Trifluoroacetic acid methylene chloride → HCID 118114781, compound
Reaction equation
[C:1]([C:4]1[C:5]([NH:22][C:23]2[CH:24]=[N:25][N:26]([CH:28]3[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]3)[CH:27]=2)=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17]([N:19]([CH3:21])[CH3:20])=[O:18])[CH2:11]2)=[CH:8][N:9]=1)(=[O:3])[NH2:2].C(Cl)Cl.C(O)(C(F)(F)F)=O>>[CH3:20][N:19]([CH3:21])[C:17](=[O:18])[NH:16][C@@H:12]1[CH2:13][CH2:14][CH2:15][N:10]([C:7]2[N:6]=[C:5]([NH:22][C:23]3[CH:24]=[N:25][N:26]([CH:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)[CH:27]=3)[C:4]([C:1]([NH2:2])=[O:3])=[N:9][CH:8]=2)[CH2:11]1Participants
Procedure
Crude (R)-tert-butyl 4-(4-(3-carbamoyl-6-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazin-2-ylamino)-1H-pyrazol-1-yl)piperidine-1-carboxylate (277, 108 mg, 0.19 mmol) was treated with 2:1 DCM/TFA at RT for 1 hour and concentrated in vacuo to get (R)-5-(3-(3,3-dimethylureido)piperidin-1-yl)-3-(1-(piperidin-4-yl)-1H-pyrazol-4-ylamino)pyrazine-2-carboxamide (278) TFA salt. It was dissolved in 10 mL DCE and 2 mL NMP. To it were added DIEA (330 μL, 1.9 mmol) and cyclopentanone (480 mg, 5.7 mmol). The mixture was stirred at RT for 5 hours, and to it were added HOAc (220 μL, 3.8 mmol) and NaBH(OAc)3 (240 mg, 1.14 mmol). The mixture was stirred at RT for overnight. It was diluted with 10 mL MeOH, concentrated in vacuo, acidified with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate (R)-3-(1-(1-cyclopentylpiperidin-4-yl)-1H-pyrazol-4-ylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide (279) as HCl salt (45 mg, 45%). MS found for C26H40N10O2 as (M+H)+ 525.6, (M−H)− 523.3. UV: λ=254, 270, 297, 331, 374 nm.
Workup
- concentrationconcentrated in vacuo
Sources & evidence
- ORD record
- ord-6e6d00d12a9845ea90e4692c33fffcfb
- Source dataset
- uspto-grants-2016_07
- Patent number
- US09382246B2
Reaction notes
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