PROCESS FOR MANUFACTURING 4-(2,2,3,3-TETRAFLUOROPROPYL)MORPHOLINE

Abstract

The present application relates to a novel, cost-saving and efficient process for preparing 4-(2,2,3,3-tetrafluoropropyl)morpholine which serves as an intermediate for production of medicaments and for production of medicaments for treatment and/or prophylaxis of cardiovascular disorders.

Claims

1. A process for preparing the compound of the formula (I) ##STR00027## comprising reacting a compound of the formula (IIa) ##STR00028## wherein R represents C.sub.1-C.sub.4 alkyl, phenyl, or naphthyl, where the phenyl is unsubstituted or substituted by one, two or three substituents independently of one another selected from the group consisting of linear or branched C.sub.1-C.sub.4 alkyl, chlorine, fluorine, bromine, amino, nitro, methylsulfonyl, (dimethyl-oxopropyl)amino, and sulfonic acid 2,2,3,3-tetrafluoropropylester, in an organic solvent or without solvent with morpholine of the formula (III) ##STR00029## in a molar ratio of (IIa) to (III) of 1 to 2-5, in a sealed vessel or flow reactor under autogenic pressure or at 1 to 50 bar, at a temperature of 100-170° C. to give the compound of the formula (I) ##STR00030## and a compound of the formula (IVa) ##STR00031## wherein R is as defined for the compounds of the formula (IIa).

2. The process according to claim 1, wherein in the compound of the formula (IIa) ##STR00032## R represents methyl or phenyl, where the phenyl is unsubstituted or substituted by one, two or three substituents independently of one another selected from the group consisting of methyl, chlorine, amino, methylsulfonyl, and sulfonic acid 2,2,3,3-tetrafluoropropylester.

3. The process for preparing the compound of the formula (I) ##STR00033## according to claim 1, wherein reacting the compound of the formula (IIa) comprises reacting the compound of the formula (II) ##STR00034## in an organic solvent or without solvent with morpholine of the formula (III) ##STR00035## in a molar ratio of (II) to (III) of 1 to 2-5, in a sealed vessel or flow reactor under autogenic pressure or at 1 to 50 bar, at a temperature of 100-170° C. to give the compound of the formula (I) ##STR00036## and the compound of the formula (IV) ##STR00037##

4. The process for preparing the compound of the formula (I) ##STR00038## according to claim 1, wherein the reaction is carried out without solvent.

5. The process according to claim 1, wherein the molar ratio of the compound of formula (IIa) to the compound of formula (III) is 1 to 2.0-2.5.

6. The process according to claim 1, wherein the molar ratio of the compound of formula (IIa) to the compound of formula (III) is 1 to 2.1.

7. The process according to claim 1, wherein the reaction is effected at a temperature of 100-150° C.

8. The process according to claim 1, wherein the reaction is effected at a temperature of 120-150° C.

9. The process according to claim 1, wherein, after the reaction yielding the compounds of the formulae (I) and (IVa) is terminated, the process further comprises cooling the sealed vessel or flow reactor to 20° C. to 80° C., diluting the reaction mixture with an organic solvent, removing the salt of the formula (IVa) via filtration, removing excess of morpholine and solvent in vacuum, and obtaining the compound of the formula (I) by distillation.

10. The process according to claim 1, wherein, after the reaction yielding the compounds of the formulae (I) and (IVa) is terminated, the process further comprises cooling the sealed vessel or flow reactor to 80° C. to 100° C., diluting the reaction mixture with water, separating the product layer, washing the aqueous layer with an organic solvent, and using the compound of the formula (I), dissolved in organic solvent, without purification or additionally purifying the compound of the formula (I) by distillation.

Description

EXAMPLE 1

[0032] The stirred mixture of 2,2,3,3-tetrafluoropropyltosylate of the formula (II) (10.0 g, 0.035 mol) and morpholine (6.08 g, 0.070 mol) was heated in autoclave for 5 h at 140° C. The autoclave was cooled to room temperature, opened and the reaction mixture was diluted with 75 ml methyltert.butyl ether (3×25 ml). The morpholine salt was filtered off and the filtrate was evaporated in vacuum (10-20 mm Hg) at 20-25° C. The compound of the formula (I) (4-(2,2,3,3-tetrafluoropropyl)morpholine) was obtained as colorless liquid by distillation under atmospheric pressure.

[0033] B.p. 165-168° C., yield 5.6 g (79%).

EXAMPLE 2

[0034] The stirred mixture of 2,2,3,3-tetrafluoropropyltosylate of the formula (II) (10.0 g, 0.035 mol) and morpholine (6.08 g, 0.070 mol) was heated in autoclave for 12 h at 120° C. The autoclave was cooled to room temperature, opened and the reaction mixture was diluted with 75 ml methyltert.butyl ether (3×25 ml). The morpholine salt was filtered off and the filtrate was evaporated in vacuum (10-20 mm Hg) at 20-25° C. The compound of the formula (I) (4-(2,2,3,3-tetrafluoropropyl)morpholine) was obtained as colorless liquid upon distillation under atmospheric pressure.

[0035] B.p. 165-168° C., yield 5.8 g (82.4%).

EXAMPLE 3

[0036] The stirred mixture of 2,2,3,3-tetrafluoropropyltosylate of the formula (II) (330.0 g, 1.10 mol) and morpholine (208.0 g, 2.39 mol) was heated in autoclave for 18 h at 130° C. The autoclave was cooled to 80° C., opened and the reaction mixture was diluted with 110 ml water and further cooled to room temperature. The lower product layer was separated and the aqueous layer was washed with methyltert.butyl ether (2×83 ml). The organic layers were combined and the solvent was evaporated at normal pressure. The compound of the formula (I) (4-(2,2,3,3-tetrafluoropropyl)morpholine) was obtained as colorless liquid upon distillation in vacuum 185 mm Hg at 115° C.

[0037] B.p. 115° C./185 mbar, yield 188.0 g (85%).

[0038] .sup.1H-NMR (400 MHz, CDCl.sub.3): δ=2.50-2.69 (m, 4H), 2.89 (tt, J=14.06, 1.83 Hz, 2H), 3.43-3.89 (m, 4H), 5.72-6.28 (m, 1H) ppm