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【结 构 式】 
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【药物名称】 【化学名称】N-[4-[2-[2(R)-Hydroxy-2-(3-pyridyl)ethylamino]ethyl]phenyl]-1-(4-octylthiazol-2-yl)-2,3-dihydro-1H-indole-5-sulfonamide 【CA登记号】173901-90-1 【 分 子 式 】C34H43N5O3S2 【 分 子 量 】633.88151 |
【开发单位】Merck & Co. (Originator) 【药理作用】Antiobesity Drugs, METABOLIC DRUGS, Treatment of Nutritional Disorders, beta3-Adrenoceptor Agonists |
合成路线1
3-Acetylpyridine (I) was chlorinated employing N-chlorosuccinimide, and the resulting chloroketone (II) was enantioselectively reduced with (-)-B-chlorodiisopinocampheylborane (DIP-Cl) to furnish the chiral chlorohydrin (III). Intramolecular cyclization of (III) in the presence of K2CO3 in refluxing acetone produced (R)-(3-pyridyl)oxirane (IV). Further ring opening with 4-aminophenethylamine (V) gave rise to diaminoalcohol (VI), which was selectively proteced with Boc2O at the aliphatic amino group, yielding carbamate (VII). In a related alternative procedure, 2-chloro-5-acetylpyridine (VIII) was brominated to (IX) by means of dibromobarbituric acid (DBBA), followed by reduction of bromoketone (IX) with (-)-DIP-Cl. The resulting (R)-bromohydrin (X) was converted to epoxide (XI) by treatment with NaOH, and subsequent ring opening with 4-nitrophenethylamine (XII) provided aminoalcohol (XIII). Protection of the amino group of (XIII) with Boc2O afforded carbamate (XIV). Further reduction of the nitro group of (XIV) with simultaneous hydrogenolysis of the halogen atom furnished the target intermediate (VII).
| 【1】 Fisher, M.H.; Naylor, E.M.; Ok, D.; Weber, A.E.; Shih, T.; Ok, H. (Merck & Co., Inc.); Substd. sulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. EP 0757674; JP 1997512275; US 5541197; US 5561142; WO 9529159 . |
| 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) | 12027 | 1-(3-Pyridinyl)-1-ethanone; 1-(3-Pyridinyl)ethanone | 350-03-8 | C7H7NO | 详情 | 详情 |
| (II) | 26549 | 2-chloro-1-(3-pyridinyl)-1-ethanone | C7H6ClNO | 详情 | 详情 | |
| (III) | 26550 | (1R)-2-chloro-1-(3-pyridinyl)-1-ethanol | C7H8ClNO | 详情 | 详情 | |
| (IV) | 26551 | 3-[(2R)oxiranyl]pyridine | C7H7NO | 详情 | 详情 | |
| (V) | 18961 | 4-(2-aminoethyl)aniline; 4-(2-aminoethyl)phenylamine | 13472-00-9 | C8H12N2 | 详情 | 详情 |
| (VI) | 26552 | (1R)-2-[(4-aminophenethyl)amino]-1-(3-pyridinyl)-1-ethanol | C15H19N3O | 详情 | 详情 | |
| (VII) | 26553 | tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C20H27N3O3 | 详情 | 详情 | |
| (VIII) | 26555 | 1-(6-chloro-3-pyridinyl)-1-ethanone | C7H6ClNO | 详情 | 详情 | |
| (IX) | 26557 | 2-bromo-1-(6-chloro-3-pyridinyl)-1-ethanone | C7H5BrClNO | 详情 | 详情 | |
| (X) | 26558 | (1R)-2-bromo-1-(6-chloro-3-pyridinyl)-1-ethanol | C7H7BrClNO | 详情 | 详情 | |
| (XI) | 26559 | 2-chloro-5-[(2R)oxiranyl]pyridine | C7H6ClNO | 详情 | 详情 | |
| (XII) | 26560 | 4-nitrophenethylamine | 24954-67-4 | C8H10N2O2 | 详情 | 详情 |
| (XIII) | 26561 | (1R)-1-(6-chloro-3-pyridinyl)-2-[(4-nitrophenethyl)amino]-1-ethanol | C15H16ClN3O3 | 详情 | 详情 | |
| (XIV) | 26562 | tert-butyl (2R)-2-(6-chloro-3-pyridinyl)-2-hydroxyethyl(4-nitrophenethyl)carbamate | C20H24ClN3O5 | 详情 | 详情 |
合成路线2
Condensation of 5-bromoindoline (XV) with KSCN produced thiourea (XVI). Subsequent cyclization of (XVI) with 1-chloro-2-decanone (XVII) generated the 4-n-octylthiazole system (XVIII). Lithium-bromine exchange in (XVIII) with butyllithium at -78 C, followed by reaction with SO2 afforded sulfinic acid (XIX), which was then oxidized with N-chlorosuccinimide to the sulfonyl chloride (XX). The condensation of sulfonyl chloride (XX) with carbamate (VII) in the presence of pyridine in CH2Cl2 gave rise to sulfonamide (XXI). Finally, the Boc protecting group of (XXI)) was cleaved by treatment with trifluoroacetic acid.
| 【1】 Tota, L.; Barritta, A.M.; Fisher, M.H.; Mathvink, R.J.; Cascieri, M.A.; Deng, L.; Candelore, M.R.; Weber, A.E.; Wyvratt, M.J.; Strader, C.D.; Potent, selective human beta3 adrenergic receptor agonists containing a substituted indoline-5-sulfonamide pharmacophore. Bioorg Med Chem Lett 1999, 9, 13, 1869. |
| 【2】 Fisher, M.H.; Naylor, E.M.; Ok, D.; Weber, A.E.; Shih, T.; Ok, H. (Merck & Co., Inc.); Substd. sulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. EP 0757674; JP 1997512275; US 5541197; US 5561142; WO 9529159 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 26653 | tert-butyl (3S,4S)-1-benzyl-4-methoxypyrrolidinyl(methyl)carbamate | C18H28N2O3 | 详情 | 详情 | |
| (XV) | 32845 | 5-bromoindoline | 22190-33-6 | C8H8BrN | 详情 | 详情 |
| (XVI) | 32846 | 5-bromo-1-indolinecarbothioamide | C9H9BrN2S | 详情 | 详情 | |
| (XVII) | 32851 | 1-chloro-2-decanone | C10H19ClO | 详情 | 详情 | |
| (XVIII) | 32847 | 5-bromo-1-(4-octyl-1,3-thiazol-2-yl)indoline | C19H25BrN2S | 详情 | 详情 | |
| (XIX) | 32848 | 1-(4-octyl-1,3-thiazol-2-yl)-5-indolinesulfinic acid | C19H26N2O2S2 | 详情 | 详情 | |
| (XX) | 32849 | 1-(4-octyl-1,3-thiazol-2-yl)-5-indolinesulfonyl chloride | C19H25ClN2O2S2 | 详情 | 详情 | |
| (XXI) | 32850 | tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl[4-([[1-(4-octyl-1,3-thiazol-2-yl)-2,3-dihydro-1H-indol-5-yl]sulfonyl]amino)phenethyl]carbamate | C39H51N5O5S2 | 详情 | 详情 |