid | C14H11Cl2NO3 | 详情 | 详情 | |
| (XI) | 20119 | 1,2,2,6,6-pentamethyl-4-piperidinamine; 1,2,2,6,6-pentamethyl-4-piperidinylamine | C10H22N2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The nitration of 2-(3,4-dichlorophenyl)acetic acid (I) with HNO3 and H2SO4 gives 2-(4,5-dichloro-2-nitrophenyl)acetic acid (II), which is treated with refluxing SOCl2 to yield the corresponding acyl chloride (III). The condensation of (III) with bis(trimethylsilyl)acetylene (IV) by means of AlCl3 in dichloromethane affords 1-(2-nitro-4,5-dichlorophenyl)-4-(trimethylsilyl)-3-butyn-2-one (V), which is submitted to a reductive cyclization by means of Fe/AcOH to provide 5,6-dichloro-2-ethynyl-1H-indole (VI) after desilylation with NaOH in methanol. The condensation of (VI) with methyl 3-bromo-2-methoxy-2-propenoate (VII) by means of Pd(PPh3)4 and CuI in hot DMF yields the penta-2-en-4-ynoic ester (VIII), which is reduced by means of H2 over Lindlar catalyst to obtain, as expected, dienoic ester (IX) as a ZZ/EZ mixture, which is treated directly with a catalytic amount of I2 in refluxing toluene to afford dienoic ester (X) as a single isomer. Alternatively, the reduction of (VIII) to (X) can also be performed with CrSO4 in DMF, however, the yields are low. The hydrolysis of (X) with LiOH in MeOH affords the corresponding carboxylic acid (XI), which is finally condensed with the amine (XII) by means of EDC and HOBT in dichloromethane to provide the target amide.
| 【1】 Conde, J.J.; McGuire, M.; Wallace, M.; Towards the synthesis of osteoclast inhibitor SB-242784. Tetrahedron Lett 2003, 44, 15, 3081. |
| 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) | 30414 | 2-(3,4-dichlorophenyl)acetic acid；2-(3,4-Dichlorophenyl)acetic acid | 5807-30-7 | C8H6Cl2O2 | 详情 | 详情 |
| (II) | 63912 | 2-(4,5-dichloro-2-nitrophenyl)acetic acid | C8H5Cl2NO4 | 详情 | 详情 | |
| (III) | 63913 | 2-(4,5-dichloro-2-nitrophenyl)acetyl chloride | C8H4Cl3NO3 | 详情 | 详情 | |
| (IV) | 27189 | trimethyl[2-(trimethylsilyl)ethynyl]silane | 14630-40-1 | C8H18Si2 | 详情 | 详情 |
| (V) | 63914 | 1-(4,5-dichloro-2-nitrophenyl)-4-(trimethylsilyl)-3-butyn-2-one | C13H13Cl2NO3Si | 详情 | 详情 | |
| (VI) | 63915 | 5,6-dichloro-2-ethynyl-1H-indole | C10H5Cl2N | 详情 | 详情 | |
| (VII) | 23638 | C5H7BrO3 | 详情 | 详情 | ||
| (VIII) | 63918 | methyl (Z)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2-penten-4-ynoate | C15H11Cl2NO3 | 详情 | 详情 | |
| (IX) | 63919 | methyl (2Z,4Z)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoate | C15H13Cl2NO3 | 详情 | 详情 | |
| (X) | 19103 | methyl (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoate | C15H13Cl2NO3 | 详情 | 详情 | |
| (XI) | 19104 | (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoic acid | C14H11Cl2NO3 | 详情 | 详情 | |
| (XIII) | 20119 | 1,2,2,6,6-pentamethyl-4-piperidinamine; 1,2,2,6,6-pentamethyl-4-piperidinylamine | C10H22N2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)Chloroacetyl chloride (I) is condensed with bis(trimethylsilyl)acetylene (II) in the presence of AlCl3 to provide 1-chloro-4-(trimethylsilyl)-3-butyn-2-one (III). Cyclization of chloro ketone (III) with thioacetamide (IV) affords the ethynylthiazole derivative (V). Finally, palladium-catalyzed coupling of (V) with 3-bromopyridine (VI) gives rise to the target diarylacetylene.
| 【1】 Cosford, N.D.P.; Tehrani, L.; Roppe, J.; Schweiger, E.; Smith, N.D.; Anderson, J.; Bristow, L.; Brodkin, J..; Jiang, X.; McDonald, I.; Rao, S.; Washburn, M.; Varney, M.A.; 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]- pyridine: A potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity. J Med Chem 2003, 46, 2, 204. |
| 【2】 McDonald, I.A.; Munoz, B.; Vernier, J.-M.; Cosford, N.D.P.; Varney, M.A.; Hess, S.D.; Bleicher, L.S.; Cube, R.V.; Schweiger, E.J. (Merck & Co., Inc.); Heterocyclic cpds. and methods of use thereof. JP 2003508390; WO 0116121 . |
| 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) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (II) | 27189 | trimethyl[2-(trimethylsilyl)ethynyl]silane | 14630-40-1 | C8H18Si2 | 详情 | 详情 |
| (III) | 63351 | 1-chloro-4-(trimethylsilyl)-3-butyn-2-one | C7H11ClOSi | 详情 | 详情 | |
| (IV) | 19170 | ethanethioamide | 62-55-5 | C2H5NS | 详情 | 详情 |
| (V) | 63352 | 2-methyl-4-[2-(trimethylsilyl)ethynyl]-1,3-thiazole | C9H13NSSi | 详情 | 详情 | |
| (VI) | 13265 | 3-Bromopyridine | 626-55-1 | C5H4BrN | 详情 | 详情 |