Triethylamine → HCID 22050227, compound

HRID 1832029Notes

Reaction equation

HRID 1832029 reaction equation
[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C:9]1[C:14]([CH2:15][N:16]2[C:21]([CH3:22])=[CH:20][C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=3[F:32])=[C:18]([Cl:33])[C:17]2=[O:34])=[CH:13][N:12]=[C:11]([CH3:35])[N:10]=1.C(N(CC)CC)C.C([O:46][CH2:47][C:48](Cl)=[O:49])(=O)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:33][C:18]1[C:17](=[O:34])[N:16]([CH2:15][C:14]2[C:9]([NH:8][C:47](=[O:46])[CH2:48][OH:49])=[N:10][C:11]([CH3:35])=[N:12][CH:13]=2)[C:21]([CH3:22])=[CH:20][C:19]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]

Participants

6

Reactant 3

HCID 8471Triethylamine2×HCID 26297Acetoxyacetyl chloride2×HCID 22050501HCID 22050501, compound

Product 1

HCID 22050227HCID 22050227, compoundYield 9.1%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
-20 °C

Procedure

To a chilled solution of 1-[(4-amino-2-methylpyrimidin-5-yl)methyl]-3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one trifluoroacetate (0.200 g, 0.38 mmol) in DMF (20 mL) and a catalytic amount of DMAP was added triethylamine (0.064 mL, 0.38 mmol). The reaction stirred at −20° C. and acetoxyacetyl chloride (0.082 mL, 0.76 mmol) was added. The reaction stirred cold for 15 minutes and then allowed to warm up to room temperature for 3 hours. The reaction was monitored by LR-ES MS m/z=466. The reaction was incomlete after 3 hours. Added acetoxyacetyl chloride (0.05 mL, 0.466 mmol), and triethylamine (0.2 mL, 1.43 mmol) to the reaction mixture and continued to stir overnight at room temperature. The next morning the reaction heated at 65° C. for 3 hours. The solvent was removed in vacuo and 1N LiOH (2.5 mL) was added to the residue. The reaction was heated at 60° C. for 5 hours. The reaction was diluted with acetonitrile and water (1:1) and purified by reverse phase HPLC in 10-90% CH3CN/water (30 minute gradient) at a flow rate of 50 mL/min. The appropriate fractions were freeze dried to afford the desired product (0.020 g, 9%). 1H NMR (CD3OD, 400 MHz) δ 8.04 (s, 1H), 7.6 (m, 1H), 7.02 (m, 1H), 6.59 (s, 1H), 5.30 (s, 2H), 5.24 (s, 2H), 4.26 (s, 1H), 2.60 (s, 3H), 2.43 (s, 3H); ES-HRMS m/z 465.1161 (M+H calculated for C21H20N4O4F2Cl requires 465.1136).

Workup

  1. stirringThe reaction stirred cold for 15 minutes
  2. temperatureto warm up to room temperature for 3 hours
  3. stirringto stir overnight at room temperature
  4. temperatureThe next morning the reaction heated at 65° C. for 3 hours
  5. customThe solvent was removed in vacuo and 1N LiOH (2.5 mL)
  6. additionwas added to the residue
  7. temperatureThe reaction was heated at 60° C. for 5 hours
  8. additionThe reaction was diluted with acetonitrile and water (1:1)
  9. custompurified by reverse phase HPLC in 10-90% CH3CN/water (30 minute gradient) at a flow rate of 50 mL/min
  10. customdried

Sources & evidence

ORD record
ord-c3117b2c8ab843dca4c3a33b7cbd7641
Source dataset
uspto-grants-2006_06
Patent number
US07067540B2

Reaction notes

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