U.S. patent application number 09/897566 was filed with the patent office on 2002-01-24 for process for preparing highly pure formylphenyboronic acids.
This patent application is currently assigned to Clariant GmbH. Invention is credited to Meudt, Andreas, Scherer, Stefan, Vollmuller, Frank.
Application Number | 20020010332 09/897566 |
Document ID | / |
Family ID | 7647428 |
Filed Date | 2002-01-24 |
United States Patent
Application |
20020010332 |
Kind Code |
A1 |
Vollmuller, Frank ; et
al. |
January 24, 2002 |
Process for preparing highly pure formylphenyboronic acids
Abstract
A process for purifying formylphenylboronic acids of the formula
(I) 1 where the formyl function is located in the ortho, meta or
para position relative to the boronic acid function, by dissolving
the crude formylphenylboronic acids in an alkaline solvent having a
pH in the range from 8 to 11 separating off the insoluble organic
impurities and subsequently acidifying the alkaline boronic acid
solution and separating off and working up the precipitated boronic
acid. The crude formylphenylboronic acid is preferably dissolved in
aqueous alkali metal or alkaline earth metal oxide, hydroxide,
carbonate or phosphate solutions at temperatures in the range from
5 to 50.degree. C. The formylphenylboronic acids obtained have a
purity of .gtoreq.99% and are suitable as precursors for
liquid-crystalline compounds, as liquid crystals or as constituents
of liquid-crystalline mixtures or as pharmaceutical
intermediates.
Inventors: |
Vollmuller, Frank;
(Frankfurt am Main, DE) ; Meudt, Andreas;
(Florsheim-Weilbach, DE) ; Scherer, Stefan;
(Buttelborn, DE) |
Correspondence
Address: |
Clariant Corporation
Industrial Property Department
4331 Chesapeake Drive
Charlotte
NC
28216
US
|
Assignee: |
Clariant GmbH
|
Family ID: |
7647428 |
Appl. No.: |
09/897566 |
Filed: |
July 2, 2001 |
Current U.S.
Class: |
544/229 ;
556/402; 562/7 |
Current CPC
Class: |
C07F 5/025 20130101 |
Class at
Publication: |
544/229 ; 562/7;
556/402 |
International
Class: |
C07F 005/04; C07F
007/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 1, 2000 |
DE |
100 32 017.1 |
Claims
1. A process for purifying formylphenylboronic acids of the formula
(I) 4where the formyl function is located in the ortho, meta or
para position relative to the boronic acid function and R.sup.1 to
R.sup.4 are each, independently of one another, hydrogen,
C.sub.1-C.sub.12-alkyl, C.sub.2-C.sub.12-alkenyl,
C.sub.2-C.sub.12-alkynyl, C.sub.3-C.sub.12-cycloalkyl,
C.sub.1-C.sub.12-alkoxy, O-phenyl, O-benzyl, aryl, heteroaryl,
fluorine, N(alkyl).sub.2, N[Si(C.sub.1-C.sub.4-alkyl).s-
ub.3].sub.2 or CF.sub.3, or R.sup.1 and R.sup.2, and/or R.sup.3 and
R.sup.4, together form an aliphatic or aromatic ring, by dissolving
the crude formylphenylboronic acids in an alkaline solvent having a
pH in the range from 8 to 11, separating off the insoluble organic
impurities and subsequently acidifying the alkaline boronic acid
solution and separating off and working up the precipitated boronic
acid.
2. The process as claimed in claim 1, wherein the crude
formylphenylboronic acid is dissolved in aqueous alkali metal or
alkaline earth metal oxide, hydroxide, carbonate or phosphate
solutions.
3. The process as claimed in claim 1, wherein the purification is
carried out temperatures in the range from 5 to 50.degree. C.
4. The process as claimed in claim 1, wherein the organic
impurities are removed by adsorption on activated carbon or
extraction with inert, water-immiscible solvents.
5. The process as claimed in claim 1, wherein the
formylphenylboronic acid obtained has a purity of .gtoreq.99%.
6. A formylphenylboronic acid of the the formula (I) having a
purity of .gtoreq.99%, obtainable by a process as claimed in claim
1.
7. The use of a formylphenylboronic acid as claimed in claim 6 as
precursor for liquid-crystalline compounds, as liquid crystals or
as a constituent of liquid-crystalline mixtures or as a
pharmaceutical intermediate.
8. The process as claimed in claim 2, wherein the purification is
carried out temperatures in the range from 5 to 50.degree. C.
9. The process as claimed in claim 2, wherein the organic
impurities are removed by adsorption on activated carbon or
extraction with inert, water-immiscible solvents.
10. The process as claimed in claim 2, wherein the
formylphenylboronic acid obtained has a purity of .gtoreq.99%.
11. A formylphenylboronic acid of the the formula (I) having a
purity of .gtoreq.99%, obtainable by a process as claimed in claim
2.
Description
BACKGROUND OF THE INVENTION
[0001] Formylphenylboronic acid and its substituted derivatives are
customarily synthesized from the corresponding haloaromatic either
as described in Liebigs Ann. 1995,1253-1257 and Chem. Ber. 123
(1990) 1841-1843 in a yield of 94% or 78% by reaction of the
corresponding protective bromoaromatic with magnesium in a Grignard
reaction and subsequent addition of trialkyl borate or as described
in Tetrahedron Lett 1998, 39, 7537-7540, in a yield of 99% by
reaction of the corresponding protected bromoaromatic with
butyllithium at -78.degree. C. and subsequent reaction with
triisopropyl borate to form the corresponding formylphenylboronic
acid.
[0002] However, for the industrial preparation it is
disadvantageous that a high purity can be achieved only at very low
(-78.degree. C.) and thus uneconomical temperatures and with the
use of expensive organolithium compounds.
[0003] Higher temperatures both in the preparation of the
organometallic compound (reflux temperature of THF in the Grignard
step) and also temperatures of >-40.degree. C. in the addition
of the trialkylboric ester onto the organometallic compound
frequently result in a product of unsatisfactory purity. The most
frequent organic impurities are the corresponding triarylboranes
and borinic acids or benzaldehyde and the correspondingly
substituted hydroxybenzaldehydes and bisformylbiphenyls which can
be formed during the Grignard reaction. 2
[0004] The impurities interfere when the product is used as
precursor for liquid-crystalline compounds, as liquid crystals or
as constituent of liquid-crystalline mixtures, in particular when
the product is used as pharmaceutical intermediate or generally in
applications which require very high purity.
[0005] Boronic acids are usually isolated from the reaction mixture
by hydrolyzing the suspension from the borate addition and, after
phase separation, distilling tetrahydrofuran (THF) from the
homogeneous organic phase. During the distillation, the boronic
acid precipitates from the solution and can be separated off by
filtration.
[0006] The organic impurities can be separated off only
incompletely, if at all, by this method.
[0007] It is possible to remove the above-described impurities by
means of multiple extraction with toluene and to recrystallize the
boronic acid as described in Chem. Ber. 123 (1990) 1841-1843, with
great losses of yield from water or from hydrochloric acid
(Synthesis 1999, 2041-2044).
[0008] Furthermore, Liebigs Ann. 1995,1253-1257, describes the
purification of 4-formylphenylboronic acid by dissolution in
aqueous potassium hydroxide at pH 14, extraction of the aqueous
solution with methyl t-butyl ether (MTBE) and subsequent
precipitation of the boronic acid by means of sulfuric acid.
Contamination visible in the NMR of 5-7% is described in the
publication. Our own experiments on this showed that, for example,
4-formylphenylboronic acid reacts to a considerable extent in a
Cannizzaro reaction in aqueous alkaline medium above a pH of
>11. The 4-carboxyphenylboronic acid and
4-(hydroxymethyl)-phenylboronic acid formed can be separated from
the mixture only with great difficulty.
SUMMARY OF THE INVENTION
[0009] It is an object of the invention to provide a process for
purifying formylphenylboronic acid and its derivatives which allows
the formylphenylboronic acid to be prepared in high purity and does
not have the disadvantages described.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0010] According to the present invention, this object is achieved
by a process for purifying formylphenylboronic acids of the formula
(I) 3
[0011] where the formyl function is located in the ortho, meta or
para position, preferably in the para position, relative to the
boronic acid function and R.sup.1 to R.sup.4 are each,
independently of one another, hydrogen, C.sub.1-C.sub.12-alkyl,
C.sub.2-C.sub.12-alkenyl, C.sub.2-C.sub.12-alkynyl,
C.sub.3-C.sub.12-cycloalkyl, C.sub.1-C.sub.12-alkoxy, O-phenyl,
O-benzyl, aryl, heteroaryl, fluorine, N(alkyl).sub.2,
N[Si(C.sub.1-C.sub.4-alkyl).sub.3].sub.2 or CF.sub.3, or R.sup.1
and R.sup.2, and/or R.sup.3 and R.sup.4, together form an aliphatic
or aromatic ring, by dissolving the crude formylphenylboronic acids
in an alkaline solvent having a pH in the range from 8 to 11,
preferably a pH in the range from 9 to 11, separating off the
insoluble organic impurities and subsequently acidifying the
alkaline boronic acid solution and separating off and working up
the precipitated boronic acid.
[0012] In formula (I), it is preferred that R.sup.1 to R.sup.4 are
each hydrogen, C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl,
C.sub.1-C.sub.4-alkoxy, O-phenyl, O-benzyl, aryl, heteroaryl,
fluorine, N(C.sub.1-C.sub.4-alkyl).sub.2, or CF.sub.3, or R.sup.1
and R.sup.2, and/or R.sup.3 and R.sup.4, together form a saturated
or unsaturated ring having not more than five or six ring
atoms.
[0013] Particularly preferably, R.sup.1 to R.sup.4 are each
hydrogen, C.sub.1-C.sub.4-alkyl, C.sub.2-C.sub.4-alkenyl,
C.sub.1-C.sub.4-alkoxy, aryl, fluorine,
N(C.sub.1-C.sub.4-alkyl).sub.2 or CF.sub.3, or R.sup.1 and R.sup.2,
and/or R.sup.3 and R.sup.4, together form a fused-on cyclohexyl
structure, cyclopentyl structure or together with the aromatic ring
a naphthyl structure.
[0014] In the present process, the isolated crude
formylphenylboronic acids are dissolved in an alkaline solvent such
as aqueous solutions of alkali metal or alkaline earth metal
oxides, hydroxides, carbonates or phosphates. Preference is given
to using sodium hydroxide and potassium hydroxide solutions.
[0015] In the dissolution, it has to be ensured that the pH is in a
range from 8 to 11, preferably from 9 to 11, particularly
preferably from 9.5 to 10.5. At pH values of >11, Cannizzaro
products are formed, as described above.
[0016] The organic impurities which are insoluble in the aqueous
solutions used can subsequently be removed by adsorption on
activated carbon or extraction with inert, water-immiscible organic
solvents, for example aliphatic hydrocarbons such as various
heptanes, octanes, cyclic aliphatic hydrocarbons such as
cyclohexane, methylcyclohexane, aromatic hydrocarbons such as
toluene, o-, m-, p-xylenes, chlorobenzene, o-, m-,
p-dichlorobenzene or ethers such as diethyl ether, diisopropyl
ether, dibutyl ether, methyl tert-butyl ether or methyl ethyl
ketone or methyl isobutyl ketone, to name only a few.
[0017] Preference is given to using toluene, xylene or xylene
derivatives, methyl tert-butyl ether.
[0018] After the impurities have been separated off, the boronic
acid is precipitated again in highly pure form by acidification of
the alkaline boronic acid solution. As inorganic mineral acids,
preference is given to using sulfuric acid, hydrochloric acid,
nitric acid or phosphoric acid. Organic acids which can be used
are, for example, formic acid or acetic acid.
[0019] Preference is given to using hydrochloric acid or sulfuric
acid for acidification. Filtration, washing and drying gives the
highly pure arylboronic acid.
[0020] The purification, i.e. the alkaline dissolution procedure,
is carried out at temperatures of from 5 to 50.degree. C.,
preferably from 5 to 25.degree. C., particularly preferably from 5
to 10.degree. C. Purification at higher temperatures leads to
decomposition products of the formyl function, e.g. in the form of
a Cannizzaro reaction to give the corresponding carboxy and
hydroxymethyl function. To avoid decomposition of the
formylphenylboronic acids, they are thus, according to the
invention, dissolved at a pH in the range from 8 to 11. This can be
achieved, for example, by suspending the crude boronic acid in
water and subsequently adjusting the pH of the solution to a value
in the range from 8 to 11 by means of an aqueous base solution or
the base itself.
[0021] The process of the invention makes it possible to prepare
arylboronic acids having a purity of .gtoreq.99%, in particular
.gtoreq.99.5%, in a suitable and economical manner. The arylboronic
acids obtained in this way are very useful as precursors for
liquid-crystalline compounds, as constituents of liquid-crystalline
mixtures or as pharmaceutical intermediates.
EXAMPLES
Example 1: 4-Formylphenylboronic Acid
[0022] 385 g of crude 4-formylphenylboronic acid (purity according
to HPLC: 95%) are suspended in 2 l of water and cooled to
10.degree. C. 1025 ml of 10% strength aqueous sodium hydroxide are
added dropwise over a period of 3.5 hours at such a rate that the
internal temperature does not exceed 10.degree. C. and the pH does
not exceed 10.5. After the mixture has been stirred for another 30
minutes, the precipitate is filtered off, the aqueous phase is then
extracted twice with 250 ml each time of toluene. The boronic acid
is subsequently precipitated again at an internal temperature of
10.degree. C by means of 230 ml of concentrated hydrochloric acid.
The precipitate is filtered off, washed with water and dried at
50.degree. C. in a stream of nitrogen. This gives 345 g of
4-formylphenylboronic acid (94% of theory) as a pale yellow solid
having a purity of 99.6% (HPLC).
Example 2: 4-Formylphenylboronic Acid
[0023] The procedure of Example 1 is repeated using adsorption on
25 g of activated carbon, giving 4-formylphenylboronic acid having
a purity of 99.4%.
Example 3: 3-Formylphenylboronic Acid
[0024] 250 g of crude 3-formylphenylboronic acid (purity according
to HPLC: 96%) are suspended in 1300 ml of water and cooled to
10.degree. C. 670 ml of 10% strength aqueous sodium hydroxide are
added dropwise over a period of 2.5 hours at such a rate that the
internal temperature does not exceed 10.degree. C. and the pH does
not exceed 10.5. After the mixture has been stirred for another 30
minutes, the precipitate is filtered off, the aqueous phase is then
extracted twice with 150 ml each time of toluene. The boronic acid
is subsequently precipitated again at an internal temperature of
10.degree. C. by means of 150 ml of concentrated hydrochloric acid.
The precipitate is filtered off, washed with water and dried at
50.degree. C. in a stream of nitrogen. This gives 237.1 g of
3-formylphenylboronic acid (95% of theory) as a pale yellow solid
having a purity of 99.5% (HPLC).
Example 4: 2-Formylnaphthyl-1-boronic Acid
[0025] 23 g of crude 2-formylnaphthyl-1-boronic acid (purity
according to HPLC: 96%) are suspended in 100 ml of water and cooled
to 10.degree. C. 48 ml of 10% strength aqueous sodium hydroxide are
added dropwise over a period of 1 hour at such a rate that the
internal temperature does not exceed 10.degree. C. and the pH does
not exceed 10.5. After the mixture has been stirred for another 10
minutes, the precipitate is filtered off, the aqueous phase is then
extracted twice with 50 ml each time of toluene. The boronic acid
is subsequently precipitated again at an internal temperature of
10.degree. C. by means of 45 ml of 10% strength hydrochloric acid.
The precipitate is filtered off, washed with water and dried at
50.degree. C. in a stream of nitrogen. This gives 20.5 g of
2-formyl-naphthyl-1-boronic acid (89% of theory) as a light-yellow
solid having a purity of 99.3% (HPLC).
Example 5: 3-Fluoro-4-formylphenylboronic acid
[0026] 33 g of crude 3-fluoro-4-formylphenylboronic acid (purity
according to HPLC: 93%) are suspended in 250 ml of water and cooled
to 10.degree. C. 75 ml of 10% strength aqueous sodium hydroxide are
added dropwise over a period of 1.5 hour at such a rate that the
internal temperature does not exceed 10.degree. C. and the pH does
not exceed 10.5. After the mixture has been stirred for another 10
minutes, the precipitate is filtered off, the aqueous phase is then
extracted twice with 50 ml each time of toluene. The boronic acid
is subsequently precipitated again at an internal temperature of
10.degree. C. by means of 77 ml of 10% strength hydrochloric acid.
The precipitate is filtered off, washed with water and dried at
50.degree. C. in a stream of nitrogen. This gives 29 g of
3-fluoro-4-formylphenylboronic acid (94.4% of theory) as a
light-yellow solid having a purity of 99.7% (HPLC).
Example 6: 3-Formyl-4-methoxyphenylboronic Acid
[0027] 25 g of crude 3-formyl-4-methoxyphenylboronic acid (purity
according to HPLC: 96%) are suspended in 200 ml of water and cooled
to 10.degree. C. 58 ml of 10% strength aqueous sodium hydroxide are
added dropwise over a period of 1.5 hour at such a rate that the
internal temperature does not exceed 10.degree. C. and the pH does
not exceed 10.5. After the mixture has been stirred for another 10
minutes, the precipitate is filtered off, the aqueous phase is then
extracted twice with 50 ml each time of toluene. The boronic acid
is subsequently precipitated again at an internal temperature of
10.degree. C. by means of 60 ml of 10% strength hydrochloric acid.
The precipitate is filtered off, washed with water and dried at
50.degree. C. in a stream of nitrogen. This gives 22.1 g of
3-formyl-4-methoxyphenylboronic acid (92% of theory) as a colorless
solid having a purity of 99.6% (HPLC).
Comparative Example: 4-Formylphenylboronic Acid
[0028] Using a method based on that in Liebigs Ann. 1995,
1253-1257, a solution of 120 g of tri-n-butyl borate in 250 g of
dry tetrahydrofuran was placed under nitrogen in a dried 2 l flask
fitted with a dropping funnel and cooled to -50.degree. C. 535 g of
a 26.5% strength solution of 4-diethoxymethylphenylmagnesium
bromide in THF are then added dropwise at such a rate that the
internal temperature does not exceed -40 to -50.degree. C. The
mixture is subsequently stirred at -50.degree. C for another 1
hour. 1 l of methyl t-butyl ether (MTBE) is subsequently added and
the mixture is hydrolyzed at 5-10.degree. C. using 650 g of 1M
sulfuric acid. The aqueous phase was separated off and extracted
three times with 500 ml each time of methyl t-butyl ether. The
solvent was distilled off under reduced pressure and the crude
boronic acid was once again taken up in 0.5 l of water and 185 ml
of 5N aqueous potassium hydroxide (pH 14) at 5.degree. C. The
aqueous phase was extracted once with 250 ml of MTBE and
subsequently, at 5.degree. C., brought to a pH of 1 using 400 ml of
1M sulfuric acid. The precipitate was filtered off, washed twice
with 150 ml of ice water and dried. This gives 66.1 g of
4-formylphenylboronic acid (88% of theory) comprising, according to
HPLC, 89% of 4-formylphenylboronic acid, 4% of
4-carboxyphenylboronic acid, 3.8% of 4-hydroxymethylphenylboronic
acid.
* * * * *