Diisopropylamine → 3-(5-Chloro-3-fluoropyridin-2-yl)-2-methyl-3-oxopropionic acid tert-butyl ester

HRID 650491

Reaction equation

HRID 650491 reaction equation
C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][C:18](=[O:21])[CH2:19][CH3:20])([CH3:16])([CH3:15])[CH3:14].C(O[C:25]([C:27]1[C:32]([F:33])=[CH:31][C:30]([Cl:34])=[CH:29][N:28]=1)=[O:26])C>CCCCCC.O1CCCC1.COC(C)(C)C.C(O)(=O)C.O>[C:13]([O:17][C:18](=[O:21])[CH:19]([CH3:20])[C:25]([C:27]1[C:32]([F:33])=[CH:31][C:30]([Cl:34])=[CH:29][N:28]=1)=[O:26])([CH3:16])([CH3:15])[CH3:14]

Participants

10

Reactant 4

HCID 7912DiisopropylamineHCID 88561tert-Butyl propionateHCID 22013569Ethyl 5-chloro-3-fluoropicolinateHCID 178418339Butyllithium

Product 1

HCID 220135773-(5-Chloro-3-fluoropyridin-2-yl)-2-methyl-3-oxopropionic acid tert-butyl ester

Reagents, catalysts & solvents 5

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8058HexaneSolventHCID 15413tert-Butyl methyl etherSolvent

Procedure

32.3 g of diisopropylamine are introduced into 200 ml of tetrahydrofuran and, with cooling with a CO2/acetone cooling bath, 200 ml of a 1.6M solution of n-butyllithium in hexane are added dropwise. 49.2 ml of propionic acid tert-butyl ester are then added dropwise at approximately −75° C. and the mixture is stirred at that temperature for 45 minutes. At approximately −75° C. a solution of 32.6 g of 3-fluoro-5-chloro-2-pyridinecarboxylic acid ethyl ester (Example P1) in 40 ml of tetrahydrofuran (THF) is then added dropwise and the mixture is stirred at that temperature for 1 hour, after which it is diluted with 250 ml of tert-butyl methyl ether. A mixture of 100 ml of water and 200 ml of glacial acetic acid is added, the phases are separated, the aqueous phase is extracted again, and the combined organic phases are washed with water. After drying over magnesium sulfate, filtration and concentration to dryness in vacuo are carried out. 51 g of the desired compound are obtained in the form of an oil (crude product).

Workup

  1. temperaturewith cooling with a CO2/acetone cooling bath
  2. customAt approximately −75° C.
  3. stirringthe mixture is stirred at that temperature for 1 hour
  4. additionis added
  5. customthe phases are separated
  6. extractionthe aqueous phase is extracted again
  7. washthe combined organic phases are washed with water
  8. dry with materialAfter drying over magnesium sulfate, filtration and concentration to dryness in vacuo

Sources & evidence

ORD record
ord-7b930a4a5a9a44cbbf65914c2d78d656
Source dataset
uspto-grants-2001_08
Patent number
US06274536B1

Linked notes

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