Diisopropylethylamine → HCID 10389061, compound

HRID 897266Notes

Reaction equation

HRID 897266 reaction equation
[F:1][CH:2]([F:23])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2OS(C(F)(F)F)(=O)=O.Cl.Cl.[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[CH2:36][N:37]1[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.CCOC(C)=O>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9](=[O:14])[CH:8]=[C:7]2[NH:43][CH:40]1[CH2:39][CH2:38][N:37]([CH2:36][C:27]2[CH:28]=[CH:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=2)[CH2:42][CH2:41]1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 69736828HCID 69736828, compoundHCID 86592637HCID 86592637, compound

Product 1

HCID 10389061HCID 10389061, compoundYield 7.8%

Reagents, catalysts & solvents 2

HCID 6212ChloroformSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
50 °C

Procedure

4,6-Dihydroxy-chromen-2-one (500 mg, 2.790 mmol) was dissolved in iPrOH (50 mL). KOH pellets (1.57 g, 27.90 mmol) were added and this mixture was stirred at 25° C. for 5 min. ClCHF2 (g) was bubbled through the reaction mixture for 5 min. The reaction was stirred an additional 10 min. at 25° C. followed by stirring for 30 min. at 60° C. The reaction mixture was diluted with EtOAc and washed with 1 N HCl (aq). The organic layer was dried over Na2SO4, concentrated, and partially purified via silica gel chromatography (20% CH3OH in CH2Cl2) to produce 490 mg of crude 6-difluoromethoxy-4-hydroxy-chromen-2-one. 626 mg of crude 6-difluoromethoxy-4-hydroxy-chromen-2-one was dissolved in CH2Cl2 (20 mL) under nitrogen, cooled to 0° C., and N,N-diisopropylethylamine (2.51 mL, 14.4 mmol) was added. Triflic anhydride (1.31 mL, 7.81 mmol) was added dropwise and the solution was stirred 30 min. at 0° C. The crude product was partially purified via silica gel chromatography (20% EtOAc in hexanes) to produce 682 mg of crude trifluoro-methanesulfonic acid 6-difluoromethoxy-2-oxo-2H-chromen-4-yl ester. 600 mg of crude trifluoro-methanesulfonic acid 6-difluoromethoxy-2-oxo-2H-chromen-4-yl ester was dissolved in CHCl3 (15 mL). 1-Naphthalen-2-ylmethyl-piperidin-4-ylamine dihydrochloride salt (448 mg, 1.43 mmol) and N,N-diisopropylethylamine (0.75 mL, 4.30 mmol) were added and the resulting solution was stirred at 50° C. for 3 h. The reaction mixture was diluted with EtOAc and washed with H2O (3×) followed by saturated aqueous NaCl (1×). The combined organics were dried over Na2SO4, concentrated, and purified on a C-18 RP HPLC system to afford 50 mg of the title compound as a white solid. MS (ESI(+)Q1MS) m/z 451 (M+H)+; 1H NMR (300 MHz, CD3OD) δ ppm 7.77-7.91 (m, 5H), 7.32-7.54 (m, 5H), 6.86 (t, J=73 Hz, 1H), 5.34 (s, 1H), 3.74 (s, 2H), 3.48-3.60 (m, 1H), 2.98-3.08 (m, 2H), 2.21-2.33 (m, 2H), 2.00-2.10 (m, 2H), 1.69-1.83 (m, 2H). Compound II-125 was prepared similarly.

Workup

  1. washwashed with H2O (3×)
  2. dry with materialThe combined organics were dried over Na2SO4
  3. concentrationconcentrated
  4. custompurified on a C-18 RP HPLC system

Sources & evidence

ORD record
ord-945e7823ac0b429385138b3c5a9b41b5
Source dataset
uspto-grants-2005_07
Patent number
US06921821B2

Reaction notes

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