Organic compounds -- part of the class 532-570 series – Organic compounds – Nitriles
Reexamination Certificate
2002-03-14
2003-09-23
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitriles
C558S332000, C558S335000, C558S346000
Reexamination Certificate
active
06624323
ABSTRACT:
AREA OF THE INVENTION
This invention relates to a method for preparing certain acids which are useful as phosphodiesterase 4 inhibitors. More specifically, this invention relates to preparing 4-(substituted-phenyl)-4-cyanocyclohexanoic acids from guaiacol and certain intermediates prepared and used in that process.
BACKGROUND OF THE INVENTION
The process of this invention relates to making compounds which are useful in treating diseases modulated by the isoforms of the phosphodiesterase 4 enzyme. Guaiacol, the starting material, undergoes a series of nine transformations to provide a 4-cyanocyclohexanoic acid which, among several possible products, can be used to make certain PDE 4 inhibitors which are useful for treating pulmonary diseases such as chronic obstructive pulmonary disease (COPD) and asthma, and other diseases. The instant process can be used to make other 4-cyanocyclohexanoic acids as well.
The primary target compounds which are prepared by the methods of this invention and the intermediates disclosed herein are disclosed and described in U.S. Pat. No. 5,554,238 issued Sep. 3, 1996 and related patents and published applications. That patent is incorporated herein by reference in full. Those compounds, particularly the 4-cyanocyclohexanoic acids, have marked effects on neutrophil activity and inhibit neutrophil chemotaxis and degranulation in vitro. In animal models, those compounds reduce neutrophil extravasation from the circulation, pulmonary sequestration and the edematous responses to a number of inflammatory insults in vitro. They have been found to be useful in treating COPD in humans, and possibly in other mammalian species which suffer from COPD.
SUMMARY OF THE INVENTION
In a first aspect this invention relates to a process for preparing substituted cyclohexanoic acids of formula (I)
where R
a
is a carbon-containing group optionally linked by oxygen, sulfur or nitrogen to the phenyl ring and j is 1-5: and
one of R and R* is hydrogen and the other is C(O)OH;
which process comprises:
catalytically reducing a ketone of formula II
where alkyl has 1-6 carbon atoms and (Ra)j is the same as defined above, using a heavy metal catalyst and hydrogen gas.
More particularly this invention relates to a process for preparing compounds of formula IA
wherein:
R
1
is —(CR
4
R
5
)
r
R
6
wherein the alkyl moieties are unsubstituted or substituted with one or more halogens;
r is 0 to 6;
R
4
and R
5
are independently selected hydrogen or C
1-2
alkyl;
R
6
is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC
1-3
alkyl, halo substituted aryloxyC
1-3
alkyl, indanyl, indenyl, C
7-11
polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C
3-6
cycloalkyl, or a C
4-6
cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl or heterocyclic moiety is unsubstituted or substituted by 1 to 3 methyl groups, one ethyl group, or an hydroxyl group:
provided that:
b) when R
6
is hydroxyl, then r is 2 to 6; or
d) when R
6
is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;
X is YR
2
;
Y is O;
X
2
is O;
R
2
is —CH
3
or —CH
2
CH
3
, unsubstituted or substituted by 1 or more halogens;
one of R and R* is hydrogen and the other is C(O)OH.
In yet a further aspect, this invention relates to intermediates which are useful for preparing formula (I) compounds, namely,
wherein, in each of formulas (A) and (C) and the X, X
2
and R
1
groups are the same as for formula (I) and L is a leaving group like halogen or a triflate.
In addition, this invention relates to a product of formula (I) as defined above made by the process of catalytically reducing a ketone of formula A using a heavy metal catalyst and hydrogen gas
where alkyl has 1-6 carbon atoms and X, X
2
and R
1
arc the same as defined above.
In yet another aspect, this invention involves a product of formula (I) as defined above made by the process of carbonylating a ketone of formula (B)
to form a compound of formula (A) and thereafter converting it to a compound of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
This invention provides a means for preparing cyclohexanoic acids. In particular it relates to a method for preparing cyclohexanoic acids which are phosphodiesterase 4 inhibitors as more fully disclosed in U.S. Pat. No. 5,554,238, which is incorporated herein by reference. The invention can also be used to prepare other cyclohexanoic acids in addition to the ones illustrated herein.
As regards the preferred substituents on formulas (I), (II), (A), (B) and (C), for R
1
they are CH
2
-cyclopropyl or C
4-6
cycloalkyl. Preferred R
2
groups are a C
1-2
alkyl unsubstituted or substituted by 1 or more halogens. The halogen atoms are preferably fluorine and chlorine, more preferably fluorine. More preferred R
2
groups are those wherein R
2
is methyl, or a fluoro-substituted alkyl group, specifically a C
1-2
alkyl such as a —CF
3
, —CHF
2
, or —CH
2
CHF
2
. Most preferred are the —CHF
2
and —CH
3
moieties. Most preferred are those compounds wherein R
1
is—CH
2
-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CHF
2
and R
2
is CF
2
H or CH
3
. Particularly preferred are those compounds where R
1
is cyclopentyl and R
2
is CH
3
.
The most preferred product made by the process of this invention is cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid].
As regards intermediates, the L group of formula (C) is any leaving group which is reactive under the general set of conditions described in Example 3 below. Preferably L is a halogen or a triflate, and most perferable Cl, Br, or I, or a triflate.
When forming the cyclohexanone from the cyclohex-2-ene-1-one, a quaternary ammonium compound or quaternary amine and a cyanide salt are used. Examplary quaternary ammonium compounds are the ammonium halides such as ammonium chloride and ammonium bromide. Exemplary quaternary amines are the trialkylamine hydrohalides such as trimethylamine hydrochloride. Cyanide salts include the halide salts such as sodium or potassium cyanide.
Scheme I illustrates the conversion of guaiacol to the acid of Formula (I).
This process can be used to prepare the other compounds for formulas (I), (II) (A), (B), or (C) by substituting for the 3 or 4 position groups illustrated here the selected group, at the appropriate step in the reaction.
In scheme I compounds 1—1 and 1-2 are bracketed to indicate they are not fully isolated but rather processed to a concentrated form and used directly in that form in the next step. Guaiacol, available and obtained from commercial sources, is dissolved in an appropriate solvent at about ambient temperature. Then the alcohol is esterified to protect it in the bromination step (bromine is used to illustrate the L group in this Scheme) which is followed by treating guaiacol with the likes of trifluoroacetic anhydride (about 1 equivalent) to which is added an alkali metal alkoxide such as potassium t-butoxide (about 0.1 equivalent). It is expected that the sodium and lithium salts of t-butoxide and other secondary and tertiary alcohols of 3 to 5 carbons could be used as well. Thereafter ring bromination is effected using N-bromosuccinimide. Solvent is removed from the flask in which the acylation reaction was carried out. The concentrated unisolated ester 1—1 is treated with N-bromosuccinimide (about 1 equivalent) preferably using the same solvent as used in the esterification, after which the solution is stirred for 10 to 30 hours at about ambient temperature. After the bromination reaction has gone to completion (compound 1-2), the ester is saponified to give compound 1-3 using an appropriate base. Herein sodium hydroxide, potassium hydroxide, lithium hydroxide or the like is preferred for carrying out the hydrolysis of the ester.
For the purposes of obtaining the preferred end product herein, an ether (1-4) is formed from the alcohol of the brominated guaiacol by effecting a replacement rea
Kanagy James M.
Kinzig Charles M.
Richter Johann
SmithKline Beecham Corporation
Venetianer Stephen
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