2-Bromoacetamide → (R)-2-(4-(2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl)acetamide

HRID 80812Notes

Reaction equation

HRID 80812 reaction equation
Cl[C:2]1[C:3]2[CH2:19][N:18]([C:20]3[N:24]([CH3:25])[N:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[CH:21]=3)[CH2:17][CH2:16][C:4]=2[N:5]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:15])[N:7]=1.C(N(C(C)C)CC)(C)C.[CH3:38][C@@H:39]1[CH2:44][NH:43][CH2:42][CH2:41][NH:40]1.Br[CH2:46][C:47]([NH2:49])=[O:48]>CC#N>[CH3:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6]1[N:7]=[C:2]([N:43]2[CH2:42][CH2:41][N:40]([CH2:46][C:47]([NH2:49])=[O:48])[C@H:39]([CH3:38])[CH2:44]2)[C:3]2[CH2:19][N:18]([C:20]3[N:24]([CH3:25])[N:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[CH:21]=3)[CH2:17][CH2:16][C:4]=2[N:5]=1

Participants

6

Reactant 4

HCID 696322-BromoacetamideHCID 81531DiisopropylethylamineHCID 73304342-Methylpiperazine, (R)-HCID 86690253HCID 86690253, compound

Product 1

HCID 71240504(R)-2-(4-(2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl)acetamide

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
100 °C

Procedure

MeCN (2 mL) was added to 4-chloro-2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, prepared as described in Example 16, (110 mg, 0.278 mmol) in a microwave vial. The vial was then charged with diisopropylethylamine (0.24 mL, 1.38 mmol) and (R)-2-methylpiperazine (56 mg, 0.556 mmol). The vial was sealed and heated via microwave irradiation at 100° C. for 45 minutes. The mixture was cooled to room temperature and then charged with 2-bromoacetamide (115 mg, 0.833 mmol), re-sealed and heated via microwave irradiation at 100° C. for 10 minutes. The reaction was then cooled to room temperature and adsorbed in vacuo onto silica and loaded onto a silica gel flash chromatography column for purification [0-10% (10% NH4OH)MeOH/DCM]. The material was then further purified by additional silica gel flash chromatography {0-35% [10% MeOH (containing 1% NH4OH)/EtOAc]/DCM} to furnish (R)-2-(4-(2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl)acetamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.27 (br. s., 1 H) 7.17 (d, J=7.58 Hz, 1 H) 7.13 (br. s., 1 H) 7.08 (d, J=7.58 Hz, 2 H) 5.72 (s, 1 H) 3.98 (s, 2 H) 3.59 (s, 3 H) 3.51-3.58 (m, 2 H) 3.25-3.32 (m, 3 H) 3.16-3.24 (m, 1 H) 3.11 (d, J=16.17 Hz, 1 H) 2.94 (br. s., 3 H) 2.71-2.85 (m, 3 H) 2.56-2.65 (m, 1 H) 2.05 (s, 6 H) 1.11-1.19 (m, 6 H) 1.00 (d, J=6.06 Hz, 3 H); MS (ESI+) m/z 517.34 (M+H)+.

Workup

  1. customprepared
  2. customThe vial was sealed
  3. temperatureThe mixture was cooled to room temperature
  4. customre-sealed
  5. temperatureheated via microwave irradiation at 100° C. for 10 minutes
  6. temperatureThe reaction was then cooled to room temperature
  7. customloaded onto a silica gel flash chromatography column for purification [0-10% (10% NH4OH)MeOH/DCM]
  8. customThe material was then further purified by additional silica gel flash chromatography {0-35% [10% MeOH (containing 1% NH4OH)/EtOAc]/DCM

Sources & evidence

ORD record
ord-b0d9ef065a444dd7bf3044e7b6e815ca
Source dataset
uspto-grants-2014_09
Patent number
US08846656B2

Reaction notes

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