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【结 构 式】 
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【分子编号】33330 【品名】4-[2-(Cyclopropylmethoxy)ethyl]phenol; p-(Cyclopropylmethoxyethyl)phenol 【CA登记号】 |
【 分 子 式 】C12H16O2 【 分 子 量 】192.25784 【元素组成】C 74.97% H 8.39% O 16.64% |
合成路线1
该中间体在本合成路线中的序号：(VI)The condensation of ethyl p-hydroxyphenylacetate (I) with benzyl chloride (II) by means of sodium ethoxide in refluxing ethanol gives ethyl p-(benzyloxy)phenylacetate (III), which is reduced with LiAlH4 in THF to 2-(p-benzyloxyphenyl)ethanol (IV). The etherification of (IV) with cyclopropyl bromide (A) by means of NaH in hot DMF affords 4-(cyclopropylmethoxyethyl)-1-benzyloxybenzene (V), which is debenzylated by hydrogenation with H2 and Pd/C in methanol giving rise to p-(cyclopropylmethoxyethyl)phenol (VI). The condensation of (VI) with epichlorohydrin (B) by means of NaOH in water yields 1-[p-(cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane (VII), which is treated with isopropylamine (C) and finally with HCl in ether.
| 【1】 Manoury, P.M.J.; et al. (Sanofi-Synthelabo ); Phenol ethers. DE 2649605; FR 2330383; GB 1515978; JP 52085146; US 4252984 . |
| 【2】 Hillier, K.; Castaner, J.; Serradell, M.N.; Blancafort, P.; Betaxolol hydrochloride. Drugs Fut 1979, 4, 12, 867. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (A) | 22277 | Cyclopropyl bromide; 1-(Bromomethyl)cyclopropane | 7051-34-5 | C4H7Br | 详情 | 详情 |
| (I) | 24994 | Ethyl 2-(4-hydroxyphenyl)acetate | 17138-28-2 | C10H12O3 | 详情 | 详情 |
| (II) | 19171 | 1-(Chloromethyl)benzene; Benzyl chloride | 100-44-7 | C7H7Cl | 详情 | 详情 |
| (III) | 28637 | Ethyl 2-[4-(benzyloxy)phenyl]acetate; p-(Benzyloxy)phenylacetate | C17H18O3 | 详情 | 详情 | |
| (IV) | 33328 | 2-(p-Benzyloxyphenyl)ethanol; 2-[4-(Benzyloxy)phenyl]-1-ethanol | C15H16O2 | 详情 | 详情 | |
| (V) | 33329 | 4-(Cyclopropylmethoxyethyl)-1-benzyloxybenzene; 1-(Benzyloxy)-4-[2-(cyclopropylmethoxy)ethyl]benzene; Benzyl 4-[2-(cyclopropylmethoxy)ethyl]phenyl ether | C19H22O2 | 详情 | 详情 | |
| (VI) | 33330 | 4-[2-(Cyclopropylmethoxy)ethyl]phenol; p-(Cyclopropylmethoxyethyl)phenol | C12H16O2 | 详情 | 详情 | |
| (VII) | 33331 | 2-([4-[2-(Cyclopropylmethoxy)ethyl]phenoxy]methyl)oxirane; 1-[p-(Cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane; 4-[2-(Cyclopropylmethoxy)ethyl]phenyl 2-oxiranylmethyl ether | C15H20O3 | 详情 | 详情 | |
| (C) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The condensation of 4-[2-(cyclopropylmethoxy)ethyl]phenol (I) with epichlorohydrin (II) in pyridine gives the phenol ether (III), which is treated with HCl to open the epoxide ring and yield the racemic chloropropanol (IV). The optical resolution of (IV) by means of Lipase SP 435-L or AK and vinyl acetate (V) gives a mixture of (S)-acetate (S)-(VI) and unreacted (R)-alcohol (R)-(VI) that is easily separated. Finally, the chiral chloropropanol (R)-(VI) is treated with isopropylamine (VII) to afford the target betaxolol. The optical resolution of racemic betaxolol by means of the previously mentioned lipases has also been tried with poor results.
| 【1】 Di Bono, G.; Scilimati, A.; Synthesis 1995, 6, 688. |
| 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) | 33330 | 4-[2-(Cyclopropylmethoxy)ethyl]phenol; p-(Cyclopropylmethoxyethyl)phenol | C12H16O2 | 详情 | 详情 | |
| (II) | 10146 | Epichlorohydrin; 2-(Chloromethyl)oxirane | 106-89-8 | C3H5ClO | 详情 | 详情 |
| (III) | 33331 | 2-([4-[2-(Cyclopropylmethoxy)ethyl]phenoxy]methyl)oxirane; 1-[p-(Cyclopropylmethoxyethyl)phenoxy]-2,3-epoxypropane; 4-[2-(Cyclopropylmethoxy)ethyl]phenyl 2-oxiranylmethyl ether | C15H20O3 | 详情 | 详情 | |
| (IV) | 55675 | 1-chloro-3-{4-[2-(cyclopropylmethoxy)ethyl]phenoxy}-2-propanol | C15H21ClO3 | 详情 | 详情 | |
| (V) | 24543 | vinyl acetate | 108-05-4 | C4H6O2 | 详情 | 详情 |
| (VI) | 55676 | (2R)-1-chloro-3-{4-[2-(cyclopropylmethoxy)ethyl]phenoxy}-2-propanol | C15H21ClO3 | 详情 | 详情 | |
| (VII) | 55676 | (2R)-1-chloro-3-{4-[2-(cyclopropylmethoxy)ethyl]phenoxy}-2-propanol | C15H21ClO3 | 详情 | 详情 | |
| (VIII) | 23933 | 2-Propanamine; Isopropylamine | 75-31-0 | C3H9N | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VIII)The oxidation of mannitol diacetonide (I) with Pb(OAc)4 in benzene gives the glyceraldehyde acetonide (II), which is reductocondensed with benzylamine (III) by means of H2 over Pd/C in methanol to yield, after acidification with HCl, (S)-3-(benzylamino)propane-1,2-diol (IV). The cyclization of (IV) with benzaldehyde (V) in refluxing toluene affords the chiral oxazolidine (VI), which is treated with tosyl chloride and pyridine to provide the corresponding tosylate (VII). The condensation of (VII) with 4-[2-(cyclopropylmethoxy)ethyl]phenol (VIII) by means of NaH in DMF gives the phenolic ether (IX), which is treated with conc. HCl to open the oxazolidine ring and yield the chiral propanolamine (X). The alkylation of the secondary amino group of (X) with isopropyl iodide (XI) in refluxing ethanol affords the tertiary amine (XII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol to provide the target betaxolol.
| 【1】 Kitteringham, J.; Mitchell, M.B. (GlaxoSmithKline plc); Stereoselective process and chiral intermediates for aryloxydropanolamines. WO 8606368 . |
| 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) | 55678 | (4S)-4-{(1S,2S)-2-[(4S)-1,3-dioxolan-4-yl]-1-methylpropyl}-2,2-dimethyl-1,3-dioxolane | C12H22O4 | 详情 | 详情 | |
| (II) | 36759 | (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | 15186-48-8 | C6H10O3 | 详情 | 详情 |
| (III) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (IV) | 55679 | (2S)-3-(benzylamino)-1,2-propanediol | C10H15NO2 | 详情 | 详情 | |
| (V) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VI) | 55680 | [(5S)-3-benzyl-2-phenyl-1,3-oxazolidin-5-yl]methanol | C17H19NO2 | 详情 | 详情 | |
| (VII) | 55681 | [(5S)-3-benzyl-2-phenyl-1,3-oxazolidin-5-yl]methyl 4-methylbenzenesulfonate | C24H25NO4S | 详情 | 详情 | |
| (VIII) | 33330 | 4-[2-(Cyclopropylmethoxy)ethyl]phenol; p-(Cyclopropylmethoxyethyl)phenol | C12H16O2 | 详情 | 详情 | |
| (IX) | 55682 | (5S)-3-benzyl-5-({4-[2-(cyclopropylmethoxy)ethyl]phenoxy}methyl)-2-phenyl-1,3-oxazolidine; 4-{[(5S)-3-benzyl-2-phenyl-1,3-oxazolidin-5-yl]methoxy}phenethyl cyclopropylmethyl ether | C29H33NO3 | 详情 | 详情 | |
| (X) | 55683 | (2S)-1-(benzylamino)-3-{4-[2-(cyclopropylmethoxy)ethyl]phenoxy}-2-propanol | C22H29NO3 | 详情 | 详情 | |
| (XI) | 19369 | 2-iodopropane | 75-30-9 | C3H7I | 详情 | 详情 |
| (XII) | 55684 | (2S)-1-[benzyl(isopropyl)amino]-3-{4-[2-(cyclopropylmethoxy)ethyl]phenoxy}-2-propanol | C25H35NO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)The 3-(isopropylamino)propane-1,2(S)-diol (IV) intermediate has been obtained by two different methods: 1. The oxidation of 1,2,5,6-O-diisopropylidene-D-mannitol (I) with Pb(OAc)4 in THF gives (R)-2,3-O-isopropylideglyceraldehyde (II), which is reductocondensed with isopropylamine by means of H2 over Pd/C in methanol to yield (S)-3-(isopropylamino)-1,2-O-isopropylidenepropane-1,2-diol (III). The cleavage of the isopropylidene protecting group of (III) in hot 6N HCl affords the desired 3-(isopropylamino)propane-1,2-diol (IV) intermediate. 2. The reductocondensation of (R)-glyceraldehyde (V) with isopropylamine by means of H2 over Pd/C in methanol gives the desired 3-(isopropylamino)propane-1,2-diol (IV) intermediate. The cyclization of (IV) with benzaldehyde (VI) by heating at 150 C gives the oxazolidine (VII), which is treated with Ts-Cl and K2CO3 in pyridine to yield the tosylate (VIII). Finally, this compound is condensed with 4-[2-(cyclopropylmethoxy)ethyl]phenol (IX) by means of NaH in DMF and hydrolyzed with conc. aq. HCl to provide the target isopropanol derivative.
| 【1】 Baldwin, J.J.; et al.; J Med Chem 1979, 22, 11, 1284. |
| 【2】 Weinstock, L.M.; et al.; J Org Chem 1976, 41, 19, 3121. |
| 【3】 Manoury, P.; Binet, J. (Sanofi-Synthelabo); S isomer of betaxolol, its preparation and its application in therapy. GB 2130585 . |
| 【4】 Manoury, P.M.; et al.; Synthesis of a series of compounds related to betaxolol, a new beta1-adrenoceptor antagonist with a pharmacological and pharmacokinetic profile optimized for the treatment of chronic cardiovascular diseases. J Med Chem 1987, 30, 6, 1003-11. |
| 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) | 45944 | (1S,2S)-1,2-bis[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1,2-ethanediol | 1707-77-3 | C12H22O6 | 详情 | 详情 |
| (II) | 36759 | (4R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | 15186-48-8 | C6H10O3 | 详情 | 详情 |
| (III) | 55685 | N-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-N-isopropylamine; N-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2-propanamine | C9H19NO2 | 详情 | 详情 | |
| (IV) | 55687 | (2S)-3-(isopropylamino)-1,2-propanediol | C6H15NO2 | 详情 | 详情 | |
| (V) | 55686 | (R)-(+)-2,3-Dihydroxypropanal; D-(+)-Glyceraldehyde; D-Glyceraldehyde | 453-17-8 | C3H6O3 | 详情 | 详情 |
| (VI) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VII) | 55688 | [(5S)-3-isopropyl-2-phenyl-1,3-oxazolidin-5-yl]methanol | C13H19NO2 | 详情 | 详情 | |
| (VIII) | 55689 | [(5S)-3-isopropyl-2-phenyl-1,3-oxazolidin-5-yl]methyl 4-methylbenzenesulfonate | C20H25NO4S | 详情 | 详情 | |
| (IX) | 33330 | 4-[2-(Cyclopropylmethoxy)ethyl]phenol; p-(Cyclopropylmethoxyethyl)phenol | C12H16O2 | 详情 | 详情 |