Methanol → 4-(4-(1-(2-(Dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-7-(2,4-dimethoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

HRID 1685197Notes

Reaction equation

HRID 1685197 reaction equation
Cl[C:2]1[C:3]2[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=3[O:21][CH3:22])[C:4]=2[N:5]=[CH:6][N:7]=1.CO.Cl.Cl.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:35]=[C:36]([CH:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)[N:37]([CH2:39][CH2:40][N:41]([CH3:43])[CH3:42])[CH:38]=2)=[CH:30][C:29]=1[C:50]([F:53])([F:52])[F:51]>>[CH3:42][N:41]([CH3:43])[CH2:40][CH2:39][N:37]1[CH:38]=[C:34]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[C:29]([C:50]([F:52])([F:51])[F:53])[CH:30]=2)[N:35]=[C:36]1[CH:44]1[CH2:45][CH2:46][N:47]([C:2]2[C:3]3[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=4[O:21][CH3:22])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:48][CH2:49]1

Participants

4

Reactant 3

HCID 887Methanol2×HCID 569717344-chloro-7-(2,4-dimethoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-oneHCID 866416122-(4-(4-Fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine dihydrochloride

Product 1

HCID 672649744-(4-(1-(2-(Dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-7-(2,4-dimethoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-oneYield 60%

Procedure

Combine a mixture of 4-chloro-7-(2,4-dimethoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (1.10 equiv; 868.3 mmol; 277.63 g) in methanol (62.44 mol; 2.53 L) at RT, a solution of 2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine dihydrochloride (1.00 equiv; 789.35 mmol; 361.0 g) and TEA (9077 mmol; 1265 mL) in methanol (62.44 mol; 2.53 L) and stir the mixture overnight at 55-60° C. Partition the reaction mixture between water (10 L) and EA (10 L). Extract the organic layer with 2 N HCl (5 L). Separate and extract the aqueous layer with EA (5 L). An oil separates in the aqueous layer. Decant the aqueous liquid and hold the oil for recovery of product. Stir the decanted aqueous layer with EA (5 L) and adjust the pH of the mixture to 10-11 with 2 N NaOH. Separate the organic layer, wash with brine, and dry over Na2SO4. Filter and evaporate the solvent to give the title compound (473.3 mmol; 316.0 g; 60%).

Workup

  1. customPartition the reaction mixture between water (10 L) and EA (10 L)
  2. extractionExtract the organic layer with 2 N HCl (5 L)
  3. customSeparate
  4. extractionextract the aqueous layer with EA (5 L)
  5. customDecant the aqueous liquid
  6. customSeparate the organic layer
  7. washwash with brine
  8. dry with materialdry over Na2SO4
  9. filtrationFilter
  10. customevaporate the solvent

Sources & evidence

ORD record
ord-6e1981659b6b407bbd322d7765fc54b1
Source dataset
uspto-grants-2012_04
Patent number
US08148387B2

Reaction notes

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