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【结 构 式】

【分子编号】69170

【品名】cyclopentylcarboxaldehyde;3-cyclopentyl-2-Propenenitrile

【CA登记号】591769-05-0

【 分 子 式 】C8H11N

【 分 子 量 】121.18208

【元素组成】C 79.29% H 9.15% N 11.56%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(VI)

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 .

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
Extended Information