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【结 构 式】 
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【分子编号】19104 【品名】(2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoic acid 【CA登记号】 |
【 分 子 式 】C14H11Cl2NO3 【 分 子 量 】312.15168 【元素组成】C 53.87% H 3.55% Cl 22.72% N 4.49% O 15.38% |
合成路线1
该中间体在本合成路线中的序号：(XVII)Bromination of methyl methoxyacetate (XIII) with NBS in the presence of benzoyl peroxide in refluxing CCl4 gave (XIV), which was treated with triphenylphosphine to produce the phosphonium salt (XV). Then, phosphonium salt (XV) was condensed with aldehyde (XII) in the presence of DBU in THF to afford indolylpentadienoate (XVI). Finally, ester (XVI) was hydrolyzed to acid (XVII) and then condensed with amine (XVIII) to provide the title amide.
| 【1】 Consolandi, E.; Nadler, G.; Gagliardi, S.; et al.; 5-(5,6-Dichloro-2-indolyl)-2-methoxy-2, 4-pentadienamides: Novel and selective inhibitors of the vacuolar H+-ATPase of osteoclasts with bone antiresorptive activity. J Med Chem 1998, 41, 10, 1568. |
| 【2】 Farina, C.; Gagliardi, S.; Parini, C.; Pinza, M.; Nadler, G.M.M.G.; Morvan, M.J.-M. (SmithKline Beecham SpA); Indole derivs. useful in the treatment of osteoporosis. JP 1998512251; WO 9621644 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XII) | 19099 | (E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propenal | C11H7Cl2NO | 详情 | 详情 | |
| (XIII) | 19100 | methyl 2-methoxyacetate | 6290-49-9 | C4H8O3 | 详情 | 详情 |
| (XIV) | 19101 | methyl 2-bromo-2-methoxyacetate | C4H7BrO3 | 详情 | 详情 | |
| (XV) | 19102 | (1,2-dimethoxy-2-oxoethyl)(triphenyl)phosphonium bromide | C22H22BrO3P | 详情 | 详情 | |
| (XVI) | 19103 | methyl (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoate | C15H13Cl2NO3 | 详情 | 详情 | |
| (XVII) | 19104 | (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoic acid | C14H11Cl2NO3 | 详情 | 详情 | |
| (XVIII) | 19105 | (1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-ylamine; (1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine | C8H16N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)3,4-Dichlorotoluene (I) was nitrated with HNO3 in H2SO4, and the resulting nitrotoluene (II) was condensed with diethyl oxalate in the presence of KOEt to give the phenylpyruvic derivative (III). Then, reductive cyclization of (III) with Fe and AcOH produced ethyl 5,6-dichloroindole-2-carboxylate (IV). Further reduction of (IV) with LiAlH4 yielded alcohol (V), which was oxidized to aldehyde (VI) with MnO2 in Et2O. Horner-Emmons reaction of (VI) with triethyl phosphonoacetate (VII) afforded the indolylpropenoate (VIII). This was reduced to the allyl alcohol (IX) with DIBAL-H, and subsequently oxidized with MnO2 to afford the propenaldehyde (X). In a shorter procedure, Wittig reaction of (VI) with formylmethylene triphenylphosphorane (XI) yielded also propenaldehyde (X) along with the homologated pentadienaldehyde. Phosphonium bromide (XIV) was prepared by bromination of methyl methoxyacetate (XII) with NBS in the presence of dibenzoyl peroxide, followed by condensation of the resulting bromide (XIII) with PPh3. Wittig reaction of this phosphonium reagent with aldehyde (X) in the presence of DBU in boiling THF gave ester (XV). Subsequent saponification of (XV) with ethanolic KOH yielded acid (XVI). The aminopiperidine (XX) was synthesized by N-methylation of tetramethylpiperidone (XVII), followed by formation of the oxime (XIX) and catalytic reduction over Rh/C. Then, condensation of amine (XX) with acid (XVI) using 1-ethyl-3-(dimethylaminopropyl)carbodiimide-HCl (EDC) and 1-hydroxy-7-azabenzotriazole (HOAt) in DMF furnished the target compound.
| 【1】 Consolandi, E.; Nadler, G.; Gagliardi, S.; et al.; 5-(5,6-Dichloro-2-indolyl)-2-methoxy-2, 4-pentadienamides: Novel and selective inhibitors of the vacuolar H+-ATPase of osteoclasts with bone antiresorptive activity. J Med Chem 1998, 41, 10, 1568. |
| 【2】 Nadler, G.; Morvan, M.; Delimoge, I.; Belfiore, P.; Zocchetti, A.; James, I.; Zembryki, D.; Lee-Rycakzewski, E.; Parini, C.; Consolandi, E.; Gagliardi, S.; Farina, C.; (2Z,4E)-5-(5,6-Dichloro-2-indolyl)-2-methoxy-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-2,4-pentadienamide, a novel, potent and selective inhibitor of the osteoclast V-ATPase. Bioorg Med Chem Lett 1998, 8, 24, 3621. |
| 【3】 Yu, M.S.; et al.; Synthesis of 2-dienylindole, SB 242784, by a three-component palladium-catalyzed coupling reaction. Tetrahedron Lett 1998, 39, 51, 9347. |
| 【4】 Farina, C.; Nadler, G.M.M.G.; Gagliardi, S. (GlaxoSmithKline SpA); Indole derivs. for the treatment of osteoporosis. US 2002173659 . |
| 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) | 20100 | 1,2-dichloro-4-methylbenzene | 95-75-0 | C7H6Cl2 | 详情 | 详情 |
| (II) | 19088 | 1,2-dichloro-4-methyl-5-nitrobenzene | C7H5Cl2NO2 | 详情 | 详情 | |
| (III) | 19089 | ethyl 3-(4,5-dichloro-2-nitrophenyl)-2-oxopropanoate | C11H9Cl2NO5 | 详情 | 详情 | |
| (IV) | 19093 | ethyl 5,6-dichloro-1H-indole-2-carboxylate | C11H9Cl2NO2 | 详情 | 详情 | |
| (V) | 19094 | (5,6-dichloro-1H-indol-2-yl)methanol | C9H7Cl2NO | 详情 | 详情 | |
| (VI) | 19095 | 5,6-dichloro-1H-indole-2-carbaldehyde | C9H5Cl2NO | 详情 | 详情 | |
| (VII) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (VIII) | 19097 | ethyl (E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propenoate | C13H11Cl2NO2 | 详情 | 详情 | |
| (IX) | 19098 | (E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propen-1-ol | C11H9Cl2NO | 详情 | 详情 | |
| (X) | 19099 | (E)-3-(5,6-dichloro-1H-indol-2-yl)-2-propenal | C11H7Cl2NO | 详情 | 详情 | |
| (XI) | 20110 | 2-(triphenylphosphoranyl)acetaldehyde | C20H19OP | 详情 | 详情 | |
| (XII) | 19100 | methyl 2-methoxyacetate | 6290-49-9 | C4H8O3 | 详情 | 详情 |
| (XIII) | 19101 | methyl 2-bromo-2-methoxyacetate | C4H7BrO3 | 详情 | 详情 | |
| (XIV) | 19102 | (1,2-dimethoxy-2-oxoethyl)(triphenyl)phosphonium bromide | C22H22BrO3P | 详情 | 详情 | |
| (XV) | 19103 | methyl (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoate | C15H13Cl2NO3 | 详情 | 详情 | |
| (XVI) | 19104 | (2Z,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-2,4-pentadienoic acid | C14H11Cl2NO3 | 详情 | 详情 | |
| (XVII) | 20116 | 2,2,6,6-tetramethyl-4-piperidinone | 826-36-8 | C9H17NO | 详情 | 详情 |
| (XVIII) | 20117 | 1,2,2,6,6-pentamethyl-4-piperidinone | C10H19NO | 详情 | 详情 | |
| (XIX) | 20118 | 1,2,2,6,6-pentamethyl-4-piperidinone oxime | C10H20N2O | 详情 | 详情 | |
| (XX) | 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3
该中间体在本合成路线中的序号：(X)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：(XI)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 |