Dichloromethane → (5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide

HRID 69550Notes

Reaction equation

HRID 69550 reaction equation
C(O)(C(F)(F)F)=O.[F:8][C:9]([F:51])([F:50])[C:10]1[CH:11]=[C:12]([C:20]([CH3:49])([CH3:48])[C:21]([N:23]([CH3:47])[C:24]2[C:25]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=3[CH3:46])=[CH:26][C:27]([C:30]3[CH2:31][CH2:32][C@:33]([CH3:38])([C:35]([NH2:37])=[O:36])[N:34]=3)=[N:28][CH:29]=2)=[O:22])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].C(Cl)[Cl:69]>O.CO>[F:51][C:9]([F:8])([F:50])[C:10]1[CH:11]=[C:12]([C:20]([CH3:48])([CH3:49])[C:21]([N:23]([CH3:47])[C:24]2[C:25]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=3[CH3:46])=[CH:26][C:27]([C@@H:30]3[NH:34][C@@:33]([CH3:38])([C:35]([NH2:37])=[O:36])[CH2:32][CH2:31]3)=[N:28][CH:29]=2)=[O:22])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1.[ClH:69].[F:51][C:9]([F:8])([F:50])[C:10]1[CH:11]=[C:12]([C:20]([CH3:48])([CH3:49])[C:21]([N:23]([CH3:47])[C:24]2[C:25]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=3[CH3:46])=[CH:26][C:27]([C@H:30]3[NH:34][C@@:33]([CH3:38])([C:35]([NH2:37])=[O:36])[CH2:32][CH2:31]3)=[N:28][CH:29]=2)=[O:22])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1.[F:51][C:9]([F:8])([F:50])[C:10]1[CH:11]=[C:12]([C:20]([CH3:48])([CH3:49])[C:21]([N:23]([CH3:47])[C:24]2[C:25]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:40]=3[CH3:46])=[CH:26][C:27]([C@H:30]3[NH:34][C@@:33]([CH3:38])([C:35]([NH2:37])=[O:36])[CH2:32][CH2:31]3)=[N:28][CH:29]=2)=[O:22])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1

Participants

10

Reactant 5

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 14798Sodium HydroxideHCID 5049666Sodium triacetoxyborohydrideHCID 57965575HCID 57965575, compound2×

Product 3

HCID 44472503(5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamideHCID 57965558HCID 57965558, compoundHCID 86636099HCID 86636099, compound

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

TFA (0.2 L) was added to a stirred solution of (2R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)pyridin-2-yl]-2-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide (intermediate 24, 0.82 Kg) in DCM (6.55 L) at room temperature. The resultant solution was cooled to 0° C. Sodium triacetoxy borohydride (0.423 Kg) was added portion-wise and the reaction stirred for 2-4 hr. MeOH (0.4 L) was added to the reaction then water (1.64 L) was added carefully, followed by 3M NaOH (4.0 L) to raise the pH to 12. The layers are separated and the DCM layer retained. The aqueous layer was washed with DCM (0.8 L) and the layers separated. The organic layers were combined and washed with saturated brine solution. The organic layer was dried over magnesium sulphate and concentrated on a rotary evaporator to give (5R)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide (Example 1) and 5S)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-D-prolinamide (Example 5) in approximately mixture of 4:1, as a white foam (859.5 g). To a such mixture (0.8 Kg), TBME (6 L) was added and the resultant solution was filtered. The solution was stirred at room temperature overnight. The resulting suspension was filtered and the cake rinsed with TBME. (0.8 L) The damp solid was dried under vacuum to furnish the title compound, in approximately 97% purity as a white crystalline solid (446.4 g.).

Workup

  1. temperatureto raise the pH to 12
  2. customThe layers are separated
  3. washThe aqueous layer was washed with DCM (0.8 L)
  4. customthe layers separated
  5. washwashed with saturated brine solution
  6. dry with materialThe organic layer was dried over magnesium sulphate
  7. concentrationconcentrated on a rotary evaporator

Sources & evidence

ORD record
ord-7dda852f11474ae2a0d782583e35b68f
Source dataset
uspto-grants-2014_09
Patent number
US08822504B2

Reaction notes

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