Filibuvir;PF-00868554;PF-868554, -Drug Synthesis Database

【结构式】

【药物名称】Filibuvir;PF-00868554;PF-868554

【化学名称】6(R)-Cyclopentyl-6-[2-(2,6-diethylpyridin-4-yl)ethyl]-3-(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-2Hpyran-2-one

【CA登记号】877130-28-4;877129-79-8 (undefined stereochemistry);877130-29-5 (enantiomer)

【分子式】C₂₉H₃₇N₅O₃

【分子量】503.6358

【开发单位】Pfizer

【药理作用】RNA-Directed RNA Polymerase (NS5B) Inhibitor;Treatment of Hepatitis C Virus Infection

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

Deprotonation of 2,2,6-trimethyl-1,3-dioxin-4-one (I) by means of LDA, generated from BuLi and (i-Pr)2NH, in THF, followed by condensation with 1-cyclopentyl-3-(trimethylsilyl)-2-propyn-1-one (II) affords the protected propargylic alcohol (III), which is then desilylated to compound (IV) by treatment with CsF in MeOH . Sonogashira coupling of propargylic alcohol (IV) with 4-bromo-2,6-diethylpyridine (V) in the presence of PdCl2(PPh3)2, CuI and (i-Pr)2NH in DMF at 90 °C provides the pyridylbutynol adduct (VI), which upon catalytic hydrogenation over Pd(OH)2 in EtOH affords the saturated alcohol (VII). Subsequent lactonization of (VII) in the presence of K2CO3 in MeOH gives rise to the perhydropyran-2,4-dione (VIIIa). Finally, racemic keto lactone (VIIIa) is submitted to reductive aldol condensation with 5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (IX) in the presence of BH3·Me2NH in MeOH, and resolved by means of chiral HPLC .
In an alternative method, optically pure β-hydroxyacid (X) is activated as the corresponding imidazolide by means of CDI , and optionally, DMAP in MTBE or THF, followed by condensation with magnesium ethyl malonate (XIa) or with potassium ethyl malonate (XIb) in the presence of MgCl2 , to give, after acidic decarboxylation, the keto hydroxy ester (XII). Subsequent lactonization of hydroxy ester (XII) in the presence of K2CO3 in MeOH yields the chiral perhydropyran-2,4-dione derivative (VIIIb). Finally, (R)-keto lactone (VIIIb) , or its dibenzoyl-L-tartrate salt , is submitted to reductive aldol condensation with the triazolopyrimidine aldehyde (IX) in the presence of BH3·pyr in MeOH , THF/MeOH or 2-MeTHF/MTBE .

参考文献中间体

【1】 Gonzalez, J., Jewell, T.M., Li, H., Linton, A., Tatlock, J.H. (Pfizer, Inc.; Agouron Pharmaceuticals, Inc.). Inhibitors of hepatitis C virus RNAdependent RNA polymerase, and compositions and treatments using the same. EP 1781662, JP 2008509984, US 2006122399, US 7151105, US 8268835, WO 2006018725.
【2】 Li, H., Tatlock, J., Linton, A. et al. Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-(1,2,4)triazolo(1,5-a)pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor. J Med Chem 2009, 52(5): 1255-8.
【3】 Johnson, S., Drowns, M., Tatlock, J. et al. Synthetic route optimization of PF-00868554, an HCV polymerase inhibitor in clinical evaluation. Synlett 2010(5): 796-800.
【4】 Matthews, C.F., Scott, R.W., Tucker, J.L. (Pfizer, Inc.). CN 102336758, EP 1928878, JP 2007056022, US 2009023921, US 7807838, WO 2007023381.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIIIa)	68336	racemic 6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)dihydro-2H-pyran-2,4(3H)-dione		C₂₁H₂₉NO₃	详情	详情
(VIIIb)	68337	(R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)dihydro-2H-pyran-2,4(3H)-dione		C₂₁H₂₉NO₃	详情	详情
(XIa)	68340	magnesium 3-ethoxy-3-oxopropanoate		C₁₀H₁₄MgO₈	详情	详情
(XIb)	14338	potassium 3-ethoxy-3-oxopropanoate	6148-64-7	C₅H₇KO₄	详情	详情
(I)	13327	2,2,6-Trimethyl-4H-1,3-dioxin-4-one；2,2,6-trimethyl-1,3-dioxin-4-one；2,2,6-trimethyl-m-Dioxin-4-one;3-(1-hydroxy-1-methylethoxy)-d-lactone Crotonicacid	5394-63-8	C₇H₁₀O₃	详情	详情
(II)	68330	1-cyclopentyl-3-(trimethylsilyl)-2-propyn-1-one		C₁₁H₁₈OSi	详情	详情
(III)	68331	6-(2-cyclopentyl-2-hydroxy-4-(trimethylsilyl)but-3-yn-1-yl)-2,2-dimethyl-4H-1,3-dioxin-4-one		C₁₈H₂₈O₄Si	详情	详情
(IV)	68332	6-(2-cyclopentyl-2-hydroxybut-3-yn-1-yl)-2,2-dimethyl-4H-1,3-dioxin-4-one		C₁₅H₂₀O₄	详情	详情
(V)	68333	4-bromo-2,6-diethylpyridine	877133-54-5	C₉H₁₂BrN	详情	详情
(VI)	68334	6-(2-cyclopentyl-4-(2,6-diethylpyridin-4-yl)-2-hydroxybut-3-yn-1-yl)-2,2-dimethyl-4H-1,3-dioxin-4-one		C₂₄H₃₁NO₄	详情	详情
(VII)	68335	6-(2-cyclopentyl-4-(2,6-diethylpyridin-4-yl)-2-hydroxybutyl)-2,2-dimethyl-4H-1,3-dioxin-4-one		C₂₄H₃₅NO₄	详情	详情
(IX)	68338	5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde		C₈H₈N₄O	详情	详情
(X)	68339	(R)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid		C₁₉H₂₉NO₃	详情	详情
(XII)	68341	(R)-ethyl 5-cyclopentyl-7-(2,6-diethylpyridin-4-yl)-5-hydroxy-3-oxoheptanoate		C₂₃H₃₅NO₄	详情	详情

合成路线2

The precursor 4-bromo-2,6-diethylpyridine (V) can be prepared by several methods. Condensation of 3-oxoglutaric acid (XIII) with propionic anhydride (XIV) in the presence of H2SO4, followed by cyclization with HCl at 100 °C leads to 2,6-diethyl-4-pyranone (XV). Subsequent treatment of pyranone (XV) with NH4OH at 50 °C yields 2,6-diethyl-4-pyridinol (XVI) , which is finally brominated with PBr5 in CHCl3 or POBr3 in DMF at 120 °C .
Alternatively, substitution of 2,6-dichloropyridine (XVII) with ethylmagnesium bromide (XVIII) in the presence of NiCl2(dppp) in Et2O gives 2,6-diethylpyridine (XIX), which can also be obtained by Wolff- Kishner reduction of 2,6-diacetylpyridine (XX) with NH2NH2 in the presence of NaOH in diethylene glycol at 120 °C. Oxidation of 2,6-diethylpyridine (XIX) with mCPBA in CHCl3, followed by nitration of the resulting 2,6-diethylpyridine-1-oxide (XXI) with HNO3 and H2SO4 at 90 °C provides the 4-nitro derivative (XXII). Substitution of nitropyridine (XXII) using AcBr in AcOH at 90 °C affords 4-bromo-2,6-diethylpyridin-1-oxide (XXIII), which is finally reduced with PBr3 in CH2Cl2 .

参考文献中间体

【1】 Gonzalez, J., Jewell, T.M., Li, H., Linton, A., Tatlock, J.H. (Pfizer, Inc.; Agouron Pharmaceuticals, Inc.). Inhibitors of hepatitis C virus RNAdependent RNA polymerase, and compositions and treatments using the same. EP 1781662, JP 2008509984, US 2006122399, US 7151105, US 8268835, WO 2006018725.
【2】 Li, H., Tatlock, J., Linton, A. et al. Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-(1,2,4)triazolo(1,5-a)pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor. J Med Chem 2009, 52(5): 1255-8.
【3】 Johnson, S., Drowns, M., Tatlock, J. et al. Synthetic route optimization of PF-00868554, an HCV polymerase inhibitor in clinical evaluation. Synlett 2010(5): 796-800.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	68333	4-bromo-2,6-diethylpyridine	877133-54-5	C₉H₁₂BrN	详情	详情
(XIII)	15530	1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid	542-05-2	C₅H₆O₅	详情	详情
(XIV)	20095	propionic anhydride	123-62-6	C₆H₁₀O₃	详情	详情
(XV)	68342	2,6-diethyl-4H-pyran-4-one		C₉H₁₂O₂	详情	详情
(XVI)	68343	2,6-diethyl-4-pyridinol;2,6-diethylpyridin-4-ol		C₉H₁₃NO	详情	详情
(XVII)	13573	2,6-Dichloropyridine	2402-78-0	C₅H₃Cl₂N	详情	详情
(XVIII)	24239	bromo(ethyl)magnesium；ethylmagnesium bromide	925-90-6	C₂H₅BrMg	详情	详情
(XIX)	68344	2,6-diethylpyridine	935-28-4	C₉H₁₃N	详情	详情
(XX)	48515	2,6-Diacetylpyridine	1129-30-2	C₉H₉NO₂	详情	详情
(XXI)	68345	2,6-diethylpyridine-1-oxide		C₉H₁₃NO	详情	详情
(XXII)	68346	2,6-diethyl-4-nitropyridine 1-oxide		C₉H₁₂N₂O₃	详情	详情
(XXIII)	68347	4-bromo-2,6-diethylpyridin-1-oxide		C₉H₁₂BrNO	详情	详情

合成路线3

The chiral precursor (X) has been obtained from pyridine (V) by two different strategies. Heck coupling of 2,6-diethyl-4-bromopyridine (V) with benzyl 3(S)-cyclopentyl-3-hydroxy-4-pentenoate (XXIV) in the presence of Pd(OAc)2, Bu4NCl and (c-Hex)2NMe in DMA at 90 °C affords benzyl 3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3(R)-hydroxypent-4-enoate (XXV), which finally undergoes double bond reduction and O-debenzylation by means of H2 over Pd/C in EtOH .
Alternatively, coupling of 4-bromo-2,6-diethylpyridine (V) with 1-cyclopentyl-2-propen-1-ol (XXVI) in the presence of Pd(OAc)2, LiBr and Et3N in DMA/H2O gives rise to 1-cyclopentyl-3-(2,6-diethyl-4-pyridinyl)-1-propanone (XXVII). Subsequent condensation of ketone (XXVII) with ethyl acetate (XXVIII) by means of LiHMDS in THF affords the hydroxy ester (XXIX), which by hydrolysis with NaOH in H2O/THF yields the racemic free acid (XXX). Finally, fractional crystallization of carboxylic acid (XXX) with (1R,2R)-2-amino-1-(4-nitrophenyl) propane-1,3-diol in THF provides the desired (R)-enantiomer (X). The undesired (S)-enantiomer (XXXI), obtained from the mother liquors of resolution of compound (XXX), can be recycled by esterification with EtOH and H2SO4 in refluxing THF, followed by retroaldol reaction of the obtained hydroxy ester in the presence of t-BuOK in MTBE to produce ketone (XXVII) .

参考文献中间体

【1】 Johnson, S., Drowns, M., Tatlock, J. et al. Synthetic route optimization of PF-00868554, an HCV polymerase inhibitor in clinical evaluation. Synlett 2010(5): 796-800.
【2】 Matthews, C.F., Scott, R.W., Tucker, J.L. (Pfizer, Inc.). CN 102336758, EP 1928878, JP 2007056022, US 2009023921, US 7807838, WO 2007023381.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	68333	4-bromo-2,6-diethylpyridine	877133-54-5	C₉H₁₂BrN	详情	详情
(X)	68339	(R)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid		C₁₉H₂₉NO₃	详情	详情
(XXIV)	68348	(S)-benzyl 3-cyclopentyl-3-hydroxypent-4-enoate;benzyl 3(S)-cyclopentyl-3-hydroxy-4-pentenoate		C₁₇H₂₂O₃	详情	详情
(XXV)	68349	3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3(R)-hydroxypent-4-enoate;(R,E)-benzyl 3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypent-4-enoate		C₂₆H₃₃NO₃	详情	详情
(XXVI)	68350	1-cyclopentylprop-2-en-1-ol		C₈H₁₄O	详情	详情
(XXVII)	68351	1-cyclopentyl-3-(2,6-diethyl-4-pyridinyl)-1-propanone		C₁₇H₂₅NO	详情	详情
(XXVIII)	17491	ethyl acetate	141-78-6	C₄H₈O₂	详情	详情
(XXIX)	68352	ethyl 3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoate		C₂₁H₃₃NO₃	详情	详情
(XXX)	68353	racemic 3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid		C₁₉H₂₉NO₃	详情	详情
(XXXI)	68354	(S)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic		C₁₉H₂₉NO₃	详情	详情

合成路线4

The triazolopyrimidine intermediate (IX) is prepared as follows. Cyclization of glycolic acid (XXXII) with aminoguanidine bicarbonate (XXXIII) in the presence of HNO3 at reflux yields 3-amino-5-(hydroxymethyl)-1,2,4-triazole (XXXIV) (1), optionally isolated as its glycolate salt , which then cyclizes with acetylacetone (XXXV) in refluxing AcOH/EtOH to afford the [1,2,4]triazolo[1,5-a]pyrimidine derivative (XXXVI) . Finally, alcohol (XXXVI) is oxidized by means of o-iodoxybenzoic acid (IBX) in DCE at 80 °C or with PhI(OAc)2 in the presence of TEMPO in CH2Cl2 .

参考文献中间体

【1】 Gonzalez, J., Jewell, T.M., Li, H., Linton, A., Tatlock, J.H. (Pfizer, Inc.; Agouron Pharmaceuticals, Inc.). Inhibitors of hepatitis C virus RNAdependent RNA polymerase, and compositions and treatments using the same. EP 1781662, JP 2008509984, US 2006122399, US 7151105, US 8268835, WO 2006018725.
【2】 Matthews, C.F., Scott, R.W., Tucker, J.L. (Pfizer, Inc.). CN 102336758, EP 1928878, JP 2007056022, US 2009023921, US 7807838, WO 2007023381.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	68338	5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde		C₈H₈N₄O	详情	详情
(XXXII)	29856	2-hydroxyacetic acid;glycolic acid	79-14-1	C₂H₄O₃	详情	详情
(XXXIII)	68355	aminoguanidine bicarbonate;aminoguanidine carbonate;1-aminoguanidine bicarbonate;aminoguanidine hydrogen carbonate	2200-97-7	CH₆N₄.CH₂O₃	详情	详情
(XXXIV)	68356	5-amino-1H-1,2,4-Triazole-3-methanol;3-amino-5-(hydroxymethyl)-1,2,4-triazole;5-amino-s-Triazole-3-methanol;(5-Amino-1H-[1,2,4]triazol-3-yl)methanol	27277-03-8	C₃H₆N₄O	详情	详情
(XXXV)	11620	2,4-Pentanedione;acetylacetone	123-54-6	C₅H₈O₂	详情	详情
(XXXVI)	68357	(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methanol		C₈H₁₀N₄O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)