(E)-3-{2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]phenyl}-2-propenoic acid -Drug Synthesis Database

【结构式】

【分子编号】53023

【品名】(E)-3-{2,3-dichloro-4-[(1-methyl-1H-indol-5-yl)sulfanyl]phenyl}-2-propenoic acid

【CA登记号】n/a

【分子式】C₁₈H₁₃Cl₂NO₂S

【分子量】378.27816

【元素组成】C 57.15% H 3.46% Cl 18.74% N 3.7% O 8.46% S 8.48%

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：(VIII)

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.

参考文献中间体

合成目标

【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：(VIII)

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.

参考文献中间体

合成目标

【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