5,6-dichloro-2-ethynyl-1H-indole -Drug Synthesis Database

【结构式】

【分子编号】63915

【品名】5,6-dichloro-2-ethynyl-1H-indole

【CA登记号】

【分子式】C₁₀H₅Cl₂N

【分子量】210.06184

【元素组成】C 57.18% H 2.4% Cl 33.75% N 6.67%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VI)

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.

参考文献中间体

合成目标

【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2

该中间体在本合成路线中的序号：(VI)

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.

参考文献中间体

合成目标

【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

Extended Information