Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2000-06-01
2001-08-07
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S681000, C568S684000
Reexamination Certificate
active
06271422
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a method for fluoromethylation of an alcohol. In particular, the present invention is directed to a method in which an alcohol is reacted with an alpha-haloester to form an alpha-alkoxy acid which is then decarboxylatively halogenated to form a chloromethyl ether. The chloromethyl ether is then converted to the desired fluoride by reacting it with a fluorinating agent.
BACKGROUND OF THE INVENTION
Anesthetics belong to a class of biochemical depressant drugs which affect the vital functions of cells. Anesthetics generally produce analgesia, loss of consciousness, diminished reflex activity, and muscular relaxation, with minimal depression of the vital functions. Anesthetics may be gaseous (volatile) or fixed (non-volatile). Gaseous anesthetics are inhaled and enter the bloodstream through the lungs while fixed anesthetics are administrated parenterally or through the alimentary canal.
Many currently used gaseous anesthetics are halogenated compounds. These compounds tend to cause less metabolic disturbance and are less flammable than traditional gaseous anesthetic compounds such as ether and cyclopropane. Examples of halogenated anesthetic compounds include halothane (CF
3
CHBrCl) and trichloroethylene (Cl
2
C═CHCl)as well as halogenated ether compounds such as enflurane (CHF
2
OCF
2
CHClF), fluroxene (CF
3
CH
2
OCH═CH
2
), methoxyflurane (Cl
2
CHCF
2
OCH
3
) and isoflurane (CF
3
CHClOCHF
2
).
A particularly useful halogenated ether anesthetic is sevoflurane, (CF
3
)
2
CHOCH
2
F, also known as 2-(fluoromethoxy)-1,1,1,3,3,3,-hexafluoropropane or fluoromethyl-1,1,1,3.3,3-hexafluoro-2-propyl ether. Sevoflurane is today one of the most important and widely used general anesthetics. Sevoflurane combines various characteristics that are most desirable in an inhalation anesthetic, including the lowest blood/gas partition coefficient of 0.63, smooth induction and recovery from anesthesia, minimal irritation to the upper respiratory tract, low metabolic rate, and rapid elimination. In addition, sevoflurane is suitable for out-patient surgery use. Although sevoflurane's definitive mechanism of action has not been elucidated, it has recently been shown that sevoflurane interacts with nicotinic acetylcholine receptors by affecting the open and closed state of the ion channels at clinical and lower concentrations. Sevoflurane may also effect reversible modulation of GABA and glycine receptors. The above suggest that at least part of the anesthetic action of sevoflurane may be due to interactions between sevoflurane and specific voltage-gated ion channels.
The preparation of fluorinated compounds such as sevoflurane tends to be difficult because of the limited number of selective fluorination reactions available. Direct fluorination of organic compounds to replace hydrogen is statistical, non-selective, and generally accompanied by the formation of many side products. Hence, fluorinated compounds are usually prepared by first synthesizing a substituted organic intermediate. wherein the substituent group is at the site to be fluorinated, and then displacing the substituent group with a fluoride ion. Metal fluorides, for example, have been used to displace chlorine substituent groups.
Several synthetic routes to sevoflurane employ hexafluoroisopropyl alcohol (HFIP) as a starting material. For example, U.S. Pat. No. 3,683,092 discloses a method for synthesizing sevoflurane involving the methylation of hexafluoroisopropyl alcohol followed by fluorination with either (a) bromine trifluoride, or (b) chlorine gas, followed by potassium fluoride. U.S. Pat. No. 4,469,898 discloses a method for synthesizing sevoflurane which includes the mixing of hexafluoroisopropyl alcohol, formaldehyde, hydrogen fluoride, and a protonating, dehydrating and fluoride ion generating agent. U.S. Pat. No. 4,250,334 discloses a method for synthesizing sevoflurane by adding HFIP to a mixture of a stoichiometric excess of paraformaldehyde and hydrogen fluoride, plus sufficient sulfuric acid to sequester most of the water produced by the reaction. U.S. Pat. No. 4,314,087 discloses a method for synthesizing sevoflurane by reacting HFIP with hydrogen fluoride and a formaldehyde.
The routes disclosed in the referenced patents can result in unwanted by-products which may be difficult to separate from sevoflurane produced by the synthesis. Moreover, the use of corrosive materials in these synthetic routes requires specialized equipment and special handling precautions.
Other methods used to make hexafluoroisopropyl ethers include the conversion of 1,1,1,3,3,3-hexachloroisopropyl ethers to 1,1,1,3,3,3-hexafluoroisopropyl ethers. For example, methyl 1,1,1,3,3,3-hexachloroisopropyl ether and chloromethyl 1,1,1,3,3,3-hexachloroisopropyl ether can be converted to sevoflurane by reaction of each of the above compounds with bromine trifluoride. Hexafluoroisopropyl ethers also can be made by reacting each of these chlorinated compounds with hydrogen fluoride, followed by reaction with bromine trifluoride. U.S. Pat. No. 4,874,901 discloses a method for fluorinating halogenated ether compounds, wherein compounds such as sevoflurane can be prepared by reacting chloromethyl hexafluoroisopropyl ether with either potassium fluoride or sodium fluoride. However, the chlorine replacement methods are not desirable because large volumes of chloride are released in the synthetic process, the yields are low, and multiple chloro-fluoro intermediates are formed. The intermediates must be removed to obtain the final ether product, sevoflurane. The purification processes increase the difficulty and cost of synthesis of 1,1,1,3,3,3-hexafluoroisopropyl ethers by these methods.
Hexafluoropropanes alternatively have been synthesized from malononitrile in the presence of bromine trifluoride, as disclosed in U.S. Pat. Nos. 5,789,630 and 5,705,710.
Another potential route to sevoflurane is by fluorodecarboxylation. Patrick et al.,
J Org. Chem
. 48, 4158-4159 (1983), reports that alkyl carboxylic acids can undergo fluorodecarboxylation with xenon difluoride (XeF
2
) in the presence of hydrogen fluoride. Although the use of xenon difluoride on a small scale can be effective, the cost of xenon difluoride makes its use impractical on a large scale. Furthermore, when alkoxyacetic acids are fluorodecarboxylated with xenon difluoride, significant amounts of side products are formed. Replacement of a carboxylic acid group with a fluorine group has also been disclosed in U.S. Pat. No. 4,996,371 and in Pat. No. RE 35,568 which teach a reaction of hydrogenated aliphatic carboxylic acid compounds with bromine trifluoride; and in U.S. Pat. No. 4,847,427, which teaches a method for preparing fluorocarbon polyethers by neutralizing a perfluorinated carboxylic acid by heating with fluorine in the presence of metal fluoride to replace the carboxylic acid group.
While the above-discussed methods are useful for preparing certain fluorinated compounds, these methods can be complex, expensive, and often provide fluorinated products in low yield together with considerable amounts of side products. Hence there is a need for improved procedures for the preparation of fluorinated compounds.
The present invention provides an improved procedure for the preparation of fluorinated compounds, including sevoflurane and other fluorinated anesthetics.
It is an object of the present invention to provide a method for the preparation of fluorine-containing organic compounds. Still a further object is to provide a method whereby a fluorine-containing organic compound may be prepared from a partially chlorinated, brominated, or iodinated organic compound. An additional object is to provide a method for preparing a fluorine containing organic compound whereby the formation of undesirable decomposition or side products is substantially avoided.
SUMMARY OF THE INVENTION
The invention is directed to a novel method for fluoromethylation of an alcohol via halogenative decarboxylation. The method includes the steps of:
(a) react
Behme Christopher
Bieniarz Christopher
Ramakrishna Kornepati V.
Abbott Laboratories
Price Elvis O.
Richter Johann
Woodworth Brian R.
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