(E)-3-cyclopentylacrylaldehyde -Drug Synthesis Database

【结构式】

【分子编号】69176

【品名】(E)-3-cyclopentylacrylaldehyde

【CA登记号】　

【分子式】C₈H₁₂O

【分子量】124.18268

【元素组成】C 77.38% H 9.74% O 12.88%

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)

N-Protection of 4-chloropyrrolo[2,3-d]pyrimidine (I) with either 2-(trimethylsilyl) ethoxymethyl chloride (SEM-Cl) in DMA or pivaloyloxymethyl chloride (POM-Cl) in THF in the presence of NaH yields the protected deazapurines (IIa) and (IIb) , respectively, which by Suzuki coupling with pinacol 1-(1-ethoxyethyl)-4-pyrazolylboronate (III) by means of Pd(PPh3)4 and K2CO3, followed by acidic hydrolysis of the ethoxyethyl group, affords the respective pyrazolyl deazapurines (Va) and (Vb) . Alternatively, intermediate (Va) can be obtained by Suzuki coupling of deazapurine (IIa) with unprotected pyrazolylboronate (IV) by means of Pd(PPh3)4 and K2CO3 in DMF/H2O at 125 °C . Michael addition of pyrazole derivative (Va) to 3-cyclopentylacrylonitrile (VI) (obtained by Wittig condensation of cyclopentylcarboxaldehyde [VII] with diethyl cyanomethylphosphonate [VIII] by means of t-BuOK in THF) in the presence of DBU in acetonitrile, followed by resolution using chiral preparative HPLC, provides the desired (R)-adduct (IXa) . Alternatively, in an enantioselective procedure, asymmetric aza-Michael reaction of (Va) or (Vb) with (E)-3-cyclopentylacrylaldehyde (X) in the presence of p-nitrobenzoic acid (p-NBA) and a chiral diarylprolinol silyl ether in CHCl3 gives aldehydes (XIa) and (XIb), which by subsequent condensation with NH4OH, followed by oxidation of the intermediate imines with I2 in aqueous solution, leads to the corresponding nitriles (IXa) and (IXb) . Finally, ruxolitinib is obtained by deprotection of compound (IXa) by sequential treatment with LiBF4 in refluxing acetonitrile/H2O followed by aqueous NH4OH , or with TFA in CH2Cl2 and subsequent basification of obtained TFA salt with ethylenediamine (EDA) in MeOH , or by deprotection of compound (IXb) by treatment with NaOH in MeOH/H2O .
In an alternative strategy, ruxolitinib can be directly obtained by Suzuki coupling of unprotected 4-chloropyrrolo[2,3-d]pyrimidine (I) with the pyrazolylboronate (XII) in the presence of Pd(PPh3)4 and K2CO3 in 1,4-dioxane/H2O at 100 °C .

参考文献中间体

合成目标

【1】 Lin, Q., Meloni, D., Pan, Y. et al. Enantioselective synthesis of Janus kinase inhibitor INCB018424 via an organocatalytic aza-Michael reaction. Org Lett 2009, 11(9): 1999-2002.
【2】 Rodgers, J.D., Shepard, S., Maduskuie, T.P. Jr. et al. (Incyte Corp.). Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors. US 20090181959.
【3】 Rodgers, J.D., Shepard, S., Maduskuie, T.P. Jr. et al. (Incyte Corp.). Heteroaryl substituted pyrrolo[2,3-b]pyridines and pyrrolo[2,3-b]pyrimidines as Janus kinase inhibitors. CA 2632466, EP 1966202, JP 2009519340, US 2007135461, US 7598257, WO 2007070514.
【4】 Friedman, P.A., Fridman, J.S., Luchi, M.E., Williams, W.V. (Incyte Corp.). Janus kinase inhibitors for treatment of dry eye and other eye related diseases. WO 2010039939.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IIa)	68079	4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine		C₁₂H₁₈ClN₃OSi	详情	详情
(IIb)	69168			C₆H₃ClN₃.POM	详情	详情
(Va)	68072	4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine		C₁₅H₂₁N₅OSi	详情	详情
(Vb)	69169			C₉H₆N₅.POM	详情	详情
(IXa)	69172	(R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanenitrile		C₂₃H₃₂N₆OSi	详情	详情
(IXb)	69175			C₁₇H₁₇N₆.POM	详情	详情
(XIa)	69173	(R)-3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)propanal		C₂₃H₃₃N₅O₂Si	详情	详情
(XIb)	69174			C₁₇H₁₈N₅O.POM	详情	详情
(I)	60046	4-chloro-7H-pyrrolo[2,3-d]pyrimidine；6-Chloro-7-deazapurine；4-chloropyrrolo[2,3-d]pyrimidine；4-Chloro-1H-pyrrolo[2,3-d]pyrimidine	3680-69-1	C₆H₄ClN₃	详情	详情
(III)	68071	1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole		C₁₃H₂₃BN₂O₃	详情	详情
(IV)	68081	4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole		C₉H₁₅BN₂O₂	详情	详情
(VI)	69170	cyclopentylcarboxaldehyde;3-cyclopentyl-2-Propenenitrile	591769-05-0	C₈H₁₁N	详情	详情
(VII)	69171	cyclopentylcarboxaldehyde；Cyclopentanecarbaldehyde;Cyclopentanealdehyde;Cyclopentyl aldehyde;Cyclopentylformaldehyde;Formylcyclopentane	872-53-7	C₆H₁₀O	详情	详情
(VIII)	10045	Diethyl cyanomethylphosphonate	2537-48-6	C₆H₁₂NO₃P	详情	详情
(X)	69176	(E)-3-cyclopentylacrylaldehyde		C₈H₁₂O	详情	详情
(XII)	69177	(S)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile		C₁₇H₂₆BN₃O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

Intermediates (X) and (XII) are prepared by Wittig olefination of cyclopentylcarboxaldehyde (VII) with (triphenylphosphoranylidene)-acetaldehyde (XIX) in benzene at 80 °C, followed by preparative HPLC separation to yield (E)-3-cyclopentylacrylaldehyde (X), which upon asymmetric aza-Michael reaction with 4-bromopyrazole (XIIIa) by means of a chiral catalyst and p-NBA in THF/H2O gives the Michael adduct (XX). Then, aldehyde (XX) is treated with NH4OH and I2 in 1,4-dioxane/H2O to give nitrile (XXI), which is finally reacted with bis(pinacolato)diboron (XXII) in the presence of Pd(PPh3)4 and KOAc in 1,4-dioxane at 120 °C .

参考文献中间体

合成目标

【1】 Lin, Q., Meloni, D., Pan, Y. et al. Enantioselective synthesis of Janus kinase inhibitor INCB018424 via an organocatalytic aza-Michael reaction. Org Lett 2009, 11(9): 1999-2002.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIIIa)	69178	4-iodopyrazole;4-Iodo-1H-pyrazole	3469-69-0	C₃H₃IN₂	详情	详情
(B)	69184	2-(bis(3,5-bis(trifluoromethyl)phenyl)((tert-butyldimethylsilyl)oxy)methyl)pyrrolidine		C₂₇H₂₉F₁₂NOSi	详情	详情
(VII)	69171	cyclopentylcarboxaldehyde；Cyclopentanecarbaldehyde;Cyclopentanealdehyde;Cyclopentyl aldehyde;Cyclopentylformaldehyde;Formylcyclopentane	872-53-7	C₆H₁₀O	详情	详情
(X)	69176	(E)-3-cyclopentylacrylaldehyde		C₈H₁₂O	详情	详情
(XII)	69177	(S)-3-cyclopentyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanenitrile		C₁₇H₂₆BN₃O₂	详情	详情
(XIX)	69183	Triphenyl phosphine;Triphenyl phosphorous;(triphenylphosphoranylidene)-acetaldehyde	2136-75-6	C₁₈H₁₅PO	详情	详情
(XX)	69185	(R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropanal		C₁₁H₁₅BrN₂O	详情	详情
(XXI)	69186	(R)-3-(4-bromo-1H-pyrazol-1-yl)-3-cyclopentylpropanenitrile		C₁₁H₁₄BrN₃	详情	详情
(XXII)	53342	4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1,3,2-dioxaborolane; Bis(pinacolato)diboron; Diboron pinacol ester	73183-34-3	C₁₂H₂₄B₂O₄	详情	详情

Extended Information