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【结 构 式】 
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【分子编号】49943 【品名】 【CA登记号】 |
【 分 子 式 】C44H48N2O11S 【 分 子 量 】812.938 【元素组成】C 65.01% H 5.95% N 3.45% O 21.65% S 3.94% |
合成路线1
该中间体在本合成路线中的序号：(XIII)Indolizinone (I) was converted to the cyclic ketal (III) upon treatment with 2,2-dimethyl-1,3-propanediol (II) in the presence of p-toluenesulfonic acid. Carbethoxylation of (III) with diethyl carbonate and NaH afforded ester (IV), which was halogenated with either bromine or N-chlorosuccinimide to produce the corresponding alpha-bromo (V) or alpha-chloro (VI) ester, respectively. Sulfonylation of (R)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (VII) with 4-biphenylylsulfonyl chloride (VIII) provided the chiral auxiliary (IX). This was then condensed with halo ester (V) or (VI) in the presence of K2CO3 to furnish adduct (X). Diastereoselective alkylation of the sodium enolate of (X) with ethyl iodide produced (XI) as the major isomer. The cyano group of (XI) was then converted to acetamide (XII) by catalytic hydrogenation over Raney nickel in the presence of Ac2O and HOAc. Subsequent nitrosation of amide (XII) with NaNO2 in Ac2O/HOAc gave acetate ester (XIII).
| 【1】 Nomura, S.; Tsujihara, K.; Kawaguchi, T. (Tanabe Seiyaku Co., Ltd.); S type 2-substd. hydroxy-2-indolidinylbutyric ester cpds. and process for preparation thereof. US 6277992 . |
| 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) | 15640 | 7-methyl-1,5-dioxo-1,2,3,5-tetrahydro-6-indolizinecarbonitrile | C10H8N2O2 | 详情 | 详情 | |
| (II) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (III) | 49934 | C15H18N2O3 | 详情 | 详情 | ||
| (IV) | 49935 | C18H22N2O5 | 详情 | 详情 | ||
| (V) | 49936 | C18H21BrN2O5 | 详情 | 详情 | ||
| (VI) | 49937 | C18H21ClN2O5 | 详情 | 详情 | ||
| (VII) | 49944 | D-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid | 41220-48-8 | C10H11NO2 | 详情 | 详情 |
| (VIII) | 49939 | 4-Biphenylsulfonyl chloride | 1623-93-4 | C12H9ClO2S | 详情 | 详情 |
| (IX) | 49938 | (3R)-2-([1,1'-biphenyl]-4-ylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid | C22H19NO4S | 详情 | 详情 | |
| (X) | 49940 | C40H39N3O9S | 详情 | 详情 | ||
| (XI) | 49941 | C42H43N3O9S | 详情 | 详情 | ||
| (XII) | 49942 | C44H49N3O10S | 详情 | 详情 | ||
| (XIII) | 49943 | C44H48N2O11S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)Treatment of (XIII) with aqueous trifluoroacetic acid produced simultaneous ketal group hydrolysis and lactonization, yielding intermediate (XIV). Optionally, basic hydrolysis of the ester groups of (XIII) with LiOH produced the lithium carboxylate salt (XV). Lactonization of (XV) with HOAc in chloroform gave (XVI). The cyclic ketal group of (XVI) was then hydrolyzed with aqueous trifluoroacetic acid to produce the intermediate (XVII). Alternatively, (XVII) was also produced by simultaneous hydrolysis and cyclization of (XV) with aqueous trifluoroacetic acid or by basic hydrolysis of (XIV), followed by acidic treatment. Intermediate (XIX) was prepared by acetylation of (XVI) followed by acidic hydrolysis of the resulting ketal (XVIII).
| 【1】 Nomura, S.; Tsujihara, K.; Kawaguchi, T. (Tanabe Seiyaku Co., Ltd.); S type 2-substd. hydroxy-2-indolidinylbutyric ester cpds. and process for preparation thereof. US 6277992 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 49943 | C44H48N2O11S | 详情 | 详情 | ||
| (XIV) | 49945 | (4S)-4-ethyl-3,6,10-trioxo-3,4,6,7,8,10-hexahydro-1H-pyrano[3,4-f]indolizin-4-yl (3R)-2-([1,1'-biphenyl]-4-ylsulfonyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate | C35H30N2O8S | 详情 | 详情 | |
| (XV) | 49946 | C18H24LiNO7 | 详情 | 详情 | ||
| (XVI) | 49947 | C18H23NO6 | 详情 | 详情 | ||
| (XVII) | 10841 | (4S)-4-Ethyl-4-hydroxy-7,8-dihydro-1H-pyrano[3,4-f]indolizine-3,6,10(4H)-trione | C13H13NO5 | 详情 | 详情 | |
| (XVIII) | 49948 | C20H25NO7 | 详情 | 详情 | ||
| (XIX) | 49949 | (4S)-4-ethyl-3,6,10-trioxo-3,4,6,7,8,10-hexahydro-1H-pyrano[3,4-f]indolizin-4-yl acetate | C15H15NO6 | 详情 | 详情 |