【结 构 式】 |
【分子编号】40770 【品名】diethyl 2-cyano-2-[cyano(4-fluorophenyl)methyl]pentanedioate 【CA登记号】 |
【 分 子 式 】C18H19FN2O4 【 分 子 量 】346.3583432 【元素组成】C 62.42% H 5.53% F 5.49% N 8.09% O 18.48% |
合成路线1
该中间体在本合成路线中的序号:(III)Knoevenagel condensation of 4-fluorobenzaldehyde (I) with ethyl cyanoacetate (A) gave adduct (II). Subsequent conjugate addition of NaCN to (II), followed by alkylation with ethyl 3-chloropropionate (B) furnished the dicyano diester (III). Acid hydrolysis of (III), with concomitant decarboxylation, afforded tricarboxylic acid (IV), which was further esterified with methanolic HCl to give ester (V). Dieckmann cyclization of (V) using NaOMe, and then hydrolysis and decarboxylation gave rise to the racemic trans ketoacid (VI). Esterification of (VI), and reduction of the resulting keto ester (VII) with NaBH4 produced a mixture of diastereomeric alcohols. The desired trans,trans-isomer (VIII) was then isolated by column chromatography. Ester hydrolysis of (VIII) and re-solution as the corresponding salt with (R)-alpha-methylbenzylamine furnished the (-)-hydroxy acid (IX) that was esterified to (X) with methanolic HCl.
【1】 MacCoss, M.; Meurer, L.C.; Finke, P.E.; et al.; Discovery of potent human NK1 antagonists having a cyclopentane-based core structure. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 98. |
【2】 Finke, P.E.; Maccoss, M.; Meurer, L.C.; Mills, S.G.; Caldwell, C.G.; Chen, P.; Durette, P.L.; Hale, J.; Holson, E.; Kopka, I.; Robichaud, A. (Merck & Co., Inc.); Cyclopentyl tachykinin receptor antagonists. EP 0858444; WO 9714671 . |
【3】 Caldwell, C.G.; Chen, P.; Durette, P.L.; Finke, P.; Hale, J.; Holson, E.; Kopka, I.; Maccoss, M.; Meurer, L.; Mills, S.G.; Robichaud, A. (Merck & Co., Inc.); Cycloalkyl tachykinin receptor antagonists. US 5750549 . |
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) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
(B) | 40769 | ethyl 3-chloropropanoate | 623-71-2 | C5H9ClO2 | 详情 | 详情 |
(+/-)-(VIII) | 40775 | (rac)-methyl (1R*,2R*,3S*)-2-(4-fluorophenyl)-3-hydroxycyclopentanecarboxylate | C13H15FO3 | 详情 | 详情 | |
(-)-(IX) | 40776 | (1R,2R,3S)-2-(4-fluorophenyl)-3-hydroxycyclopentanecarboxylic acid | C12H13FO3 | 详情 | 详情 | |
(-)-(X) | 40777 | (-)-methyl (1R,2R,3S)-2-(4-fluorophenyl)-3-hydroxycyclopentanecarboxylate | C13H15FO3 | 详情 | 详情 | |
(I) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
(II) | 40768 | ethyl (E)-2-cyano-3-(4-fluorophenyl)-2-propenoate | C12H10FNO2 | 详情 | 详情 | |
(III) | 40770 | diethyl 2-cyano-2-[cyano(4-fluorophenyl)methyl]pentanedioate | C18H19FN2O4 | 详情 | 详情 | |
(IV) | 40771 | 1-(4-fluorophenyl)-1,2,4-butanetricarboxylic acid | C13H13FO6 | 详情 | 详情 | |
(V) | 40772 | trimethyl 1-(4-fluorophenyl)-1,2,4-butanetricarboxylate | C16H19FO6 | 详情 | 详情 | |
(VI) | 40773 | (1R,2R)-2-(4-fluorophenyl)-3-oxocyclopentanecarboxylic acid | C12H11FO3 | 详情 | 详情 | |
(VII) | 40774 | methyl (1R,2R)-2-(4-fluorophenyl)-3-oxocyclopentanecarboxylate | C13H13FO3 | 详情 | 详情 |