Ammonium Chloride → 2-Cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid ethyl ester

HRID 1753906Notes

Reaction equation

HRID 1753906 reaction equation
[CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[CH:20]1([Mg]Br)[CH2:22][CH2:21]1.[Cl-].[NH4+]>O1CCCC1.CN1CCCC1=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH:20]2[CH2:22][CH2:21]2)=[N:8][C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2]

Participants

6

Reactant 3

HCID 25517Ammonium ChlorideHCID 866719032-Chloro-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid ethyl esterHCID 178418630HCID 178418630, compound

Product 1

HCID 708168332-Cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid ethyl esterYield 211.4%

Reagents, catalysts & solvents 2

HCID 5483663Ferric acetylacetonateCatalystHCID 22156051tetrahydrofuran N-methylpyrrolidinoneSolvent

Conditions

Temperature
-20 °C

Procedure

To a solution 2-chloro-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid ethyl ester (7.0 g, 24.6 mmol) in tetrahydrofuran-N-methyl-2-pyrrolidone (2:3) (250 ml) is added iron(III) acetylacetonate (1.74 g, 4.92 mmol) and the mixture is cooled to −20° C. At this temperature, a solution of cyclopropylmagnesium bromide (0.7 M in tetrahydrofuran) (105 ml, 73.8 mmol) is slowly added and the mixture is warmed to 0° C. within 30 min. After completion of the reaction, 10% aqueous ammonium chloride is added and the mixture is extracted with ethyl acetate (2×). The combined organic layers are washed with water and brine, dried over magnesium sulphate and evaporated to dryness. The reaction is repeated once and the combined crude products are purified by flash chromatography (silica gel, 75% ethyl acetate/cyclohexane) to yield 2-cyclopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid ethyl ester (15.1 g).

Workup

  1. temperaturethe mixture is warmed to 0° C. within 30 min
  2. additionis added
  3. extractionthe mixture is extracted with ethyl acetate (2×)
  4. washThe combined organic layers are washed with water and brine
  5. dry with materialdried over magnesium sulphate
  6. customevaporated to dryness
  7. customthe combined crude products are purified by flash chromatography (silica gel, 75% ethyl acetate/cyclohexane)

Sources & evidence

ORD record
ord-915eb9545be342ed95a6283ba0b07327
Source dataset
uspto-grants-2015_10
Patent number
US09168259B2

Reaction notes

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