Diethyl Carbonate → Ethyl 2-[5-(morpholin-4-ylmethyl)pyridin-2-yl]acetate

HRID 423145Notes

Reaction equation

HRID 423145 reaction equation
[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=O)[O:19]CC)[CH3:16].C([N-]C(C)C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1>[CH2:15]([O:17][C:18](=[O:19])[CH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][N:7]=1)[CH3:16]

Participants

6

Reactant 4

HCID 7766Diethyl CarbonateHCID 25517Ammonium ChlorideHCID 2724682Lithium diisopropylamideHCID 207917014-[(6-Methylpyridin-3-yl)methyl]morpholine

Product 1

HCID 44248634Ethyl 2-[5-(morpholin-4-ylmethyl)pyridin-2-yl]acetateYield 92%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-13 °C

Procedure

4-(6-Methyl-pyridin-3-ylmethyl)-morpholine (30 g, 156 mmol) and diethylcarbonate (23.96 g, 202.9 mmol) were dissolved in tetrahydrofuran (150 ml) under an inert atmosphere. The solution was cooled to −13° C. and lithium diisopropylamide solution (190.8 ml, 1.8M, 343.3 mmol) added dropwise over 1 hr 45 min. After stirring for an additional 35 min the reaction mixture was added to a cold aqueous solution of ammonium chloride (204.5 ml, 4.58M, 936.2 mmol) at 0° C. The biphasic mixture was warmed to 30° C. and separated. The aqueous layer was extracted twice with toluene (120 ml) and the combined organic layers were concentrated by vacuum distillation to give (5-Morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester as a toluene solution (204 ml) (55.38 g, 92% yield (based on assay of 74.5 w/w %). An aliquot was removed and purified by column chromatography eluting with dichloromethane/methanol (40:1), which gave (5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester as a yellow oil. 1H NMR (400 MHz; CDCl3,): δ 8.45 (d, J=1.88 Hz, 1H), 7.65 (dd, J=2.21, 7.93 Hz, 1H), 7.25 (d, J=6.12 Hz, 1H), 4.15 (q, J=7.17, 14.29 Hz, 2H), 3.82 (s, 2H), 3.69 (t, J=4.61, 9.28 Hz, 4H), 3.45 (s, 2H), 2.42 (t, J=4.52, 9.1 Hz, 4H), 1.25 (t, J=7.13, 14.29 Hz, 3H); 13C NMR: (100 MHz, CDCl3): δ 170.7, 153.4, 150.1, 137.4, 131.6, 123.5, 66.9, 61.03, 60.3, 53.5, 43.6, 14.2 ppm; MS (ESI) m/z 265 [M+1]+.

Workup

  1. temperatureThe biphasic mixture was warmed to 30° C.
  2. customseparated
  3. extractionThe aqueous layer was extracted twice with toluene (120 ml)
  4. concentrationthe combined organic layers were concentrated by vacuum distillation

Sources & evidence

ORD record
ord-0d5fbd185904417f92878f723eefd54f
Source dataset
uspto-grants-2012_01
Patent number
US08101750B2

Reaction notes

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