1,2-Dichloroethane → Hydrochloric Acid

HRID 1050532Notes

Reaction equation

HRID 1050532 reaction equation
[CH3:1][N:2]([CH3:34])[C:3](=[O:33])[NH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]2[N:12]=[C:13]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=2)[CH2:6]1.CCN(C(C)C)C(C)C.[C:44]1(=O)[CH2:47][CH2:46][CH2:45]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[Cl:67]CCCl>O1CCOCC1.CO>[CH:44]1([N:30]2[CH2:29][CH2:28][CH:27]([C:24]3[CH:25]=[CH:26][C:21]([NH:20][C:13]4[C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=[C:11]([N:7]5[CH2:8][CH2:9][CH2:10][C@@H:5]([NH:4][C:3]([N:2]([CH3:34])[CH3:1])=[O:33])[CH2:6]5)[N:12]=4)=[CH:22][CH:23]=3)[CH2:32][CH2:31]2)[CH2:47][CH2:46][CH2:45]1.[ClH:67]

Participants

10

Reactant 6

HCID 111,2-DichloroethaneHCID 176Acetic AcidHCID 14496CyclobutanoneHCID 81531DiisopropylethylamineHCID 5049666Sodium triacetoxyborohydrideHCID 118114627HCID 118114627, compound

Product 2

HCID 313Hydrochloric AcidHCID 118114895HCID 118114895, compound

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 312751,4-DioxaneSolvent

Procedure

(R)-5-(3-(3,3-Dimethylureido)piperidin-1-yl)-3-(4-(piperidin-4-yl)phenylamino)pyrazine-2-carboxamide (189) TFA salt (115 mg, 0.20 mmol) was dissolved in 10 mL dioxane and 10 mL 1,2-dichloroethane (DCE) with DIEA (175 μL, 1.0 mmol). To it was added cyclobutanone (450 μL, 6.0 mmol), and the mixture was stirred at RT for overnight. To it were added HOAc (112 μL, 2.0 mmol) and then NaBH(OAc)3 (212 mg, 1.0 mmol). The mixture was stirred at RT for 2 hours, diluted with 10 mL MeOH, concentrated in vacuo, acidified with 0.5 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-(4-(1-cyclobutylpiperidin-4-yl)phenylamino)-5-(3-(3,3-dimethylureido)piperidin-1-yl)pyrazine-2-carboxamide (217) as HCl salt (73 mg). MS found for C28H40N8O2 as (M+H)+ 521.7, (M−H)− 519.3. UV: λ=268, 277, 306, 336, 373 nm. Proton NMR (CD3OD): δ 7.65 (1H, s), 7.61 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 4.29 (1H, m), 4.20 (1H, m), 3.78 (1H, m), 3.70 (1H, m), 3.60 (1H, s), 3.57 (1H, s), 3.30-3.20 (2H, m), 2.92 (2H, m), 2.87 (6H, s), 2.86 (1H, m), 2.37 (2H, m), 2.27 (2H, m), 2.14 (2H, m), 2.03 (1H, m), 1.90 (5H, m), 1.67 (2H, m) ppm.

Workup

  1. stirringThe mixture was stirred at RT for 2 hours
  2. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-021b529aecf640749d179599494d75f5
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

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