Citric Acid → 149267-74-3

HRID 1291769Notes

Reaction equation

HRID 1291769 reaction equation
C(N(CC)CC)C.[C:8]([NH:15][C@H:16]([C:25](O)=[O:26])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(OC(Cl)=O)C(C)C.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C1COCC1>[C:8]([NH:15][C@H:16]([CH2:25][OH:26])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=1)([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9]

Participants

8

Reactant 5

HCID 311Citric AcidHCID 8471TriethylamineHCID 62365Isobutyl chloroformateHCID 4311764Sodium borohydrideHCID 7020910N-(tert-Butoxycarbonyl)-4-fluoro-L-phenylalanine

Product 1

HCID 22874327149267-74-3

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

At from -5° C. to -10° C. 9.66 ml (69 mmol) of triethylamine are added to a solution of 17.9 g (63 mmol) of N-Boc-(p-fluorophenylalanine) in 73 ml of abs. THF, and a solution of 9.05 ml (69 mmol) of chloroformic acid isobutyl ester in 44 ml of abs. THF is added dropwise thereto. After stirring for 0.5 h at RT, the resulting precipitate is filtered off with suction. The filtrate is added dropwise, with cooling, to 4.77 g (126 mmol) of sodium borohydride in 28 ml of water. The mixture is stirred for 4 h at RT and acidified with 10% citric acid, the THF is partially removed by evaporation using a RE and the residue is partitioned between 3 portions of ethyl acetate and 2 portions of 2N sodium hydroxide solution, water, saturated sodium hydrogen carbonate solution and brine. The organic phases are dried with sodium sulfate, concentrated by evaporation, dissolved in a small amount of methylene chloride and crystallised by the addition of hexane to yield the title compound: TLC Rf (N)=0.36; tRet (I)=16.8 min; 1H-NMR (200 MHz, CD3OD): 7.24 (dd, 8 and 5 Hz, 2H), 6.98 (t, 8 Hz, 2H), 3.73 (m, 1H), 3.47 (d, 5 Hz, 2H), 2.88 (dd, 13 and 6 Hz, 1H), 2.62 (dd, 13 and 8 Hz, 1H), 1.36 (s, 9H).

Workup

  1. customAt from -5° C. to -10° C
  2. filtrationthe resulting precipitate is filtered off with suction
  3. additionThe filtrate is added dropwise
  4. stirringThe mixture is stirred for 4 h at RT
  5. customthe THF is partially removed by evaporation
  6. customis partitioned between 3 portions of ethyl acetate and 2 portions of 2N sodium hydroxide solution, water, saturated sodium hydrogen carbonate solution and brine
  7. dry with materialThe organic phases are dried with sodium sulfate
  8. concentrationconcentrated by evaporation
  9. dissolutiondissolved in a small amount of methylene chloride
  10. customcrystallised by the addition of hexane

Sources & evidence

ORD record
ord-190476e83a674fb78c752c299558d078
Source dataset
uspto-grants-1998_05
Patent number
US05753652

Reaction notes

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