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【结 构 式】 
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【分子编号】26553 【品名】tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate 【CA登记号】 |
【 分 子 式 】C20H27N3O3 【 分 子 量 】357.4528 【元素组成】C 67.2% H 7.61% N 11.76% O 13.43% |
合成路线1
该中间体在本合成路线中的序号：(XI)Chlorination of 3-acetylpyridine (V) with N-chlorosuccinimide in HCl-AcOH gave (chloroacetyl)pyridine (VI). Subsequent enantioselective reduction of (VI) using (-)-B-chlorodiisopinocampheylborane yielded (R)-chlorohydrin (VII), which was cyclized to pyridyloxirane (VIII) with K2CO3 in boiling acetone. Opening of epoxide (VIII) with 4-aminophenethylamine (IX) produced amino alcohol (X). After protection as the tert-butyl carbamate (XI), coupling with sulfonyl chloride (IV) furnished sulfonamide (XII). Finally, Boc deprotection of (XII) using TFA produced the title compound.
| 【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 |
|---|---|---|---|---|---|---|
| (IV) | 26548 | 4-[[(hexylamino)carbonyl]amino]benzenesulfonyl chloride | C13H19ClN2O3S | 详情 | 详情 | |
| (V) | 12027 | 1-(3-Pyridinyl)-1-ethanone; 1-(3-Pyridinyl)ethanone | 350-03-8 | C7H7NO | 详情 | 详情 |
| (VI) | 26549 | 2-chloro-1-(3-pyridinyl)-1-ethanone | C7H6ClNO | 详情 | 详情 | |
| (VII) | 26550 | (1R)-2-chloro-1-(3-pyridinyl)-1-ethanol | C7H8ClNO | 详情 | 详情 | |
| (VIII) | 26551 | 3-[(2R)oxiranyl]pyridine | C7H7NO | 详情 | 详情 | |
| (IX) | 18961 | 4-(2-aminoethyl)aniline; 4-(2-aminoethyl)phenylamine | 13472-00-9 | C8H12N2 | 详情 | 详情 |
| (X) | 26552 | (1R)-2-[(4-aminophenethyl)amino]-1-(3-pyridinyl)-1-ethanol | C15H19N3O | 详情 | 详情 | |
| (XI) | 26553 | tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C20H27N3O3 | 详情 | 详情 | |
| (XII) | 26554 | tert-butyl 4-[[(4-[[(hexylamino)carbonyl]amino]phenyl)sulfonyl]amino]phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C33H45N5O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Alternatively, reaction of 6-chloronicotinic acid (XIII) with methyllithium-lithium bromide complex gave methyl ketone (XIV). This was brominated by means of dibromobarbituric acid (XV) to produce bromoketone (XVI). Asymmetric reduction of (XVI) with (-)-B-chlorodiisopinocampheylborane provided the (R)-bromohydrin (XVII), which was converted to epoxide (XVIII) with NaOH in aqueous THF. Epoxide (XVIII) opening with 4-nitrophenethylamine (XIX) produced amino alcohol (XX), which by further protection with Boc2O gave carbamate (XXI). Concomitant dechlorination and nitro group reduction in (XXI) by hydrogenation using Raney Nickel as catalyst provided amine (XI). This was finally converted to the target compound by means of sulfonylation and deprotection as above.
| 【1】 Naylor, E.M.; Colandrea, V.J.; Candelore, M.R.; Cascieri, M.A.; Colwell, L.F. Jr; Deng, L.; Feeney, W.P.; Forrest, M.J.; Hom, G.J.; MacIntyre, D.E.; Strader, C.D.; Tota, L.; Wang, P.R.; Wyvratt, M.J.; Fisher, M.H.; Weber, A.E.; 3-Pyridylethanolamines: Potent and selective human beta3 adrenergic receptor agonists. Bioorg Med Chem Lett 1998, 8, 21, 3087. |
| 【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 |
|---|---|---|---|---|---|---|
| (IV) | 26548 | 4-[[(hexylamino)carbonyl]amino]benzenesulfonyl chloride | C13H19ClN2O3S | 详情 | 详情 | |
| (XI) | 26553 | tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C20H27N3O3 | 详情 | 详情 | |
| (XIII) | 12996 | 6-Chloronicotinic acid | 5326-23-8 | C6H4ClNO2 | 详情 | 详情 |
| (XIV) | 26555 | 1-(6-chloro-3-pyridinyl)-1-ethanone | C7H6ClNO | 详情 | 详情 | |
| (XV) | 26556 | 5,5-dibromo-2,4,6(1H,3H,5H)-pyrimidinetrione | 511-67-1 | C4H2Br2N2O3 | 详情 | 详情 |
| (XVI) | 26557 | 2-bromo-1-(6-chloro-3-pyridinyl)-1-ethanone | C7H5BrClNO | 详情 | 详情 | |
| (XVII) | 26558 | (1R)-2-bromo-1-(6-chloro-3-pyridinyl)-1-ethanol | C7H7BrClNO | 详情 | 详情 | |
| (XVIII) | 26559 | 2-chloro-5-[(2R)oxiranyl]pyridine | C7H6ClNO | 详情 | 详情 | |
| (XIX) | 26560 | 4-nitrophenethylamine | 24954-67-4 | C8H10N2O2 | 详情 | 详情 |
| (XX) | 26561 | (1R)-1-(6-chloro-3-pyridinyl)-2-[(4-nitrophenethyl)amino]-1-ethanol | C15H16ClN3O3 | 详情 | 详情 | |
| (XXI) | 26562 | tert-butyl (2R)-2-(6-chloro-3-pyridinyl)-2-hydroxyethyl(4-nitrophenethyl)carbamate | C20H24ClN3O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Condensation of the protected aniline derivative (I) with 4-cyanobenzenesulfonyl chloride (II) in the presence of pyridine afforded sulfonamide (III). Subsequent reaction of he nitrile group of (III) with hydroxylamine provided the corresponding amidoxime (IV), which was reacted with 3,4-difluorophenylacetic acid (V) and EDC to produce the oxadiazole (VI). Finally, the Boc protecting group of (VI) was removed by treatment with trifluoroacetic acid.
| 【1】 Biftu, T.; Feng, D.D.; Fisher, M.H.; Kuo, C.-H.; Liang, G.-B.; Weber, A.E.; Naylor, E.M. (Merck & Co., Inc.); Oxadiazole benzenesulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. EP 0906310; US 6034106; WO 9746556 . |
| 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) | 26553 | tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C20H27N3O3 | 详情 | 详情 | |
| (II) | 29284 | 4-cyanobenzenesulfonyl chloride | 49584-26-1 | C7H4ClNO2S | 详情 | 详情 |
| (III) | 29285 | tert-butyl 4-[[(4-cyanophenyl)sulfonyl]amino]phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C27H30N4O5S | 详情 | 详情 | |
| (IV) | 29286 | tert-butyl 4-[([4-[amino(hydroxyimino)methyl]phenyl]sulfonyl)amino]phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C27H33N5O6S | 详情 | 详情 | |
| (V) | 29287 | 2-(3,4-difluorophenyl)acetic acid | 658-93-5 | C8H6F2O2 | 详情 | 详情 |
| (VI) | 29288 | tert-butyl 4-[([4-[5-(3,4-difluorobenzyl)-1,2,4-oxadiazol-3-yl]phenyl]sulfonyl)amino]phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C35H35F2N5O6S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Condensation of the protected aniline derivative (I) with 4-cyanobenzenesulfonyl chloride (II) in the presence of pyridine afforded sulfonamide (III). Subsequent reaction of he nitrile group of (III) with hydroxylamine provided the corresponding amidoxime (IV), which was reacted with 4-(trifluoromethoxy)phenylacetic acid (V) and EDC to produce the oxadiazole (VI). Finally, the Boc protecting group of (VI) was removed by treatment with trifluoroacetic acid.
| 【1】 Biftu, T.; Feng, D.D.; Fisher, M.H.; Kuo, C.-H.; Liang, G.-B.; Weber, A.E.; Naylor, E.M. (Merck & Co., Inc.); Oxadiazole benzenesulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. EP 0906310; US 6034106; WO 9746556 . |
| 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) | 26553 | tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C20H27N3O3 | 详情 | 详情 | |
| (II) | 29284 | 4-cyanobenzenesulfonyl chloride | 49584-26-1 | C7H4ClNO2S | 详情 | 详情 |
| (III) | 29285 | tert-butyl 4-[[(4-cyanophenyl)sulfonyl]amino]phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C27H30N4O5S | 详情 | 详情 | |
| (IV) | 29286 | tert-butyl 4-[([4-[amino(hydroxyimino)methyl]phenyl]sulfonyl)amino]phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C27H33N5O6S | 详情 | 详情 | |
| (V) | 29289 | 2-[4-(trifluoromethoxy)phenyl]acetic acid | 4315-07-5 | C9H7F3O3 | 详情 | 详情 |
| (VI) | 29290 | tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl(4-[[(4-[5-[4-(trifluoromethoxy)benzyl]-1,2,4-oxadiazol-3-yl]phenyl)sulfonyl]amino]phenethyl)carbamate | C36H36F3N5O7S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The chlorination of 2-acetylpyridine (I) with N-chlorosuccinimide in ethereal HCl gives 2-(chloroacetyl)pyridine (II), which is reduced with (-)-B-chlorodiisopinocampheylborane [(-)-DIP-Cl] in THF yielding (R)-2-chloro-1-(2-pyridyl)ethanol (III). The epoxidation of (III) with K2CO3 in refluxing acetone affords the epoxide (IV), which is condensed with 4-(2-aminoethyl)aniline (V) in refluxing methanol providing (R)-2-[2-(4-aminophenyl)ethylamino]-1-(2-pyridyl)ethanol (VI). The selective protection of the secondary amino group of (VI) with tert-butoxycarbonyl anhydride in THF gives the carbamate (VII) (1), which is condensed with 4-[2-(2-cyclopentylethyl)oxazol-5-yl]phenylsulfonyl chloride (VIII) in pyridine yielding the sulfonamide (IX). Finally, this compound is deprotected with trifluoroacetic acid.
| 【1】 Ok, H.O.; Candelore, M.R.; Reigle, L.B.; et al.; Substituted oxazole benzenesulfonamides as potent human beta3 adrenergic receptor agonists. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 114. |
| 【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 |
|---|---|---|---|---|---|---|
| (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) | 26552 | (1R)-2-[(4-aminophenethyl)amino]-1-(3-pyridinyl)-1-ethanol | C15H19N3O | 详情 | 详情 | |
| (VI) | 26553 | tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C20H27N3O3 | 详情 | 详情 | |
| (VII) | 26718 | 4-[2-(2-cyclopentylethyl)-1,3-oxazol-5-yl]benzenesulfonyl chloride | C16H18ClNO3S | 详情 | 详情 | |
| (VIII) | 26719 | tert-butyl 4-[([4-[2-(2-cyclopentylethyl)-1,3-oxazol-5-yl]phenyl]sulfonyl)amino]phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C36H44N4O6S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IX)The cyclization of phenacyl bromide (I) with acetamide (II) by heating at 130 C gives 2-methyl-5-phenyloxazole (III), which is brominated with NBS in CCl4 to yield the dibromo derivative (IV). The condensation of (IV) with cyclopentylmethylmagnesium bromide (V) by means of Li2CuCl4 affords 4-bromo-2-(2-cyclopentylethyl)-5-phenyloxazole (VI), which is debrominated by hydrogenation with H2 over Pd(OH)2 in methanol, providing 2-(2-cyclopentylethyl)-5-phenyloxazole (VII). The sulfonation of the phenyl ring of (VII) with chlorosulfonic acid gives the sulfonyl chloride (VIII), which is condensed with the aniline derivative (IX) by means of pyridine in dichloromethane to yield the sulfonamide (X). Finally, elimination of the Boc protecting group of (X) by means of HCl in methanol affords the target compound.
| 【1】 Candelore, M.R.; Ok, H.O.; Reigle, L.B.; et al.; Substituted oxazole benzenesulfonamides as potent human beta3-adrenergic receptor agonist. Bioorg Med Chem Lett 2000, 10, 14, 1531. |
| 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) | 10315 | 2-Bromo-1-phenyl-ethanone; 2-Bromo-1-phenyl-1-ethanone | 70-11-1 | C8H7BrO | 详情 | 详情 |
| (II) | 50352 | Acetamide; Acetic acid amide; Ethanamide | 60-35-5 | C2H5NO | 详情 | 详情 |
| (III) | 50348 | 2-methyl-5-phenyl-1,3-oxazole | C10H9NO | 详情 | 详情 | |
| (IV) | 50349 | 4-bromo-2-(bromomethyl)-5-phenyl-1,3-oxazole | C10H7Br2NO | 详情 | 详情 | |
| (V) | 50350 | bromo(cyclopentylmethyl)magnesium | C6H11BrMg | 详情 | 详情 | |
| (VI) | 50351 | 4-bromo-2-(2-cyclopentylethyl)-5-phenyl-1,3-oxazole | C16H18BrNO | 详情 | 详情 | |
| (VII) | 26723 | 2-(2-cyclopentylethyl)-5-phenyl-1,3-oxazole | C16H19NO | 详情 | 详情 | |
| (VIII) | 26718 | 4-[2-(2-cyclopentylethyl)-1,3-oxazol-5-yl]benzenesulfonyl chloride | C16H18ClNO3S | 详情 | 详情 | |
| (IX) | 26553 | tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C20H27N3O3 | 详情 | 详情 | |
| (X) | 26718 | 4-[2-(2-cyclopentylethyl)-1,3-oxazol-5-yl]benzenesulfonyl chloride | C16H18ClNO3S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(VII)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8
该中间体在本合成路线中的序号：(VII)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9
该中间体在本合成路线中的序号：(VII)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10
该中间体在本合成路线中的序号：(IV)2-Phenyl-1,2,3-triazole-4-carboxylic acid (I) was converted to acid chloride, which was further treated with N-methoxy-N-methylamine to provide the corresponding Weinreb amide (II). Subsequent chlorosulfonylation of (II) gave rise to sulfonyl chloride (III), which was coupled with the known amine (IV), yielding sulfonamide (V). The Boc protecting group of (V) was then cleaved by means of trifluroacetic acid to afford (VI). Addition of Grignard reagent (VII) to the N-methoxyamide (VI) furnished ketone (VIII).
| 【1】 Parmee, E.R.; Ok, H.O.; Brockunier, L.L.; et al.; Human beta3-adrenergic receptor agonist containing 1,2,3-triazole-substituted benzenesulfonamides. Bioorg Med Chem Lett 2000, 10, 18, 2111. |
| 【2】 Brockunier, L.L.; Parme, E.R.; Ok, H.O.; et al.; Human beta3 adrenergic receptor agonists containing 1,2,3-triazole-substituted benzenesulfonamides. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 252. |
| 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) | 39306 | 2-phenyl-2H-1,2,3-triazole-4-carboxylic acid | C9H7N3O2 | 详情 | 详情 | |
| (II) | 39307 | N-methoxy-N-methyl-2-phenyl-2H-1,2,3-triazole-4-carboxamide | C11H12N4O2 | 详情 | 详情 | |
| (III) | 39308 | 4-(4-[[methoxy(methyl)amino]carbonyl]-2H-1,2,3-triazol-2-yl)benzenesulfonyl chloride | C11H11ClN4O4S | 详情 | 详情 | |
| (IV) | 26553 | tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C20H27N3O3 | 详情 | 详情 | |
| (V) | 39309 | tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl[4-([[4-(4-[[methoxy(methyl)amino]carbonyl]-2H-1,2,3-triazol-2-yl)phenyl]sulfonyl]amino)phenethyl]carbamate | C31H37N7O7S | 详情 | 详情 | |
| (VI) | 39310 | 2-(4-[[4-(2-[[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl)anilino]sulfonyl]phenyl)-N-methoxy-N-methyl-2H-1,2,3-triazole-4-carboxamide | C26H29N7O5S | 详情 | 详情 | |
| (VII) | 39311 | bromo[4-(trifluoromethyl)phenyl]magnesium | C7H4BrF3Mg | 详情 | 详情 | |
| (VIII) | 39312 | N-[4-(2-[[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl)phenyl]-4-[4-[4-(trifluoromethyl)benzoyl]-2H-1,2,3-triazol-2-yl]benzenesulfonamide | C31H27F3N6O4S | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(VII)Chlorination of 3-acetylpyridine (I) by means of N-chlorosuccinimide (NCS) and HCl/HOAc in ethyl ether affords chloroacetyl derivative (II), which is then reduced with (-)-B-chlorodiisopinocampheylborane ((-)-DIP-Cl) and Et3N in THF to yield ethanol (III). Alcohol (III) is treated with K2CO3 in refluxing acetone to provide (R)-(3-pyridyl)oxirane (IV), which is then condensed with 4-aminophenethylamine (V) to give derivative (VI). N-Protection of (VI) by means of Boc2O in THF furnishes Boc derivative (VII), which is coupled to benzenesulfonyl chloride (VIII) in CH2Cl2 in the presence of pyridine to afford benzene sulfonamide (IX), which is then treated with H2S and Et3N in pyridine to yield thiocarboxamide derivative (X). Derivative (X) is then condensed in refluxing EtOH with chloromethylketone (XII), which can be obtained by reaction of 4-(trifluoromethyl)benzoyl chloride (XI) first with diazomethane (CH2N2) and then with HCl in ether. Finally, the N-Boc group is removed by means of TFA in CH2Cl2 to provide the target compound.
| 【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 . |
| 【3】 Mathvink, R.J.; Parmee, E.R.; Weber, A.E.; Tolman, S. (Merck & Co., Inc.); Thiazole benzenesulfonamides as beta3 agonists for the treatment of diabetes and obesity. EP 0968209; US 6011048; WO 9832753 . |
| 【2】 Mathvink, R.J.; Chitty, D.; Tolman, J.S.; et al.; Potent, selective, and orally bioavailable 3-pyridylethanolamine beta3 adrenergic receptor agonists possessing a thiazole benzenesulfonamide pharmacophore. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 302. |
| 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) | 29284 | 4-cyanobenzenesulfonyl chloride | 49584-26-1 | C7H4ClNO2S | 详情 | 详情 |
| (IX) | 29285 | tert-butyl 4-[[(4-cyanophenyl)sulfonyl]amino]phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C27H30N4O5S | 详情 | 详情 | |
| (X) | 44829 | tert-butyl 4-([[4-(aminocarbothioyl)phenyl]sulfonyl]amino)phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C27H32N4O5S2 | 详情 | 详情 | |
| (XI) | 44830 | 4-(trifluoromethyl)benzoyl chloride | 329-15-7 | C8H4ClF3O | 详情 | 详情 |
| (XII) | 44831 | 2-chloro-1-[4-(trifluoromethyl)phenyl]-1-ethanone | C9H6ClF3O | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(IX)Reaction of 6-chloronicotinic acid (I) with methyllithium lithium bromide complex gives methyl ketone (II), which is treated with dibromobarbituric acid (III) in refluxing THF to afford bromoketone (IV). Asymmetric reduction of (IV) with (-)-DIP-chloride [(-)-B-chlorodiisopinocampheylborane] provides bromohydrin (V), which is converted into epoxide (VI) by treatment with NaOH in THF/H2O. Opening of the epoxide moiety of (VI) with p-nitrophenethylamine hydrochloride (VII) in MeOH in the presence of Et3N followed by N-protection with Boc2O in THF yields ethanolamine (VIII), which is then hydrogenated over Ni-Raney in EtOH/NaOH to furnish dechlorinated aniline (IX). Condensation of (IX) with 1,1-bis(methylsulfanyl)-2-nitroethylene (X) in isopropanol gives compound (XI), which is then subjected to reaction with aniline (XII) in isopropanol to afford nitroethylenediamine (XIII). Finally, the desired product is obtained by Boc removal of (XIII) by treatment with TFA in CH2Cl2.
| 【1】 Wyvratt, M.J.; Cascieri, M.A.; Liu, Y.; Parmee, E.R.; Tota, L.; Brockunier, L.L.; Candelore, M.R.; Fisher, M.H.; Weber, A.E.; Human beta3 adrenergic receptor agonists containing cyanoguanidine and nitroethylenediamide moieties. Bioorg Med Chem Lett 2001, 11, 3, 379. |
| 【2】 Naylor, E.M.; Colandrea, V.J.; Candelore, M.R.; Cascieri, M.A.; Colwell, L.F. Jr; Deng, L.; Feeney, W.P.; Forrest, M.J.; Hom, G.J.; MacIntyre, D.E.; Strader, C.D.; Tota, L.; Wang, P.R.; Wyvratt, M.J.; Fisher, M.H.; Weber, A.E.; 3-Pyridylethanolamines: Potent and selective human beta3 adrenergic receptor agonists. Bioorg Med Chem Lett 1998, 8, 21, 3087. |
| 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) | 12996 | 6-Chloronicotinic acid | 5326-23-8 | C6H4ClNO2 | 详情 | 详情 |
| (II) | 26555 | 1-(6-chloro-3-pyridinyl)-1-ethanone | C7H6ClNO | 详情 | 详情 | |
| (III) | 26556 | 5,5-dibromo-2,4,6(1H,3H,5H)-pyrimidinetrione | 511-67-1 | C4H2Br2N2O3 | 详情 | 详情 |
| (IV) | 26557 | 2-bromo-1-(6-chloro-3-pyridinyl)-1-ethanone | C7H5BrClNO | 详情 | 详情 | |
| (V) | 26558 | (1R)-2-bromo-1-(6-chloro-3-pyridinyl)-1-ethanol | C7H7BrClNO | 详情 | 详情 | |
| (VI) | 26559 | 2-chloro-5-[(2R)oxiranyl]pyridine | C7H6ClNO | 详情 | 详情 | |
| (VII) | 26560 | 4-nitrophenethylamine | 24954-67-4 | C8H10N2O2 | 详情 | 详情 |
| (VIII) | 26562 | tert-butyl (2R)-2-(6-chloro-3-pyridinyl)-2-hydroxyethyl(4-nitrophenethyl)carbamate | C20H24ClN3O5 | 详情 | 详情 | |
| (IX) | 26553 | tert-butyl 4-aminophenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C20H27N3O3 | 详情 | 详情 | |
| (X) | 13853 | Methyl 1-(methylsulfanyl)-2-nitrovinyl sulfide; 1,1-Bis(methylthio)-2-nitroethylene; 1,1-Bis(methylsulfanyl)-2-nitroethylene | 13623-94-4 | C4H7NO2S2 | 详情 | 详情 |
| (XI) | 48294 | tert-butyl (2R)-2-hydroxy-2-(3-pyridinyl)ethyl(4-[[(Z)-1-(methylsulfanyl)-2-nitroethenyl]amino]phenethyl)carbamate | C23H30N4O5S | 详情 | 详情 | |
| (XII) | 48295 | 3-aminobenzamide | 3544-24-9 | C7H8N2O | 详情 | 详情 |
| (XIII) | 48296 | tert-butyl 4-([(Z)-1-[3-(aminocarbonyl)anilino]-2-nitroethenyl]amino)phenethyl[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]carbamate | C29H34N6O6 | 详情 | 详情 |