Ammonium Chloride → 2-(5-Chloro-3-fluoro-pyridin-2-yl)-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

HRID 69530Notes

Reaction equation

HRID 69530 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.[N:10]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12][CH:11]1[C:14]([O:16][CH3:17])=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH4+].[Cl-]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:14]([C:11]1([C:5]2[C:4]([F:9])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:12][CH2:13][N:10]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:15]

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 27832485-Chloro-2,3-difluoropyridineHCID 3251421Potassium bis(trimethylsilyl)amideHCID 14821735Azetidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

Product 1

HCID 866919042-(5-Chloro-3-fluoro-pyridin-2-yl)-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of 5-chloro-2,3-difluoropyridine (1.39 g, 9.29 mmol, Eq: 1.00) and 1-tert-butyl 2-methyl azetidine-1,2-dicarboxylate (2 g, 9.29 mmol, Eq: 1.00) in toluene (15 ml) was added dropwise at 0° C. over 15 min a 0.5 M solution of KHMDS (18.6 ml, 9.29 mmol, Eq: 1.00) in toluene. The colorless solution turned into light brown. After stirring at 0° C. for 45 min, the reaction mixture was allowed to warm up to 25° C. The reaction mixture was stirred for 2.5 h. Saturated aqueous NH4Cl solution (100 ml) was added and the aqueous phase was extracted with AcOEt (2×150 ml). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 60% AcOEt in heptane) to yield a colorless viscous oil as a racemate (1.746 g; 55%). m/z=345.2 [M+H]+.

Workup

  1. temperatureto warm up to 25° C
  2. stirringThe reaction mixture was stirred for 2.5 h
  3. extractionthe aqueous phase was extracted with AcOEt (2×150 ml)
  4. washThe combined organic layers were washed with brine
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe crude material was purified by flash chromatography (silica gel, 40 g, 10% to 60% AcOEt in heptane)
  9. customto yield a colorless viscous oil as a racemate (1.746 g; 55%)

Sources & evidence

ORD record
ord-a9150386219d466bb30ddcfb11091587
Source dataset
uspto-grants-2014_09
Patent number
US08822505B2

Reaction notes

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