|
【结 构 式】 
|
【分子编号】45760 【品名】methyl (1S,2S,3S,4R)-3-[(1S)-1-amino-2-ethylbutyl]-4-[(tert-butoxycarbonyl)amino]-2-hydroxycyclopentanecarboxylate 【CA登记号】 |
【 分 子 式 】C18H34N2O5 【 分 子 量 】358.47844 【元素组成】C 60.31% H 9.56% N 7.81% O 22.32% |
合成路线1
该中间体在本合成路线中的序号：(VI)The stereospecific synthesis of BCX-1812(RWJ-270201) has been reported: Ring opening of (-)-2-azabicyclo[2.2.1]hept-5-en-3-one (I) with methanolic HCl gives the methyl ester (II), which is N-protected with Boc2O and TEA yielding the carbamate (III). Cyclization of (III) with 2-ethyl-1-nitrobutane (IV) by means of phenyl isocyanate and TEA affords the bicyclic compound (V) and other isomers. Compound (V) is isolated from the mixture and then hydrogenated with H2 over PtO2 in MeOH and a catalytic amount of HCl to provide amine (VI). Reaction of (VI) with acetic anhydride gives the acetamide (VII), which is Boc-deprotected with ethereal HCl yielding amine (VIII). The guanylation of (VIII) with pyrazolecarboxamidine hydrochloride (IX) and DIEA affords the guanidino derivative (X), which is finally hydrolyzed with NaOH to the desired (1S,2S,3R,4R,1'S)-diastereomer.
| 【1】 Babu, Y.S.; Chad, P.; Bantia, S.; et al.; BCX-1812 (RWJ-270201): Discovery of a novel, highly potent, orally active, and selective influenza neuraminidase inhibitor through structure-based drug design. J Med Chem 2000, 43, 19, 3482. |
| 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) | 33410 | cis-2-azabicyclo[2.2.1]hept-5-en-3-one | C6H7NO | 详情 | 详情 | |
| (II) | 33412 | methyl cis-4-amino-2-cyclopentene-1-carboxylate | C7H11NO2 | 详情 | 详情 | |
| (III) | 33413 | methyl cis-4-[(tert-butoxycarbonyl)amino]-2-cyclopentene-1-carboxylate | C12H19NO4 | 详情 | 详情 | |
| (IV) | 33414 | 3-(nitromethyl)pentane | C6H13NO2 | 详情 | 详情 | |
| (V) | 33415 | methyl (3aR*,4R*,6S*,6aS*)-4-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-6-carboxylate | C18H30N2O5 | 详情 | 详情 | |
| (VI) | 45760 | methyl (1S,2S,3S,4R)-3-[(1S)-1-amino-2-ethylbutyl]-4-[(tert-butoxycarbonyl)amino]-2-hydroxycyclopentanecarboxylate | C18H34N2O5 | 详情 | 详情 | |
| (VII) | 45761 | methyl (1S,2S,3S,4R)-3-[(1S)-1-(acetamido)-2-ethylbutyl]-4-[(tert-butoxycarbonyl)amino]-2-hydroxycyclopentanecarboxylate | C20H36N2O6 | 详情 | 详情 | |
| (VIII) | 45762 | methyl (1S,2S,3R,4R)-3-[(1S)-1-(acetamido)-2-ethylbutyl]-4-amino-2-hydroxycyclopentanecarboxylate | C15H28N2O4 | 详情 | 详情 | |
| (IX) | 15983 | 1H-pyrazole-1-carboximidamide | 4023-00-1 | C4H6N4 | 详情 | 详情 |
| (X) | 45763 | methyl (1S,2S,3R,4R)-3-[(1S)-1-(acetamido)-2-ethylbutyl]-4-[[amino(imino)methyl]amino]-2-hydroxycyclopentanecarboxylate | C16H30N4O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)The ring opening of (-)-2-azabicyclo [2,2,1]hept-5-en-3-one (I) with methanolic HCl gives the methyl ester (II), which is N-protected with Boc2O and TEA, yielding the carbamate (III). The cyclization of (III) with 2-ethyl-1-nitrobutane (IV) by means of phenyl isocyanate and TEA affords the bicyclic compound (V) along with other isomers that are separated by column chromatography. Compound (V) is hydrogenated with H2 over PtO2 in methanol to provide amine (VI), which is acylated with Ac2O, giving the acetamide (VII). N-Boc deprotection of (VII) by means of HCl in ethyl ether yields the amine (VIII), which is condensed with protected isothiourea (IX) by means of HgCl2 to afford the guanidine derivative (X). The hydrolysis of (X) with NaOH provides the carboxylic acid (XI), which is finally deprotected with trifluoroacetic acid to yield the target cyclopentanecarboxylic acid derivative.
| 【1】 Chand, P.; et al.; Systematic structure-based design and stereoselective synthesis of novel multisubstituted cyclopentane derivatives with potent antiinfluenza activity. J Med Chem 2001, 44, 25, 4379. |
| 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) | 33410 | cis-2-azabicyclo[2.2.1]hept-5-en-3-one | C6H7NO | 详情 | 详情 | |
| (II) | 33412 | methyl cis-4-amino-2-cyclopentene-1-carboxylate | C7H11NO2 | 详情 | 详情 | |
| (III) | 33413 | methyl cis-4-[(tert-butoxycarbonyl)amino]-2-cyclopentene-1-carboxylate | C12H19NO4 | 详情 | 详情 | |
| (IV) | 33414 | 3-(nitromethyl)pentane | C6H13NO2 | 详情 | 详情 | |
| (V) | 33415 | methyl (3aR*,4R*,6S*,6aS*)-4-[(tert-butoxycarbonyl)amino]-3-(1-ethylpropyl)-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-6-carboxylate | C18H30N2O5 | 详情 | 详情 | |
| (VI) | 45760 | methyl (1S,2S,3S,4R)-3-[(1S)-1-amino-2-ethylbutyl]-4-[(tert-butoxycarbonyl)amino]-2-hydroxycyclopentanecarboxylate | C18H34N2O5 | 详情 | 详情 | |
| (VII) | 45761 | methyl (1S,2S,3S,4R)-3-[(1S)-1-(acetamido)-2-ethylbutyl]-4-[(tert-butoxycarbonyl)amino]-2-hydroxycyclopentanecarboxylate | C20H36N2O6 | 详情 | 详情 | |
| (VIII) | 45762 | methyl (1S,2S,3R,4R)-3-[(1S)-1-(acetamido)-2-ethylbutyl]-4-amino-2-hydroxycyclopentanecarboxylate | C15H28N2O4 | 详情 | 详情 | |
| (IX) | 22345 | tert-butyl (E)-[(tert-butoxycarbonyl)amino](methylsulfanyl)methylidenecarbamate | C12H22N2O4S | 详情 | 详情 | |
| (X) | 55003 | methyl (1S,2S,3R,4R)-3-[(1S)-1-(acetylamino)-2-ethylbutyl]-4-({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)-2-hydroxycyclopentanecarboxylate | C26H46N4O8 | 详情 | 详情 | |
| (XI) | 55004 | (1S,2S,3R,4R)-3-[(1S)-1-(acetylamino)-2-ethylbutyl]-4-({[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)-2-hydroxycyclopentanecarboxylic acid | C25H44N4O8 | 详情 | 详情 |