Cyclopropylamine → US9656988, Example 352

HRID 1050627Notes

Reaction equation

HRID 1050627 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH3:31])[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]3[CH:27]=[N:26][C:25]([C:28]#[N:29])=[C:24](Cl)[N:23]=3)[CH2:17]2)=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1>CN1C(=O)CCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:12]([CH3:31])[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]3[CH:27]=[N:26][C:25]([C:28]#[N:29])=[C:24]([NH:35][CH:32]4[CH2:34][CH2:33]4)[N:23]=3)[CH2:17]2)=[O:14])[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=1

Participants

5

Reactant 2

HCID 69828CyclopropylamineHCID 118114389(R)-1-(3-chloro-5-(trifluoromethyl)phenyl)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methylurea

Product 1

HCID 118115013US9656988, Example 352

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
70 °C

Procedure

(R)-1-(3-Chloro-5-(trifluoromethyl)phenyl)-3-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1-methylurea (521, 50 mg, 0.10 mmol) was dissolved in 2 mL NMP in a sealed tube. To it was added cyclopropylamine (210 μL, 3.0 mmol), and the mixture was stirred in 70° C. bath for overnight. It was diluted with 50 mL EtOAc, washed with saturated NH4Cl (aq) solution and water ×2, concentrated in vacuo to give crude (R)-1-(3-chloro-5-(trifluoromethyl)phenyl)-3-(1-(5-cyano-6-(cyclopropylamino)pyrazin-2-yl)piperidin-3-yl)-1-methylurea (522). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were added one NaOH solid pellet (about 50-100 mg) and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 1 hour, diluted with 10 mL MeCN, stirred for 5 min, concentrated on rotavap. The residue was treated 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)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(cyclopropylamino)pyrazine-2-carboxamide (523 as HCl salt (32 mg, 62% yield). LC-MS (ESI): m/z (M+1) 512.2 (chloro pattern). UV: λ=282, 318, 369 nm. Proton NMR (CD3OD): δ 7.53 (1H, m), 7.51 (1H, broad s), 7.48 (1H, broad s), 7.46 (1H, s), 3.98 (1H, dd, J=13.5; 3.5 Hz), 3.90 (1H, m), 3.81 (1H, m), 3.66 (1H, m), 3.52 (1H, m), 3.25 (3H, s), 2.71 (1H, m), 1.96 (1H, m), 1.78 (2H, m), 1.62 (1H, m), 0.76 (2H, m), 0.45 (2H, m) ppm.

Workup

  1. washwashed with saturated NH4Cl (aq) solution and water ×2
  2. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-aa8b2727a18345a18d49559bea1cb621
Source dataset
uspto-grants-2016_07
Patent number
US09382246B2

Reaction notes

Loading…