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【结 构 式】 
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【分子编号】48543 【品名】Ethyl methylthioacetate; (Methylthio)acetic acid ethyl ester; ethyl 2-(methylsulfanyl)acetate 【CA登记号】4455-13-4 |
【 分 子 式 】C5H10O2S 【 分 子 量 】134.1992 【元素组成】C 44.75% H 7.51% O 23.84% S 23.89% |
合成路线1
该中间体在本合成路线中的序号：(II)The cyclization of 2-amino-4'-bromobenzophenone (I) with ethyl 2-(methylthio)acetate (II) by means of tert-butyl hypochlorite in dichloromethane at 70 C gives 7-(4-bromobenzoyl)-3-(methylthio)-2,3-dihydro-1H-indol-2-one (III), which is desulfurized by a treatment with Raney Nickel in THF yielding 7-(4-bromobenzoyl)-2,3-dihydro-1H-indol-2-one (IV). Finally, this compound is hydrolyzed with refluxing 3N NaOH and acidified with concentrated HCl.
| 【1】 Moran, H.W.; Welstead, W.J. Jr. (A.H. Robins Co. Inc.); 2-Aminophenylacetic acid derivs.. US 4126635 . |
| 【2】 Prous, J.; Castaner, J.; BROMFENAC SODIUM < Rec INNM; USAN >. Drugs Fut 1988, 13, 11, 943. |
| 【3】 Walsh, D.A.; Moran, H.W.; Shamblee, D.A.; Uwaydah, I.M.; Welstead, W.J. Jr.; Sancilio, L.F.; Dannenburg, W.N.; Anti-inflammatory agents. 3. Synthesis and pharmac. J Med Chem 1984, 27, 11, 1379-88. |
| 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) | 23396 | (2-aminophenyl)(4-bromophenyl)methanone | C13H10BrNO | 详情 | 详情 | |
| (II) | 48543 | Ethyl methylthioacetate; (Methylthio)acetic acid ethyl ester; ethyl 2-(methylsulfanyl)acetate | 4455-13-4 | C5H10O2S | 详情 | 详情 |
| (III) | 23398 | 7-(4-bromobenzoyl)-3-(methylsulfanyl)-1,3-dihydro-2H-indol-2-one | C16H12BrNO2S | 详情 | 详情 | |
| (IV) | 23399 | 7-(4-bromobenzoyl)-1,3-dihydro-2H-indol-2-one | C15H10BrNO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(A)Iodination of 3-(trifluoromethyl)nitrobenzene (I) was accomplished by using N-iodosuccinimide in concentrated sulfuric acid to provide (II), which was then reduced to aniline (III) with SnCl2 in refluxing EtOH. Treatment of aniline (III) with sulfuryl chloride, followed by addition of ethyl (methylthio)acetate and Et3N gave rise to a mixture of regioisomeric 3-(methylthio)oxindoles (IV) and (V). Oxidation of this mixture with CuCl2/CuO generated the respective isatins (VI) and (VII) (1). After N-alkylation with 2-(diethylamino)ethyl chloride and NaH, the desired regioisomer (VIII) could be separated by column chromatography. Addition to (VIII) of the Grignard reagent (IX) provided the racemic 3-aryl-3-hydroxy oxindole (X). The enantiomers of (X) were separated using chiral, preparative HPLC, and the desired (S)-enantiomer (XI) was then converted to nitrile (XII) by iodide displacement with zinc cyanide in the presence of palladium catalyst. Finally, partial hydrolysis of nitrile (XII) with KOH in tert-butanol furnished the title amide
| 【1】 Tokunaga, T.; Hume, W.E.; Umezome, T.; Okazaki, K.; Yasuyuki, U.; Kumagai, K.; Hourai, S.; Nagamine, J.; Seki, H.; Taiji, M.; Noguchi, H.; Nagata, R.; Oxindole derivatives as orally active potent growth hormone secretagogues. J Med Chem 2001, 44, 26, 4641. |
| 【2】 Okazaki, K.; Kumagai, K.; Tokunaga, T.; Ueki, Y.; Nagata, R.; Umezome, T.; Hume, W.E. (Sumitomo Pharmaceuticals Co., Ltd.); Oxindole derivs. as growth hormone releasers. EP 1105376; JP 2002523400; WO 0010975 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 16194 | 2-chloro-N,N-diethyl-1-ethanamine; N-(2-chloroethyl)-N,N-diethylamine | 100-35-6 | C6H14ClN | 详情 | 详情 |
| (A) | 48543 | Ethyl methylthioacetate; (Methylthio)acetic acid ethyl ester; ethyl 2-(methylsulfanyl)acetate | 4455-13-4 | C5H10O2S | 详情 | 详情 |
| (I) | 26346 | 1-nitro-3-(trifluoromethyl)benzene | 98-46-4 | C7H4F3NO2 | 详情 | 详情 |
| (II) | 60054 | 1-iodo-3-nitro-5-(trifluoromethyl)benzene | C7H3F3INO2 | 详情 | 详情 | |
| (III) | 60055 | 3-iodo-5-(trifluoromethyl)phenylamine; 3-iodo-5-(trifluoromethyl)aniline | C7H5F3IN | 详情 | 详情 | |
| (IV) | 60057 | 4-iodo-3-(methylsulfanyl)-6-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one | C10H7F3INOS | 详情 | 详情 | |
| (V) | 60056 | 6-iodo-3-(methylsulfanyl)-4-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one | C10H7F3INOS | 详情 | 详情 | |
| (VI) | 60059 | 4-iodo-6-(trifluoromethyl)-1H-indole-2,3-dione | C9H3F3INO2 | 详情 | 详情 | |
| (VII) | 60058 | 6-iodo-4-(trifluoromethyl)-1H-indole-2,3-dione | C9H3F3INO2 | 详情 | 详情 | |
| (VIII) | 60060 | 1-[2-(diethylamino)ethyl]-6-iodo-4-(trifluoromethyl)-1H-indole-2,3-dione | C15H16F3IN2O2 | 详情 | 详情 | |
| (IX) | 60061 | (2-chlorophenyl)(iodo)magnesium | C6H4ClIMg | 详情 | 详情 | |
| (X) | 60062 | 3-(2-chlorophenyl)-1-[2-(diethylamino)ethyl]-3-hydroxy-6-iodo-4-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one | C21H21ClF3IN2O2 | 详情 | 详情 | |
| (XI) | 60063 | (3S)-3-(2-chlorophenyl)-1-[2-(diethylamino)ethyl]-3-hydroxy-6-iodo-4-(trifluoromethyl)-1,3-dihydro-2H-indol-2-one | C21H21ClF3IN2O2 | 详情 | 详情 | |
| (XII) | 60064 | (3S)-3-(2-chlorophenyl)-1-[2-(diethylamino)ethyl]-3-hydroxy-2-oxo-4-(trifluoromethyl)-2,3-dihydro-1H-indole-6-carbonitrile | C22H21ClF3N3O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)The condensation of 6-aminobenzothiazole (I) with ethyl 2-(methylsulfanyl)acetate (II) in the presence of tert-butyl hypochlorite produced the oxindole derivative (III). The methylsulfanyl group was then reductively removed using zinc in acetic acid to afford (IV). Reaction of (IV) with diethoxymethyl acetate in refluxing HOAc furnished the ethoxymethylene derivative (V). This was finally condensed with sulfapyridine (VI) to give the title compound.
| 【1】 Frye, S.V.; Davis, S.T.; Lackey, K.E.; Dickerson, S.H.; Luzzio, M.J.; Kuyper, L.F.; Veal, J.M.; Hunter, R.N. III; Walker, D.H.; Harris, P.A. (Glaxo Group Ltd.); Substd. oxindole derivs. as protein tyrosine kinase and as protein serine/threonine kinase inhibitors. EP 1009738; WO 9915500 . |
| 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) | 17908 | 1,3-benzothiazol-6-ylamine; 1,3-benzothiazol-6-amine; 6-Aminobenzothiazole | 533-30-2 | C7H6N2S | 详情 | 详情 |
| (II) | 48543 | Ethyl methylthioacetate; (Methylthio)acetic acid ethyl ester; ethyl 2-(methylsulfanyl)acetate | 4455-13-4 | C5H10O2S | 详情 | 详情 |
| (III) | 48544 | 8-(methylsulfanyl)-6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-one | C10H8N2OS2 | 详情 | 详情 | |
| (IV) | 48545 | 6,8-dihydro-7H-[1,3]thiazolo[5,4-e]indol-7-one | C9H6N2OS | 详情 | 详情 | |
| (V) | 48546 | 8-[(Z)-ethoxymethylidene]-6H-[1,3]thiazolo[5,4-e]indol-7-one | C12H10N2O2S | 详情 | 详情 | |
| (VI) | 48547 | 2-(4-Aminobenzenesulfonamido)pyridine; 4-Amino-N-2-pyridylbenzenesulfonamide; Sulfapyridine | 144-83-2 | C11H11N3O2S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(II)Condensation of iodoaniline (I) with ethyl 2-(methylsulfanyl)acetate (II) in the presence of sulfuryl chloride gives rise to the oxindole derivative (III). Desulfuration of (III) by means of Raney-nickel then affords (IV). The Vilsmeier-Haack reaction of oxindole (IV) with POBr3 and DMF leads to the bromo aldehyde (V). This is finally subjected to Suzuki coupling with 3-benzothienylboronic acid (VI) to furnish the title compound.
| 【1】 Watterson, S.H.; Dhar, T.G.M.; Ballentine, S.K.; Shen, Z.; Barrish, J.C.; Cheney, D.; Fleener, C.A.; Rouleau, K.A.; Townsend, C.; Hollenbaugh, D.L.; Iwanowicz, E.J.; Novel indole-based inhibitors of IMPDH: Introduction of hydrogen bond acceptors at indole C-3. Bioorg Med Chem Lett 2003, 13, 7, 1273. |
| 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) | 64043 | 2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)aniline; 2-iodo-5-(methyloxy)-4-(1,3-oxazol-5-yl)phenylamine | C10H9IN2O2 | 详情 | 详情 | |
| (II) | 48543 | Ethyl methylthioacetate; (Methylthio)acetic acid ethyl ester; ethyl 2-(methylsulfanyl)acetate | 4455-13-4 | C5H10O2S | 详情 | 详情 |
| (III) | 64333 | 6-(methyloxy)-3-(methylsulfanyl)-5-(1,3-oxazol-5-yl)-1,3-dihydro-2H-indol-2-one | C13H12N2O3S | 详情 | 详情 | |
| (IV) | 64334 | 6-(methyloxy)-5-(1,3-oxazol-5-yl)-1,3-dihydro-2H-indol-2-one | C12H10N2O3 | 详情 | 详情 | |
| (V) | 64335 | 2-bromo-6-(methyloxy)-5-(1,3-oxazol-5-yl)-1H-indole-3-carbaldehyde | C13H9BrN2O3 | 详情 | 详情 | |
| (VI) | 64336 | 1-benzothiophen-3-ylboronic acid | C8H7BO2S | 详情 | 详情 |