Benzoic Acid → HCID 86597684, compound

HRID 1951682Notes

Reaction equation

HRID 1951682 reaction equation
[F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C:13]([CH3:41])([CH3:40])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:36][CH2:35][C@H:34]([OH:37])[C@H:33]3[CH2:38][OH:39])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C(O)(=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[F:42][C:2]([F:1])([F:43])[C:3]1[CH:4]=[C:5]([C:13]([CH3:41])([CH3:40])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:36][CH2:35][C@@H:34]([OH:37])[C@H:33]3[CH2:38][OH:39])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:8]=1.[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:41])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:32]3[CH2:36][CH:35]=[CH:34][C@H:33]3[CH2:38][OH:39])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1

Participants

8

Reactant 5

HCID 243Benzoic AcidHCID 10340Sodium CarbonateHCID 11776TriphenylphosphineHCID 75555Diisopropyl diazene-1,2-dicarboxylateHCID 44241710HCID 44241710, compound

Product 2

HCID 60196441PharmaGSID_48513Yield 29%HCID 86597684HCID 86597684, compoundYield 40%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-78 °C

Procedure

To a solution of 400 mg (0.65 mmol) (2R,3S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide in 6.5 ml tetrahydrofuran were added at 0° C. 0.67 ml (3.26 mmol) diisopropyl azodicarboxylate and 398 mg (3.26 mmol) benzoic acid. The reaction mixture was cooled to −78° C., followed by addition of 855 mg (3.26 mmol) triphenylphosphine. The reaction mixture was allowed to slowly warm to room temperature over night. Addition of 75 ml of a saturated sodium carbonate solution was followed by extraction with two 75-ml portions of tert-butyl methyl ether. The organic layers were washed with 75 ml brine, dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography. The residue was dissolved in 20 ml methanol and treated with 0.1 ml of a 5.5 M sodium methylate solution in methanol. After stirring 3 h at room temperature the reaction mixture was concentrated in vacuo. The residue was dissolved in 75 ml dichloromethane and washed with 60 ml water, dried over sodium sulfate and purified by flash chromatography to give 117 mg (29%) of (2R,3R)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(3-hydroxy-2-hydroxymethyl-pyrrolidin-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide as a white foam and 155 mg (40%) of (S)-2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(4-fluoro-2-methyl-phenyl)-6-(2-hydroxymethyl-2,5-dihydro-pyrrol-1-yl)-pyridin-3-yl]-N-methyl-isobutyramide as a white foam.

Workup

  1. temperatureto slowly warm to room temperature over night
  2. extractionwas followed by extraction with two 75-ml portions of tert-butyl methyl ether
  3. washThe organic layers were washed with 75 ml brine
  4. dry with materialdried over sodium sulfate
  5. concentrationconcentrated in vacuo
  6. custompurified by flash chromatography
  7. dissolutionThe residue was dissolved in 20 ml methanol
  8. additiontreated with 0.1 ml of a 5.5 M sodium methylate solution in methanol
  9. concentrationwas concentrated in vacuo
  10. dissolutionThe residue was dissolved in 75 ml dichloromethane
  11. washwashed with 60 ml water
  12. dry with materialdried over sodium sulfate
  13. custompurified by flash chromatography

Sources & evidence

ORD record
ord-562f8f125a104a8db1e695951da45fc1
Source dataset
uspto-grants-2013_03
Patent number
US08404708B2

Reaction notes

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