Process for the preparation of chiral isofluoroenes

Details Process for the preparation of chiral isofluoroenes Process for the preparation of chiral isofluoroenes

2001-08-02

2004-08-03

Prats, Francisco (Department: 1651)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

Preparing heterocyclic carbon compound having only o, n, s,...

C435S197000, C435S122000, C435S128000, C435S132000, C435S155000, C568S639000, C568S634000, C568S630000, C568S631000, C568S647000, C558S411000, C558S423000, C546S346000, C548S578000

Reexamination Certificate

active

06770463

ABSTRACT:

BACKGROUND OF THE INVENTION
1,4-diaryl-2-fluoro-2-butenes and a method for their preparation are described in U.S. Pat. No. 5,998,673. Said compounds are useful as insecticidal and acaricidal agents and for protecting plants from damage caused by insect and acarid attack and infestation. Although U.S. Pat. No. 5,998,673 discloses and claims optical isomers of said 1,4-diaryl-2-fluoro-2-butenes, it does not provide a method for their preparation.
It is therefore an object of the present invention to provide a process for the preparation of chiral 1,4-diaryl-2-fluoro-2-butenes.
It is also an object of the present invention to provide intermediates useful in said process.
These and other objects of the present invention will become more apparent from the detailed description thereof set forth below.
SUMMARY OF THE INVENTION
There is provided a process for the preparation of a chiral compound of formula I
wherein
Ar is phenyl optionally substituted with any combination of from one to three halogen, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy, C
1
-C
4
haloalkoxy or hydroxy groups,
1- or 2-naphthyl optionally substituted with any combination of from one to three halogen, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy or C
1
-C
4
haloalkoxy groups, or
a 5- or 6-membered heteroaromatic ring optionally substituted with any combination of from one
to three halogen, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy or C
1
-C
4
haloalkoxy groups;
R is C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, C
3
-C
6
cycloalkyl or C
3
-C
6
halocycloalkyl;
Ar
1
is phenoxyphenyl optionally substituted with any combination of from one to six halogen, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy or C
1
-C
4
haloalkoxy groups,
phenyl optionally substituted with any combination of from one to five halogen, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy or C
1
-C
4
haloalkoxy groups,
biphenyl optionally substituted with any combination of from one to five halogen, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy or C
1
-C
4
haloalkoxy groups,
phenoxypyridyl optionally substituted with any combination of from one to five halogen, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy or C
1
-C
4
haloalkoxy groups,
benzylpyridyl optionally substituted with any combination of from one to five halogen, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy or C
1
-C
4
haloalkoxy groups,
benzylphenyl optionally substituted with any combination of from one to five halogen, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy or C
1
-C
4
haloalkoxy groups,
benzoylphenyl optionally substituted with any combination of from one to five halogen, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy or C
1
-C
4
haloalkoxy groups,
1- or 2-naphthyl optionally substituted with any combination of from one to three halogen, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy or C
1
-C
4
haloalkoxy groups, or
a 5- or 6-membered heteroaromatic ring optionally substituted with any combination of from one to three halogen, C
1
-C
4
alkyl, C
1
-C
4
haloalkyl, C
1
-C
4
alkoxy or C
1
-C
4
haloalkoxy groups, and
the (E)- and (Z)-isomers thereof, which process comprises the following steps:
a) treating a racemic ester of formula II
wherein Ar and R are defined as hereinabove and R
4
is C
1
-C
4
alkyl with an esterase to form a first mixture of either R-acid IIIa and S-ester IIIb
or of S-acid IIIc and R-ester IIId
b) separating said acid IIIa or IIIc from said ester IIIb or IIId;
c) reducing said acid IIIa or IIIc or said ester IIIb or IIId to obtain a chiral alcohol IV having the R- or S-configuration
b) reacting said chiral alcohol with an arylsulfonyl halide Ar
2
SO
2
X
wherein Ar
2
is phenyl, p-chlorophenyl, or p-tolyl, and X is chloro, bromo or fluoro to afford a sulfonate of formula V
e) reacting said sulfonate V with a cyanide-delivering agent to afford a nitrile of formula VI
f) hydrolysing said nitrile VI to afford an acid of formula VII
g) esterifying said acid VII with an alcohol R
1
OH, wherein R
1
is C
1
-C
4
alkyl to afford an ester of formula VIII
h) fluorinating said ester to afford a fluoro-ester of formula IX
i) reacting said fluoro ester with an aldehyde Ar
1
CH
2
CHO, wherein Ar
1
is defined as hereinabove, in a solvent in the presence of a base to afford a second mixture of 4 chiral diastereomeric hydroxy-esters of formula X
j) optionally separating said second mixture X into a third mixture Xa and a fourth mixture Xb, each mixture having two chiral diastereomers;
k) treating said hydroxy-ester mixture X, Xa or Xb with an acylating agent R
2
COX
1
, wherein R
2
is C
1
-C
4
alkyl and X
1
is Cl, Br or R
2
COO, to afford a fifth mixture of 4 chiral diastereomeric acyloxy esters XI, a sixth mixture of 2 acyloxy esters of formula XIa, or a seventh mixture of 2 chiral diastereomeric acyloxy esters XIb
l) optionally separating said sixth or seventh mixture into essentially pure chiral diastereomeric acyloxy esters;
m) hydrolyzing said pure chiral acyloxy esters or mixtures of esters of formula XI to afford a hydroxy-acid of formula XII
and
n) heating said hydroxy-acid XII with an arylsulfonyl halide Ar
3
SO
2
X
2
, wherein Ar
3
is phenyl, p-chlorophenyl, or p-tolyl, and
X
2
is chloro or bromo to afford the desired chiral compound of formula I.
The invention further provides chiral intermediate compounds useful in the process of this invention.
DETAILED DESCRIPTION OF THE INVENTION
Although chiral 1,4-diaryl-2-fluoro-2-butenes are described in U.S. Pat. No. 5,998,673, no method for their preparation is disclosed.
Advantageously, the present invention provides a method for the preparation of chiral compounds of formula I
wherein Ar, R and Ar
1
are defined as above.
In accordance with the process of this invention racemic ester II is enzymatically hydrolyzed with an esterase to afford a first mixture of acid IIIa having the R-configuration, and unhydrolyzed ester IIIb, having the S-configuration, which is separated. Said acid IIIa or said ester IIIb is reduced to obtain a chiral alcohol IV having the R- or S-configuration; said alcohol is reacted with an arylsulfonyl halide Ar
2
SO
2
X to afford a sulfonate of formula V; said sulfonate is treated with a cyanide-delivering agent to afford a nitrile of formula VI; said nitrile is hydrolyzed to yield an acid of formula VII; said acid is esterified with an alcohol R
1
OH to yield an ester of formula VIII; said ester is fluorinated to afford a fluoro-ester of formula IX; said fluoro-ester is reacted with an aldehyde Ar
1
CH
2
CHO in a solvent in the presence of a base to afford a second mixture of 4 chiral diasteromeric hydroxy-esters of formula X; optionally said second mixture can be separated into a third mixture Xa and a fourth mixture Xb, each mixture having two chiral diastereomers; said hydroxy-ester mixture X, Xa, or Xb is treated with an acylating agent R
2
COX, to afford a fifth mixture of 4 chiral diasteromeric acyloxy esters XI, a sixth mixture of 2 acyloxy esters of formula XIa, or seventh mixture of chiral diasteromeric acyloxy esters XIb; optionally, said sixth or seventh mixture can be separated into to essentially pure chiral diastereomeric acyloxy esters; said pure chiral acyloxy esters or mixtures of esters of formula XI are hydrolyzed to a hydroxy acid of formula XII; and finally, said hydroxy acids are heated with an arylsulfonyl halide Ar
3
SO
2
X
2
to afford the desired chiral compound of formula I. The process is depicted in Flow Diagram I wherein R
4
is depicted as methyl.
The wavy lines in structural formula I represent either the E isomeric or the Z isomeric configuration about the carbon-carbon double bond.
Non-polar solvents suitable for use in the process of the invention are essentially water-free solvents such as aromatic hydrocarbons (e.g. toluene, benzene, xylene, naphthalene or the like, preferably toluene), halogenated aromatic hydrocarbones (e.g. chlorobenzene, dichlorobenzene or the like), hydrocarbons (e.g. chloroform, methylene chloride, dichlorethane, or the like, or any of the conventional, prefe

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