Diisopropylethylamine → 5-[(3R,5S)-4-(cyanomethyl)-3,5-dimethylpiperazin-1-yl]-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide

HRID 16835

Reaction equation

HRID 16835 reaction equation
Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]2[NH:12][N:13]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=3)[CH:15]=2)=[O:9])=[N:6][CH:7]=1.CN1[C@@H](C)CNC[C@H]1C.[CH3:37][C@H:38]1[CH2:43][NH:42][CH2:41][C@@H:40]([CH3:44])[N:39]1[CH2:45][C:46]#[N:47].C(N(C(C)C)C(C)C)C>CS(C)=O.CO>[C:46]([CH2:45][N:39]1[C@@H:38]([CH3:37])[CH2:43][N:42]([C:2]2[N:3]=[CH:4][C:5]([C:8]([NH:10][C:11]3[NH:12][N:13]=[C:14]([O:16][CH2:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=4)[CH:15]=3)=[O:9])=[N:6][CH:7]=2)[CH2:41][C@H:40]1[CH3:44])#[N:47]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 30720221(2R,6S)-1,2,6-TrimethylpiperazineHCID 866210735-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamideHCID 866210742-[(2S,6R)-2,6-dimethylpiperazin-1-yl]acetonitrile

Product 1

HCID 866210765-[(3R,5S)-4-(cyanomethyl)-3,5-dimethylpiperazin-1-yl]-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamideYield 18.3%

Reagents, catalysts & solvents 2

HCID 679Dimethyl SulfoxideSolventHCID 887MethanolSolvent

Procedure

5-Chloro-N-[5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-yl]pyrazine-2-carboxamide (273 mg, 0.70 mmol) was added in one portion to a 3:1 mixture of (2R,6S)-1,2,6-trimethylpiperazine and 2-[(2S,6R)-2,6-dimethylpiperazin-1-yl]acetonitrile (180 mg, 1.40 mmol) in anhydrous dimethylsulfoxide (1.40 ml) at 25° C. The resulting solution was stirred at ambient temperature for 2 h. The reaction was incomplete and N-ethyldiisopropylamine (0.24 ml, 1.40 mmol) was added and the solution was stirred at 60° C. for a further 2 h. The reaction mixture was diluted with methanol (20 mL) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH to afford impure material. The concentrated eluent was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM. Pure fractions were evaporated to dryness to afford the title compound (65 mg, 18%) as a yellow solid.

Workup

  1. stirringthe solution was stirred at 60° C. for a further 2 h
  2. custompurified by ion exchange chromatography
  3. washThe desired product was eluted from the column
  4. customto afford impure material
  5. customThe concentrated eluent was purified by silica column chromatography
  6. washeluting with a gradient of 0 to 5% 7M NH3/MeOH in DCM
  7. customPure fractions were evaporated to dryness

Sources & evidence

ORD record
ord-fa309ccc59824a5cad86028e8650f064
Source dataset
uspto-grants-2010_06
Patent number
US07737149B2

Linked notes

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