【结 构 式】 |
【分子编号】47535 【品名】(1S)-2-chloro-1-[(3,4-difluorophenoxy)methyl]ethyl butyrate 【CA登记号】 |
【 分 子 式 】C13H15ClF2O3 【 分 子 量 】292.7098064 【元素组成】C 53.34% H 5.17% Cl 12.11% F 12.98% O 16.4% |
合成路线1
该中间体在本合成路线中的序号:(V)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 |