Water → tert-Butyl 1-[3-({N-[(benzyloxy)carbonyl]-4,4,4-trifluorovalyl}amino)-4-fluorobenzyl]cyclopropanecarboxylate

HRID 626426Notes

Reaction equation

HRID 626426 reaction equation
[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([OH:21])=O)[CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:26][C:27]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:29][CH2:28]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C.N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([NH:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:26][C:27]1([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]1)=[O:21])[CH:13]([C:15]([F:16])([F:17])[F:18])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 962WaterHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 58136688tert-Butyl 1-(3-amino-4-fluorobenzyl)cyclopropanecarboxylateHCID 90024118N-[(benzyloxy)carbonyl]-4,4,4-trifluorovaline

Product 1

HCID 118106680tert-Butyl 1-[3-({N-[(benzyloxy)carbonyl]-4,4,4-trifluorovalyl}amino)-4-fluorobenzyl]cyclopropanecarboxylate

Reagents, catalysts & solvents 2

HCID 1049PyridineSolventHCID 6228DimethylformamideSolvent

Procedure

4.80 g (15.7 mmol) of N-[(benzyloxy)carbonyl]-4,4,4-trifluorovaline (racemic diastereomer mixture) and 5.01 g (18.9 mmol) of tert-butyl 1-(3-amino-4-fluorobenzyl)cyclopropanecarboxylate were dissolved in a mixture of 40 ml of DMF and 10 ml of pyridine, and 6.58 g (17.3 mmol) of HATU were added at RT. The reaction mixture was stirred at RT overnight and then added to water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were then washed successively with sat. sodium bicarbonate solution, 1 N hydrochloric acid and sat. sodium chloride solution, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1→10:1). This gave 5.34 g of the target product (61.5% of theory, diastereomer ratio about 2.5:1).

Workup

  1. additionwere added at RT
  2. extractionThe mixture was extracted three times with ethyl acetate
  3. washthe combined organic phases were then washed successively with sat. sodium bicarbonate solution, 1 N hydrochloric acid and sat. sodium chloride solution
  4. dry with materialdried over magnesium sulphate
  5. concentrationconcentrated under reduced pressure
  6. customThe crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1→10:1)

Sources & evidence

ORD record
ord-d1a5657944cd442e85b6acb3ad728432
Source dataset
uspto-grants-2016_04
Patent number
US09309198B2

Reaction notes

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