合成路线:4-Bromo-2-fluoroaniline (I) was protected as the N-Boc derivative (II) upon treatment with di-tert-butyl dicarbonate.Subsequent palladium-catalyzed bromide displacement in (II) with bis-pinacolatodiborane (III) furnished the arylboronate derivative (IV).The (dioxaspirodecyl)pyrimidine (VII) was prepared by coupling between 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (V) and 4-hydroxycyclohexanone ethylene ketal (VI) under Mitsunobu conditions.Subsequent Suzuki coupling of iodopyrrolopyrimidine (VII) with boronate (IV) afforded adduct (VIII).Displacement of the 4-chloro of (VIII) with simultaneous N-Boc group cleavage with ammonium hydroxide in dioxan at 120 C in a sealed vessel furnished the diamino compound (IX).
合成路线:Acid hydrolysis of the ethylene ketal function of (IX) afforded ketone (X).This was subjected to a reductive amination with N-methylpiperazine (XI) in the presence of sodium triacetoxyborohydride to produce the corresponding disubstituted cyclohexane compound as a 3:1 mixture of cis- and trans-isomers.The desired trans-compound (XII) was then isolated by column chromatography.Finally,acylation of (XII) with 2,3-dichlorobenzenesulfonyl chloride (XIII) provided the title sulfonamide.
参考文献标题:Pyrrolopyrimidines as tyrosine kinase inhibitors
文献作者:Hirst,G.C.; Rafferty,P.; Arnold,L.D.; Johnston,D.N.; Calderwood,D.; Munschaufer,R.(BASF AG)
参考来源:WO 0172751
合成路线:4-Bromo-2-fluoroaniline (I) was protected as the N-Boc derivative (II) upon treatment with di-tert-butyl dicarbonate.Subsequent palladium-catalyzed bromide displacement in (II) with bis-pinacolatodiborane (III) furnished the arylboronate derivative (IV).The (dioxaspirodecyl)pyrimidine (VII) was prepared by coupling between 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (V) and 4-hydroxycyclohexanone ethylene ketal (VI) under Mitsunobu conditions.Subsequent Suzuki coupling of iodopyrrolopyrimidine (VII) with boronate (IV) afforded adduct (VIII).Displacement of the 4-chloro of (VIII) with simultaneous N-Boc group cleavage with ammonium hydroxide in dioxan at 120 C in a sealed vessel furnished the diamino compound (IX).
合成路线:Acid hydrolysis of the ethylene ketal function of (IX) afforded ketone (X).This was subjected to a reductive amination with N-methylpiperazine (XI) in the presence of sodium triacetoxyborohydride to produce the corresponding disubstituted cyclohexane compound as a 3:1 mixture of cis- and trans-isomers.The desired trans-compound (XII) was then isolated by column chromatography.Finally,acylation of (XII) with 2,3-dichlorobenzenesulfonyl chloride (XIII) provided the title sulfonamide.
参考文献标题:Structure activity relationships for a novel series of pyrrolo[2,3-d]pyrimidine Tie-2 inhibitors
文献作者:Wishart,N.; Barlozzari,T.; Arnold,L.D.; et al.
参考来源:Proc Am Assoc Cancer Res 2002,43Abst 4205
产品链接: CAS No. 262442-90-0››