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【结 构 式】 
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【分子编号】12891 【品名】3-Methylenedihydro-2,5-furandione; Itaconic anhydride 【CA登记号】2170-03-8 |
【 分 子 式 】C5H4O3 【 分 子 量 】112.08496 【元素组成】C 53.58% H 3.6% O 42.82% |
合成路线1
该中间体在本合成路线中的序号：(II)The Friedel-Crafts condensation of toluene (I) with itaconic anhydride (2-methylenesuccinic anhydride) (II) by means of AlCl3 in methylene chloride or 1,2-dichloroethane gives 3-(4-methylbenzoyl)-2-methylenepropionic acid (III), which is then treated with thioacetic acid (IV) and K2CO3 in DMF/water.
| 【1】 Onodera, A.; Tomisawa, K.; Noguchi, T.; Yokomori, S.; A practical procedure for the synthesis of esonarimod, (R,S)-2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanoic acid, an antirheumatic agent (Part 1). Chem Pharm Bull 2002, 50, 10, 1407. |
| 【2】 Mealy, N.; Castaner, J.; KE-298. Drugs Fut 1996, 21, 7, 691. |
| 【3】 Tomisawa, K.; Kameo, K.; Matsunaga, T.; Saito, S.; Sota, K. (Taisho Pharmaceutical Co., Ltd.); Benzoylpropionic acid derivs., their use and pharmaceutical compsns. EP 0164101; ES 8603818; JP 1985258160 . |
| 【4】 Tomisawa, K.; Kameo, K.; Matsunaga, Y.; Saito, H.; Sodu, H. (Taisho Pharmaceutical Co., Ltd.); 2-Acylthiomethyl-3-benzoylpropionic acid derivs. JP 1987132825 . |
| 【5】 Kameo, K.; Ogawa, K.; Takeshita, K.; Nakaike, S.; Tomisawa, K.; Sota, K.; Studies on antirheumatic agents: 3-Benzoylpropionic acid derivatives. Chem Pharm Bull 1988, 36, 6, 2050-60. |
合成路线2
该中间体在本合成路线中的序号：(II)The Friedel-Crafts condensation of 4-chlorobiphenyl (I) with 3-methylenetetrahydrofuran-2,5-dione (II) by means of AlCl3 in tetrachloroethane gives 4-(4'-chlorobiphenyl-4-yl)-2-methylene-4-oxobutyric acid (III), which is treated with thiophenol (IV) and K2CO3 in DMF/water, yielding racemic 4-(4'-chlorobiphenyl-4-yl)-4-oxo-2-(phenylsulfanylmethyl)butyric acid (V). Finally, racemic (V) is resolved by means of crystallization with (+)-cinchonine in acetone.
| 【1】 Sorbera, L.A.; Castañer, J.; Graul, A.; Silvestre, J.S.; Bay-12-9566. Drugs Fut 1999, 24, 1, 16. |
| 【2】 Kluender, H.C.E.; Benz, G.H.H.H.; Brittelli, D.R.; Bullock, W.H.; Combs, K.J.; Dixon, B.R.; Schneider, S.; Wood, J.E.; Vanzandt, M.C.; Wolanin, D.J.; Wilhelm, S.M. (Bayer AG); Substd. 4-biarylbutyric or 5-biarylpentanoic acids and derivs. as matrix metalloprotease inhibitors. EP 0790974; JP 1998509146; US 5789434; US 5859047; WO 9615096 . |
| 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) | 20252 | 4-chloro-1,1'-biphenyl | 2051-62-9 | C12H9Cl | 详情 | 详情 |
| (II) | 12891 | 3-Methylenedihydro-2,5-furandione; Itaconic anhydride | 2170-03-8 | C5H4O3 | 详情 | 详情 |
| (III) | 20254 | 2-[2-(4'-chloro[1,1'-biphenyl]-4-yl)-2-oxoethyl]acrylic acid | C17H13ClO3 | 详情 | 详情 | |
| (IV) | 12951 | Benzenethiol; Phenylmercaptan; Phenylhydrosulfide | 108-98-5 | C6H6S | 详情 | 详情 |
| (V) | 20256 | 4-(4'-chloro[1,1'-biphenyl]-4-yl)-4-oxo-2-[(phenylsulfanyl)methyl]butyric acid | C23H19ClO3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)p-Methoxybenzyl itaconate (III) was prepared by reaction of itaconic anhydride (I) with p-methoxybenzyl alcohol (II) at 55-60 C (1). Condensation of the lithium enolate of (III) with nonanal (IV) in THF at -78 C gave adduct (V), which upon treatment with trifluoroacetic acid underwent cyclization and benzyl ester deprotection to yield the corresponding butyrolactone as a diastereomeric mixture. The major trans isomer was finally isolated by flash chromatography.
| 【1】 Mani, N.S.; Li, J.N.; Frehywot, G.; Pizer, E.S.; Kuhajda, F.P.; Townsend, G.A.; Syntesis and antitumor activity of an inhibitor fatty acid synthase. Proceedings of the National Academy of Sciences of the United States of America 2000, 97, 7, 3450. |
| 【2】 Kuhajda, F.P.; Mani, N.S.; Pasternack, G.R.; Townsend, C.A. (Johns Hopkins University); Inhibition of fatty acid synthase as a means to reduce adipocyte mass. WO 9718806 . |
| 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) | 12891 | 3-Methylenedihydro-2,5-furandione; Itaconic anhydride | 2170-03-8 | C5H4O3 | 详情 | 详情 |
| (II) | 38861 | 4-Methoxybenzenemethanol; (4-methoxyphenyl)methanol; 4-Methoxybenzyl alcohol; Anis alcohol; Anisyl Alcohol; 4-Anisic Alcohol; p-Anisyl alcohol; Anise alcohol | 105-13-5 | C8H10O2 | 详情 | 详情 |
| (III) | 38862 | 2-[2-[(4-methoxybenzyl)oxy]-2-oxoethyl]acrylic acid | C13H14O5 | 详情 | 详情 | |
| (IV) | 38863 | nonanal | 124-19-6 | C9H18O | 详情 | 详情 |
| (V) | 38864 | 2-(2-hydroxy-1-[[(4-methoxybenzyl)oxy]carbonyl]decyl)acrylic acid | C22H32O6 | 详情 | 详情 |