U.S. patent application number 10/005547 was filed with the patent office on 2002-06-27 for method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids.
This patent application is currently assigned to SmithKline Beecham Corporation. Invention is credited to Chen, Jianhao, Mendelson, Wilford, Webb, Kevin.
Application Number | 20020082440 10/005547 |
Document ID | / |
Family ID | 26741278 |
Filed Date | 2002-06-27 |
United States Patent
Application |
20020082440 |
Kind Code |
A1 |
Webb, Kevin ; et
al. |
June 27, 2002 |
METHOD FOR PREPARING SUBSTITUTED 4-PHENYL-4-CYANOCYCLOHEXANOIC
ACIDS
Abstract
This invention relates to a method of preparing a compound type
where at least one of R' or R" is a carboxyl group (I) by treating
a compound of formula (II) with a Group I(a) or Group II(a) metal
halide, with an aprotic dipolar amide-based solvent and water.
Inventors: |
Webb, Kevin; (Newtown,
CT) ; Mendelson, Wilford; (King of Prussia, PA)
; Chen, Jianhao; (Audubon, PA) |
Correspondence
Address: |
GLAXOSMITHKLINE
Corporate Intellectual Property - UW2220
P.O. Box 1539
King of Prussia
PA
19406-0939
US
|
Assignee: |
SmithKline Beecham
Corporation
|
Family ID: |
26741278 |
Appl. No.: |
10/005547 |
Filed: |
November 8, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10005547 |
Nov 8, 2001 |
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09529235 |
Apr 7, 2000 |
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09529235 |
Apr 7, 2000 |
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PCT/US98/21061 |
Oct 7, 1998 |
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60061613 |
Oct 10, 1997 |
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Current U.S.
Class: |
560/15 ; 549/498;
549/79; 560/38; 564/152; 564/154 |
Current CPC
Class: |
C07D 303/48 20130101;
C07C 255/46 20130101; C07C 2601/08 20170501; C07C 45/71 20130101;
C07C 47/575 20130101; C07C 2601/14 20170501; C07C 45/71 20130101;
C07C 47/575 20130101 |
Class at
Publication: |
560/15 ; 549/498;
549/79; 560/38; 564/152; 564/154 |
International
Class: |
C07D 333/24; C07D
307/02; C07C 069/76 |
Claims
What is claimed is:
1. A method for making a compound of formula I 7R.sub.1 is
--(CR.sub.4R.sub.5).sub.nC(O)O(CR.sub.4R.sub.5).sub.mR.sub.6,
--(CR.sub.4R.sub.5).sub.nC(O)NR.sub.4(CR.sub.4R.sub.5).sub.mR.sub.6,
--(CR.sub.4R.sub.5).sub.nO(CR.sub.4R.sub.5).sub.mR.sub.6, or
--(CR.sub.4R.sub.5).sub.rR.sub.6 wherein the alkyl moieties may be
optionally substituted with one or more halogens; m is 0 to 2; n is
1 to 4; r is 0 to 6; R.sub.4 and R.sub.5 are independently selected
from hydrogen or a C.sub.1-2 alkyl; R.sub.6 is hydrogen, methyl,
hydroxyl, aryl, halo substituted aryl, aryloxyC.sub.1-3 alkyl, halo
substituted aryloxyC.sub.1-3 alkyl, indanyl, indenyl, C.sub.7-11
polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl,
pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl,
thiopyranyl, C.sub.3-6 cycloalkyl, or a C.sub.4-6 cycloalkyl
containing one or two unsaturated bonds, wherein the cycloalkyl and
heterocyclic moieties may be optionally substituted by 1 to 3
methyl groups or one ethyl group; provided that: a) when R.sub.6 is
hydroxyl, then m is 2; or b) when R.sub.6 is hydroxyl, then r is 2
to 6; or c) when R.sub.6 is 2-tetrahydropyranyl,
2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or
2-tetrahydrothienyl, then m is 1 or 2; or d) when R.sub.6 is
2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl,
or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is
0, then R.sub.6 is other than H in
--(CR.sub.4R.sub.5).sub.nO(CR.sub.4R.sub.5).sub.mR.sub.6; X is
YR.sub.2, halogen, nitro, NH.sub.2, or formyl amine; X.sub.2is O or
NR.sub.8; Y is O or S(O).sub.m'; m' is 0, 1, or 2; R.sub.2 is
independently selected from --CH.sub.3 or --CH.sub.2CH.sub.3
optionally substituted by 1 or more halogens; R.sub.3 is hydrogen,
halogen, C.sub.1-4 alkyl, CH.sub.2NHC(O)C(O)NH.sub.2,
halo-substituted C.sub.1-4 alkyl, --CH.dbd.CR.sub.8'R.sub.8',
cyclopropyl optionally substituted by R.sub.8', CN, OR.sub.8,
CH.sub.2OR.sub.8, NR.sub.8R.sub.10, CH.sub.2NR.sub.8R.sub.10,
C(Z)H, C(O)OR.sub.8, C(O)NR.sub.8R.sub.10, or C.ident.CR.sub.8'
R.sub.8 is hydrogen or C.sub.1-4 alkyl optionally substituted by
one to three fluorines; R.sub.8' is R.sub.8 or fluorine; R.sub.10
is OR.sub.8 or R.sub.11; R.sub.11 is hydrogen, or C.sub.1-4 alkyl
optionally substituted by one to three fluorines; Z' is O,
NR.sub.9, NOR.sub.8, NCN, C(--CN).sub.2, CR.sub.8CN,
CR.sub.8NO.sub.2, CR.sub.8C(O)OR.sub.8,
CR.sub.8C(O)NR.sub.8R.sub.8, C(--CN)NO.sub.2, C(--CN)C(O)OR.sub.9,
or C(--CN)C(O)NR.sub.8R.sub.8; R' and R" are independently hydrogen
or --C(O)OX where X is hydrogen or metal or ammonium cation; which
method comprises: a) combining a Group I(a) or Group II(a) metal
halide, with an aprotic dipolar amide-based solvent and water and a
compound of formula II(a) or II(b), 8where R.sub.1, R.sub.3,
X.sub.2 and X are the same as for formula (I) b) heating the
combination to a temperature of at least about 60.degree. for
several hours, optionally under an inert atmosphere; c)
precipitating out a compound of formula (I) by adding a strong base
to said combination; d) removing the amide-based solvent and water
from said precipitate, and optionally 1) purifying further the
precipitate, or 2) acidifying the precipitate to obtain the free
acid.
2. The process of claim 1 wherein the product is a compound wherein
R.sub.1 is --CH.sub.2-cyclopropyl, cyclopentyl,
3-hydroxycyclopentyl, methyl or CF.sub.2H; X is YR.sub.2; Y is
oxygen; X.sub.2 is oxygen; and R.sub.2 is CF.sub.2H or methyl; and
R.sub.3 is CN.
3. The process of claim 1 or 2 wherein the Group I(a) or II(a)
metal halide is lithium or magnesium halide.
4. The process of any one of claims 1-3 wherein the Group I(a) or
II(a) metal halide is lithium bromide or magnesium bromide.
5. The process of any one of claims 1-4 in which the aprotic
dipolar amide-based solvent is dimethylformamide,
dimethylacetamide, or N-methyl pyrrolidinone.
6. The process of any one of claims 1-5 wherein the Group I(a) or
II(a) metal halide is lithium bromide and the amide-based solvent
is dimethylformamide.
7. The process of any one of claim 1-6 wherein water is present in
an amount greater than 0.1% by weight/weight of the contents of the
reaction vessel.
8. The process of any one of claims 1-7 in which the strong base is
lithium hydroxide.
9. The process of any one of claim 1-8 wherein the compound of
formula II(a) or II(b) is
cis-6-[3-(cyclopentyloxy)-4-methoxyphenyl)]-1-oxaspiro[-
2.5]octane-2,6-dicarbonitrile.
10. A product of the process of any one of claims 1-9 which is
cis-lithium-4-cyano-4-(3-cyclopentyloxy4methoxyphenyl)-r-1-cyclohexanecar-
boxylate.
11. A compound which is
cis-lithium4-cyano-4-(3-cyclopentyloxy-4-methoxyph-
enyl)-r-1-cyclohexanecarboxylate.
12. A compositon of matter comprising essentially pure
cis-lithium4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-1-cyclohexaneca-
rboxylate.
Description
SCOPE OF THE INVENTION
[0001] This invention covers intermediates and a synthetic route
for making
4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexanoic acid and
its analogs. This acid and its named analogs are selective for
inhibiting the catalytic site in the phosphodiesterase isoenzyme
denominated IV (PDE IV hereafter) and as such the acids are useful
in treating a number of diseases which can be moderated by
affecting the PDE IV enzyme and its subtypes.
AREA OF THE INVENTION
[0002] Bronchial asthma is a complex, multifactorial disease
characterized by reversible narrowing of the airway and
hyper-reactivity of the respiratory tract to external stimuli.
[0003] Identification of novel therapeutic agents for asthma is
made difficult by the fact that multiple mediators are responsible
for the development of the disease. Thus, it seems unlikely that
eliminating the effects of a single mediator will have a
substantial effect on all major components of chronic asthma. An
alternative to the "mediator approach" is to regulate the activity
of the cells responsible for the pathophysiology of the
disease.
[0004] One such way is by elevating levels of cAMP (adenosine
cyclic 3',5'-monophosphate). Cyclic AMP has been shown to be a
second messenger mediating the biologic responses to a wide range
of hormones, neurotransrmitters and drugs; [Krebs Endocrinology
Proceedings of the 4th International Congress Excerpta Medica,
17-29, 1973]. When the appropriate agonist binds to specific cell
surface receptors, adenylate cyclase is activated, which converts
Mg.sup.+2-ATP to cAMP at an accelerated rate.
[0005] Cyclic AMP modulates the activity of most, if not all, of
the cells that contribute to the pathophysiology of extrinsic
(allergic) asthma. As such, an elevation of cAMP would produce
beneficial effects including: 1) airway smooth muscle relaxation,
2) inhibition of mast cell mediator release, 3) suppression of
neutrophil degranulation, 4) inhibition of basophil degranulation,
and 5) inhibition of monocyte and macrophage activation. Hence,
compounds that activate adenylate cyclase or inhibit
phosphodiesterase should be effective in suppressing the
inappropriate activation of airway smooth muscle and a wide variety
of inflammatory cells. The principal cellular mechanism for the
inactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by
one or more of a family of isozymes referred to as cyclic
nucleotide phosphodiesterases (PDEs).
[0006] It has now been shown that a distinct cyclic nucleotide
phosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMP
breakdown in airway smooth muscle and inflammatory cells. [Torphy,
"Phosphodiesterase Isozymes: Potential Targets for Novel
Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC
Technical Services Ltd., 1989]. Research indicates that inhibition
of this enzyme not only produces airway smooth muscle relaxation,
but also suppresses degranulation of mast cells, basophils and
neutrophils along with inhibiting the activation of monocytes and
neutrophils. Moreover, the beneficial effects of PDE IV inhibitors
are markedly potentiated when adenylate cyclase activity of target
cells is elevated by appropriate hormones or autocoids, as would be
the case in vivo. Thus PDE IV inhibitors would be effective in the
asthmatic lung, where levels of prostaglandin E.sub.2 and
prostacyclin (activators of adenylate cyclase) are elevated. Such
compounds would offer a unique approach toward the pharmacotherapy
of bronchial asthma and possess significant therapeutic advantages
over agents currently on the market.
[0007] The process and intermediates of this invention provide a
means for making certain
4-substituted-4-(3,4-disubstitutedphenyl)cyclohexanoic acids which
are useful for treating asthma, and other diseases which can be
moderated by affecting the PDE IV enzyme and its subtypes. The
final products of particular interest are fully described in U.S.
Pat. No. 5,552,483 issues Sep. 3, 1996. The information and
representations disclosed therein, in so far as that information
and those representations are necessary to the understanding of
this invention and its practice, in total, are incorporated herein
by reference.
SUMMARY OF THE INVENTION
[0008] This invention relates a method for making a compound of
formula I 1
[0009] wherein
[0010] R.sub.1 is
--(CR.sub.4R.sub.5).sub.nC(O)O(CR.sub.4R.sub.5).sub.mR.s- ub.6,
--(CR.sub.4R.sub.5).sub.nC(O)NR.sub.4(CR.sub.4R.sub.5).sub.mR.sub.6,
--(CR.sub.4R.sub.5).sub.nO(CR.sub.4R.sub.5).sub.mR.sub.6, or
--(CR.sub.4R.sub.5).sub.rR.sub.6 wherein the allyl moieties may be
optionally substituted with one or more halogens;
[0011] m is 0 to 2;
[0012] n is 1 to 4;
[0013] r is 0 to 6;
[0014] R.sub.4 and R.sub.5 are independently selected from hydrogen
or a C.sub.1-2 alkyl;
[0015] R.sub.6 is hydrogen, methyl, hydroxyl, aryl, halo
substituted aryl, aryloxyC.sub.1-3 alkyl, halo substituted
aryloxyC.sub.1-3 alkyl, indanyl, indenyl, C.sub.7-11
polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl,
pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl,
thiopyranyl, C.sub.3-6 cycloalkyl, or a C.sub.4-6 cycloalkyl
containing one or two unsaturated bonds, wherein the cycloalkyl and
heterocyclic moieties may be optionally substituted by 1 to 3
methyl groups or one ethyl group;
[0016] provided that:
[0017] a) when R.sub.6 is hydroxyl, then m is 2; or
[0018] b) when R.sub.6 is hydroxyl, then r is 2 to 6; or
[0019] c) when R.sub.6 is 2-tetrahydropyranyl,
2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or
2-tetrahydrothienyl, then m is 1 or 2; or p2 d) when R.sub.6 is
2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl,
or 2-tetrahydrothienyl, then r is 1 to 6;
[0020] e) when n is 1 and m is 0, then R.sub.6 is other than H in
--(CR.sub.4R.sub.5).sub.nO(CR.sub.4R.sub.5).sub.mR.sub.6;
[0021] X is YR.sub.2, halogen, nitro, NH.sub.2, or formyl
amine;
[0022] X.sub.2 is O or NR.sub.8;
[0023] Y is O or S(O).sub.m';
[0024] m' is 0, 1, or 2;
[0025] R.sub.2 is independently selected from --CH.sub.3 or
--CH.sub.2CH.sub.3 optionally substituted by 1 or more
halogens;
[0026] R.sub.3 is hydrogen, halogen, C.sub.1-4 alky,
CH.sub.2NHC(O)C(O)NH.sub.2, halo-substituted C.sub.1-4 alkyl,
--CH.dbd.CR.sub.8'R.sub.8', cyclopropyl optionally substituted by
R.sub.8', CN, OR.sub.8, CH.sub.2OR.sub.8, NR.sub.8R.sub.10,
CH.sub.2NR.sub.8R.sub.10, C(Z')H, C(O)OR.sub.8,
C(O)NR.sub.8R.sub.10, or C.ident.CR.sub.8';
[0027] R.sub.8 is hydrogen or C.sub.1-4 alkyl optionally
substituted by one to three fluorines;
[0028] R.sub.8' is R.sub.8 or fluorine;
[0029] R.sub.10 is OR.sub.8 or R.sub.11;
[0030] R.sub.11 is hydrogen, or C.sub.1-4 alkyl optionally
substituted by one to three fluorines;
[0031] Z' is O, NR.sub.9, NOR.sub.8, NCN, C(--CN).sub.2,
CR.sub.8CN, CR.sub.8NO.sub.2, CR.sub.8C(O)OR.sub.8,
CR.sub.8C(O)NR.sub.8R.sub.8, C(--CN)NO.sub.2, C(--CN)C(O)OR.sub.9,
or C(--CN)C(O)NR.sub.8R.sub.8;
[0032] R' and R" are independently hydrogen or --C(O)OX where X is
hydrogen or metal or ammonium cation;
[0033] which method comprises:
[0034] a) combining a Group I(a) or Group II(a) metal halide, with
an aprotic dipolar amide-based solvent and water and a compound of
formula A or B, 2
[0035] where R.sub.1, R.sub.3, X.sub.2 and X are the same as for
formula (I);
[0036] b) heating the combination to a temperature of at least
about 60.degree. for several hours, optionally under an inert
atmosphere;
[0037] c) precipitating out a compound of formula (I) by adding a
strong base to said combination;
[0038] d) removing the amide-based solvent and water from said
precipitate, and optionally
[0039] 1) purifying further the precipitate, or
[0040] 2) acidifying the precipitate to obtain the free acid.
[0041] Specific Embodiments of the Invention
[0042] This process involves the synthesis of certain
4-substituted-4-(3,4-disubstitutedphenyl)cyclohexanoic acids. It
allows for converting a cyanoepoxide to its corresponding
homologated acid via the use of a Group I(a) or II(b) salt
intermediate.
[0043] The compounds which are made by this process are PDE IV
inhibitors. They are useful for treating a number of diseases as
described in U.S. Pat. No. 5,552,438 issued Sep. 3, 1996.
[0044] The preferred compounds which can be made by this process
are as follows:
[0045] Preferred R.sub.1 substitutents for the compounds of all
named formulas are CH.sub.2-cyclopropyl, CH.sub.2-C.sub.5-6
cycloalkyl, C.sub.4-6 cycloalkyl unsubstituted or substituted with
OHC.sub.7-11 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl,
tetrahydrofuran-3-yl, benzyl or C.sub.1-2 alkyl unsubstituted or
substituted by 1 or more fluorines,
--(CH.sub.2).sub.1-3C(O)O(CH.sub.2).sub.0-2CH.sub.3,
--(CH.sub.2).sub.1-3O(CH.sub.2).sub.0-2CH.sub.3, and
--(CH.sub.2).sub.2-4OH.
[0046] Preferred X groups for Formula (I) or (II) are those wherein
X is YR.sub.2 and Y is oxygen. The preferred X.sub.2 group for
Formula (I) is that wherein X.sub.2 is oxygen. Preferred R.sub.2
groups are a C.sub.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.sub.2 groups
are those wherein R.sub.2 is methyl, or the fluoro-substituted
alkyls, specifically a C.sub.1-2 alkyl, such as a --CF.sub.3,
--CHF.sub.2, or --CH.sub.2CHF.sub.2 moiety. Most preferred are the
--CHF.sub.2 and --CH.sub.3 moieties.
[0047] Most preferred are those compounds wherein R.sub.1 is
--CH.sub.2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl
or CF.sub.2H; X is YR.sub.2; Y is oxygen; X.sub.2 is oxygen; and
R.sub.2 is CF.sub.2H or methyl; and R.sub.3 is CN.
[0048] The lithium salt of these compound represent a sub-set of
preferred compounds. In particular the lithium salt of
4-cyano-4-(3-cyclopentyloxy--
4-methoxyphenyl)-r-1-cyclohexanecarboxylic acid, i.e.,
lithium-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-1-cyclohexanecarbo-
xylate represents a preferred embodiment. More particularly, the
compound
cis-lithium-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-1-cyclohexanec-
arboxylate is most preferred.
[0049] The carboxylate is made by opening the epoxide with a Group
I(a) or II(a) metal halide to get the acyl nitrile which hydrolyzes
to the acid in the presence of water. A problem in preparing the
acid from the acyl nitrile is that when the carboxylate is formed
from the acyl nitrile, hydrogen cyanide (HCN) is generated. The
challenge is one of removing this HCN in a cost-effective way. A
feature of this invention is a means for effecting a more efficient
removal of HCN. It has been discovered that if the reaction is run
in an aprotic dipolar amide-based solvent containing water, when a
strong base is added a cyanide salt forms and remains in solution
and the carboxylate salt which forms at the same time precipitates
out of solution. This permits one to collect the precipitate and
remove the solvent, and by that means remove most or essentially
all of the cyanide salt from the alkanoic acid salt precipitate.
This avoids having to run an extra purification step, such as
oxidizing the HCN.
[0050] The Group I(a) or II(a) metal halides used in this invention
are any of the halides of the alkali metals and the alkali earth
metals, i.e., lithium, sodium, potassium, rubidium, cesium or
francium; and beryllium, magnesium, calcium, strontium, barium, or
radium. The preferred metals are lithium and magnesium. The halides
include fluoride, chloride, bromide and iodide. The preferred
halide is bromide. Lithium and magnesium halides are preferred.
Lithium bromide and magnesium bromide are most preferred. Lithium
bromide is particularly preferred.
[0051] In regards to the amide-based solvents, they are illustrated
by the likes of dimethylformamide (DMF), dimethylacetamide, and
N-methyl pyrrolidinone. DMF is most preferred. A second organic
solvent can be used in addition to the amide-based solvent. For
example acetonitrile has been used successfully in the reaction
illustrated below. Normally water is added to the reaction pot as
it hydrolyzes the acyl nitrile in situ to give the alkanoic acid.
Hence a further preferred embodiment of this invention is to use an
aprotic dipolar solvent which is water miscible. DMF,
dimethylacetamide, and N-methyl pyrrolidinone meet this standard.
While it is essential to have water in the reaction medium, the
amount of water can vary widely. The reaction goes even when a
minor amount of water is present. It is preferred to have at least
0.1% by weight/weight (wt/wt) present in the reaction vessel,
calculated on the basis of both the liquids and the solids, if any,
present in the vessel. A more preferred amount of water is at least
about 1% wt/wt, and most preferably about 1-5% water by wt/wt.
While not all possible combinations of water and amide-based
solvent systems have been tested, it is known that the reaction
will proceed with 20% water (wt/wt). Hence it is believed that even
higher percentages of water can be used. Optimization of the
organic solvent-to-water ratios can be achieved by the skilled
practioner. The use of any amount of water in combination with an
amide-based solvent is considered to be within the scope of this
invention.
[0052] The reaction can be run at any temperature above about
60.degree. C. Since there are numerous combinations of amide-based
solvent and water that can be used, it is not practical to set an
exact upper limit to the temperature since that will vary based on
solvent selection and the ratio of the selected solvents.
[0053] The Group I(a) or II(a) metal halide opens the epoxide to
give an acyl nitrile. It is hydrolyzed to the acid in the presence
of water. But rather than isolate the free acid, an insoluble salt
of the carboxylate is formed by adding about 2 or more equivalents
of a strong base to the reaction vessel. This base forms two salts,
a salt of the cyclohexanoic acid and a salt of HCN which is
released in the hydrolysis of the acyl nitrile group. The metal
cyanide it turns out is soluble in the solvent and the salt of the
alkanoic acid precipitates out of solution. This makes it possible
to separate the alkanoic acid salt from the cyanide salt by simply
removing the solvent. The invention can be practiced using less
than 2 equivalents of base, but that would possibly result in loss
of the alkanoic acid because it would not precipitate out of
solution, undesirable from an economic standpoint. And unreacted
HCN could contaminate the alkanoic acid that did precipitate out of
solution. Hence the preferred practice is to use 2 or more
equivalents of the base.
[0054] A strong base for the purposes of this invention is any base
that will form a salt with the cyanide ion. One can use any base
strong enough to form these salts; formation of the cyanide salt is
the more critical of the two criteria for determining if a
particular base is useful in this step. Inorganic hydroxides are
preferred. For example one can use LiOH, NaOH, or KOH. One can also
use ammonium salts, for example tetra-alkylammonium hydroxides or
NH.sub.4OH. Lithium hydroxide is preferred because the lithium
cyanide salt is highly soluble in the aqueous aprotic dipolar
amide-based solvent, and thus effects more efficient and more
complete removal of the cyanide ion from the acid salt when the
amide-based solvent is removed. Lithium cyanide is more soluble in
DMF than is sodium cyanide or potassium cyanide. So it is more
advantageous to make lithium the cation in the strong base in the
salt-forming step of the process.
[0055] A perferred practice of this invention is one in which the
solvent(s) are charged to the reaction vessel, lithium bromide is
added, and then the epoxide. Once the reaction has gone to
completion essentially, two or more equivalents of an aqueous
solution of lithium hydroxide are added, the cyclohexanoic acid
salt is precipitated out of solution and filtered out, and the
solvent discarded. The lithium salt of the cyclohexanoic acid can
be further purified if needs be to remove residual contaminants
such as cyanide salts, or converted to the acid by dissolving or
suspending the salt in a solvent and acidifying that material to
obtain the free acid.
[0056] A representative schematic of the process is set out in
Scheme I and Scheme II. These graphical representations use
specific examples to illustrate the general methodology used in
this invention. 3
[0057] Scheme II illustrates a second very similar set of
conditions that can be used in this invention. This scheme follows
the same route as the one outlined in Scheme I; some of the
conditions in certain steps are changed. 4
[0058] The chemistries illustrated in Scheme I are set out in a
co-pending U.S. application which has been assigned U.S. Ser. No.
60/061,613 (filed Feb. 12, 1997) and also filed as PCT application
Ser. No. PCT/US98/02749 designating inter alia the U.S.; it has
been published as WO98/34584. That application is incorporated
herein by reference, particularly as regards the chemistries
underpinning steps 1-7.
[0059] The chemistries in Scheme II are set out in PCT application
No. PCT/EP98/05504 filed Aug. 26, 1998 which, inter alia,
designates the U.S. as a selected State. The full disclosure of
that application is incorporated herein by reference. In addition
the details of this second set of chemistries are given below.
[0060] A general description of the chemistries in Schemes I and II
follows:
[0061] A mixture of cyclopentyl chloride, isovanillin and potassium
carbonate in dimethylformamide is stirred at about 125.degree. C.
until formation of the cyclopentyloxy product is deemed to be
complete (approximately 2 hours). The mixture is cooled to
20-25.degree. C., the solid (potassium chloride and potassium
bicarbonate) is removed by centrifugation and is washed with
methanol before being discarded. The dimethylformamide liquors and
methanol wash are combined for use in the next step.
[0062] The solution of the cyclopentyloxy compound in
dimethylformamide and methanol is cooled to about 0.degree. C. and
treated with sodium borohydride (approximately 1.5 hours). The
temperature is maintained below 5.degree. C. After that the mixture
is stirred at 0 to 10.degree. C. for 30 minutes and at
25-30.degree. C. until the reduction reaction is deemed to be
complete (approximately 1 hour). Acetic acid 50% is added to
destroy the excess borohydride and the dimethylformamide and
methanol are removed by distillation in vacuo. After cooling to
20-25.degree. C. the mixture is partitioned between water and
toluene. The toluene phase, containing the alcohol is washed with
demineralised water, passed through a filter for use in the next
step.
[0063] The solution of alcohol in toluene is treated with
concentrated hydrochloric acid (min 36%) at 15 to 25.degree. C. The
organic phase, containing the chloro compound is separated and
treated with sodium bicarbonate to neutralize the HCl traces. The
solid (sodium chloride, sodium bicarbonate) is removed by
filtration.
[0064] The solution of the chloro compound is concentrated by
distillation in vacuo. After cooling to about 20.degree. C.,
demineralised water, tetrabutylammonium bromide and sodium cyanide
are added. After that the mixture is heated to 80.degree. C. and
stirred at this temperature until the cyanidation reaction is
deemed to be complete (approximately 2 hours).
[0065] After cooling to <60.degree. C. the mixture is
partitioned between water and toluene. The toluene phase,
containing the cyano compound is washed at 30 to 25.degree. C. with
demineralised water, distilled in vacuo to minimum volume and to
this is added acetonitrile. The product solution in acetonitrile is
used directly in the next step.
[0066] Solutions of methyl acrylate in acetonitrile and Triton B
and acetonitrile are prepared. About 16.6% of the methyl acrylate
solution is added to the cyano compound solution at <25.degree.
C. About 12.5% of the Triton B solution is the added, the mixture
is stirred for some minutes and then cooled back to <25.degree.
C. This addition sequence is repeated three more times, then the
final 33% of the methyl acrylate solution and the final 50% of the
Triton B solution are added in two portions. The reaction mixture
is stirred at 20 to 25.degree. C. until the reaction is deemed to
be complete (approximately 2-3 hours). The acetonitrile is removed
by vacuum distillation to minimum volume. The mixture is
partitioned between cyclohexane/toluene and water at 50.degree. C.
The cyclohexane/toluene phases, containing the pimelate is aged for
about 1 hour at about 0.degree. C.
[0067] The product is isolated by centrifugation and washed with
cold (<0.degree. C.) cyclohexane/toluene. The wet cake vacuum
dried at max 50.degree. C. to give the pimelate as an off white to
beige powder.
[0068] A 29% methanolic solution of sodium methoxide is added in
one lot to a solution of the pimelate in dioxane. The mixture is
heated to about 75.degree. C. (reflux) and maintained at this
temperature until formation of the 2-carbomethoxycyclohexan-1-one
is deemed complete (approximately 1 hour). Much of the methanol is
distilled out and replaced with dioxane. Sodium bicarbonate and
deminieralised water are added to the the mixture is heated to
reflux (about 85 to 88.degree. C.) and maintained at this
temperature until formation of the cyclohexan-1-one is deemed to be
complete (approximately 10 hours).
[0069] After that the mixture is cooled to <60.degree. C. and
concentrated hydrochloric acid solution is added to reduce the pH
from >10 to 7.5.
[0070] Much of the dioxane and methanol is removed by distillation
in vacuo. After that the mixture is partitioned between
cyclohexane/toluene and water at about 70.degree. C. The organic
phase, containing the ketone is washed twice with demineralised
water at about 70.degree. C.
[0071] The product solution is cooled to 10.degree. C. and aged for
about 1 hour at 9 to 11.degree. C. The product is isolated by
filtration and washed with cold (10.degree. C.)
cyclohexane/toluene. the wet cake is vacuum dried at max 50.degree.
C. to give the ketone as an off white powder.
[0072] The dicarbonitrile is prepared from the ketone by treating
the ketone with chloroacetonitrile in the presence of an inorganic
base and a catalytic amount of benzyltriethylammonium chloride
(BTEAC). The ketone and a slight excess of chloroacetonitrile in a
suitable solvent such as THF is charged into a mixture of strong
base (aqueous potassium hydroxide) and BTEAC and a water miscible
solvent such as tetrahydrofuran at reduced temperature, about
0.degree. C. or thereabouts. The reaction is maintained at about
that temperature for the duration of the reaction, usually about 1
hour. The product can be isolated or used as a crude oil.
[0073] The dicarbonitrile is converted to the cyclohexanecarboxylic
acid using a Group I(a) or II(a) metal halide. This reaction is
carried out by charging a vessel with solvents; in this instance
exemplified by DMF, acetonitrile and water, and the Group I(a) or
II(a) metal halide (preferably about 1.5 equivalents), LiBr is
illustrated; sweeping the vessel with an inert gas; adding the
dicarbonitrile A or B, or a mixture of A and B; and heating the
vessel and its contents to about 100.degree. C. for a number of
hours, 8 hours being an example. The reaction is diluted with DMF
and optionally water. LiOH dissolved in water is added (about a 50%
molar excess is preferred). A suspension is formed. This is stirred
at a slightly elevated temperature(40 to 80.degree. C.) for about
an hour or so. The lithium salt is recovered by conventional
means.
[0074] The acid is prepared, for example, by suspending the lithium
salt in an organic solvent of the likes of ethyl acetate, and
treating the suspension with aqueous mineral acid. The organic
solvent is then recovered, washed, and concentrated. The product is
isolated by conventional means.
[0075] The following examples are provided to illustrate specific
embodiments of the invention, not to limit it. What is reserved to
the inventors is set forth in the claims appended hereto.
SPECIFIC EXAMPLES
Example 1
Preparation of 3-cyclopentyloxy-4-methoxybenzaldehyde
[0076] A mixture of cyclopentyl chloride (8.48 g, 0.08 moles),
isovanillin (6.12 g, 0.04 moles) and potassium carbonate (1.1 g,
0.08 moles) in dimethylformamide (4.04 g) was stirred in the
reactor (100 mL) at 120 to 125.degree. C. for 1.5 hours. A sample
was taken to verify the batch conversion. Result (GC): 0.5 area %
isovanillin (target: .ltoreq.1.0 area %). The mixture was cooled to
20.degree. C. and filtered to remove the solid (potassium
bicarbonate, potassium chloride). The wet cake was washed with
methanol.
Example 2
Preparation of 3-cyclopentyloxy-4-methoxybenzyl alcohol
[0077] The dimethylformamide liquors and methanol wash from Example
1 were combined and retransferred into the cleaned reactor. An
additional amount of methanol (8.52 g) was added and the batch was
cooled to 0.degree. C. Sodium borohydride (0.49 g, 0.0129 moles)
was added in small portions over 1 hour and 10 minutes maintaining
the temperature between 4 and 9.degree. C. The batch was stirred at
7.2 to 10.degree. C. for 30 minutes and then heated to 25.degree.
C. A sample was taken after 110 minutes stirring at 25 to
31.degree. C. and analysed (GC) and the reaction was deemed to be
complete. Acetic acid 50% (1.80 g) was charged to the reactor to
quench any remaining sodium borohydride. The batch temperature of
24 to 25.degree. C. was maintained during this charge. The
dimethylformamide and methanol were removed by distillation in
vacuo (end of distillation: 58.degree. C., 6 mbar). After cooling
to 20-25.degree. C. the mixture was partitioned between water (3.13
g) and toluene (28.07 g). The toluene phase (containing the
captioned compound) was washed with demineralised water (2.65
g).
Example 3
Preparation of 4-Chloromethyl-2-cyclopentyloxy-1-methoxybenzene
[0078] The toluene solution from Example 2 was cooled to 20.degree.
C. and concentrated hydrochloric acid (37.5%; 9.80 g) was added
keeping the temperature between 20 and 22.7.degree. C. A sample was
taken 40 minutes after the addition was complete and analysed (GC)
and the reaction was deemed to be complete. The phases were allowed
to separate and the lower, aqueous phase discarded. Sodium
bicarbonate (1.20 g) was charged to the reactor to neutralize the
remaining hydrochloric acid. After stirring for 15 minutes the
mixture was cooled to 23.degree. C. and filtered to remove the
solid (sodium bicarbonate, sodium chloride). A part of the toluene
(17.07 g) was removed by distillation in vacuo (end of
distillation: 28.degree. C., 7 mbar).
Example 4
Preparation of 4-Cyanomethyl-2-cyclopentyloxy-1-methoxybenzene
[0079] After cooling the solution from Example 3 to <25.degree.
C. tetra-butylammonium bromide (0.205 g, 0.63 mmoles),
demineralised water (2.775 g) and sodium cyanide (1.976 g, 0.039
moles) were added, the mixture was heated to 80.degree. C. and then
stirred at 78.1 to 80.4.degree. C. for 1 hour and 50 minutes. A
sample was taken to verify the batch conversion.
[0080] Toluene (5.841 g) and demineralised water (8.76 g) were
added, the phases were allowed to separate (at about 54.degree. C.)
and the lower, aqueous phase discarded. The toluene phase
(containing the product) was washed with demineralised water (13.32
g). The toluene was removed by distillation in vacuo (end of
distillation: 55.degree. C., 1 mbar).
Example 5
Preparation of
Dimethyl-4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)pimel-
ate
[0081] The cyanomethyl compound prepared in Example 4 (9.05 g at
85.4%; 7.73 g at 100%; 0.0334 moles) was charged in the reactor
(0.5 L) at room temperature. Acetonitrile (28.56 g) and
demineralised water (0.07 g) was charged to the reactor. Solutions
of methyl acrylate (6.88 g, 0.029 moles) in acetonitrile (4.02 g)
and methanolic Triton B (40.2% 0.94 g, 2.269 mmoles Triton B) in
acetonitrile (4.06 g) were prepared. A first portion, about 16.6%
of the methyl acrylate solution (1.81 g) was added at 20.degree. C.
A first portion, about 12.5% of the Triton B solution (0.63 kg) was
then added. The batch temperature after the addition was 31.degree.
C. A second portion, about 16.6% of the methyl acrylate solution
(1.82 g) was added at 28.degree. C. A second portion, about 12.5%
of the Triton B solution (0.63 g) was then added. The batch
temperature after the addition was 36.degree. C. A third portion,
about 16.6% of the methyl acrylate solution (1.81 g) was added at
35.degree. C. A third portion, about 12.5% of the Triton B solution
(0.62 g) was then added. The batch temperature after the addition
was 32.degree. C. A fourth portion, about 16.6% of the methyl
acrylate solution (1.81 g) was added at 32.degree. C. A fourth
portion, about 12.5% of the Triton B solution (0.63 g) was then
added. The batch temperature after the addition was 36.degree. C. A
fifth portion, about 33.2% of the methyl acrylate solution (3.64 g)
was added at 34.degree. C. A fifth portion, about 25% of the Triton
B solution (1.25 g) was then added. The batch temperature after the
addition was 38.degree. C. The last portion, about 25% of the
Triton B solution (1.25 g) was then added. The batch temperature
after the addition was 36.degree. C. The reaction mixture was
stirred for 1.5 hours at 20-25.degree. C. The acetonitrile was
removed by distillation in vacuo (end of distillation: 59.degree.
C., 20 mbar). The mixture was partitioned at about 50.degree. C.
between cyclohexane/toluene (1145.9/254.6 g) and water (559.8 g).
The cyclohexane/toluene phase (containing the product was washed
with demineralised water (559.8 g) at 50 to 52.degree. C. To
crystallize the captioned product, the batch was cooled over 50
minutes to 0.degree. C. The batch was then seeded with pimelate and
aged for 1 hour at -1 to 1.degree. C. The pimelate was filtered and
washed with cyclohexane/toluene (6.51 g/1.44 g) and recovered by
conventional means.
Example 6
Preparation of
4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-on- e
[0082] The pimelate made in Example 5 (76.52 g, 1,8112 moles) was
charged into the reactor (100 mL). Dioxane (2214 g) and a 29.1%
methanolic of sodium methoxide (0.44 g, 24 mmoles) were added. The
mixture was heated to reflux (77.degree. C.) and stirred at this
temperature for 1 hour. A sample was taken to verify the batch
conversion. The methanol was removed by distillation (16.82 g
distillate) to a bottom temperature of 97.degree. C. the loss of
dioxane during this distillation was compensated by adding of fresh
dioxane (121.6 g). Sodium bicarbonate (22.2 g, 26. mmoles) and
demineralised water (2.47 g) were added. The mixture was heated to
reflux (87.degree. C.) and stirred at about to 87.degree. C. for 10
hours. A sample was taken to verify the batch conversion. The
content of the reactor was cooled to 78.degree. C. Dioxane (0.13 g)
and demineralised water (0.12 g) were added to simulate a flush.
After cooling to <60.degree. C. concentrated hydrochloric acid
(37%, 0.265 g) was added to adjust the pH to 7.5. The dioxane,
methanol and a part of water (27.73 g distilled) were removed by
vacuum distillation (end of distillation: 66.degree. C., 305
mbar).
[0083] Under stirring, cyclohexane (180.0 g) and toluene (65.5 g)
were charged to the reactor. The mixture was heated to 70.degree.
C. and the phases were allowed to separate at 70.degree. C. and the
lower, aqueous phase was discarded. The organic phase, containing
the captioned ketone was washed in two portions with demineralised
water (169.4 g total) at about 70.degree. C. Cyclohexane (165.0 g)
was added to the reactor to simulate a flush. To crystallize the
product, the batch was cooled to 10.degree. C. over 1 hour. Then it
was aged for 6 hours at 9 to 11.degree. C. to complete the
crystallization. The product batch was filtered and washed with
cyclohexane/toluene (81.5 g/27.2 g).
Example 7
Preparation of
cis-6-[3-(cyclopentyloxy)-4-methoxyphenyl)]-1-oxaspiro[2.5]-
octane-2,6-dicarbonitrile
[0084] A 500 mL round bottom flask equipped with an overhead
stirrer, internal thermometer, and a nitrogen inlet was flushed
with nitrogen. The flask was charged with 50% potassium hydroxide
in water (22.0 g) and tetrahydrofuran (55.0 mL). While stirring at
room temperature, benzyltriethylammonium chloride (0.81 g, 35 mmol,
0.05 equivalent) was added. The solution was cooled to 0.degree. C.
To a pressure-equalizing addition funnel was charged a solution
containing tetrahydrofuran (55.0 mL),
4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (23.0
g, 73 mmol, 1.0 equivalent), and chloroacetonitrile (5.9 g, 78
mmol, 1.07 equivalent) at room temperature. While stirring the
flasks contents at 0.degree. C., the solution in the pressure
addition funnel was added over 15 minutes. The temperature was
maintained between 0 and 5.degree. C., and stirred for one hour.
The reaction was warmed to 25.degree. C., diluted with water (90.0
mL), and ethyl acetate (90.0 mL). The solution was stirred and
allowed to settle for 30 minutes. The layers were separated, the
organic layer was isolated, and concentrated by vacuum distillation
to a residue. Methylcyclohexane/THF (5:1) (54.0 mL) was added and
the solution was heated to 60.degree. C. then cooled to 20.degree.
C. over 90 minutes; the product began to crystallize at about
40.degree. C. The suspension was then cooled to 0.degree. C. and
held at -0 to 5.degree. C. for two hours. The product was filtered
and washed with a methanol mixture (46.0 mL) at 0.degree. C. The
product was dried to afford the captioned product as a white
crystalline solid.
Example 8
Preparation of
cis-Lithium-4-cyano-4-(3-cyclopentloxy-4-methoxyphenyl)-r-1-
-cyclohexanecarboxylate, 2
[0085] 5
[0086] To a 1.0 L, 3-neck round bottom flask equipped with an
overhead stirrer, internal thermometer and a reflux condenser
connect to a caustic scrubber was charged dimethylformamide (200
mL), acetonitrile (200 mL), lithium bromide (32.4 g, 0.37 mol) and
water (5.6 g, 0.31 mol). The suspension was stirred until a
solution was evident, followed by the addition of
cis-6-[3-(cyclopentyloxy)-4-methoxyphenyl)]-1-oxaspiro[2.5]oc-
tane-2,6-dicarbonitrile1, (90.0 g, 0.25 mol). The contents of the
flask were heated between 90 and 95.degree. C. for 8 to 12 hours.
The reaction was cooled to 60.degree. C. and diluted with
dimethylformamide (270 mL). To the amber solution (60.degree. C.)
was quickly added an aqueous solution of lithium hydroxide (21.65
g, 0.51 mol of lithium hydroxide monohydrate dissolved in 112.5 mL
of water). The suspension was stirred at 60.degree. C. for 1 hour,
cooled to 5.degree. C., and held at 5.degree. C. for 1 hour. The
suspension was filtered, washed with ethyl acetate (100 mL) and air
dried to provide 2 in 79.5% corr yield.
Example 9
Preparation of
cis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-1-cycloh-
exanecarboxylate, 3
[0087] 6
[0088] To a 1.0 L, 3-neck round bottom flask equipped with an
overhead stirrer and an internal thermometer was added
cis-lithium-4-cyano-4-(3-cy-
clopentyloxy-4-methoxyphenyl)-r-1-cyclohexanecarboxylate, 2 (58.5
g, 0.167 mol) and ethyl acetate (500 mL). The light suspension was
stirred at ambient temperature followed by the addition of 3N
aqueous HCl (70 mL, 0.21 mol). The reaction was stirred for ten
minutes and transferred to a separatory funnel. The organic layer
was isolated and washed once with water (100 mL). The organic layer
was isolated and filtered into a clean 1.0 L, 3-neck round bottom
flask equipped with a distillation head and an overhead stirrer.
The reaction was concentrated by distilling off ethyl acetate (200
mL). The contents of the flask were cooled to 60.degree. C.
followed by the addition of heptane (275 mL). The suspension was
cooled to 5.degree. C., held at 5.degree. C. for 2 hours, filtered,
and washed with cold (5.degree. C.) heptane (50 mL). The product
was dried in a vacuum oven to constant weight to afford 50.0 g
(85%) of 3.
* * * * *