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【结 构 式】 
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【分子编号】26782 【品名】Cyanuric fluoride; 2,4,6-trifluoro-1,3,5-triazine 【CA登记号】675-14-9 |
【 分 子 式 】C3F3N3 【 分 子 量 】135.0484296 【元素组成】C 26.68% F 42.2% N 31.11% |
合成路线1
该中间体在本合成路线中的序号：(XVI)1-Butanesulfonyl chloride (XII) was reacted with ammonia in acetonitrile, and the resulting sulfonamide (XIII) was then converted to the N-trimethylsilyl derivative (XIV). This was coupled with acid fluoride (XVII), (obtained from Boc-valine (XV) and cyanuric fluoride (XVI)), to provide Boc-valinesulfonamide (XVIII). The Boc group of (XVIII) was then removed by acid treatment to give (XIX). Finally, coupling of this chiral intermediate with the previously obtained racemic acid (XI) furnished the title compound as a 7:3 mixture of diastereoisomers.
| 【1】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Frueh, T.; Pitterna, T.; Iwasaki, G.; Oda, K.; Yamamura, T.; Hayakawa, K.; Discovery of IRL 3461: A novel and potent endothelin antagonist with balanced ETA/ETB affinity. Bioorg Med Chem Lett 1998, 8, 16, 2241. |
| 【2】 Fruh, T.; Pitterna, T.; Murata, T.; Svensson, L.D.; Yuumoto, Y.; Sakaki, J. (Novartis Japan KK); Antagonists of endothelin receptors. EP 0753004; JP 1997510720; US 5703106; WO 9526360 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 26778 | N-(3,5-dimethylbenzoyl)-4-(5-isoxazolyl)-N-methylphenylalanine | C22H22N2O4 | 详情 | 详情 | |
| (XII) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
| (XIII) | 26780 | 1-butanesulfonamide | C4H11NO2S | 详情 | 详情 | |
| (XIV) | 26781 | N-(trimethylsilyl)-1-butanesulfonamide | C7H19NO2SSi | 详情 | 详情 | |
| (XV) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (XVI) | 26782 | Cyanuric fluoride; 2,4,6-trifluoro-1,3,5-triazine | 675-14-9 | C3F3N3 | 详情 | 详情 |
| (XVII) | 26783 | tert-butyl (1S)-1-(fluorocarbonyl)-2-methylpropylcarbamate | C10H18FNO3 | 详情 | 详情 | |
| (XVIII) | 26784 | tert-butyl (1S)-1-[[(butylsulfonyl)amino]carbonyl]-2-methylpropylcarbamate | C14H28N2O5S | 详情 | 详情 | |
| (XIX) | 26785 | N-[(2S)-2-amino-3-methylbutanoyl]-1-butanesulfonamide | C9H20N2O3S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XVI)1-Butanesulfonyl chloride (XII) was reacted with ammonia in acetonitrile, and the resulting sulfonamide (XIII) was then converted to the N-trimethylsilyl derivative (XIV). This compound was coupled with acid fluoride (XVII), (obtained from Boc-valine (XV) and cyanuric fluoride (XVI)), to provide Boc-valinesulfonamide (XVIII). The Boc group of (XVIII) was then removed by acid treatment to give (XIX). Coupling of this chiral intermediate (XIX) with racemic acid (XI) in a biphasic solvent system, with partial isomerization of acid (XI), furnished the amide (XX) as a 12:1 diastereomeric mixture. The major D,L diastereoisomer was then isolated either by preparative HPLC or by recrystallization from isopropanol.
| 【1】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Hayakawa, K.; Stereoselective synthesis of a novel and bifunctional endothelin antagonist, IRL 3630. Bioorg Med Chem Lett 1998, 8, 16, 2247. |
| 【2】 Sakaki, J.; Murata, T.; Yuumoto, Y.; Nakamura, I.; Okada, T. (Novartis Japan KK); Antagonists of endothelin receptors. JP 1999512702; WO 9711960 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 26778 | N-(3,5-dimethylbenzoyl)-4-(5-isoxazolyl)-N-methylphenylalanine | C22H22N2O4 | 详情 | 详情 | |
| (XII) | 26779 | 1-butanesulfonyl chloride | 2386-60-9 | C4H9ClO2S | 详情 | 详情 |
| (XIII) | 26780 | 1-butanesulfonamide | C4H11NO2S | 详情 | 详情 | |
| (XIV) | 26781 | N-(trimethylsilyl)-1-butanesulfonamide | C7H19NO2SSi | 详情 | 详情 | |
| (XV) | 19733 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid | C10H19NO4 | 详情 | 详情 | |
| (XVI) | 26782 | Cyanuric fluoride; 2,4,6-trifluoro-1,3,5-triazine | 675-14-9 | C3F3N3 | 详情 | 详情 |
| (XVII) | 26783 | tert-butyl (1S)-1-(fluorocarbonyl)-2-methylpropylcarbamate | C10H18FNO3 | 详情 | 详情 | |
| (XVIII) | 26784 | tert-butyl (1S)-1-[[(butylsulfonyl)amino]carbonyl]-2-methylpropylcarbamate | C14H28N2O5S | 详情 | 详情 | |
| (XIX) | 26785 | N-[(2S)-2-amino-3-methylbutanoyl]-1-butanesulfonamide | C9H20N2O3S | 详情 | 详情 | |
| (XX) | 26786 | N-[2-[((1S)-1-[[(butylsulfonyl)amino]carbonyl]-2-methylpropyl)amino]-1-[4-(5-isoxazolyl)benzyl]-2-oxoethyl]-N,3,5-trimethylbenzamide | C31H40N4O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(A)The compound was originally isolated from Aspergillus fumigatus. The synthesis of this compound was further described. Treatment of N-phthaloyltryptophan methyl ester (I) with tert-butyl hypochlorite and triethylamine at -78 C led to the formation of the intermediate 3-chloroindolenine (II). Reaction of tributyl prenyl stannane (III) with boron trichloride generated in situ the transient boron reagent (IV), which after condensation with chloroindolenine (II) produced the 3-prenylindole (V). Subsequent removal of the phthalimide protecting group of (V) by hydrazinolysis provided aminoester (VI). Coupling of (VI) with acid fluoride (VIII), (generated from N-Boc-L-proline (VII) and cyanuric fluoride), gave rise to amide (IX). The Boc protecting group of (IX) was cleaved employing iodotrimethylsilane, and the resulting aminoester (X) was then cyclized with methanolic ammonia to produce the target diketopiperazine.
| 【1】 Schkeryantz, J.M.; et al.; Total synthesis of gypsetin, deoxybrevianamide E, brevianamide E, and tryprostatin B: Novel constructions of 2,3-disubstituted indoles. J Am Chem Soc 1999, 121, 51, 11964. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 26782 | Cyanuric fluoride; 2,4,6-trifluoro-1,3,5-triazine | 675-14-9 | C3F3N3 | 详情 | 详情 |
| (I) | 31493 | methyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-(1H-indol-3-yl)propanoate | C20H16N2O4 | 详情 | 详情 | |
| (II) | 31494 | methyl (2S)-3-(3-chloro-3H-indol-3-yl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propanoate | C20H15ClN2O4 | 详情 | 详情 | |
| (III) | 31502 | tributyl(3-methyl-2-butenyl)stannane | C17H36Sn | 详情 | 详情 | |
| (IV) | 31503 | dichloro(1,1-dimethyl-2-propenyl)borane | C5H9BCl2 | 详情 | 详情 | |
| (V) | 31504 | methyl (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]propanoate | C25H24N2O4 | 详情 | 详情 | |
| (VI) | 31505 | methyl (2S)-2-amino-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]propanoate | C17H22N2O2 | 详情 | 详情 | |
| (VII) | 16734 | (2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid | C10H17NO4 | 详情 | 详情 | |
| (VIII) | 31506 | tert-butyl (2S)-2-(fluorocarbonyl)-1-pyrrolidinecarboxylate | C10H16FNO3 | 详情 | 详情 | |
| (IX) | 31507 | tert-butyl (2S)-2-[[((1S)-2-methoxy-1-[[2-(3-methyl-2-butenyl)-1H-indol-3-yl]methyl]-2-oxoethyl)amino]carbonyl]-1-pyrrolidinecarboxylate | C27H37N3O5 | 详情 | 详情 | |
| (X) | 31508 | methyl (2S)-3-[2-(3-methyl-2-butenyl)-1H-indol-3-yl]-2-[[(2S)pyrrolidinylcarbonyl]amino]propanoate | C22H29N3O3 | 详情 | 详情 |