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【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

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 .

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 .

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) .

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 .

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