methyl 2-{[(trifluoromethyl)sulfonyl]oxy}acetate -Drug Synthesis Database

【结构式】

【分子编号】63493

【品名】methyl 2-{[(trifluoromethyl)sulfonyl]oxy}acetate

【CA登记号】

【分子式】C₄H₅F₃O₅S

【分子量】222.1419096

【元素组成】C 21.63% H 2.27% F 25.66% O 36.01% S 14.43%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VII)

4(R)-Aminocyclopentane-(1S,2R,3S)-triol 2,3-acetonide (I) is condensed with 4,6-dichloro-5-nitro-2-propylthiopyrimidine (II) in the presence of diisopropylethylamine in THF to afford the aminopyrimidine adduct (III), which is reduced to the diamine (IV) by means of iron powder in acetic acid. Cyclization of diamine (IV) employing isoamyl nitrite in hot acetonitrile followed by displacement of the resulting 6-chloro-8-azapurine (V) with ammonia in THF gives the azaadenine (VI). The lithium alkoxide of cyclopentanol (VI) is then alkylated with methoxycarbonylmethyl triflate (VII), producing ether (VIII). After conversion of amine (VIII) to the corresponding bromide (IX) by diazotization with isoamyl nitrite in bromoform, bromide displacement with 2-(3,4-difluorophenyl)cyclopropylamine (X) gives adduct (XI). Finally, DIBAL reduction of the ester function of (XI) provides acetonide (XII), which is finally hydrolyzed under acidic conditions to furnish the title compound (1, 2). Scheme 1.

参考文献中间体

合成目标

【1】 Guile, S., Hardern, D., Willis, P., Springthorpe, B., Ingall, A. (AstraZeneca AB; AstraZeneca plc). Novel triazolo(4,5-d)pyrimidine compounds. EP 1135391, JP 2002531567, JP 2007084551, US 2003144305, US 2006025590, US 6525060, WO 0034283.
【2】 Bohlin, M., Lassen, B., Cosgrove, S. (AstraZeneca AB). New crystalline and amorphous form of triazolo(4,5-d)pyrimidine compound. CA 2408596, EP 1289992, EP 1493745, JP 2003535092, US 2003181469, US 2007173518, WO 0192262.

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)	65443	(3aR,4S,6R,6aS)-6-Aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol; (3aS,4R,6S,6aR)-6-Hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine	155899-66-4	C₈H₁₅NO₃	详情	详情
(II)	65444	4,6-Dichloro-5-nitro-2-propylthiopyrimidine	145783-14-8	C₇H₇Cl₂N₃O₂S	详情	详情
(III)	65445	(3aR,4S,6R,6aS)-6-[[6-Chloro-5-nitro-2-(propylthio)-4-pyrimidinyl]amino]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol	220241-59-8	C₁₅H₂₁ClN₄O₅S	详情	详情
(IV)	65446	(3aR,4S,6R,6aS)-6-[[5-Amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol	220241-60-1	C₁₅H₂₃ClN₄O₃S	详情	详情
(V)	65447	(3aR,4S,6R,6aS)-6-[7-Chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol	220241-61-2	C₁₅H₂₀ClN₅O₃S	详情	详情
(VI)	65448	(3aR,4S,6R,6aS)-6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol	274693-22-0	C₁₅H₂₂N₆O₃S	详情	详情
(VII)	63493	methyl 2-{[(trifluoromethyl)sulfonyl]oxy}acetate		C₄H₅F₃O₅S	详情	详情
(VIII)	65449	2-[[(3aR,4S,6R,6aS)-6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-acetic acid methyl ester	274693-23-1	C₁₈H₂₆N₆O₅S	详情	详情
(IX)	65450	2-[[(3aR,4S,6R,6aS)-6-[7-Bromo-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-acetic acid methyl ester	274693-24-2	C₁₈H₂₄BrN₅O₅S	详情	详情
(X)	65451	(1R,2S)-rel-2-(3,4-Difluorophenyl)cyclopropanamine	1006614-49-8	C₉H₉F₂N	详情	详情
(XI)	65452	2-[[(3aR,4S,6R,6aS)-6-[7-[[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-acetic acid methyl ester	274693-25-3	C₂₇H₃₂F₂N₆O₅S	详情	详情
(XII)	65453	2-[[(3aS,4R,6S,6aR)-4-[7-[[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy]ethanol	274693-26-4	C₂₆H₃₂F₂N₆O₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IX)

Condensation between ethyl 2-oxocyclopentanecarboxylate (I) and thiourea (II) gives rise to the thiouracil derivative (III) (1,2). This is then alkylated with 4-fluorobenzyl chloride (IV) to yield thioether (V). Subsequent alkylation of (V) with tert-butyl iodoacetate (VI) furnishes adduct (VII). Further acidic cleavage of the tert-butyl ester group of (VII) leads to carboxylic acid (VIII) (2,3). Alternatively, intermediate (VIII) is prepared by alkylation of (V) with triflate (IX), followed by alkaline hydrolysis of the resultant methyl ester (X)

参考文献中间体

合成目标

【1】 The identification of clinical candidate SB-480848: A potent inhibitor of lipoprotein-associated phospholipase A2. Bioorg Med Chem Lett 2003, 13, 6, 1067.
【2】 Ife, R.J.; Leach, C.A.; Hickey, D.M.B.; Pinto, I.L.; Smith, S.A.; Stanway, S.J. (GlaxoSmithKline plc); Pyrimidine-4-one derivs. as LDL-PLA 2 inhibitors. EP 1263740; JP 2003523335; US 2002103213; US 6649619; WO 0160805 .
【3】 Mulholland, K.R.; Ross, A.R.; Smith, G.E.; Slater, G.R. (GlaxoSmithKline plc); Novel processes. WO 0316287 .

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)	29947	ethyl 2-oxocyclopentanecarboxylate	611-10-9	C₈H₁₂O₃	详情	详情
(II)	10180	Thiourea	62-56-6	CH₄N₂S	详情	详情
(III)	63490	2-sulfanyl-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one		C₇H₈N₂OS	详情	详情
(IV)	12354	4-Fluorobenzyl chloride; 1-(Chloromethyl)-4-fluorobenzene	352-11-4	C₇H₆ClF	详情	详情
(V)	63491	2-{[(4-fluorophenyl)methyl]sulfanyl}-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one		C₁₄H₁₃FN₂OS	详情	详情
(VI)	24735	tert-Butyl 2-iodoacetate		C₆H₁₁IO₂	详情	详情
(VII)	63492	1,1-dimethylethyl 2-(2-{[(4-fluorophenyl)methyl]sulfanyl}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetate		C₂₀H₂₃FN₂O₃S	详情	详情
(VIII)	63494	2-(2-{[(4-fluorophenyl)methyl]sulfanyl}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid		C₁₆H₁₅FN₂O₃S	详情	详情
(IX)	63493	methyl 2-{[(trifluoromethyl)sulfonyl]oxy}acetate		C₄H₅F₃O₅S	详情	详情
(X)	63495	methyl 2-(2-{[(4-fluorophenyl)methyl]sulfanyl}-4-oxo-4,5,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetate		C₁₇H₁₇FN₂O₃S	详情	详情

Extended Information