|
【结 构 式】 
|
【分子编号】26558 【品名】(1R)-2-bromo-1-(6-chloro-3-pyridinyl)-1-ethanol 【CA登记号】 |
【 分 子 式 】C7H7BrClNO 【 分 子 量 】236.49542 【元素组成】C 35.55% H 2.98% Br 33.79% Cl 14.99% N 5.92% O 6.77% |
合成路线1
该中间体在本合成路线中的序号：(XVII)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2
该中间体在本合成路线中的序号：(X)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3
该中间体在本合成路线中的序号：(X)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4
该中间体在本合成路线中的序号：(V)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 |