Sodium hydride → HCID 86739960, compound

HRID 2164319Notes

Reaction equation

HRID 2164319 reaction equation
[H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]([CH3:30])=[C:7]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[CH3:41][C:42]1[CH:43]=[CH:44][C:45]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:46][CH:47]=1.O>CN(C=O)C.CCOC(C)=O.O>[C:42]1([CH3:41])[CH:43]=[CH:44][C:45]([S:48]([OH:51])(=[O:49])=[O:50])=[CH:46][CH:47]=1.[CH3:3][C:4]1[N:5]([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)[C:6]([CH3:30])=[C:7]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:22])([F:24])[F:23])[C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]

Participants

8

Reactant 4

HCID 24758Sodium hydrideHCID 77210Morpholine, 4-(2-chloroethyl)-, hydrochloride (1:1)HCID 1680891,4-Dihydro-2,6-dimethyl-4-(2-(trifluoromethyl)phenyl)-3,5-pyridinedicarboxylic acid diethyl esterHCID 521998p-Toluenesulfonic acid monohydrate

Product 1

HCID 86739960HCID 86739960, compoundYield 67%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent3×

Conditions

Temperature
3 °C

Procedure

A suspension of 30.3 g (0.758 mol) of 60% NaH in mineral oil in 164 ml of DMF was cooled to 3° C. and a solution of 100.0 g (0.252 mol) of diethyl 1,4-dihydro-2,6-dimethyl-4-[2-(trifluoromethyl)phenyl]3,5-pyridinedicarboxylate in 100 ml of warm DMF was added dropwise over 30 min, keeping the temperature at 15° C. or less. After the addition was complete, 75.5 g (0.406 mol) of N-(2-chloroethyl)morpholine hydrochloride was added in portions over 25 min, keeping the temperature at approximately 15° C. The cooling bath was then replaced with a heating mantle and the reaction mixture was heated at 84°-100° C.for 4.5 hrs. After cooling to 31° C. over 50 min, the reaction mixture was poured into a stirred mixture of 500 ml of H2O and 300 ml of EtOAc. When all the solids dissolved, the phases were separated and the EtOAc phase was dried over anhydrous Na2SO4 and filtered. To this stirred EtOAc solution was added a solution of 47.9 g (0.252 mol) of p-TSA H2O in 300 ml of EtOAc, giving immediate precipitation of diethyl 1,4-dihydro-2,6-dimethyl-1-[2-(4-morpholinyl)-ethyl]-4-[2-(trifluoromethyl)-phenyl]-3,5-pyridinecarboxylate p-toluenesulfonate salt. After stirring for 20 min, the product was collected, washed with EtOAc, and dried in vacuo to yield 114.5 g (67%) of diethyl 1,4-dihydro-2,6-dimethyl-1-[2-(4-morpholinyl)ethyl]-4-[2-(trifluoromethyl)-phenyl]-3,5-pyridinedicarboxylate p-toluenesulfonate salt as a white solid: mp 204°-206° C. (dec.).

Workup

  1. customat 15° C. or less
  2. additionAfter the addition
  3. customat approximately 15° C
  4. temperaturethe reaction mixture was heated at 84°-100° C
  5. temperatureAfter cooling to 31° C. over 50 min
  6. dissolutionWhen all the solids dissolved
  7. customthe phases were separated
  8. dry with materialthe EtOAc phase was dried over anhydrous Na2SO4
  9. filtrationfiltered
  10. customgiving immediate
  11. customprecipitation of diethyl 1,4-dihydro-2,6-dimethyl-1-[2-(4-morpholinyl)-ethyl]-4-[2-(trifluoromethyl)-phenyl]-3,5-pyridinecarboxylate p-toluenesulfonate salt
  12. customthe product was collected
  13. washwashed with EtOAc
  14. customdried in vacuo

Sources & evidence

ORD record
ord-15ab6965b8df4e3fa010b08fb3c11a8a
Source dataset
uspto-grants-1985_03
Patent number
US04503223

Reaction notes

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