Dimethylformamide → (R)-N-{1-[8-Acetyl-3-(4-ethoxy-phenyl)-4-oxo-3,4,5,6,7,8-hexahydro-pyrido[2,3-d]pyrimidin-2-yl]-ethyl}-N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-2-(4-fluoro-3-trifluoromethyl-phenyl)-acetamide

HRID 2223148Notes

Reaction equation

HRID 2223148 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[C:27]([N:30]1[C:35]2[N:36]=[C:37]([C@H:50]([NH:52][CH2:53][C:54]3[N:55]([CH3:60])[N:56]=[C:57]([CH3:59])[CH:58]=3)[CH3:51])[N:38]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=3)[C:39](=[O:40])[C:34]=2[CH2:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28].C(N(CC)CC)C>ClCCl>[C:27]([N:30]1[C:35]2[N:36]=[C:37]([C@H:50]([N:52]([CH2:53][C:54]3[N:55]([CH3:60])[N:56]=[C:57]([CH3:59])[CH:58]=3)[C:9](=[O:11])[CH2:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=3)[CH3:51])[N:38]([C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=3)[C:39](=[O:40])[C:34]=2[CH2:33][CH2:32][CH2:31]1)(=[O:29])[CH3:28]

Participants

7

Reactant 5

HCID 6228DimethylformamideHCID 8471TriethylamineHCID 65578Oxalyl chlorideHCID 27375934-Fluoro-3-(trifluoromethyl)phenylacetic acidHCID 58617388(R)-8-Acetyl-2-{1-[(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-amino]-ethyl}-3-(4-ethoxy-phenyl)-5,6,7,8-tetrahydro-3H-pyrido[2,3-d]pyrimidin-4-one

Product 1

HCID 58617380(R)-N-{1-[8-Acetyl-3-(4-ethoxy-phenyl)-4-oxo-3,4,5,6,7,8-hexahydro-pyrido[2,3-d]pyrimidin-2-yl]-ethyl}-N-(2,5-dimethyl-2H-pyrazol-3-ylmethyl)-2-(4-fluoro-3-trifluoromethyl-phenyl)-acetamideYield 61.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

4-fluoro-3-trifluoromethylphenylacetic acid (45 mg, 0.20 mmol) was dissolved in dichloromethane and cooled to 0° C. Oxalyl chloride (18 μL, 0.20 mmol) was added, then after 5 min, dimethylformamide (1.6 μL, 0.02 mmol) was added. The reaction stirred at 0° C. for 30 min and room temperature for 1 h. The solution was added slowly to a mixture of D5 (55 mg, 0.12 mmol) and triethylamine (50 μL, 0.36 mmol) in dichloromethane at −78° C. This stirred for 30 min, then was washed with saturated aqueous sodium bicarbonate and brine. It was dried over magnesium sulfate, filtered, and concentrated in vacuo. Purified by reverse-phase HPLC to yield 49 mg of a colorless solid, 3. MS (MH+): 669.1. 1H NMR (500 MHz; CDCl3; T=298 K): δ 7.47-7.02 (m, 7H), 5.74-5.42 (m, 1H), 5.30-5.04 (m, 1H), 4.63-4.31 (m, 2H), 4.09-3.86 (m, 3H), 3.75-3.59 (m, 3H), 2.81-2.60 (m, 1H), 2.60-2.43 (m, 5H), 2.18 (m, 3H), 1.93 (broad s, 2H), 1.46 (t, 3H, J=6.7 Hz), 1.30 (t, 3H, J=7.7 Hz) ppm.

Workup

  1. stirringThis stirred for 30 min
  2. washwas washed with saturated aqueous sodium bicarbonate and brine
  3. dry with materialIt was dried over magnesium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customPurified by reverse-phase HPLC

Sources & evidence

ORD record
ord-2965b68d220348299eb2aa2196a032ea
Source dataset
uspto-grants-2008_05
Patent number
US07375102B2

Reaction notes

Loading…