(R)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid -Drug Synthesis Database

【结构式】

【分子编号】68339

【品名】(R)-3-cyclopentyl-5-(2,6-diethylpyridin-4-yl)-3-hydroxypentanoic acid

【CA登记号】　

【分子式】C₁₉H₂₉NO₃

【分子量】319.4442

【元素组成】C 71.44% H 9.15% N 4.38% O 15.03%

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：(X)

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

合成目标

【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

该中间体在本合成路线中的序号：(X)

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

合成目标

【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

Extended Information