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【结 构 式】 
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【分子编号】29648 【品名】2-oxiranylmethanol 【CA登记号】556-52-5 |
【 分 子 式 】C3H6O2 【 分 子 量 】74.07944 【元素组成】C 48.64% H 8.16% O 43.2% |
合成路线1
该中间体在本合成路线中的序号：(XI)A shorter synthetic pathway is through the condensation of the above chlorohydrin (II) with m-cyanobenzyloxyaniline (X), prepared by alkylation of p-nitrophenol (VIII) with m-cyanobenzyl bromide (VII) in the presence of KI and further reduction of the nitro group with Fe-NH4Cl, then cyclization with ethyl carbonate. Cimoxatone can also be obtained by opening glycidol (XI) with m-cyanobenzyloxyaniline (X) in ethanol under reflux, and cyclizing with ethyl carbonate (A) to obtain a 5-hydroxymethyl-2-oxazolidinone (XIII), which is methylated by CH3I under phase-transfer catalysis.
| 【1】 Ancher, J.F.; Bourgery, G.; Dostert, P.; Douzon, C.; Guerret, P.; Lacour, A.; Laglois, M.; Nouvelles oxazolidinones, oxazolidinethiones et pyrrilidinones, leur procédé de préparation et leur application en thérapeutique. FR 2428032; JP 55051064; JP 56167666 . |
| 【2】 Ancher, J.F.; Cimoxatone. Drugs Fut 1984, 9, 6, 412. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 17470 | diethyl carbonate; diethylcarbonate | 105-58-8 | C5H10O3 | 详情 | 详情 |
| (II) | 34214 | 1-chloro-3-methoxy-2-propanol | 4151-97-7 | C4H9ClO2 | 详情 | 详情 |
| (VII) | 13244 | alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile | 28188-41-2 | C8H6BrN | 详情 | 详情 |
| (VIII) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
| (IX) | 34216 | 3-[(4-nitrophenoxy)methyl]benzonitrile | C14H10N2O3 | 详情 | 详情 | |
| (X) | 34217 | 3-[(4-aminophenoxy)methyl]benzonitrile | C14H12N2O | 详情 | 详情 | |
| (XI) | 29648 | 2-oxiranylmethanol | 556-52-5 | C3H6O2 | 详情 | 详情 |
| (XII) | 34218 | 3-([4-[(2,3-dihydroxypropyl)amino]phenoxy]methyl)benzonitrile | C17H18N2O3 | 详情 | 详情 | |
| (XIII) | 34219 | 3-([4-[5-(hydroxymethyl)-2-oxo-1,3-oxazolidin-3-yl]phenoxy]methyl)benzonitrile | C18H16N2O4 | 详情 | 详情 | |
| (XIV) | 34220 | 3-([4-[(2-hydroxy-3-methoxypropyl)amino]phenoxy]methyl)benzonitrile | C18H20N2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)The condensation in DMF of 1,1-dimethyl-2-[(aminocarbonyl)amino]ethylamine (III) [prepared from 1,2-diamino-2-methylpropane (I) and urea (II)] and 2,3-epoxypropyl o-fluorobenzoate (VI) [prepared from o-fluorobenzoyl chloride (VI) and glycidol (V) in diethyl ether using triethylamine as a proton scavenger], followed by salt formation using 98% sulfuric acid in ethanol yields ACC-9089.
| 【1】 Mai, K.X.; Kam, S.T.; Matier, W.L.; O'Donnel, J.P.; Sum, C.Y.; Gorczynski, R.J.; Lee, R.J.; Stamfli, H.F.; Barcelon-Yang, C.; Anderson, W.G.; Borgman, R.J.; [(Arylcarbonyl)oxy]propanolamines. 1. Novel beta-blockers with ultrashort duration of action. J Med Chem 1984, 27, 8, 1007. |
| 【2】 Day, B.W.; Pento, J.T.; ACC-9089. Drugs Fut 1985, 10, 6, 447. |
| 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) | 29645 | 2-amino-1,1-dimethylethylamine; 2-methyl-1,2-propanediamine | 811-93-8 | C4H12N2 | 详情 | 详情 |
| (II) | 19310 | urea | 57-13-6 | CH4N2O | 详情 | 详情 |
| (III) | 29646 | N-(2-amino-2-methylpropyl)urea | C5H13N3O | 详情 | 详情 | |
| (IV) | 19551 | 2-Fluorobenzoyl chloride | 393-52-2 | C7H4ClFO | 详情 | 详情 |
| (V) | 29648 | 2-oxiranylmethanol | 556-52-5 | C3H6O2 | 详情 | 详情 |
| (VI) | 29647 | 2-oxiranylmethyl 2-fluorobenzoate | C10H9FO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)By condensation of m-toluidine (I) and glycidol (II) in methanol to give 3-(m-toluidino)-1,2-propanediol (III), which was then cyclized by condensation with ethyl carbonate (A) by means of NaOCH3.
| 【1】 Douzon, C.; Fauvan, C.; Une nouvelle serie d'antidepresseurs: les derives de l'hydroxymethyl-5-oxazolidinone-2. Chimie Therapeutique 1973, 3, 324-327. |
| 【2】 Sungurbey, K.; Castaner, J.; Toloxatone. Drugs Fut 1976, 1, 12, 569. |
合成路线4
该中间体在本合成路线中的序号：(VI)The reaction of cyclohexane-1,3-dione (I) with ammonia gives 3-amino-2-cyclohexen-1-one (II), which is cyclized with acrylic acid (III) by heating at 140 C yielding 1,2,3,4,5,6,7,8-octahydroquinoline-2,5-dione (IV). The dehydrogenation of (IV) by means of Pd/C in refluxing decaline affords 5-hydroxy-1,2,3,4-tetrahydroquinolin-2-one (V), which is condensed with epichlorohydrin (VI) by means of NaOMe or NaOH in methanol giving 5-(2,3-epoxypropoxy)-1,2,3,4-tetrahydroquinolin-2-one (VII). Finally, this compound is treated with tert-butylamine in methanol.
| 【1】 Castaner, J.; Sungurbey, K.; Carteolol. Drugs Fut 1977, 2, 5, 288. |
| 【2】 Shono, T.; et al.; A new practical synthesis of 5-hydroxy-3,4-dihydrocarbostyril and 5-hydroxycarbostyril. J Org Chem 1981, 46, 3719. |
| 【3】 Von Winkler, W.; Chemical and analytical data for the pharmaceutically active substance carteolol hydrochloride. Arzneim-Forsch Drug Res 1983, 33, 2a, 279. |
| 【4】 Mori, H.; Tamura, Y,.; Tominaga, M.; Yoshiaki, S.; Nakagawa, K.; Murakami, N. (Otsuka Pharmaceutical Co., Ltd.); 3,4-Dihydrocarbostyril derivs., their preparation, and pharmaceutical compsns. thereof. DE 2302027; GB 1424571 . |
| 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) | 11244 | 1,3-Cyclohexanedione | 504-02-9 | C6H8O2 | 详情 | 详情 |
| (II) | 31475 | 3-amino-2-cyclohexen-1-one | 5220-49-5 | C6H9NO | 详情 | 详情 |
| (III) | 19139 | acrylic acid | 79-10-7 | C3H4O2 | 详情 | 详情 |
| (IV) | 31476 | 4,6,7,8-tetrahydro-2,5(1H,3H)-quinolinedione | C9H11NO2 | 详情 | 详情 | |
| (V) | 31477 | 5-hydroxy-3,4-dihydro-2(1H)-quinolinone | C9H9NO2 | 详情 | 详情 | |
| (VI) | 29648 | 2-oxiranylmethanol | 556-52-5 | C3H6O2 | 详情 | 详情 |
| (VII) | 31478 | 5-(2-oxiranylmethoxy)-3,4-dihydro-2(1H)-quinolinone | C12H13NO3 | 详情 | 详情 | |
| (VIII) | 17895 | 2-Amino-2-methylpropane; tert-butylamine; 2-methyl-2-propanamine | 75-64-9 | C4H11N | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(II)A new synthesis of lubeluzole has been reported: The condensation of 3,4-difluorophenol (I) with racemic glycidol (II) by means of PPh3 and DEAD in THF gives 2-(3,4-difluorophenoxymethyl)oxirane (III), which is opened by means of Li2CuCl4 in THF yielding racemic 1-chloro-3-(3,4-difluorophenoxy)-2-propanol (IV). Racemic compound (IV) is kinetically resolved by transesterification with vinyl butyrate using Rhizomucor miehei lipase (RML) as catalyst, providing a mixture of (R)-1-chloro-3-(3,4-difluorophenoxy)-2-propanol (V) and the (S)-butyrate (VI). This mixture is easily separated by column chromatography. Finally, the (R)-alcohol (V) is condensed with N-methyl-N-(piperidin-4-yl)benzothiazol-2-amine (VII) by means of NaHCO3 in hot DMF. The key intermediate N-methyl-N-(piperidin-4-yl)benzothiazol-2-amine (VII) has been obtained as follows: Reductive amination of 4-oxopiperidine-1-carboxylic acid ethyl ester (VIII) with methylamine and borane/pyridine complex in methanol gives 4-(methylamino)piperidine-1-carboxylic acid ethyl ester (IX), which is condensed with isothiocyanatobenzene (X) in isopropyl ether to yield the thiourea (XI). Cyclization of compound (XI) by means of Br2 in refluxing CCl4 affords the benzothiazole derivative (V), which is finally decarboxylated by means of HBr in refluxing water, followed by treatment with NaOH.
| 【1】 Liu, H.L.; Helgehoff, B.; Berg, T.C.; Anthonsen, T.; Synthesis of the antistroke drug lubeluzole and its enantiomer. Lipase-catalyzed resolution of chiral building block. Chirality 2001, 13, 3, 135. |
| 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) | 16739 | 3,4-difluorophenol | 2713-33-9 | C6H4F2O | 详情 | 详情 |
| (II) | 29648 | 2-oxiranylmethanol | 556-52-5 | C3H6O2 | 详情 | 详情 |
| (III) | 47537 | 2-[(3,4-difluorophenoxy)methyl]oxirane; 3,4-difluorophenyl 2-oxiranylmethyl ether | C9H8F2O2 | 详情 | 详情 | |
| (IV) | 47534 | 1-chloro-3-(3,4-difluorophenoxy)-2-propanol | C9H9ClF2O2 | 详情 | 详情 | |
| (V) | 47535 | (1S)-2-chloro-1-[(3,4-difluorophenoxy)methyl]ethyl butyrate | C13H15ClF2O3 | 详情 | 详情 | |
| (VI) | 47536 | (2R)-1-chloro-3-(3,4-difluorophenoxy)-2-propanol | C9H9ClF2O2 | 详情 | 详情 | |
| (VII) | 13486 | Ethyl 4-oxo-1-piperidinecarboxylate; N-Carbethoxy-4-piperidone | 29976-53-2 | C8H13NO3 | 详情 | 详情 |
| (VIII) | 22145 | ethyl 4-(methylamino)-1-piperidinecarboxylate | C9H18N2O2 | 详情 | 详情 | |
| (IX) | 22146 | 1-isothiocyanatobenzene; phenyl isothiocyanate | 103-72-0 | C7H5NS | 详情 | 详情 |
| (X) | 22147 | ethyl 4-[(anilinocarbothioyl)(methyl)amino]-1-piperidinecarboxylate | C16H23N3O2S | 详情 | 详情 | |
| (XI) | 22148 | ethyl 4-[1,3-benzothiazol-2-yl(methyl)amino]-1-piperidinecarboxylate | C16H21N3O2S | 详情 | 详情 | |
| (XII) | 16742 | N-(1,3-benzothiazol-2-yl)-N-methyl-N-(4-piperidinyl)amine; N-methyl-N-(4-piperidinyl)-1,3-benzothiazol-2-amine | C13H17N3S | 详情 | 详情 |