Diisopropylethylamine → tert-Butyl 3-(4-chloro-3-{[4,4,4-trifluoro-3-methyl-2-(4-methylpiperidin-1-yl)butanoyl]amino}phenyl)propanoate

HRID 626448Notes

Reaction equation

HRID 626448 reaction equation
[F:1][C:2]([F:17])([F:16])[CH:3]([CH3:15])[CH:4]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]1)[C:5]([OH:7])=O.[NH2:18][C:19]1[CH:20]=[C:21]([CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:22]=[CH:23][C:24]=1[Cl:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>N1C=CC=CC=1.CN(C=O)C.O>[Cl:25][C:24]1[CH:23]=[CH:22][C:21]([CH2:26][CH2:27][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])=[CH:20][C:19]=1[NH:18][C:5](=[O:7])[CH:4]([N:8]1[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]1)[CH:3]([CH3:15])[C:2]([F:1])([F:17])[F:16]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)2×HCID 58136497Tert-butyl 3-(3-amino-4-chlorophenyl)propanoateHCID 900236104,4,4-Trifluoro-3-methyl-2-(4-methylpiperidin-1-yl)butanoic acid

Product 1

HCID 118106789tert-Butyl 3-(4-chloro-3-{[4,4,4-trifluoro-3-methyl-2-(4-methylpiperidin-1-yl)butanoyl]amino}phenyl)propanoate

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 1049PyridineSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

270 mg of 4,4,4-trifluoro-3-methyl-2-(4-methylpiperidin-1-yl)butanoic acid (crude product, racemic diastereomer mixture) were dissolved in 2.5 ml of pyridine and 4.9 ml of DMF, and 286 mg (1.12 mmol) of tert-butyl 3-(3-amino-4-chlorophenyl)propanoate and 527 mg (1.37 mmol) of HATU were added at RT. The mixture was stirred at 40° C. overnight. A further 0.5 eq. of HATU and 2 ml of N,N-diisopropylethylamine were added, and the reaction mixture was once more stirred at 50° C. for 5 h and then added to water. The mixture was extracted three times with ethyl acetate and the combined organic phases were washed with a little 1 N hydrochloric acid, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by preparative RP-HPLC (mobile phase acetonitrile/water). This gave 50 mg of the target product (9.6% of theory) as a diastereomer mixture (about 3:2).

Workup

  1. stirringthe reaction mixture was once more stirred at 50° C. for 5 h
  2. extractionThe mixture was extracted three times with ethyl acetate
  3. washthe combined organic phases were washed with a little 1 N hydrochloric acid
  4. dry with materialdried over magnesium sulphate
  5. concentrationconcentrated under reduced pressure
  6. customThe crude product was purified by preparative RP-HPLC (mobile phase acetonitrile/water)

Sources & evidence

ORD record
ord-26d875f01b2a4d11908aa465fca3eef6
Source dataset
uspto-grants-2016_04
Patent number
US09309198B2

Reaction notes

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