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【结 构 式】 
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【药物名称】L-770644 【化学名称】4-[4-(3-Cyclopentylpropyl)-5-oxo-4,5-dihydro-1H-tetrazol-1-yl]-N-[4-[2-[2(R)-hydroxy-2-(3-pyridyl)ethylamino]ethyl]phenyl]benzenesulfonamide 【CA登记号】173901-95-6 【 分 子 式 】C30H37N7O4S 【 分 子 量 】591.73789 |
【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 converted to the hydrochloride salt and then chlorinated with N-chlorosuccinimide to afford (chloroacetyl)pyridine (II). Asymmetric reduction of (II) by means of (-)-B-chlorodiisopinocampheylborane in THF produced the (R)-alcohol (III), which was cyclized to oxirane (IV) upon heating with K2CO3 in acetone. Epoxide (IV) opening with 4-aminophenethyl amine (V) in boiling MeOH gave aminoalcohol (VI). Then, selective protection of the aliphatic amine of (VI) as the tert-butyl carbamate yielded the target intermediate (VII). In a similar procedure, 2-chloro-5-acetylpyridine (VIII) was brominated employing dibromobarbituric acid in THF to afford bromide (IX), which was enantioselectively reduced to the (R)-alcohol (X). After cyclization of (X) to epoxide (XI), its opening with 4-nitrophenethyl amine (XII) yielded aminoalcohol (XIII). This was protected as the N-Boc derivative (XIV) and then, hydrogenation of the nitro group of (XIV) with concomitant halogen hydrogenolysis in the presence of Raney Nickel provided an alternative access to 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 . |
| 【2】 Smith, R.G. (Merck & Co., Inc.); Combination therapy for the treatment of diabetes and obesity. JP 1999515027; WO 9716189 . |
| 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
Cyclopentylpropanol (XV) was converted to mesylate (XVI) and subsequently treated with NaI to give iodide (XVII). Then, alkylation of phenyltetrazolone (XIX), (obtained from phenyl isocyanate (XVIII) and aluminum azide), with iodide (XVII) afforded the substituted tetrazolone (XX). Nitration of the phenyl ring of (XX) employing nitronium tetrafluoborate produced the 4-nitro derivative (XXI) along with minor amounts of the 2-nitro isomer, which was separated by flash chromatography. After catalytic hydrogenation of the nitro group of (XXI) to aniline (XXII), diazotization, followed by treatment with an AcOH solution of SO2 in the presence of CuCl furnished sulfonyl chloride (XXIII). Coupling of this sulfonyl chloride with the intermediate amine (VII) in the presence of pyridine gave sulfonamide (XXIV). Finally, the Boc protecting group of (XXIV) was removed by acidic treatment to provide the title compound.
| 【1】 Shih, T.L.; Candelore, M.R.; Cascieri, M.A.; L-770,644: A potent and selective human beta3 adrenergic receptor agonist with improved oral bioavailability. Bioorg Med Chem Lett 1999, 9, 9, 1251. |
| 【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 . |
| 【3】 Smith, R.G. (Merck & Co., Inc.); Combination therapy for the treatment of diabetes and obesity. JP 1999515027; WO 9716189 . |
| 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) | 26553 | tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C20H27N3O3 | 详情 | 详情 | |
| (XV) | 27752 | 3-cyclopentyl-1-propanol | 767-05-5 | C8H16O | 详情 | 详情 |
| (XVI) | 27753 | 3-cyclopentylpropyl methanesulfonate | C9H18O3S | 详情 | 详情 | |
| (XVII) | 27754 | 1-(3-iodopropyl)cyclopentane | C8H15I | 详情 | 详情 | |
| (XVIII) | 11289 | 1-Isocyanatobenzene; phenyl isocyanate; Phenylisocyanate | 103-71-9 | C7H5NO | 详情 | 详情 |
| (XIX) | 27755 | 1-phenyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one | C7H6N4O | 详情 | 详情 | |
| (XX) | 27756 | 1-(3-cyclopentylpropyl)-4-phenyl-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one | C15H20N4O | 详情 | 详情 | |
| (XXI) | 27757 | 1-(3-cyclopentylpropyl)-4-(4-nitrophenyl)-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one | C15H19N5O3 | 详情 | 详情 | |
| (XXII) | 27758 | 1-(4-aminophenyl)-4-(3-cyclopentylpropyl)-1,4-dihydro-5H-1,2,3,4-tetraazol-5-one | C15H21N5O | 详情 | 详情 | |
| (XXIII) | 27759 | 4-[4-(3-cyclopentylpropyl)-5-oxo-4,5-dihydro-1H-1,2,3,4-tetraazol-1-yl]benzenesulfonyl chloride | C15H19ClN4O3S | 详情 | 详情 | |
| (XXIV) | 27760 | tert-butyl 4-[([4-[4-(3-cyclopentylpropyl)-5-oxo-4,5-dihydro-1H-1,2,3,4-tetraazol-1-yl]phenyl]sulfonyl)amino]phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C35H45N7O6S | 详情 | 详情 |
合成路线3
A further procedure for the synthesis of the intermediate sulfonyl chloride (XXIII) has been reported. Cyclopentylpropanol (XV) was prepared by borane reduction of carboxylic acid (XXV). Subsequent conversion of (XV) to mesylate (XVI), followed by displacement with NaN3 provided azide (XXVI). Then, cycloaddition of isocyanate (XXVIII), (obtained by treatment of sulfanilic acid (XXVII) with phosgene in boiling o-dichlorobenzene), to azide (XXVI) generated the required tetrazolone (XXIII).
| 【1】 Ho, G.J. (Merck & Co., Inc.); Process for the preparation of a beta3-agonist. WO 9734880 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 27752 | 3-cyclopentyl-1-propanol | 767-05-5 | C8H16O | 详情 | 详情 |
| (XVI) | 27753 | 3-cyclopentylpropyl methanesulfonate | C9H18O3S | 详情 | 详情 | |
| (XXIII) | 27759 | 4-[4-(3-cyclopentylpropyl)-5-oxo-4,5-dihydro-1H-1,2,3,4-tetraazol-1-yl]benzenesulfonyl chloride | C15H19ClN4O3S | 详情 | 详情 | |
| (XXV) | 27761 | 3-cyclopentylpropionic acid | 140-77-2 | C8H14O2 | 详情 | 详情 |
| (XXVI) | 27762 | 1-(3-azidopropyl)cyclopentane | C8H15N3 | 详情 | 详情 | |
| (XXVII) | 27763 | 4-aminobenzenesulfonic acid | 121-57-3 | C6H7NO3S | 详情 | 详情 |
| (XXVIII) | 27764 | 4-isocyanatobenzenesulfonyl chloride | C7H4ClNO3S | 详情 | 详情 |