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【结 构 式】 
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【药物名称】NSC-708199 【化学名称】(+)-2-Methyl-3(S)-(3-methylphenyl)-2,3-dihydro-1,2-benzisothiazole 1,1-dioxide 【CA登记号】256221-01-9, 256221-00-8 (racemate) 【 分 子 式 】C15H15NO2S 【 分 子 量 】273.3563 |
【开发单位】University of Tennessee, Knoxville (Originator) 【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Reverse Transcriptase Inhibitors |
合成路线1
Reaction of benzenesulfonyl chloride (I) with methylamine afforded sulfonamide (II). Regioselective ortho lithiation of (II) with n-butyllithium, followed by condensation with 3-methylbenzaldehyde (III) gave carbinol (IV), which was cyclized to the sultam (V) by treatment with concentrated H2SO4. The desired (S)-enantiomer was finally isolated by chiral HPLC.
| 【1】 Johnson, S.C.; Yan, S.; Mayasundari, A.; Mao, J.; Baker, D.C. (University of Tennessee, Knoxville); Methods of synthesizing sultams and anti-viral compsns.. WO 0004004 . |
| 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) | 14713 | benzenesulfonyl chloride | 98-09-9 | C6H5ClO2S | 详情 | 详情 |
| (II) | 41076 | N-methylbenzenesulfonamide | 5183-78-8 | C7H9NO2S | 详情 | 详情 |
| (III) | 41077 | 3-methylbenzaldehyde | 620-23-5 | C8H8O | 详情 | 详情 |
| (IV) | 41078 | 2-[hydroxy(3-methylphenyl)methyl]-N-methylbenzenesulfonamide | C15H17NO3S | 详情 | 详情 | |
| (V) | 41079 | 2-methyl-3-(3-methylphenyl)-2,3-dihydro-1H-1,2-benzisothiazole-1,1-dione | C15H15NO2S | 详情 | 详情 |
合成路线2
An enantioselective synthesis of the desired (S)-isomer was further developed starting from saccharin (VI). After conversion to the magnesium amide enolate (VII) by means of phenylmagnesium bromide, addition of Grignard reagent (VIII) produced the aryl sulfonimide (IX). Enantioselective reduction to the (S)-sulfonamide (X) was then accomplished using a chiral rhodium catalyst. Then, N-methylation of (X) with yodomethane in the presence of Cs2CO3 provided the title compound.
| 【1】 Condo, A.M.; et al.; Synthesis and molecular modeling studies of 3-aryl-2-methyl-2,3-dihydrobenzo[d]isothiazole 1,1-dioxides: Nonnucleoside reverse transcriptase inhibitors of HIV-1. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 124. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 11298 | 1H-1,2-Benzisothiazole-1,1,3(2H)-trione; Saccharin | 81-07-2 | C7H5NO3S | 详情 | 详情 |
| (VII) | 41080 | C7H4BrMgNO3S | 详情 | 详情 | ||
| (VIII) | 32527 | bromo(3-methylphenyl)magnesium | C7H7BrMg | 详情 | 详情 | |
| (IX) | 41081 | 3-(3-methylphenyl)-1H-1,2-benzisothiazole-1,1-dione | C14H11NO2S | 详情 | 详情 | |
| (X) | 41082 | (3S)-3-(3-methylphenyl)-2,3-dihydro-1H-1,2-benzisothiazole-1,1-dione | C14H13NO2S | 详情 | 详情 |