SHR1258 synthesis
- Product Name:SHR1258
- CAS Number:1269662-73-8
- Molecular formula:C32H31ClN6O3
- Molecular Weight:583.08
![Phosphonic acid, P-[2-[[4-[[3-chloro-4-(2-pyridinylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]amino]-2-oxoethyl]-, diethyl ester](/CAS/20180527/GIF/1269662-79-4.gif)
Yield:1269662-73-8 46 mg
Reaction Conditions:
Stage #1:diethyl ({[4-({3-chloro-4-[(pyridin-2-yl)methoxy]phenyl}amino)-3-cyano-7-ethoxyquinolin-6-yl]carbamoyl}methyl)phosphonate with lithium hexamethyldisilazane in tetrahydrofuran;toluene for 0.5 h;Cooling with ice;Inert atmosphere;Wittig Olefination;
Stage #2:(2R)-1-methylpyrrolidine-2-formaldehyde in tetrahydrofuran;toluene at 20 - 30; for 12.5 h;Inert atmosphere;Wittig Olefination;
Steps:
5.3 Step 3 (E)-N-[4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-3-[(2R)-1-methylpyrrolidin-2-yl]propan-2-enecarboxamide
Under dry ice bath, N-[4-[[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-2-diethylphosphonoacetamide 1d (250 mg, 0.40 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran. It was added dropwise 1 M toluene solution of bis(trimethylsilyl)amine lithium (440μL, 0.44 mmol). React for 30 minutes. Add dropwise 5 mL (2R)-1-methylpyrrolidin-2-carbaldehyde 5c (90 mg, 0.80 mmol) in tetrahydrofuran. The reaction was stirred for 30 minutes. Reaction was continued for 12 hours at room temperature, the reaction solution concentrated under reduced pressure, by column chromatography with silica gel eluting A surfactant system resulting residue, to give the title product (E) -N- [4 - [[3- chloro-4- (pyridin-2- ylmethoxy) benzene yl] amino] -3-cyano-7-ethoxy-6-quinolinyl] -3 - [(2R) -1- methyl-pyrrolidin-2-yl] propan-2-ene-amide 5 (46 mg, yellow solid), yield: 19.7%.
References:
JIANGSU HENGRUI MEDICINE CO., LTD.;SHANGHAI HENGRUI PHARMACEUTICAL CO., LTD.;TANG, PENG CHO;LI, XIN;WANG, BIN;WANG, JUN;CHEN, LIJUN TWI524893, 2016, B Location in patent:Page/Page column 44; 45; 46
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