U.S. patent application number 09/784535 was filed with the patent office on 2001-09-13 for process for preparing 4-(4'-carboxyphenyl)pyridine.
This patent application is currently assigned to Clariant GmbH. Invention is credited to Demmer, Gerhard, Koch, Peter, Meudt, Andreas, Scherer, Stefan, Vollmuller, Frank.
Application Number | 20010021778 09/784535 |
Document ID | / |
Family ID | 7630919 |
Filed Date | 2001-09-13 |
United States Patent
Application |
20010021778 |
Kind Code |
A1 |
Meudt, Andreas ; et
al. |
September 13, 2001 |
Process for preparing 4-(4'-carboxyphenyl)pyridine
Abstract
The invention relates to a process for preparing
4-(4'-carboxyphenyl)pyrid- ine, which comprises oxidizing a
4-phenyl-N-acyldihydropyridine of the formula (II) 1 where R.sup.1
is a bulky alkyl, alkylaryl, arylalkyl or alkoxy group and R.sup.2
is a straight-chain or branched, substituted or unsubstituted alkyl
radical having from 1 to 8 carbon atoms, by means of an oxidizing
agent selected from the group consisting of permanganates, nitric
acid, Cr(VI) compounds, oxygen and air to give the compound of the
formula (I) 2 where M is a cation.
Inventors: |
Meudt, Andreas;
(Florsheim-Weilbach, DE) ; Scherer, Stefan;
(Buttelborn, DE) ; Koch, Peter; (Frankfurt am
Main, DE) ; Demmer, Gerhard; (Kelkheim, DE) ;
Vollmuller, Frank; (Frankfurt am Main, DE) |
Correspondence
Address: |
CLARIANT CORPORATION
4331 CHESAPEAKE DR
ATTN: INDUSTRIAL PROPERTY DEPT
CHARLOTTE
NC
28216
US
|
Assignee: |
Clariant GmbH
|
Family ID: |
7630919 |
Appl. No.: |
09/784535 |
Filed: |
February 15, 2001 |
Current U.S.
Class: |
546/342 |
Current CPC
Class: |
C07D 213/55 20130101;
C07D 211/82 20130101 |
Class at
Publication: |
546/342 |
International
Class: |
C07D 211/70; C07D
211/82; C07D 213/55 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 15, 2000 |
DE |
10006601.1 |
Claims
1. A process for preparing 4-(4'-carboxyphenyl)pyridine, which
comprises oxidizing a 4-phenyl-N-acyldihydropyridine of the formula
(II) 8where R.sup.1 is a bulky alkyl, alkylaryl, arylalkyl or
alkoxy group and R.sup.2 is a straight-chain or branched,
substituted or unsubstituted alkyl radical having from 1 to 8
carbon atoms, by means of an oxidizing agent selected from the
group consisting of permanganates, nitric acid, Cr(VI) compounds,
oxygen and air to give the compound of the formula (I) 9where M is
a cation.
2. The process as claimed in claim 1, wherein R.sup.1 is
tert-butyl, isopropyl, (dimethyl)phenylmethyl,
methyl(diphenyl)methyl, trityl, diphenylmethyl, triethylmethyl,
tert-butoxy or isopropoxy.
3. The process as claimed in claim 1, wherein R.sup.2 is methyl,
ethyl, n-propyl, i-propyl, n-butyl, methoxymethyl or
hydroxymethyl.
4. The process as claimed in claim 1, wherein the oxidizing agent
is potassium permanganate, sodium permanganate, nitric acid, an
alkali metal chromate, an alkali metal dichromate, O.sub.2 or
air.
5. The process as claimed in claim 1, wherein the oxidation is
carried out using permanganates in the presence of phase transfer
catalysts, preferably tetraalkylammonium salts,
tetraphenylphosphonium salts or crown ethers.
6. The process as claimed in claim 1, wherein the oxidation is
carried out using air in the presence of heavy metal salts.
7. The process as claimed in claim 6, wherein a mixture of cobalt
bromide and manganese bromide is used as heavy metal salt.
8. The process as claimed in claim 1, wherein the compound of the
formula (II) is prepared by acylating pyridine by means of a
compound of the formula (IV) to give a compound of the formula
(VI), or using a compound of the formula (VI), and coupling the
compound of the formula (VI) with a Grignard compound of the
formula (V) in the presence of from 0.01 to 10 mol %, preferably
from 0.1 to 5 mol %, based on the Grignard compound, of a Cu
compound and in the presence of a Pd or Ni cocatalyst, 10where X is
Cl or Br.
9. The process as claimed in claim 8, wherein the cocatalyst is a
salt, a complex or a metallic form of palladium or nickel.
10. The process as claimed in claim 8, wherein the cocatalyst is
used in an amount of from 10-5 to 10 mol %, preferably from
10.sup.-4 to 7.5 mol %, based on the Grignard compound of the
formula (V).
11. The process as claimed in claim 8, wherein the coupling is
carried out at a temperature of from -70 to +60.degree. C.,
preferably from -50 to +50.degree. C.
12. The process as claimed in claim 8, wherein the Cu compound is
Cul, CuBr, CuCl or CUCl.sub.2.
Description
FIELD OF THE INVENTION
[0001] The invention relates to a novel process for preparing
4-(4'-carboxyphenyl)-pyridine of the formula (I). 3
BACKGROUND OF THE INVENTION
[0002] 4-(4'-Carboxyphenyl)pyridine of the formula (I) and the
corresponding esters and acid chlorides are important intermediates
in the synthesis of active compounds for the pharmaceutical and
agrochemical industries.
[0003] Possible synthetic routes to compounds of the formula (I)
are the Suzuki coupling of 4-halopyridines with suitable
organometallic reagents, for example 4-carboxyphenylboronic acid or
4-carboxyphenylboronic esters. However, such pyridines, for
example, 4-bromopyridine or 4-chloropyridine, are firstly very
expensive and difficult-to-obtain raw materials which are also
unstable in pure form and can be used only in the form of
derivatives, for example as hydrochloride. Secondly, they are very
corrosive and place high demands on the materials of construction
used.
[0004] It is an object of the present invention to develop a
process for preparing 4-(4'-carboxyphenyl)pyridine of the formula
(I) which makes it possible to obtain the target compound in very
few, technically simple steps starting from readily available and
inexpensive raw materials. Furthermore, the process to be developed
has to give the target product in a good total yield and in a
purity sufficient for pharmaceutical applications.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0005] It has surprisingly been found that the compound of the
formula (I) can be prepared in good total yields and in good purity
in few steps starting from pyridine. The individual steps can each
be carried out in a technically simple manner and use only
commercially available and inexpensive reagents, solvents and
catalysts.
[0006] The present invention provides a process for preparing
4-(4'-carboxyphenyl)pyridine, which comprises oxidizing a
4-phenyl-N-acyldihydropyridine of the formula (II) 4
[0007] where
[0008] R.sup.1 is a bulky alkyl, alkylaryl, arylalkyl or alkoxy
group and
[0009] R.sup.2 is a straight-chain or branched, substituted or
unsubstituted alkyl radical having from 1 to 8 carbon atoms,
[0010] by means of an oxidizing agent selected from the group
consisting of permanganates, nitric acid, Cr(VI) compounds, oxygen
and air to give the compound of the formula (I) 5
[0011] where M is a cation, preferably hydrogen, ammonium or an
alkali metal cation.
[0012] Preferred radicals R.sup.1 are tert-butyl, isopropyl,
(dimethyl)phenylmethyl, methyl(diphenyl)methyl, trityl,
diphenylmethyl, triethylmethyl, tert-butoxy and isopropoxy.
[0013] Preferred radicals R.sup.2 are straight-chain or branched
alkyl radicals which have from 1 to 4 carbon atoms and may be
unsubstituted or substituted by one or more hydroxy or
C.sub.1-C.sub.4-alkoxy radicals; particular preference is given to
methyl, ethyl, n-propyl, i-propyl, n-butyl, methoxymethyl and
hydroxymethyl, most preferably methyl.
[0014] The preparation of dihydropyridines of the formula (II) from
pyridine by addition of organometallic compounds, for example
Grignard compounds, cannot be carried out directly; prior
activation of the pyridine ring is necessary. This can be achieved,
for example, by N-acylation (Scheme 1). The N-acylpyridinium salts
which can be obtained in this way do react with Grignard compounds,
but the reaction gives mixtures of 2- and 4-aryldihydropyridines
which are difficult to separate. According to Akiba et al.,
Tetrahedron Lett. 23, 4, 429-432, 1982, a high selectivity to the
4-aryldihydropyridines can be achieved by using bulky radicals on
the pyridine nitrogen and using equimolar amounts of organocopper
compounds. However, for a number of reasons, the preparation and
handling of organocopper compounds is problematical for industrial
processes. 6
[0015] X can be Cl or Br.
[0016] The problem is solved more elegantly by Comins et al., J.
Org. Chem. 1982, 47, 4315-4319. The authors react Grignard
compounds with pyridine and pivaloyl chloride in the presence of
catalytic amounts of CuI and obtain yields of somewhat above 60% in
this way. The amounts of Cu required do not stand in the way of
industrial utilization. However, such a low yield combined with the
disposal problems associated with the sometimes problematical
by-products resulting from the starting materials not converted
into product makes the viability of the overall process
questionable.
[0017] It has surprisingly been found that the addition of
palladium or nickel salts or complexes or of metallic Pd or Ni as
cocatalysts leads to a significant increase in yield in the
preparation of a dihydropyridine of the formula (II). Yields of
usually above 90%, based on the organometallic reagent used, are
then achieved.
[0018] In a preferred embodiment of the process of the invention,
the compound of the formula (II) is therefore prepared by acylating
pyridine by means of a compound of the formula (IV) to give a
compound of the formula (VI), or using a compound of the formula
(VI), and coupling the compound of the formula (VI) with a Grignard
compound of the formula (V) in the presence of from 0.01 to 10 mol
%, preferably from 0.1 to 5 mol %, based on the Grignard compound,
of a Cu compound, and in the presence of a Pd or Ni cocatalyst,
7
[0019] where X is Cl or Br.
[0020] Suitable solvents for the coupling of the compound of the
formula (IV) with (V) are, for example, aliphatic or aromatic
ethers or hydrocarbons, preferably THF or THF/toluene mixtures. The
coupling can be carried out at temperatures in the range from
-80.degree. C. to the boiling point of the solvent used. However,
the proportion of the 2-substitution product increases at the
expense of the desired 4-substitution product at high temperatures,
so that temperatures of from -70 to +60.degree. C. are preferred.
Particular preference is given to temperatures of from -50 to
+50.degree. C., particularly preferably from -35 to +40.degree. C.
Suitable Cu compounds are Cu(I) and Cu(II) compounds, preferably
CuI, CuBr, CuCl or CUCl.sub.2.
[0021] Suitable cocatalysts for the coupling reactions are salts,
complexes or the metallic form of nickel or palladium. The amounts
employed can be from 10.sup.-5 to 10 mol %, preferably from
10.sup.-4 to 7.5 mol %, in particular from 10-3 to 5 mol %, based
on the Grignard compound.
[0022] Particular preference is given to salts or complexes of
nickel or palladium and also metallic forms, if desired on a
suitable support, e.g. Pd on C or on BaSO.sub.4, very particularly
preferably PdCl.sub.2(dppf), PdCl.sub.2(PPh.sub.3).sub.2,
PdCl.sub.2(dppe), PdCl.sub.2(dppp), PdCl.sub.2(dppb),
Pd(PPh.sub.3).sub.4, Pd(OAc).sub.2, PdCl.sub.2, PdBr.sub.2 or
NiCl.sub.2(PPh.sub.3).sub.2, where "dppf" is
1,2-bis(diphenylphosphino)ferrocene, "dppe" is
1,2-bis(diphenylphosphino)- ethane, "dppp" is
1,2-bis(diphenylphosphino)propane, "dppb" is
1,2-bis(diphenylphosphino)butane, "Ph" is phenyl and "Ac" is
acetyl.
[0023] The conversion of the dihydropyridine of the formula (II)
into 4-(4'-carboxyphenyl)-pyridine of the formula (I) is achieved
according to the invention by oxidation using an oxidizing agent
selected from the group consisting of permanganates, e.g. sodium or
potassium permanganate, nitric acid, chromium(VI) reagents, e.g.
alkali metal chromates or alkali metal dichromates, oxygen and air,
particularly preferably by air oxidation.
[0024] According to Comins et al., it is possible to convert
N-acylated 4-aryldihydropyridines into the corresponding
4-arylpyridines by heating with elemental sulfur.
[0025] However, large amounts of hydrogen sulfide and other sulfur
compounds are formed in the treatment with sulfur and, furthermore,
high temperatures are required, resulting in a very impure, black
product. This is very cumbersome to purify to the extent required
for further oxidation.
[0026] It has surprisingly been found that the dihydropyridine of
the formula (II) can be oxidized in a single step to give a very
pure product of the formula (I). Despite the successive oxidations
of the N-acyl group, of the dihydropyridine to give the pyridine
and of the aromatic alkyl group to give the acid group, good yields
of a pure product are obtained.
[0027] The oxidation can be carried out by means of permanganates,
nitric acid, air, O.sub.2, or chromium(VI) reagents; however,
oxidation by means of air has been found to be particularly
advantageous. Almost quantitative yields and a high purity are
obtained in this way. Small amounts of the only detectable
impurity, namely terephthalic acid, can be easily and
quantitatively removed by washing with dilute alkalis.
[0028] The oxidation by means of permanganate can be carried out
either in aqueous solution or in a nonaqueous medium, preferably at
temperatures of from 0 to 100.degree. C., in particular from 10 to
80.degree. C. In aqueous solution, the presence of suitable phase
transfer catalysts, for example tetraalkylammonium salts,
tetraphenylphosphonium salts or crown ethers, is necessary to
achieve good yields. The work-up is carried out by filtering off
the manganese dioxide formed, acidifying the filtrate and filtering
off the pyridylbenzoic acid which precipitates.
[0029] The oxidation using air or oxygen is carried out in
aliphatic carboxylic acids, if desired in admixture with water.
Preference is given to using acetic acid, particularly preferably a
mixture of acetic acid and water. Heavy metal salts, e.g. mixtures
of cobalt bromide and manganese bromide, are employed as catalysts.
The heavy metal salts are used in amounts of from 0.01 to 5.0 mol %
each, preferably from 0.1 to 4.0 mol % each, particularly
preferably from 1.0 to 2.0 mol % each, based on the dihydropyridine
(II). The ratio of cobalt to manganese can be varied within wide
limits and can be, for example, from 1:5 to 5:1. The two salts are
preferably used in equimolar amounts. The reaction is carried out
at temperatures of from 100 to 200.degree. C., preferably from 120
to 180.degree. C. and particularly preferably from 150 to
170.degree. C. The pressure is in the range from atmospheric
pressure to 50 bar. The work-up is carried out by cooling and, if
appropriate, concentrating the reaction mixture by evaporation,
then filtering off, washing and drying the resulting precipitated
carboxylic acid.
EXAMPLES
Preparation of 4-p-tolyl-N-pivaloyldihydropyridine
Example 1
[0030] 1.0 mol of p-tolylmagnesium chloride (25% strength by weight
solution in THF) are added dropwise at -15.degree. C. to a solution
of 121 ml of pyridine (1.5 mol), 3.8 g of CuI (0.02 mol) and 9 mg
of PdCl.sub.2(dppf) in 200 ml of tetrahydrofuran. Subsequently, at
the same temperature, 123 ml of pivaloyl chloride (1.0 mol) are
added dropwise over a period of 15 minutes. The reaction is
strongly exothermic, so that good cooling is necessary. After
stirring for another 15 minutes at -15.degree. C., the cold bath is
removed and the reaction mixture is stirred overnight at room
temperature. After hydrolysis with 500 ml of 20% strength by weight
aqueous ammonium chloride solution, extraction of the aqueous phase
with toluene, drying over magnesium sulfate and distilling off the
major part of the solvent, the dihydropyridine crystallizes as a
colorless solid and can be obtained in very pure form by
filtration. The yield of dihydropyridine is 364.7 g (1.43 mol,
95%).
Example 2
[0031] 1.0 mol of p-tolylmagnesium chloride (25% strength by weight
solution in THF) are added dropwise at -15.degree. C. to a solution
of 121 ml of pyridine (1.5 mol), 1.5 g of CuI (0.0079 mol) and 0.9
mg of PdCl.sub.2(dppf) in 200 ml of tetrahydrofuran. Subsequently,
at the same temperature, 123 ml of pivaloyl chloride (1.0 mol) are
added dropwise over a period of 15 minutes. The work-up described
in Example 1 gives 85% of the dihydropyridine.
Example 3
(Comparative example from D. L. Comins et al., J. Org. Chem. 1982,
47, 4315-4319)
[0032] 952 mg of CuI are added at room temperature to a solution of
12.1 ml of pyridine in 200 ml of tetrahydrofuran and the mixture is
stirred until a homogeneous solution has been formed. After cooling
to -20.degree. C., a solution of 0.1 mol of phenylmagnesium
chloride in 50 ml of THF is added. 12.3 ml of pivaloyl chloride in
10 ml of THF are added dropwise over a period of 5 minutes. After
stirring further for 15 minutes at -15.degree. C. and another 15
minutes at room temperature, the mixture is hydrolyzed with 75 ml
of 20% strength by weight ammonium chloride solution, admixed with
200 ml of ether, and the organic phase is washed in succession with
50 ml of NH.sub.4Cl/NH.sub.40H 50:50, 50 ml of water, 50 ml of 10%
strength HCl, 50 ml of water and 50 ml of saturated sodium chloride
solution. After drying over MgSO.sub.4, the solvents are distilled
off in a gentle vacuum. The product remains as a yellow solid in a
yield of 63%.
Example 4
Oxidation of the dihydropyridine using potassium permanganate
[0033] 1.0 g of anhydrous sodium carbonate, 0.05 g of
benzyltributylammonium chloride and 0.8 g of
4-p-tolyl-N-pivaloyldihydrop- yridine are added at room temperature
to 75 ml of a 2% strength by weight aqueous potassium permanganate
solution. After stirring at 100.degree. C. for 1.5 hours, excess
permanganate is reduced by means of sodium dithionite, the
precipitated manganese dioxide is filtered off, the filtrate is
acidified and the precipitated product is filtered off to give
4-(4'-carboxyphenyl)-pyridine in a yield of 81%.
Example 5
Oxidation of dihydropyridine using air
[0034] 177.2 g (0.75 mol) of 4-p-tolyl-N-pivaloyldihydropyridine,
1511.2 g of acetic acid, 3.74 g (15.0 mmol) of cobalt(II) acetate
tetrahydrate, 3.68 g (15.0 mmol) of manganese(II) acetate
tetrahydrate and 3.09 g (30.0 mmol) of sodium bromide are placed in
a 3.5 l autoclave. The autoclave is made inert using nitrogen and
is heated to 160-165.degree. C. When this temperature has been
reached, about 450 l/h of air are introduced and an internal
pressure of 16-18 bar is maintained by means of a pressure
maintenance device. Air is introduced for about 30-40 minutes, the
autoclave is then once again made inert by injection of nitrogen
and the mixture is cooled. The greenish solution (becomes
orange-red on cooling) is taken from the autoclave and evaporated
to a weight of 370 g on a rotary evaporator. The thick suspension
is filtered on a suction filter and the crystals are washed 3 times
with 50 g each time of 75% strength by weight acetic acid. The
crude product obtained in this way is taken up in 75 ml of 0.4%
strength by weight sodium bicarbonate solution, stirred for 30
minutes at about 50.degree. C. and filtered off. Drying leaves
4-(4'-carboxyphenyl)pyridine in a yield of 90%. HPLC purity:
>98% (a/a).
* * * * *