Isopropanol → (1S,2S,3R,4R)-3-(2-Chloro-5-trifluoromethylpyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide

HRID 1687502Notes

Reaction equation

HRID 1687502 reaction equation
FC(F)(F)C(O)=O.[NH2:8][C@@H:9]1[C@@H:14]2[CH2:15][C@@H:11]([CH:12]=[CH:13]2)[C@@H:10]1[C:16]([NH2:18])=[O:17].C(=O)(O)[O-].[Na+].[Cl:24][C:25]1[N:30]=[C:29]([Cl:31])[C:28]([C:32]([F:35])([F:34])[F:33])=[CH:27][N:26]=1.C(O)(C)C>CO.O>[Cl:24][C:25]1[N:26]=[C:27]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[C:28]([C:32]([F:35])([F:33])[F:34])=[CH:29][N:30]=1.[Cl:31][C:29]1[C:28]([C:32]([F:34])([F:33])[F:35])=[CH:27][N:26]=[C:25]([NH:8][C@@H:9]2[C@@H:14]3[CH2:15][C@@H:11]([CH:12]=[CH:13]3)[C@@H:10]2[C:16]([NH2:18])=[O:17])[N:30]=1

Participants

8

Reactant 4

HCID 3776IsopropanolHCID 516892Sodium BicarbonateHCID 27827742,4-Dichloro-5-(trifluoromethyl)pyrimidineHCID 67264207(1S,2S,3R,4R)-3-Amino-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide trifluoroacetic acid salt

Product 2

HCID 86633950(1S,2S,3R,4R)-3-(2-Chloro-5-trifluoromethylpyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amideYield 45%HCID 86633951(1S,2S,3R,4R)-3-(4-Chloro-5-trifluoromethylpyrimidin-2-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amideYield 37%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Procedure

(1S,2S,3R,4R)-3-Aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide trifluoroacetic acid salt (403 mg, 1.51 mmol) was combined with sodium bicarbonate (369 mg, 4.40 mmol) in a mixture of methanol (66 mL) and water (33 mL). 2,4-Dichloro-5-trifluoromethylpyrimidine (318 mg, 1.46 mmol) was added and the reaction was stirred for several minutes. Isopropanol (20 mL) was added to aid solubility and the reaction was stirred at room temperature for six hours. The reaction was concentrated and organics were extracted into dichloromethane. The dichloromethane extract was washed with saturated sodium bicarbonate solution, was dried (sodium sulfate), and was concentrated. Reverse phase chromatography (Gilson) employing gradient elution (30-60% acetonitrile:water) afforded two regioisomers (in order of elution): (1S,2S,3R,4R)-3-(2-Chloro-5-trifluoromethylpyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (221 mg, 45%) and (1S,2S,3R,4R)-3-(4-Chloro-5-trifluoromethylpyrimidin-2-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (180 mg, 37%) both being isolated as white foams.

Workup

  1. stirringthe reaction was stirred at room temperature for six hours
  2. concentrationThe reaction was concentrated
  3. extractionorganics were extracted into dichloromethane
  4. extractionThe dichloromethane extract
  5. washwas washed with saturated sodium bicarbonate solution
  6. dry with materialwas dried (sodium sulfate)
  7. concentrationwas concentrated
  8. washgradient elution (30-60% acetonitrile:water)
  9. customafforded
  10. washtwo regioisomers (in order of elution)

Sources & evidence

ORD record
ord-efd3bcd97cec4f48b272e11e68db287d
Source dataset
uspto-grants-2012_04
Patent number
US08148391B2

Reaction notes

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