Production method for 1,2,2,2-tetrafluoroethyl difluoromethyl ether (desflurane)

Patent metadata

Field	Value
Publication number	US-10683252-B2
Application number	US-201716474136-A
Country	US
Kind code	B2
Filing date	Dec 15, 2017
Priority date	Dec 29, 2016
Publication date	Jun 16, 2020
Grant date	Jun 16, 2020

Abstract

Fluoral is obtained by gas-phase fluorination of chloral in the presence of a catalyst and then reacted with trimethyl orthoformate, thereby readily forming 1,2,2,2-tetrafluoroethyl methyl ether as an intermediate for production of desflurane. 1,2,2,2-Tetrafluoroethyl difluoromethyl ether (desflurane) is produced with high yield from the thus-formed 1,2,2,2-tetrafluoroethyl methyl ether by chlorination and fluorination. This method enables efficient industrial-scale production of desflurane useful as an inhalation anesthetic.

First claim

The invention claimed is:

1. A production method of 1,2,2,2-tetrafloroethyl difluoromethyl ether, comprising the following four steps:
a first step of reacting 2,2,2-trichloroacetaldehyde of the formula [1] with hydrogen fluoride in a gas phase in the presence of a catalyst, thereby obtaining 2,2,2-trifluoroacetaldehyde of the formula [2]

a second step of reacting the 2,2,2-trifluoroacetaldehyde obtained in the first step with hydrogen fluoride and trimethyl orthoformate, thereby obtaining 1,2,2,2-tetrafluoroethyl methyl ether of the formula [3]

a third step of reacting the 1,2,2,2-tetrafluoroethyl methyl ether obtained in the second step with chlorine (Cl 2 ) in the presence of a radical initiator or under light irradiation, thereby obtaining 1,2,2,2-tetrafluoroethyl dichloromethyl ether of the formula [4]

and
a fourth step of reacting the 1,2,2,2-tetrafluoroethyl dichloromethyl ether obtained in the third step with hydrogen fluoride, thereby obtaining 1,2,2,2-tetrafloroethyl difluoromethyl ether of the formula [5]

2. The production method according to claim 1 , wherein the catalyst used in the first step is a metal compound-supported catalyst having, supported on a metal oxide or activated carbon, a metal compound containing at least one metal selected from the group consisting of chromium, titanium, manganese, iron, nickel, cobalt, magnesium, zirconium and antimony.

3. The production method according to claim 2 , wherein the metal compound is at least one kind of metal halide or metal oxyhalide selected from the group consisting of a fluoride, a chloride, a fluorochloride, an oxyfluoride, an oxychloride and an oxyfluorochloride of the at least one metal.

4. The production method according to claim 2 , wherein the metal oxide is at least one kind selected from the group consisting of alumina, zirconia, titania, chromia and magnesia.

5. The production method according to claim 1 , wherein the 2,2,2-trifluoroacetaldehyde obtained in the first step is used as it is, without purification operation, as a raw material in the second step.

6. The production method according to claim 1 , wherein, in the second step, the reacting is conducted without the use of an organic solvent.

7. The production method according to claim 1 , wherein the radical initiator used in the third step is at least one kind selected from the group consisting of an organic peroxide and an azo-based radical initiator.

8. The production method according to claim 1 , wherein the light irradiation used in the third step is at least one kind selected from the group consisting of those from a mercury lamp, an ultraviolet LED, an organic EL, an inorganic EL, an ultraviolet laser and a halogen lamp.

9. The production method according to claim 1 , wherein, in the third step, the reacting is conducted in the presence of a fluoride ion scavenger.

10. The production method according to claim 9 , wherein fluoride ion scavenger is at least one kind selected from the group consisting of a halide of an alkali metal, a sulfate of an alkali metal, a hydroxide of an alkaline-earth metal, a halide of an alkaline-earth metal, a sulfate of an alkaline-earth metal, a hydroxide of a Group 13 metal of the periodic table, a halide of a Group 13 metal of the periodic table and a sulfate of a Group 13 metal of the periodic table.

11. The production method according to claim 1 , wherein, in the third step, the reacting is conducted with the use of a reaction solvent.

12. The production method according to claim 1 , wherein, in the third step, the 1,2,2,2-tetrafluoroethyl dichloromethyl ether of the formula [4] is obtained as a mixture thereof with a 1,2,2,2-tetrafluoroethyl chloromethyl ether of the formula [7]

13. The production method according to claim 12 , further comprising performing distillation purification on the mixture to separate and remove the 1,2,2,2-tetrafluoroethyl chloromethyl ether of the formula [7] from the mixture.

14. The production method according to claim 13 , wherein the 1,2,2,2-tetrafluoroethyl chloromethyl ether of the formula [7] separated and removed by the distillation purification is recovered and used as a raw material in the third step.

15. The production method according to claim 1 , wherein, in the fourth step, the reacting is conducted in a gas phase.

16. The production method according to claim 1 , wherein, in the fourth step, the reacting is conducted in the presence of a catalyst.

17. The production method according to claim 16 , wherein the catalyst used in the fourth step is at least one kind selected from the group consisting of tin tetrachloride, tin dichloride, tin tetrafluoride, tin difluoride, titanium tetrachloride, antimony trichloride, antimony pentachloride and antimony pentafluoride.

18. The production method according to claim 1 , wherein, in the fourth step, the reacting is conducted without the presence of a catalyst.

19. The production method according to claim 1 , wherein, in the fourth step, the reacting is conducted in a liquid phase.

20. The production method according to claim 19 , wherein in the fourth step, the reacting is conducted in the liquid phase in a temperature range of −10° C. to +150° C. and a pressure range of 0.1 MPa to 2.0 MPa.

21. The production method according to claim 1 , wherein, in the fourth step, the reacting is conducted by reacting the 1,2,2,2-tetrafluoroethyl dichloromethyl ether with a “salt or complex of an organic base and the hydrogen fluoride” in the liquid phase.

22. The production method according to claim 21 , wherein the organic base in the “salt or complex of the organic base and the hydrogen fluoride” is at least one kind selected from the group consisting of triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2,6-lutidine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

Assignees

• Central Glass Co Ltd

Inventors

• Hosoi Kenji
• Watanabe Mineo
• Imura Hideaki
• Hirotaki Kensuke
• Ueshima Naoya

Classifications

• C07C45/63 Primary

  by introduction of halogen; by substitution of halogen atoms by other halogen atoms · CPC title

• C07C41/22 Primary

  by introduction of halogens; by substitution of halogen atoms by other halogen atoms · CPC title

• C07C41/01

  Preparation of ethers · CPC title

• C07C43/123

  both carbon chains are substituted by halogen atoms · CPC title

• C07C47/14

  containing halogen · CPC title