Water → 4-Azetidin-1-yl-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid methyl ester

HRID 251612Notes

Reaction equation

HRID 251612 reaction equation
[CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Cl)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])C.Cl.[NH:25]1[CH2:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[CH3:1][O:3][C:4](=[O:23])[C:5]1[C:10]([N:25]2[CH2:28][CH2:27][CH2:26]2)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22]

Participants

7

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 12308726Azetidine hydrochlorideHCID 59678345Ethyl 4-chloro-6-(2,6-diethylphenyl)-2-methylnicotinate

Product 1

HCID 669935764-Azetidin-1-yl-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid methyl ester

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid methyl ester (Example 2, step 1) (500 mg, 1.57 mmol), azetidine hydrochloride (588 mg, 6.29 mmol) and K2CO3 (1.08 g, 7.87 mmol) in DMF (5 mL) is heated at 80° C. in a sealed tube overnight. On cooling, water (20 mL) and EtOAc (20 mL) are added. The organic layer is separated and the aqueous layer is extracted with EtOAc (10 mL). The combined organic layer is washed with water, dried, and concentrated to give 4-azetidin-1-yl-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid methyl ester as a crude product. A solution of LiAlH4 (1M in THF, 4.5 mL) is added to a solution of this crude product in THF (5 mL). The reaction mixture is stirred at room temperature overnight, diluted with ether (10 mL), and the reaction quenched with solid Na2SO4.10H2O (1.0 g). The resulting mixture is stirred for 1 hour, filtered through celite and concentrated at reduced pressure. The crude product is purified by PTLC (10% MeOH in CH2Cl2) to give the title product. 1H NMR (CDCl3) 7.20 (t, 1H), 7.10 (d, 2H), 6.09 (s, 1H), 4.66 (s, 2H), 4.17 (t, 4H), 2.58 (s, 3H), 2.38 (m, 6H), 1.08 (t, 6H).

Workup

  1. temperatureOn cooling
  2. customThe organic layer is separated
  3. extractionthe aqueous layer is extracted with EtOAc (10 mL)
  4. washThe combined organic layer is washed with water
  5. customdried
  6. concentrationconcentrated

Sources & evidence

ORD record
ord-f21680502d224645a341c5f616292595
Source dataset
uspto-grants-2011_01
Patent number
US07863454B2

Reaction notes

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