Benzyl chloroformate → HCID 68293158, compound

HRID 72341Notes

Reaction equation

HRID 72341 reaction equation
Cl.[NH2:2][C@H:3]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:4][C:5]([O:7]C)=O.[CH:16](N(C(C)C)CC)(C)[CH3:17].ClC(OCC1C=CC=CC=1)=O>C1COCC1>[NH2:2][C@H:3]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[CH2:4][C:5]1([OH:7])[CH2:17][CH2:16]1

Participants

5

Reactant 3

HCID 10387Benzyl chloroformateHCID 81531DiisopropylethylamineHCID 86706045methyl (3S)-3-amino-3-(4-fluorophenyl)propanoate hydrochloride

Product 1

HCID 68293158HCID 68293158, compoundYield 2.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

(S)-Methyl 3-amino-3-(4-fluorophenyl)propionate hydrochloride (4.5 g) was dissolved in THF (30 ml) and cooled to 0° C. After the addition of diisopropylethylamine (8.8 g), benzyl chloroformate (4.3 g) was slowly added dropwise and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was concentrated by rotary evaporation, dichloromethane (50 ml) was added and the mixture was washed twice with NH4Cl solution. Subsequently, the organic phase was dried with MgSO4, filtered and concentrated. The residue (5.72 g) was taken up in THF, titanium tetraisopropoxide (0.49 g) was added, and ethylmagnesium bromide (3 N, 17.9 ml) was added dropwise over the course of 1 hour. After 24 hours, the reaction solution was poured into cold 2 N sulfuric acid (150 ml) and extracted three times with dichloromethane. The combined organic phases were dried with MgSO4, filtered and concentrated. The residue was purified by preparative HPLC. The resulting (S)-1-(4-fluorophenyl)-2-(1-hydroxycyclopropyl)ethyl]carbamic acid benzyl ester (0.76 g) was dissolved in methanol (20 ml), 5% Pd/C was added and hydrogenation was effected under hydrogen pressure 2 bar. After filtration and concentration, the product (87 mg) was thus obtained with a molecular weight of 329.3 g/mol (C19H20FNO3), MS (ESI): m/e=330 (M+H+).

Workup

  1. additionwas slowly added dropwise
  2. concentrationThe reaction mixture was concentrated by rotary evaporation, dichloromethane (50 ml)
  3. additionwas added
  4. washthe mixture was washed twice with NH4Cl solution
  5. dry with materialSubsequently, the organic phase was dried with MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. additiontitanium tetraisopropoxide (0.49 g) was added
  9. additionethylmagnesium bromide (3 N, 17.9 ml) was added dropwise over the course of 1 hour
  10. waitAfter 24 hours
  11. additionthe reaction solution was poured into cold 2 N sulfuric acid (150 ml)
  12. extractionextracted three times with dichloromethane
  13. dry with materialThe combined organic phases were dried with MgSO4
  14. filtrationfiltered
  15. concentrationconcentrated
  16. customThe residue was purified by preparative HPLC
  17. dissolutionThe resulting (S)-1-(4-fluorophenyl)-2-(1-hydroxycyclopropyl)ethyl]carbamic acid benzyl ester (0.76 g) was dissolved in methanol (20 ml)
  18. addition5% Pd/C was added
  19. filtrationAfter filtration and concentration

Sources & evidence

ORD record
ord-2195cd8bdb2e446bb2bc010cf27fbe5b
Source dataset
uspto-grants-2014_09
Patent number
US08828995B2

Reaction notes

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