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【结 构 式】 
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【分子编号】18956 【品名】4-(Benzyloxy)phenol; 4-Benzyloxyphenol 【CA登记号】103-16-2 |
【 分 子 式 】C13H12O2 【 分 子 量 】200.23708 【元素组成】C 77.98% H 6.04% O 15.98% |
合成路线1
该中间体在本合成路线中的序号：(II)The alkylation of 4-benzyloxyphenol (I) with 2-(cyclopropylmethoxy)ethyl mesylate (II) by means of NaOCH3 in refluxing methanol gives 4-[2-(cyclopropylmethoxy)-1-ethoxy]phenylmethoxybenzene (III), which is debenzylated by hydrogenolysis with H2 over PdC in methanol yielding 4-[2-(cyclopropylmethoxy)-1-ethoxy]phenol (IV). The treatment of (IV) with epichlorohydrin (V) in aqueous NaOH affords 1-[4-[2-(cyclopropylmethoxy)ethoxyphenoxy]-2,3-epoxy]propane (VI). Finally, this compound is treated with an excess of isopropylamine at room temperature to yield cicloprolol.
| 【1】 Leclerc, G.; Cicloprolol Hydrocloride. Drugs Fut 1985, 10, 12, 975. |
| 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) | 29332 | (6E,10E)-3,7,11,15-tetramethyl-6,10,14-hexadecatrienoic acid | C20H34O2 | 详情 | 详情 | |
| (II) | 18956 | 4-(Benzyloxy)phenol; 4-Benzyloxyphenol | 103-16-2 | C13H12O2 | 详情 | 详情 |
| (III) | 29833 | benzyl 4-[2-(cyclopropylmethoxy)ethoxy]phenyl ether; 1-(benzyloxy)-4-[2-(cyclopropylmethoxy)ethoxy]benzene | C19H22O3 | 详情 | 详情 | |
| (IV) | 29834 | 4-[2-(cyclopropylmethoxy)ethoxy]phenol | C12H16O3 | 详情 | 详情 | |
| (V) | 29776 | 1-(chloromethyl)cyclopropane | 5911-08-0 | C4H7Cl | 详情 | 详情 |
| (VI) | 29835 | 2-([4-[2-(cyclopropylmethoxy)ethoxy]phenoxy]methyl)oxirane; 4-[2-(cyclopropylmethoxy)ethoxy]phenyl 2-oxiranylmethyl ether | C15H20O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)The reaction of (S)(-)-lactic acid methyl ester (I) with Ts-Cl and TEA in dichloromethane gives the corresponding tosylate (II), which is condensed with 4-(benzyloxy)phenol (III) by means of NaH in DMF to yield (R)(+)-2-[4-(benzyloxy)phenoxy]propionic acid methyl ester (IV). The hydrogenolysis of the benzyl group of (IV) with H2 over Pd/C in ethyl acetate affords the 4-hydroxyphenoxy compound (V), which is condensed with 2,7-dichloroquinoxaline (VI) by means of K2CO3 in refluxing acetone, provides the ester precursor (VII). The hydrolysis of (VII) with KOH in THF/water, followed by acidification with HCl, gives the chiral propionic acid (VIII), which is finally converted into its sodium salt with NaOH in water.
| 【1】 Behrens, C.H.; Dusak, B.A.; Harrison, B.A.; Orwat, M.J. (Bristol-Myers Squibb Co.); (2-Quinoxalinyloxy)phenoxypropanoic acids and related derivs. as anticancer agents. WO 9413647 . |
| 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) | 17075 | propionic acid, 2-hydroxy-, methyl ester, (S)-; methyl (2S)-2-hydroxypropanoate | 27871-49-4 | C4H8O3 | 详情 | 详情 |
| (II) | 56722 | methyl (2S)-2-{[(4-methylphenyl)sulfonyl]oxy}propanoate | C11H14O5S | 详情 | 详情 | |
| (III) | 18956 | 4-(Benzyloxy)phenol; 4-Benzyloxyphenol | 103-16-2 | C13H12O2 | 详情 | 详情 |
| (IV) | 56723 | methyl (2R)-2-[4-(benzyloxy)phenoxy]propanoate | C17H18O4 | 详情 | 详情 | |
| (V) | 56724 | methyl (2R)-2-(4-hydroxyphenoxy)propanoate | C10H12O4 | 详情 | 详情 | |
| (VI) | 56725 | 2,7-dichloroquinoxaline | 59489-31-5 | C8H4Cl2N2 | 详情 | 详情 |
| (VII) | 56726 | methyl (2R)-2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propanoate | C18H15ClN2O4 | 详情 | 详情 | |
| (VIII) | 56727 | (2R)-2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propanoic acid | C17H13ClN2O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The silylation of 4-benzyloxyphenol (I) with tert-butyldimethylsilyl chloride (TBDMS-Cl) and imidazole in DMF gives the silyl ether (II), which is debenzylated by hydrogenation with H2 over Pd/C in ethyl acetate yielding the silylated phenol (III). The condensation of (III) with 2(S)-glycidyl 3-nitrobenzenesulfonate (IV) by means of NaH in DMF affords the glycicyl ether (V), which is treated with 2-(4-aminophenyl)ethylamine (VI) in refluxing methanol to give the addition compound (VII). The reaction of (VII) with di-tert-butyl dicarbonate in THF affords compound (VIII) with the secondary aliphatic amine protected as carbamate. Finally, the reaction of (VIII) with N-[4-(chlorosulfonyl)phenyl]-N'-hexylurea (IX) (obtained by reaction of the isocyanate (X) with hexylamine) by means of pyridine in dichloromethane, followed by deprotection with HCl provides the target product.
| 【1】 Parmee, E.R.; et al.; Synthesis and activity of conformationally restrained human beta3-adrenergic receptor agonists. 213th ACS Natl Meet (April 13-17, San Francisco) 1997, Abst MEDI 031. |
| 【2】 Fisher, M.H.; Mathvink, R.J.; Ok, H.O.; Parmee, E.R.; Weber, A.E. (Merck & Co., Inc.); Substd. phenyl sulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. CA 2114712; EP 0611003; JP 1995010827; US 5451677; WO 9418161 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 26546 | n-hexylamine; hexylamine | 111-26-2 | C6H15N | 详情 | 详情 | |
| (I) | 18956 | 4-(Benzyloxy)phenol; 4-Benzyloxyphenol | 103-16-2 | C13H12O2 | 详情 | 详情 |
| (II) | 18957 | [4-(benzyloxy)phenoxy](tert-butyl)dimethylsilane; benzyl 4-[[tert-butyl(dimethyl)silyl]oxy]phenyl ether | C19H26O2Si | 详情 | 详情 | |
| (III) | 18958 | 4-[[tert-butyl(dimethyl)silyl]oxy]phenol | C12H20O2Si | 详情 | 详情 | |
| (IV) | 24765 | (2S)oxiranylmethyl 3-nitrobenzenesulfinoperoxoate | C9H9NO6S | 详情 | 详情 | |
| (V) | 18960 | tert-butyl(dimethyl)[4-[(2S)oxiranylmethoxy]phenoxy]silane; tert-butyl(dimethyl)silyl 4-[(2S)oxiranylmethoxy]phenyl ether | C15H24O3Si | 详情 | 详情 | |
| (VI) | 18961 | 4-(2-aminoethyl)aniline; 4-(2-aminoethyl)phenylamine | 13472-00-9 | C8H12N2 | 详情 | 详情 |
| (VII) | 18962 | (2S)-1-[(4-aminophenethyl)amino]-3-(4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy)-2-propanol | C23H36N2O3Si | 详情 | 详情 | |
| (VIII) | 18963 | tert-butyl 4-aminophenethyl[(2S)-3-(4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy)-2-hydroxypropyl]carbamate | C28H44N2O5Si | 详情 | 详情 | |
| (IX) | 24770 | N-[4-[(chlorooxy)sulfinyl]phenyl]-N'-hexylurea | C13H19ClN2O3S | 详情 | 详情 | |
| (X) | 24771 | (chlorooxy)(4-isocyanatophenyl)oxo-lambda(4)-sulfane | C7H4ClNO3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)1) 4-(Benzyloxy)phenol (I) was protected as the silyl ether (II) by treatment with tert-butyldimethylsilyl chloride (TBDMS-Cl) in the presence of imidazole in DMF. Then, the benzyl group of (II) was removed by hydrogenolysis on Pd(OH)2/C to give 4-(tert-butyldimethylsilyloxy)phenol (III). This phenol was treated with NaH in DMF, and the resulting sodium phenoxide was alkylated with (S)-glycidyl 3-nitrobenzenesulfonate (IV) to provide epoxide (V) (1,2). Subsequent reaction of (V) with 4-aminophenethyl amine (VI) in refluxing MeOH gave the chiral phenoxypropanolamine (VII). Selective protection of the resultant secondary aliphatic amine with one equivalent of di-tert-butyl dicarbonate in THF afforded carbamate (VIII). Then, acylation of the aniline N atom with 4-bromobenzenesulfonyl chloride (IX) in the presence of pyridine gave sulfonamide (X). Finally, removal of both silyl ether and tert-butyl carbamate protecting groups using methanolic HCl provided the desired product.
| 【1】 Weber, A.E.; Mathvink, R.J.; Perkins, L.; Hutchins, J.E.; Candelore, M.R.; Tota, L.; Strader, C.D.; Wyvratt, M.J.; Fisher, M.H.; Potent, selective benzenesulfonamide agonists of the human beta3 adrenergic receptor. Bioorg Med Chem Lett 1998, 8, 9, 1101. |
| 【2】 Fisher, M.H.; Mathvink, R.J.; Ok, H.O.; Parmee, E.R.; Weber, A.E. (Merck & Co., Inc.); Substd. phenyl sulfonamides as selective beta3 agonists for the treatment of diabetes and obesity. CA 2114712; EP 0611003; JP 1995010827; US 5451677; WO 9418161 . |
| 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) | 18956 | 4-(Benzyloxy)phenol; 4-Benzyloxyphenol | 103-16-2 | C13H12O2 | 详情 | 详情 |
| (II) | 18957 | [4-(benzyloxy)phenoxy](tert-butyl)dimethylsilane; benzyl 4-[[tert-butyl(dimethyl)silyl]oxy]phenyl ether | C19H26O2Si | 详情 | 详情 | |
| (III) | 18958 | 4-[[tert-butyl(dimethyl)silyl]oxy]phenol | C12H20O2Si | 详情 | 详情 | |
| (IV) | 16259 | (2S)oxiranylmethyl 3-nitrobenzenesulfonate; (S)-(+)-Glycidyl nosylate | 115314-14-2 | C9H9NO6S | 详情 | 详情 |
| (V) | 18960 | tert-butyl(dimethyl)[4-[(2S)oxiranylmethoxy]phenoxy]silane; tert-butyl(dimethyl)silyl 4-[(2S)oxiranylmethoxy]phenyl ether | C15H24O3Si | 详情 | 详情 | |
| (VI) | 18961 | 4-(2-aminoethyl)aniline; 4-(2-aminoethyl)phenylamine | 13472-00-9 | C8H12N2 | 详情 | 详情 |
| (VII) | 18962 | (2S)-1-[(4-aminophenethyl)amino]-3-(4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy)-2-propanol | C23H36N2O3Si | 详情 | 详情 | |
| (VIII) | 18963 | tert-butyl 4-aminophenethyl[(2S)-3-(4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy)-2-hydroxypropyl]carbamate | C28H44N2O5Si | 详情 | 详情 | |
| (IX) | 18964 | 4-bromobenzenesulfonyl chloride | 98-58-8 | C6H4BrClO2S | 详情 | 详情 |
| (X) | 18965 | tert-butyl 4-[[(4-bromophenyl)sulfonyl]amino]phenethyl[(2S)-3-(4-[[tert-butyl(dimethyl)silyl]oxy]phenoxy)-2-hydroxypropyl]carbamate | C34H47BrN2O7SSi | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(III)The reaction of 4-chloro-3-nitrophenol (I) with ethyl iodide and K2CO3 in hot acetone gives the aryl ether (II), which is condensed with 4-benzyloxyphenol (III) by means of t-BuOK in DMF at 150 C to yield the adduct (IV). The reductive debenzylation of (IV), with simultaneous reduction of the nitro group by means of H2 over Pd/C in THF/ethanol affords 5-ethoxy-2-(4-hydroxyphenoxy)aniline (V), which is finally condensed with 2,5-difluorobenzyl bromide (VI) by means of tBu-OK in DMF to provide the target aniline.
| 【1】 Tomisawa, K.; Taguchi, M.; Nakanishi, M.; Ota, T.; Aibe, I. (Taisho Pharmaceutical Co., Ltd.); 2-Phenoxyaniline derivs.. EP 1031556; JP 1999193263; US 6162832; WO 9920598 . |
| 【2】 Taguchi, M.; Ohta, T.; Nakanishi, M.; Tomizawa, K.; Soube, I. (Taisho Pharmaceutical Co., Ltd.); Na+/Ca2+ exchange inhibitors. JP 2000355537 . |
| 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) | 57419 | 3-Nitro-4-chlorophenol; 4-Chloro-3-nitrophenol | 610-78-6 | C6H4ClNO3 | 详情 | 详情 |
| (II) | 57420 | 4-chloro-3-nitrophenyl ethyl ether; 1-chloro-4-ethoxy-2-nitrobenzene | C8H8ClNO3 | 详情 | 详情 | |
| (III) | 18956 | 4-(Benzyloxy)phenol; 4-Benzyloxyphenol | 103-16-2 | C13H12O2 | 详情 | 详情 |
| (IV) | 57421 | 1-[4-(benzyloxy)phenoxy]-4-ethoxy-2-nitrobenzene; benzyl 4-(4-ethoxy-2-nitrophenoxy)phenyl ether | C21H19NO5 | 详情 | 详情 | |
| (V) | 57422 | 4-(2-amino-4-ethoxyphenoxy)phenol | C14H15NO3 | 详情 | 详情 | |
| (VI) | 57423 | 2,5-Difluorobenzyl bromide; alpha-Bromo-2,5-difluorotoluene | 85117-99-3 | C7H5BrF2 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)4-Benzyloxyphenol (I) was protected as the silyl ether (II) upon treatment with tert-butyldiphenylsilyl chloride and imidazole. Then, benzyl ether cleavage in (II) by means of transfer hydrogenolysis with cyclohexene and Pd/C furnished the silyloxy phenol (III). Coupling of phenol (III) with (R)-glycidol (IV) under Mitsunobu conditions yielded the intermediate glycidyl ether (V).
| 【1】 Solvibile, W.R.; et al.; Potent, selective agonists of the human beta3-adrenergic receptor. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 35. |
| 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) | 18956 | 4-(Benzyloxy)phenol; 4-Benzyloxyphenol | 103-16-2 | C13H12O2 | 详情 | 详情 |
| (II) | 52062 | [4-(benzyloxy)phenoxy](tert-butyl)diphenylsilane; benzyl 4-[[tert-butyl(diphenyl)silyl]oxy]phenyl ether | C29H30O2Si | 详情 | 详情 | |
| (III) | 52063 | 4-[[tert-butyl(diphenyl)silyl]oxy]phenol | C22H24O2Si | 详情 | 详情 | |
| (IV) | 16260 | (R)-(+)-Glycidol; (2R)-Oxiranemethanol; (2R)oxiranylmethanol | 57044-25-4 | C3H6O2 | 详情 | 详情 |
| (V) | 52064 | tert-butyl[4-[(2S)oxiranylmethoxy]phenoxy]diphenylsilane; tert-butyl(diphenyl)silyl 4-[(2S)oxiranylmethoxy]phenyl ether | C25H28O3Si | 详情 | 详情 |