Method of making fluorinated alcohols

Details Method of making fluorinated alcohols Method of making fluorinated alcohols

2001-01-12

2002-11-05

Shippen, Michael L. (Department: 1621)

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

Organic compounds

Oxygen containing

C568S437000, C568S812000, C568S814000

Reexamination Certificate

active

06476279

ABSTRACT:

FIELD OF INVENTION
The present invention relates to new methods for making fluorinated alcohols.
BACKGROUND OF THE INVENTION
Fluorinated alcohols find particular use in the syntheses of numerous pharmaceutical drug candidates. For example, 4,4,4-trifluorobutanol is used as a key intermediate in the preparation of the antiparkinson drug 3-(2-methoxyethyl)-5[4-(4,4,4,-trifluorobutoxy)phenyl]-1,3,4,-oxadiazolo-2(3H)-one.
Applicants believe that known methods for making fluorinated alcohols are highly inefficient, often using disfavored reaction ingredients and/or reaction conditions. For example, one known prior art process for forming fluorinated alcohols comprises reacting Grignard reagents derived from 3-chloro-1,1,1-trifluoropropane with ethyl orthoformate in ether at refluxing temperatures for extended periods of time to form fluorinated aldehydes, and subsequently reducing the aldehydes to alcohols using lithium aluminum hydride. McBee et al., “Compounds Derived from 3-Halo-1,1,1-trifluoropropane”,
J. Am. Chem. Soc.,
72, p. 5071 (1950); Walborsky, H. M. et al., “The Syntheses of Trifluoromethyl Amino Acids. II. Their Microbiological Activities”,
J Am. Chem. Soc.,
77, pp. 3637-3640 (1955). Such processes are reported to have produced yields of fluorinated alcohols of only about 37% or less.
The present inventors have come to appreciate that prior art processes of the type disclosed by Walborsky, et al. are disadvantageous for several reasons. In addition to long reaction times and low yields, another disadvantage of the prior art process is that it requires reaction times and low yields, another disadvantage of the prior art process is that it requires the use of fluorinated starting materials which are not readily available and lithium aluminum hydride, which is relatively expensive. Additionally, the prior art process is disadvantageous in that it requires the use of lithium aluminum hydride in conjunction with ethereal solvents. Because lithium aluminum hydride is pyrophoric and ethereal solvents are highly flammable, there is a high risk of hazard associated with their combined use.
Recognizing these and other drawbacks of the prior art, the present inventors have perceived a need for a new, efficient and more desirable method for producing a wide range of fluorinated alcohols. These and other objects are achieved by the present invention as described below.
DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
The present invention is directed to methods of producing a wide range of fluorinated alcohols, many of which find particular use in the syntheses of pharmaceutical drug candidates. An important aspect of the invention is the discovery that fluorinated alcohols can be advantageously produced using halogenated alkanes as a principal reagent. Particularly preferred alkanes are illustrated in Formula I below:
R
F
—C(X)Cl
2
  (I)
wherein R
F
is a fully or partially fluorinated alkyl group and X is hydrogen or chlorine.
Applicants have discovered that halogenated alkanes can be used with great advantage in a process which comprises converting the halogenated alkane, and preferably a halogenated alkane of Formula I, to a fluorinated alcohol. Applicants have discovered that the process of the present invention is highly advantageous in at least two respects. First, the cost of producing fluorinated alcohols according to the present method is greatly reduced relative to conventional fluorinated alcohol production techniques. The lowered cost results, at least in part, because the halogenated alkanes of Formula I are readily available in commercial quantities and are relatively inexpensive, and because the present methods avoid the use of relatively expensive hydrides, such as lithium aluminum hydride, used commonly in conventional fluorinated alcohol preparation techniques. Second, the preferred form of the present conversion process involves fewer synthetic steps, and is more efficient, than known fluorinated alcohol preparation techniques.
According to preferred embodiments of the present invention, the step of converting the halogenated alkane to a fluorinated alcohol comprises the steps of: (a) reacting a halogenated alkane with an alkyl vinyl ether to form an unsaturated halogenated aldehyde; (b) reducing the unsaturated halogenated aldehyde to form an unsaturated halogenated alcohol; and (c) reducing the unsaturated halogenated alcohol to form a fluorinated alcohol.
As used herein, the term “unsaturated halogenated aldehyde” refers generally to a compound comprising an aldehyde moiety bonded to a carbon chain containing at least one carbon-carbon double bond and substituted with at least one fluorine group. An unsaturated halogenated aldehyde, for purposes of the present invention, may further comprise other substituents, including non-fluorine halogens, such as chlorine. The term “unsaturated halogenated alcohol”, as used herein, refers generally to a compound comprising an alcohol moiety bonded to a carbon chain containing at least one carbon-carbon double bond and substituted with at least one fluorine group. An unsaturated halogenated alcohol, for purposes of the present invention, may further comprise other substituents, including non-fluorine halogens, such as chlorine. operation, it is believed that the methods according to the preferred aspects of the present invention involve the reaction steps shown below.
wherein R
F
is a fully or partially fluorinated alkyl group and X is H or Cl
Reaction step (a) comprises generally reacting a halogenated alkane of Formula I with an alkyl vinyl ether to form an unsaturated halogenated aldehyde.
Examples of halogenated alkanes for use in the present invention include halogenated alkanes of Formula I wherein R
F
is a fully or partially fluorinated alkyl group which does not interfere with the formation of the unsaturated halogenated aldehyde. According to preferred embodiments, the halogenated alkane is a compound of Formula I wherein R
F
is a fully or partially fluorinated alkyl group having from about one to about ten carbons, including, for example: fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, heptafluoropropyl, as well as fluorinated derivatives of t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl groups and the like. In more preferred embodiments, R
F
is a fluorinated alkyl group having from about one to about three carbons, such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, fluoropropyl, difluoropropyl, trifluoropropyl, tetrafluoropropyl, pentafluoropropyl, hexafluoropropyl, heptafluoropropyl. In a particularly preferred embodiment, R
F
is a trifluoromethyl group. Any partially fluorinated R
F
groups may be further substituted with substituents which do not interfere with the formation of the unsaturated halogenated aldehyde. Examples of substituents groups which are adaptable for use in the present invention include: alkyl groups, including cyclic alkyls such as cyclohexyl; aryl groups, such as, phenyl, halogenated aryl groups; and the like.
X in a compound of Formula I may be hydrogen or chlorine. In preferred embodiments of the present invention, X is a chlorine.
A wide range of alkyl vinyl ethers may be used in the practice of the present method. Generally, any alkyl vinyl ether capable of radical addition is suitable for use in the present method. Examples of suitable alkyl vinyl ethers include compounds of Formula II:
R—O—C(H)=CH
2
  (II)
wherein R is an alkyl, cycloalkyl or aryl group. R as an alkyl group may be a group having from about one to about twelve carbons such as a methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. Preferred alkyl groups include those having from about one to about six carbons such as met

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