Peramivir, RWJ-270201, BCX-1812, -Drug Synthesis Database

【结构式】

【药物名称】Peramivir, RWJ-270201, BCX-1812

【化学名称】3(R)-[1(S)-Acetamido-2-ethylbutyl]-4(R)-guanidino-2(S)-hydroxycyclopentane-1(S)-carboxylic acid
　　　　　　(1S,2S,3R,4R)-3-[1(S)-(Acetylamino)-2-ethylbutyl]-4-[[amino(imino)methyl]amino]-2-hydroxycyclopentanecarboxylic acid

【CA登记号】229614-55-5, 229615-12-7 ((+)-enantiomer), 229614-56-6 (undefined isomer)

【分子式】C₁₅H₂₈N₄O₄

【分子量】328.41481

【开发单位】BioCryst (Originator)

【药理作用】ANTIINFECTIVE THERAPY, Anti-Influenza Virus Drugs, Antiviral Drugs, Neuraminidase (Sialidase) Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

Ring opening of cis-2-azabicyclo[2.2.1]hept-5-en-3-one (I) with HCl in refluxing methanol gives cis-4-amino-2-cyclopentene-1-carboxylic acid (II), which is esterified with HCl/methanol, yielding the methyl ester (III). The protection of (III) with tert-butoxycarbonyl anhydride and triethylamine in dichloromethane affords carbamate (IV), which is cyclized with 2-ethyl-1-nitrobutane (V) by means of phenyl isocyanate in refluxing benzene to give the cyclopenta-oxazoline (VI). Ring opening of (VI) by hydrogenation with H2 over PtO2 in HCl/methanol yields amine (VII), which is acylated with acetic anhydride and triethylamine in dichloromethane to afford acetamide (VIII). The deprotection of (VIII) with HCl in ethyl ether gives the cyclopentylamine (IX), which is condensed with N,N'-bis(tert-butoxycarbonyl)-O-methylisourea (X) by means of HgCl2 in DMF to yield the protected guanidino compound (XI). Deprotection of the guanidino group of (XI) with trifluoroacetic acid in dichloromethane affords the methyl ester (XII), which is finally hydrolyzed with NaOH in THF/methanol.

参考文献中间体

【1】 Sorbera, L.A.; Castañer, J.; Graul, A.; RWJ-270201. Drugs Fut 2000, 25, 3, 249.
【2】 Montgomery, J.A.; Babu, Y.S.; Chand, P. (BioCryst Pharmaceuticals, Inc.); Substd. cyclopentane and cyclopentene cpds. useful as neuraminidase inhibitors. WO 9933781 .

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)	33411	cis-4-amino-2-cyclopentene-1-carboxylic acid	168471-40-7	C₆H₉NO₂	详情	详情
(III)	33412	methyl cis-4-amino-2-cyclopentene-1-carboxylate		C₇H₁₁NO₂	详情	详情
(IV)	33413	methyl cis-4-[(tert-butoxycarbonyl)amino]-2-cyclopentene-1-carboxylate		C₁₂H₁₉NO₄	详情	详情
(V)	33414	3-(nitromethyl)pentane		C₆H₁₃NO₂	详情	详情
(VI)	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
(VII)	33416	methyl (1R,2R,3R,4S)-3-[(1S*)-1-amino-2-ethylbutyl]-4-[(tert-butoxycarbonyl)amino]-2-hydroxycyclopentanecarboxylate		C₁₈H₃₄N₂O₅	详情	详情
(VIII)	33417	methyl (1R,2R,3R,4S)-3-[(1S*)-1-(acetamido)-2-ethylbutyl]-4-[(tert-butoxycarbonyl)amino]-2-hydroxycyclopentanecarboxylate		C₂₀H₃₆N₂O₆	详情	详情
(IX)	33418	methyl (1R,2R,3S,4S)-3-[(1S*)-1-(acetamido)-2-ethylbutyl]-4-amino-2-hydroxycyclopentanecarboxylate		C₁₅H₂₈N₂O₄	详情	详情
(X)	33419	tert-butyl (E)-[(tert-butoxycarbonyl)amino](methoxy)methylidenecarbamate		C₁₂H₂₂N₂O₅	详情	详情
(XI)	33420	methyl (1R,2R,3S,4S)-3-[(1S*)-1-(acetamido)-2-ethylbutyl]-4-([[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl]amino)-2-hydroxycyclopentanecarboxylate		C₂₆H₄₆N₄O₈	详情	详情
(XII)	33421	methyl (1R,2R,3S,4S)-3-[(1S*)-1-(acetamido)-2-ethylbutyl]-4-[[amino(imino)methyl]amino]-2-hydroxycyclopentanecarboxylate		C₁₆H₃₀N₄O₄	详情	详情

合成路线2

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.

参考文献中间体

【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3

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.

参考文献中间体

【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	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

Extended Information

Drug NewChemical Entity Original Patent(2)