Ammonium Chloride → 4-[(6-Methylpyridin-3-yl)methyl]morpholine

Temperatur

-5 °C

To a solution of 4-(6-Chloro-pyridin-3-ylmethyl)-morpholine (212 g, 1 mol) in tetrahydrofuran (1.5 L) and N-methylpyrollidinone (318 ml) was added iron (III) 2,4-pentanedionate (35.2 g, 0.01 mol) and the mixture cooled to −5° C. under nitrogen. A solution of methylmagnesium chloride in tetrahydrofuran (498 ml, 3.0M, 1.5 mol) was added dropwise over 40 mins and after an additional 30 mins the reaction mixture was poured into a saturated aqueous ammonium chloride solution (1.7 L) at 0° C. The resulting biphasic solution was filtered through a Celite® plug. The filtrate was separated and the aqueous layer extracted with ethylacetate (600 ml). The combined organic layer was concentrated and diluted with ethylacetate (200 ml) then extracted with aqueous hydrochloric acid (10%, 200 ml). The acidic layer was separated and washed with ethylacetate, then cooled in an ice bath and basified to pH 11 with sodium carbonate (solid). Sodium chloride (125 g) was added to the aqueous layer which was then extracted twice with ethylacetate (300 ml). The combined organic layer was concentrated to a solid, which was dissolved in hexane (600 ml) at 50° C. then placed in the fridge at −5° C. overnight. Two crops were obtained, which gave a total of 126.6 g, 68% yield of 4-(6-Methyl-pyridin-3-ylmethyl)-morpholine as beige solid. 1H NMR (400 MHz; CDCl3): δ 8.4 (d, J=1.72 Hz, 1H), 7.54 (dd, J=2.1, 7.91 Hz, 1H), 7.1 (d, J=7.92 Hz, 1H), 3.68 (apparent t, J=4.6, 9.28 Hz, 4H), 3.4 (s, 2H), 2.5 (s, 3H), 2.4 (apparent t, J=4.5, 8.93 Hz, 4H); 13C NMR (100 MHz, CDCl3): δ 157.3, 149.8, 137.2, 129.9, 122.9, 66.9, 60.3, 53.5, 24.1 ppm; MS (ESI) m/z 193 [M+1]+; Melting point: 51-52° C.

1. filtrationThe resulting biphasic solution was filtered through a Celite® plug
2. customThe filtrate was separated
3. extractionthe aqueous layer extracted with ethylacetate (600 ml)
4. concentrationThe combined organic layer was concentrated
5. additiondiluted with ethylacetate (200 ml)
6. extractionthen extracted with aqueous hydrochloric acid (10%, 200 ml)
7. customThe acidic layer was separated
8. washwashed with ethylacetate
9. temperaturecooled in an ice bath
10. additionSodium chloride (125 g) was added to the aqueous layer which
11. extractionwas then extracted twice with ethylacetate (300 ml)
12. concentrationThe combined organic layer was concentrated to a solid, which
13. dissolutionwas dissolved in hexane (600 ml) at 50° C.
14. customTwo crops were obtained

ORD-Eintrag

ord-c41245f2e33a4ee7a762932f7a0a786e

Quelldatensatz

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08101750B2