Pyridine → 2-({5-[3-(Dimethylamino)propyl]-2-methylpyridin-3-yl}amino)-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepine-6-thione

HRID 2387992Notes

Reaction equation

HRID 2387992 reaction equation
[CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[CH2:18][C:19](=O)[NH:20][C:21]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:22]=4[C:23]=3[N:24]=2)[C:9]([CH3:12])=[N:10][CH:11]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:36].N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([NH:13][C:14]2[N:15]=[CH:16][C:17]3[CH2:18][C:19](=[S:36])[NH:20][C:21]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:22]=4[C:23]=3[N:24]=2)[C:9]([CH3:12])=[N:10][CH:11]=1

Participants

6

Reactant 4

HCID 1049PyridineHCID 10340Sodium CarbonateHCID 14817Phosphorus sulfide (P2S5)HCID 59404987HCID 59404987, compound

Product 1

HCID 462359222-({5-[3-(Dimethylamino)propyl]-2-methylpyridin-3-yl}amino)-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepine-6-thioneYield 77%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of 2-({5-[3-(dimethylamino)propyl]-2-methylpyridin-3-yl}amino)-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (175 g, 372 mmol), phosphorus pentasulfide (82.7 g, 372 mmol) and pyridine (1.35 L) was heated at 50° C. for 18 hours. HPLC analysis showed completion of the reaction. After the reaction mixture was cooled below room temperature, a solution of sodium carbonate (525 g, 4.95 mol) in 5.1 L of water was slowly added while the temperature was kept at below room temperature. The resulting biphasic solution was separated and the organic layer was washed with the same amount of sodium carbonate solution two times. The organic phase was then reduced to ca. 1.1 L in volume. The solution was diluted with water (1.0 L) and stirred at room temperature overnight resulting in a yellow suspension. The solid was filtered and washed with 200 mL EtOH/water (1 vol/2vol), and water 200 mL. After drying overnight under vacuo at 40° C., the crude product was dissolved in 1.2 L of EtOH at reflux. Water (2.0 L) was slowly added at 75° C. to induce crystallization. The suspension was then slowly cooled to room temperature and stirred overnight. The solid 2-({5-[3-(Dimethylamino)propyl]-2-methylpyridin-3-yl}amino)-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepine-6-thione was filtered and dried under vac at 40° C. to a constant weight (140.0 g, HPLC purity >98%, 77% yield). LCMS (FA): Rt=6.26 min, m/z=485.2 (M−H).

Workup

  1. customcompletion of the reaction
  2. temperatureAfter the reaction mixture was cooled below room temperature
  3. customwas kept at below room temperature
  4. customThe resulting biphasic solution was separated
  5. washthe organic layer was washed with the same amount of sodium carbonate solution two times
  6. additionThe solution was diluted with water (1.0 L)
  7. customresulting in a yellow suspension
  8. filtrationThe solid was filtered
  9. washwashed with 200 mL EtOH/water (1 vol/2vol), and water 200 mL
  10. customAfter drying overnight under vacuo at 40° C.
  11. dissolutionthe crude product was dissolved in 1.2 L of EtOH
  12. temperatureat reflux
  13. additionWater (2.0 L) was slowly added at 75° C.
  14. customcrystallization
  15. temperatureThe suspension was then slowly cooled to room temperature
  16. stirringstirred overnight
  17. filtrationThe solid 2-({5-[3-(Dimethylamino)propyl]-2-methylpyridin-3-yl}amino)-9-(trifluoromethyl)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepine-6-thione was filtered
  18. customdried under vac at 40° C. to a constant weight (140.0 g, HPLC purity >98%, 77% yield)

Sources & evidence

ORD record
ord-b6838e4a0a5a48cf9616bb7c62c77452
Source dataset
uspto-grants-2012_09
Patent number
US08268992B2

Reaction notes

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