Tetrahydroisoquinoline derivative, and preparation method and medical application thereof
A technology of compounds and mixtures, applied in the field of medicine
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Embodiment 1
[0398] N-(3,5-difluoro-4-((1S,3R)-3-methyl-6-(1H-pyrazol-4-yl)-2-(2,2,2trifluoroethyl) -1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)-1-(3-fluoropropyl)azetidinyl-3-amine 1
[0399]
[0400]
[0401] first step
[0402] (R)-tert-butyl(1-(3-(benzyloxy)phenyl)propyl-2-yl)carbamate 1c
[0403] Dissolve benzyloxy-3-bromobenzene 1a (4.00g, 15.20mmol) in tetrahydrofuran (45mL), under argon protection, stir well, add n-butyllithium (15.20mmol, 9.5mL, 1.6M), -78°C Stir for 30 minutes. Then (R)-4-methyl-1,2,3-oxathiazolidine-3-carboxylic acid tert-butyl ester 2,2-dioxide 1b (3.60g, 15.17mmol, using the patent application "WO2016162325, implemented (prepared by the method disclosed in Example 1") was dissolved in 20 mL of tetrahydrofuran, the above solution was added to the reaction solution, and the reaction was stirred at -78°C for 0.5 hours. When the temperature was slowly raised to 0°C, the reaction was stopped after stirring in an ice bath for 30 minutes. The reaction was q...
Embodiment 2
[0451] N-(3,5-difluoro-4-((1S,3R)-3-methyl-6-(1-methyl-1H-pyrazol-4-yl)-2-(2,2,2 -Trifluoroethyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)-1-(3-fluoropropyl)azetidinyl-3-amine 2
[0452]
[0453] Using the synthetic route of compound 1 in Example 1, the raw material compound 1r was replaced by the raw material compound 1-methyl-4-pyrazole boronic acid pinacol ester 2r (94mg, 451.78μmol), anhydrous sodium carbonate (56mg, 528.36umol ), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (17mg, 23.23umol) and compound 1q (140mg, 225.97umol) were reacted to obtain the title compound 2 (60mg), Yield: 39%.
[0454] MS m / z(ESI):552.2[M+1]
[0455] 1 H NMR (400MHz, CD 3 OD)7.91(s,1H),7.77(s,1H),7.26(s,1H),7.20(d,1H),6.71(d,1H),6.18-6.12(m,2H),5.18(s, 1H),4.74-4.64(m,1H),4.62(t,1H),4.50(t,1H),4.48-4.34(m,2H),4.22-4.12(m,1H),3.97-3.93(m, 1H),3.90(s,3H),3.58-3.50(m,1H),3.48-3.39(m,2H),3.37-3.33(m,1H),3.29-3.23(m,1H),2.97-2.86( m,1H),2.65(dd,1H),2.08-1.95(m,2H),1.07(d,...
Embodiment 3
[0457] N-(4-((1S,3R)-6-(1-ethyl-1H-pyrazol-4-yl)-3-methyl-2-(2,2,2-trifluoroethyl)- 1,2,3,4-Tetrahydroisoquinolin-1-yl)-3,5-difluorophenyl)-1-(3-fluoropropyl)azetidinyl-3-amine
[0458]
[0459] Using the synthetic route of compound 1 in Example 1, the raw material compound 1r was replaced by the raw material compound 1-ethyl-4-pyrazole borate pinacol ester 3r (100 mg, 450.27 μmol), anhydrous sodium carbonate (56 mg, 528.36 μmol ), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (17mg, 23.23umol) and compound 1q (140mg, 225.97umol) were reacted to obtain the title compound 3 (40mg), Yield: 31%.
[0460] MS m / z(ESI):566.3[M+1]
[0461] 1 H NMR (400MHz, CD 3 OD)7.93(s,1H),7.77(s,1H),7.28(s,1H),7.21(d,1H),6.72(d,1H),6.07(d,2H),5.15(s,1H) ,4.52(t,1H),4.41(t,1H),4.19(q,2H),4.10-4.04(m,1H),3.86-3.82(m,2H),3.55-3.51(m,1H),3.38 -3.34(m,1H),3.28-3.20(m,1H),3.07-3.03(m,2H),2.98-2.87(m,1H),2.70(t,2H),2.63(dd,1H),1.84 -1.71(m,2H),1.47(t,3H),1.07(d,3H).
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