2-Hydrazinopyridine → Verdinexor

HRID 1523331Notes

Reaction equation

HRID 1523331 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](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[NH2:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl>[F:23][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:26][NH:25][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1

Participants

7

Reactant 4

HCID 786452-HydrazinopyridineHCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 86703006(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid

Product 1

HCID 71492799VerdinexorYield 48%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-40 °C

Procedure

A 500-mL, 3-necked, round-bottomed flask was charged with a suspension of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (10 g, 1.0 eq.) in 1:1 CH2Cl2:AcOEt (200 mL). 2-Hydrazinopyridine (3.11 g) was added at −40° C. T3P (50% in ethylacetate) (21.75 g) was added dropwise followed by DIPEA (7.36 g) and the reaction mixture was stirred for 30 min at −40° C. before being concentrated under reduced pressure (35° C., 20 mm Hg) to afford a crude brown oil that was purified by column chromatography (the compound eluted with 1.3% MeOH in CH2Cl2). Fractions containing desired compound were combined to afford 6.0 g (yield: 48%) (Z)-3-(3-(3,5-bis-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyridin-2-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ, 10.41 (s, 1H), 9.66 (s, 1H), 8.59 (s, 1H), 8.53 (s, 2H), 8.28 (s, 1H), 8.06-8.08 (d, J=5.2 Hz, 1H), 7.48-7.53 (m, 1H), 7.49-7.52 (d, J=10.4, 1H), 6.71-6.75 (m, 1H), 6.66-6.68 (d, J=8.4 Hz, 1H), 6.07-6.09 (d, J=10.4, 1H). LCMS for C18H12F6N6O [M+H]+ predicted: 443.33. found: 443.44 (RT 2.45 min, purity: 100%).

Workup

  1. concentrationbefore being concentrated under reduced pressure (35° C., 20 mm Hg)
  2. customto afford a crude brown oil that
  3. customwas purified by column chromatography (the compound
  4. washeluted with 1.3% MeOH in CH2Cl2)
  5. additionFractions containing desired compound

Sources & evidence

ORD record
ord-dddab11e4a0c4aeaa4a602034a5e5ced
Source dataset
uspto-grants-2015_07
Patent number
US09079865B2

Reaction notes

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