Production of fluoromethyl...

Details Production of fluoromethyl... Production of fluoromethyl...

2000-03-16

2002-10-22

Keys, Rosalynd (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C568S693000

Reexamination Certificate

active

06469219

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention is a method of preparing the inhalation anesthetic, fluoromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether (also known as sevoflurane), by an equilibrium process wherein the equilibrium is favorably shifted by removal of the product by distillation under active equilibrium conditions or by extraction of the product from the equilibrium mixture. This method is based on commercially available starting materials, produces higher yields of the desired product, and is more economical than prior art methods.
2. Description of Related Art
A number of methods have been disclosed for preparing sevoflurane (SVF). U.S. Pat. No. 3,683,092 and 3,689,571 describe the replacement of chlorine in chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether with fluorine using potassium fluoride in a solvent, sulfolane, at 120° C., and U.S. Pat. No. 4,874,901 discloses the replacement without added solvent at high temperature (185° C.) and pressure (280 psi). Other fluorinating reagents were also used to replace the chlorine. U.S. Pat. No. 5,886,239 uses diisopropylethylamine hydrofluoride, and the European Patent Appl. EP 0 901 999 A1 uses a mixture of an amine and hydrogen fluoride (HF). The starting material, chloromethyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, is not commercially available. According to U.S. Pat. No. 3,683,092 it is prepared by the chlorination of methyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether, which can be synthesized from 1,1,1,3,3,3-hexafluoro-2-propanol, as described in U.S. Pat. No. 3,911,024.
Direct fluorination of methyl 2,2,2-trifluoro-1-(trifluoromethyl)ethyl ether to SVF is claimed using extremely reactive and expensive reagents such as bromine trifluoride in U.S. Pat. No. 3,683,092, and 20% molecular fluorine in argon in U.S. Pat. No. 3,897,502.
Another route to SVF, disclosed in U.S. Pat. No. 4,874,902, uses 1,1,1,3,3,3-hexachloro-2-propanol as starting material which is converted to methyl 2,2,2-trichloro-1-(trichloromethyl)ethyl ether, and then fluorinated with bromine trifluoride to give SVF. Alternatively, methyl 2,2,2-trichloro-1-(trichloromethyl)ethyl ether is chlorinated, and the corresponding chloromethyl ether is multipli-fluorinated using bromine trifluoride.
U.S. Pat. No. 5,705,710 describes preparation of SVF by fluorination of methoxymalononitrile using bromine trifluoride.
The above-mentioned methods of preparation of SVF are multi-step, or based on commercially unavailable starting materials, or use dangerous reagents.
Direct fluoromethylation to SVF of commercially available 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) is described in several patents. In U.S. Pat. No. 4,250,334, HFIP, HF and formaldehyde (CH
2
O) are heated in the presence of concentrated sulfric acid to continuously produce SVF collected in a cold trap.
According to U.S. Pat. No. 4,469,898, the yields of SVF are improved by adding excess sulfuric acid or other additives to sequester the water produced in the fluoromethylation of HFIP.
(CF
3
)
2
CH—OH+HF+CH
2
O⇄(CF
3
)
2
CH—O—CH
2
F+H
2
O
However, a substantial amount of concentrated sulfuric acid or other Bronsted and/or Lewis acid (ca. 3 times greater then HFIP by weight) should be used to achieve 76-78% yield. As a result, large amounts of wastes (inorganic and organic) are made by the process.
PCT Int. Appl. WO 97/25303 discloses preparation of SVF by the reaction of HFIP with bis(fluoromethyl)ether in the presence of sulfuric acid, in which the desired product is produced with 55-60% yield along with an acetal by-product.
If no sulfuric acid or dehydrating, protonating and fluoride ion generating agent is used, the yields of SVF were very low, as was shown in the abandoned U.S. patent application Ser. No. 771,365, filed Oct. 28, 1968, and also in U.S. Pat. No. 3,689,571.
SUMMARY OF THE INVENTION
The present invention provides a method for the preparation of SVF by reacting HFIP with CH
2
O and HF under conditions wherein the desired product SVF is removed from the ongoing equilibrium either A) by distillation or B) by extraction.
A low-boiling azeotrope of SVF and HF was discovered so where SVF is removed by distillation, it is removed as an azeotrope with HF. During this process, water is also removed by distillation of the constant boiling mixture of water and HF (b.p. 115° C.). SVF, removed as the HF azeotrope, is separated from HF by several methods: (i), washing the mixture with water, (ii), extracting with solvents dissolving SVF but not HF, (iii), cooling the azeotrope to separate layers, and (iv), distilling the SVF/HF azeotrope at the different pressures to obtain a mixture enriched in SVF.
In the extraction process, SVF is removed from the equilibrium by a solvent capable of selectively dissolving SVF and other reaction products but not starting materials and water.
DETAILED DESCRIPTION OF THE INVENTION
1. Removal of SVF by Distillation during Reaction
One preferred embodiment of the invention involves running the fluoromethylation reaction during distillation. This is accomplished by having a reactor equipped with two columns. One is used to separate, as an overhead product, the HF/SVF mixture from the vapor over the equilibrium mixture. We discovered that SVF and HF form the low-boiling azeotrope described in Table 4. The other column is fed from the liquid in the reactor and removes the HF/water constant boiling mixture as a bottoms product. The overhead distillate from this second column is recycled to the reactor.
In practice, the HF/SVF azeotrope distillate may contain excess HF because the azeotrope boils only slightly lower than HF. [The use of the words SVF/HF azeotrope throughout the text is meant to include the actual azeotrope and the azeotrope when it includes excess HF.] The overhead from the first column, which is called “HF/SVF azeotrope” will proceed to one of several separation methods to obtain pure SVF and return HF to the reaction/distillation process.
A. Separation of the HF/SVF Azeotrope to Obtain Pure SVF
The HF/SVF azeotrope can be separated very simply by washing the HF out with water. The SVF has a purity of about 99%.
As an alternative to water, SVF can be separated from HF by extraction with a large variety of suitable solvents, which are insoluble in hydrogen fluoride (see Section 2, infra). Following the extraction of SVF, HF can be recycled to the reaction and the SVF can be separated from the solvent and purified to the desired purity.
Another approach to separating SVF from HF is to cool the mixture. Upon cooling, separation begins at a lower temperature depending upon the composition of the HF/SVF mixture. The SVF/HF ratios are different in each layer. The separated layer with the enriched SVF can be distilled to obtain the SVF/HF azeotrope as the lower boiling product and excess SVF as the higher boiling product. The layer enriched in HF can be returned to the reaction/distillation process.
Still another means of separating SVF/HF is by varying the composition of the SVF/HF azeotrope through the use of different pressures (Table 4). An azeotropic composition that has a higher SVF content can be distilled at a different pressure to give an azeotrope containing less SVF as the lower boiling product and the excess SVF as the pure higher boiling product.
B. Recovery of Byproducts
Four major byproducts: bis{[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]methyl}ether (compound A), formaldehyde di[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]acetal (compound B), formaldehyde fluoromethyl[2,2,2-trifluoro- 1 -(trifluoromethyl)ethyl]acetal (compound C), and bis(fluoromethyl) ether (compound D) were found. In a batch run it was found that their concentrations decreased to almost undetected levels by the end of distillation. All four compounds will react as well during a continuous distillation generating additional SVF by way of the following equilibria.
These byproducts are reported in the literature (U.S. Pat. Nos. 3,689,571 and 4,469,

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