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

HRID 1685196Notes

Reaction equation

HRID 1685196 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][CH:14]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.CN1C(=O)CCC1.Cl.Cl.[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]=[C:39]([CH:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[N:40]([CH2:42][CH2:43][N:44]([CH3:46])[CH3:45])[CH:41]=2)=[CH:33][C:32]=1[C:53]([F:56])([F:55])[F:54].CCN(C(C)C)C(C)C.OP(O)(O)=O>>[CH3:45][N:44]([CH3:46])[CH2:43][CH2:42][N:40]1[CH:41]=[C:37]([C:34]2[CH:35]=[CH:36][C:31]([F:30])=[C:32]([C:53]([F:55])([F:54])[F:56])[CH:33]=2)[N:38]=[C:39]1[CH:47]1[CH2:48][CH2:49][N:50]([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][CH:14]=4)[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:51][CH2:52]1

Participants

6

Reactant 5

HCID 1004Phosphoric AcidHCID 13387N-methyl-2-pyrrolidoneHCID 81531DiisopropylethylamineHCID 866416104-Chloro-7-(4-methoxybenzyl)-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 672650864-(4-(1-(2-(Dimethylamino)ethyl)-4-(4-fluoro-3-(trifluoromethyl)phenyl)-1H-imidazol-2-yl)piperidin-1-yl)-7-(4-methoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-oneYield 44.8%

Conditions

Temperature
50 °C

Procedure

Add a solution of 4-chloro-7-(4-methoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (18.11 g; 1.05 equiv; 62.52 mmol) in NMP (156.50 mL; 1.62 mol) at RT to 2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine dihydrochloride (31.30 g; 1.00 equiv; 59.54 mmol) and DIPEA (51.92 mL; 297.71 mmol) and stir overnight at 50° C. Quench the reaction with water (900 mL) and EA (200 mL) and adjust the pH of the mixture to 1-2 with H3PO4 [85% aqueous (aq.)]. Stir for 15 min and separate the phases. Extract the organic phase with a H3PO4 solution (15% aq. 3×100 mL). Wash the combined aqueous phases with EA/tert-butylmethyl ether (tBuOMe) (4/1) (3×150 mL). Adjust the pH of the aqueous phase to 9 with solid K2CO3 and extract with EA (3×15 mL). Wash the combined organic phases with brine, decolor with charcoal, and filter over Celite®. Combine the filtrates and evaporate. Crystallize the residue from EA/tBuOMe to obtain the title compound (17.00 g; 26.66 mmol; 44.77% yield) as pale rose solid. 1H NMR (300 MHz, CDCl3): 8.36 (s, 1H), 7.91-7.83 (m, 2H), 7.43-7.40 (m, 2H), 7.17-7.11 (m, 2H), 6.86-6.81 (m, 2H), 4.87 (s, 2H), 4.56 (d, J=13.4 Hz, 2H), 4.13-4.07 (m, 2H), 3.77 (s, 3H), 3.63 (s, 2H), 3.40-3.36 (m, 2H), 3.21-3.05 (m, 3H), 2.74 (t, J=6.6 Hz, 2H), 2.40-2.35 (m, 6H), 2.09-1.99 (m, 2H).

Workup

  1. customQuench
  2. customthe reaction with water (900 mL) and EA (200 mL)
  3. stirringStir for 15 min
  4. customseparate the phases
  5. extractionExtract the organic phase with a H3PO4 solution (15% aq. 3×100 mL)
  6. washWash the combined aqueous phases with EA/tert-butylmethyl ether (tBuOMe) (4/1) (3×150 mL)
  7. extractionextract with EA (3×15 mL)
  8. washWash the combined organic phases with brine, decolor with charcoal
  9. filtrationfilter over Celite®
  10. customCombine the filtrates and evaporate
  11. customCrystallize the residue from EA/tBuOMe

Sources & evidence

ORD record
ord-152a9aef3bb2423993c72b9b05d26c22
Source dataset
uspto-grants-2012_04
Patent number
US08148387B2

Reaction notes

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