Fumaric Acid → (R)-2-hydroxymethylmorpholine fumarate

Temperature

10 °C

To a mixture of 2-hydroxymethylmorpholine and 1,4-oxazepane compound (20.0 g, 2-hydroxymethylmorpholine:1,4-oxazepane compound=75.8:24.2) synthesized in Example 5 were added methanol (100 ml) and fumaric acid (17.5 g, 0.151 mol) and the mixture was stirred for 30 min. Methanol was evaporated under reduced pressure. To the residue was added 2-propanol (50 ml) and the mixture was subjected twice to azeotropic distillation with dehydrating. To the residue after azeotropic distillation with dehydrating was added ethyl acetate (100 ml) at 40° C., and the mixture was cooled to 10° C. After crystallization, the mixture was cooled to 0° C. and stirred for 1 hr. The crystals were collected by filtration, washed withed twice with ethyl acetate (25 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine fumarate (14.8 g) (2-hydroxymethylmorpholine:fumaric acid=1:1, yield from (S)-epichlorohydrin: 42.2%). The obtained (R)-2-hydroxymethylmorpholine fumarate was analyzed by HPLC to find an optical purity of 99% ee.

1. customsynthesized in Example 5
2. customMethanol was evaporated under reduced pressure
3. additionTo the residue was added 2-propanol (50 ml)
4. distillationthe mixture was subjected twice to azeotropic distillation with dehydrating
5. distillationTo the residue after azeotropic distillation with dehydrating
6. additionwas added ethyl acetate (100 ml) at 40° C.
7. customAfter crystallization
8. temperaturethe mixture was cooled to 0° C.
9. stirringstirred for 1 hr
10. filtrationThe crystals were collected by filtration
11. washwashed
12. customdried (1 mmHg, 40° C.)

ORD record

ord-7aefa997d3034f0ea2218f9aad852492

Source dataset

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08648190B2