Hydrochloric Acid → 3-(((1R,2R)-2-amino-3,3-difluorocyclohexyl)amino)-5-((3-(pyrimidin-2-yl)phenyl)amino)-1,2,4-triazine-6-carboxamide

HRID 577420Notes

Reaction equation

HRID 577420 reaction equation
CS[C:3]1[N:4]=[N:5][C:6]([C:22]([NH2:24])=[O:23])=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:11]=2)[N:8]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.CCN(C(C)C)C(C)C.Cl.Cl.[F:47][C:48]1([F:56])[CH2:53][CH2:52][CH2:51][C@@H:50]([NH2:54])[C@H:49]1[NH2:55].C(O)(C(F)(F)F)=O.Cl>CN1C(=O)CCC1>[NH2:55][C@H:49]1[C:48]([F:56])([F:47])[CH2:53][CH2:52][CH2:51][C@H:50]1[NH:54][C:3]1[N:4]=[N:5][C:6]([C:22]([NH2:24])=[O:23])=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:11]=2)[N:8]=1

Participants

8

Reactant 6

HCID 313Hydrochloric AcidHCID 6422Trifluoroacetic acidHCID 70297m-Chloroperbenzoic acidHCID 81531DiisopropylethylamineHCID 86685557(1R,2R)-3,3-difluorocyclohexane-1,2-diamine dihydrochlorideHCID 867064133-(Methylthio)-5-(3-(pyrimidin-2-yl)phenylamino)-1,2,4-triazine-6-carboxamide

Product 1

HCID 727032273-(((1R,2R)-2-amino-3,3-difluorocyclohexyl)amino)-5-((3-(pyrimidin-2-yl)phenyl)amino)-1,2,4-triazine-6-carboxamideYield 66.1%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

3-(Methylthio)-5-(3-(pyrimidin-2-yl)phenylamino)-1,2,4-triazine-6-carboxamide (40 mg, 0.12 mmol) was dissolved in 4 mL NMP. To it was added mCPBA (77%) (108 mg, 0.48 mmol). The mixture was stirred at RT for 1 h. To it was added DIEA (0.21 mL, 1.20 mmol) and (1R,2R)-3,3-difluorocyclohexane-1,2-diamine dihydrochloride (53 mg, 0.24 mmol). The mixture was stirred at 80° C. for 1 h. It was cooled to RT, acidified with TFA (0.3 mL) and subjected to reverse phase preparative HPLC to isolate the title compound (35 mg) as HCl salt. MS found for C20H21F2N9O as (M+H)+ 442.5. UV: λ=240 nm. Proton NMR: (CD3OD) δ 8.94-8.92 (3H, m), 8.41 (1H, d, J=8.0 Hz), 7.79 (1H, d, J=8.0 Hz), 7.64 (1H, t, J=8.0 Hz), 7.45 (1H, t, J=4.8 Hz), 4.90 (1H, m), 4.13 (1H, m), 2.24-1.82 (6H, m) ppm.

Workup

  1. stirringThe mixture was stirred at 80° C. for 1 h
  2. temperatureIt was cooled to RT

Sources & evidence

ORD record
ord-401d987570874833b73dd58a3b875d23
Source dataset
uspto-grants-2015_05
Patent number
US09040530B2

Reaction notes

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