N-Aminomorpholine → HCID 71493324, compound

HRID 1500374Notes

Reaction equation

HRID 1500374 reaction equation
[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:25]1([NH2:31])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl.CO.CCOC(C)=O>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:31][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1

Participants

8

Reactant 4

HCID 20315N-AminomorpholineHCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 86703006(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid

Product 1

HCID 71493324HCID 71493324, compoundYield 33%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-60 °C

Procedure

A 50-mL, 3-necked, round-bottomed flask was charged with (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.250 g), morpholin-4-amine (0.072 g, 1.0 eq.) and EtOAc (10 mL). The solution was cooled to −60° C. and treated with T3P (50% in EtOAc; 0.63 mL, 1.5 eq.) and DIPEA (0.24 mL, 2.0 eq.) under a nitrogen atmosphere. The progress of the reaction was followed by TLC analysis using 10% MeOH:CH2Cl2 as mobile phase and visualization under UV light. Upon completion, the reaction mixture was quenched with water and extracted with EtOAc (3×15 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure (25° C., 20 mmHg) to afford 0.35 g of a crude solid. Purification (Combi-flash, elution with 3% MeOH:CH2Cl2) afforded 100 mg (yield: 33%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-morpholinoacrylamide. 1H NMR (400 MHz, DMSO-d6) δ=9.52 (s, NH exchange, 1H), 8.51 (s, 2H), 8.28 (s, 1H), 7.38-7.42 (m, 1H), 6.50-6.53 (d, J=10.4 Hz, 1H), 5.84-5.86 (d, J=10.4 Hz, 1H), 3.63 (s, 4H), 2.87 (s, 4H); LCMS for C17H16F6N5O2 [M+H]+ 436.33; found 436.18 (RT 2.64 min, purity: 100%).

Workup

  1. customUpon completion, the reaction mixture was quenched with water
  2. extractionextracted with EtOAc (3×15 mL)
  3. dry with materialThe combined organic extracts were dried over anhydrous Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure (25° C., 20 mmHg)
  6. customto afford 0.35 g of a crude solid
  7. customPurification (Combi-flash, elution with 3% MeOH:CH2Cl2)

Sources & evidence

ORD record
ord-9645b024cf574e988340e2708ce26492
Source dataset
uspto-grants-2015_12
Patent number
US09206158B2

Reaction notes

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