|
【结 构 式】 
|
【药物名称】 【化学名称】1-[3-[2,3-Dichloro-4-(1-methyl-1H-indol-5-ylsulfanyl)phenyl]-2(E)-propenoyl]piperidine-4-carboxylic acid sodium salt 【CA登记号】301178-64-3, 280752-02-5 (free base), 280753-09-5 (Li salt) 【 分 子 式 】C24H21Cl2N2NaO3S 【 分 子 量 】511.40637 |
【开发单位】Abbott (Originator) 【药理作用】Antiarthritic Drugs, Asthma Therapy, RESPIRATORY DRUGS, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, LFA-1/ICAM-1 Interaction Inhibitors |
合成路线1
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
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 |