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【结 构 式】

【分子编号】53020

【品名】1-methyl-5-[(triisopropylsilyl)sulfanyl]-1H-indole; 1-methyl-1H-indol-5-yl triisopropylsilyl sulfide

【CA登记号】n/a

【 分 子 式 】C18H29NSSi

【 分 子 量 】319.5865

【元素组成】C 67.65% H 9.15% N 4.38% S 10.03% Si 8.79%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(II)

The intermediate silyl sulfide (II) was prepared by palladium-catalyzed displacement of 5-bromo-1-methylindole (I) with potassium (triisopropylsilyl)sulfide. Alternatively, 5-iodoindole (III) was N-methylated with iodomethane and NaH, yielding 5-iodo-1-methylindole (IV), which was then reacted with potassium (triisopropylsilyl)sulfide to give (II). Condensation of silyl sulfide (II) with the aryl triflate (V) in the presence of CsF as the desilylating reagent furnished the diaryl sulfide (VI). Knoevenagel condensation of aldehyde (VI) with malonic acid (VII) gave rise to the cinnamic acid derivative (VIII). This was then coupled with ethyl isonipecotate (IX), producing amide (X). The ethyl ester of (X) was finally hydrolyzed with NaOH to yield the title sodium carboxylate salt.

1 Reilly, E.B.; Liu, G.; Winn, M.; et al.; Discovery of novel p-arylthio cinnamides as antagonists of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. 4. Structure-activity relationships of substituents on the benzene ring of the cinnamide. J Med Chem 2001, 44, 25, 4393.
2 Jae, H.-S.; Pei, Z.; Staeger, M.A.; Gunawardana, I.W.; Winn, M.; Freeman, J.C.; Liu, G.; Link, J.; Boyd, S.A.; Zhu, G.-D.; Von Geldern, T.W.; Xin, Z.; Lynch, J.K.; Wang, S. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory and immune-suppressive cpds.. WO 0059880 .
3 Lynch, J.K.; Link, J.; Zhu, G.-D.; Boyd, S.A.; Winn, M.; Pei, Z.; Gunawardana, I.W.; Liu, G.; Xin, Z.; Jae, H.-S.; Freeman, J.C.; Von Geldern, T.; Staeger, M.A. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory and immune-suppressive cpds.. US 6110922; WO 0039081 .
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) 29521 5-bromo-1-methyl-1H-indole C9H8BrN 详情 详情
(II) 53020 1-methyl-5-[(triisopropylsilyl)sulfanyl]-1H-indole; 1-methyl-1H-indol-5-yl triisopropylsilyl sulfide n/a C18H29NSSi 详情 详情
(III) 40983 5-iodo-1H-indole C8H6IN 详情 详情
(IV) 53021 5-iodo-1-methyl-1H-indole n/a C9H8IN 详情 详情
(V) 52029 2,3-dichloro-4-formylphenyl trifluoromethanesulfonate C8H3Cl2F3O4S 详情 详情
(VI) 53022 2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]benzaldehyde n/a C16H11Cl2NOS 详情 详情
(VII) 12963 Malonic acid 141-82-2 C3H4O4 详情 详情
(VIII) 53023 (E)-3-{2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]phenyl}-2-propenoic acid n/a C18H13Cl2NO2S 详情 详情
(IX) 17410 Ethyl isonipecotate; ethyl 4-piperidinecarboxylate 1126-09-6 C8H15NO2 详情 详情
(X) 53024 ethyl 1-((E)-3-{2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]phenyl}-2-propenoyl)-4-piperidinecarboxylate n/a C26H26Cl2N2O3S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(II)

In a related method, electrophilic bromination of 2,3-dichlorophenol (XI) gave (XII). Heck reaction of bromide (XII) with methyl acrylate (XIII) produced the cinnamic acid derivative (XIV). Sulfonylation of the phenolic hydroxyl of (XIV) with trifluoromethanesulfonic anhydride in pyridine furnished the aryl triflate (XV). This was coupled with the silyl sulfide intermediate (II) in the presence of CsF to produce the diaryl sulfide (XVI). After methyl ester (XVI) hydrolysis, the resultant cinnamic acid (VIII) was coupled with methyl isonipecotate (XVII) to furnish amide (XVIII). The title compound was then obtained by methyl ester (XVIII) hydrolysis with LiOH, followed by treatment with methanolic NaOH.

1 Jae, H.-S.; Pei, Z.; Staeger, M.A.; Gunawardana, I.W.; Winn, M.; Freeman, J.C.; Liu, G.; Link, J.; Boyd, S.A.; Zhu, G.-D.; Von Geldern, T.W.; Xin, Z.; Lynch, J.K.; Wang, S. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory and immune-suppressive cpds.. WO 0059880 .
2 Lynch, J.K.; Link, J.; Zhu, G.-D.; Boyd, S.A.; Winn, M.; Pei, Z.; Gunawardana, I.W.; Liu, G.; Xin, Z.; Jae, H.-S.; Freeman, J.C.; Von Geldern, T.; Staeger, M.A. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory and immune-suppressive cpds.. US 6110922; WO 0039081 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 53020 1-methyl-5-[(triisopropylsilyl)sulfanyl]-1H-indole; 1-methyl-1H-indol-5-yl triisopropylsilyl sulfide n/a C18H29NSSi 详情 详情
(VIII) 53023 (E)-3-{2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]phenyl}-2-propenoic acid n/a C18H13Cl2NO2S 详情 详情
(XI) 53025 2,3-Dichlorophenol 576-24-9 C6H4Cl2O 详情 详情
(XII) 53026 4-bromo-2,3-dichlorophenol n/a C6H3BrCl2O 详情 详情
(XIII) 14156 methyl acrylate 96-33-3 C4H6O2 详情 详情
(XIV) 53027 methyl (E)-3-(2,3-dichloro-4-hydroxyphenyl)-2-propenoate n/a C10H8Cl2O3 详情 详情
(XV) 53028 methyl (E)-3-(2,3-dichloro-4-{[(trifluoromethyl)sulfonyl]oxy}phenyl)-2-propenoate n/a C11H7Cl2F3O5S 详情 详情
(XVI) 53029 methyl (E)-3-{2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]phenyl}-2-propenoate n/a C19H15Cl2NO2S 详情 详情
(XVII) 38418 methyl 4-piperidinecarboxylate; Isonipecotic acid methyl ester; 4-piperidinecarboxylic acid methyl ester 2971-79-1 C7H13NO2 详情 详情
(XVIII) 53030 methyl 1-((E)-3-{2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]phenyl}-2-propenoyl)-4-piperidinecarboxylate n/a C25H24Cl2N2O3S 详情 详情
Extended Information