Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2000-02-22
2002-04-09
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S492000, C562S469000, C548S216000
Reexamination Certificate
active
06369271
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a process which can be used on an industrial scale for preparing biphenyl-2-carboxylic acid derivatives (I)
wherein R
1
and R
2
may have the meanings given in the specification and claims.
BACKGROUND OF THE INVENTION
Biphenyl-2-carboxylic acids of formula (I) are very important as intermediate products in the production of pharmaceutically valuable active substances, particularly in the production of pharmaceutical substances which may be used as angiotensin-II-antagonists.
Processes for preparing biphenyl-2-carboxylic acid and the derivatives (I) thereof are known from the prior art. One method essential to the background of the invention is the coupling of aromatic Grignard compounds (II) with optionally substituted (2-methoxy-phenyl)-2-oxazolines (III) according to Diagram 1, as described by Meyers et al. (e.g. Tetrahedron (1985) Vol. 41, 837-860), in which the corresponding (2-oxazolinyl)-2-biphenyl derivatives (IV) are obtained to begin with.
Diagram 1:
The group R
Ox
denotes an optionally substituted oxazolin-2-yl group. The definition of the groups R
1
and R
2
can be found in the later part of the specification and in the claims. Conversion into the corresponding carboxylic acids of formula (I) is effected by saponification of the oxazolines (IV). This saponification of (IV) can be carried out by two different reaction methods, from a formal point of view. In Diagram 2 these reaction methods are illustrated by way of example with reference to the preparation of biphenyl-2-carboxylic acid, starting from biphenyl-oxazoline unsubstituted at the oxazoline group (i.e. R
1
and R
2
=hydrogen; R
Ox
=oxazolin-2-yl).
Diagram 2:
The saponification of the oxazoline under reaction conditions known in the art leads in the first step to the formation of the aminoester (Vb) (Meyers et al.
J. Org. Chem
. (1974) Vol. 39, 2787-2793). The aminoester (Vb) can then be saponified to the carboxylic acid (I) in a second reaction step, e.g. by boiling for several hours in 10-25% sodium hydroxide solution.
For a large-scale manufacturing process, however, it is desirable to carry out the saponification process as a one-pot process.
The acid saponification by a one-pot process (e.g. according to EP59983) carried out using the methods known from the prior art, however, led to unsatisfactory results when done on a large scale.
It was observed that because of the low solubility in the solvents which are used according to the prior art (e.g. aqueous hydrochloric acid according to EP 59983) aminoester (Vb) is partially precipitated after being formed. A precipitate of (Vb) is formed on the stirring mechanism and on the walls of the reaction vessel. This causes aminoester (Vb) to be removed successively from the reaction solution and, because of the poor solubility, it is then virtually no longer available for farther reaction to form the desired end compound (I). A further reduction in yield occurs as a result of the inclusion of product (I) in the crystallised aminoester (Vb) which is clumping normally.
The abovementioned disadvantages lead to an increased cost in the large-scale production of (I), since within the scope of the working up and processing of the end product, on the one hand, the aminoester (Vb) has to be separated off and, on the other hand, a separate synthesis step has to take place for reacting the precipitated aminoester (Vb) to form the end product.
The aim and objective of the present invention is therefore to provide a process for preparing derivatives/homologues of biphenyl-2-carboxylic acid on a large scale which overcomes the disadvantages of the processes known from the prior art.
DETAILED DESCRIPTION OF THE INVENTION
Surprisingly, it has been found that the disadvantages encountered in the methods of preparing biphenyl-2-carboxylic acid derivatives known from the prior art can be avoided if the saponification of the oxazoline (IV) is carried out with hydrochloric acid at elevated temperature under pressure, in the presence of an inert organic solvent which is immiscible with water.
The present invention is consequently directed to a large-scale process for preparing biphenyl-2-carboxylic acid derivatives of general formula (I)
wherein
R
1
and R
2
which may be identical or different denote hydrogen, C
1
-C
6
-alkyl, which may optionally be substituted by halogen, C
1
-C
6
-alkoxy, C
1
-C
6
-acyl, C
1
-C
6
-alkoxycarbonyl, COOH, phenyl, benzyl, halogen, hydroxy, nitro or amino, or wherein
R
1
and R
2
together with adjacent carbon atoms of the phenyl ring form a saturated or unsaturated 5- or 6-membered carbocyclic group which may optionally be substituted by C
1
-C
4
-alkyl, halogen, COOH, phenyl or hydroxy;
characterised in that a (2-oxazolinyl)-2-biphenyl derivative of general formula (IV)
wherein
R
1
and R
2
are as hereinbefore defined and
R
Ox
denotes an oxazolin-2-yl group, which may optionally be mono-, di-, tri- or tetra-substituted by one or more of the groups C
1
-C
6
-alkyl, which may optionally be substituted by halogen, hydroxy or C
1
-C
4
-alkoxy, C
1
-C
6
-alkoxy, phenyl, which may optionally be substituted by C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, hydroxy, nitro or amino, benzyl, pyridyl or C
1
-C
6
-alkoxycarbonyl,
is saponified with hydrochloric acid at elevated temperature under pressure, in the presence of an inert organic solvent which is immiscible with water.
A preferred process according to the invention is a process for preparing biphenyl-2-carboxylic acid derivatives of general formula (I) wherein
R
1
and R
2
, which may be identical or different, denote hydrogen, C
1
-C
4
-alkyl, which may optionally be substituted by fluorine, chlorine or bromine, C
1
-C
4
-alkoxy, C
1
-C
4
-acyl, C
1
-C
4
-alkoxycarbonyl, COOH, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, nitro or amino, or wherein
R
1
and R
2
together with adjacent carbon atoms of the phenyl ring form an unsaturated 6-membered carbocyclic group which may optionally be substituted by C
1
-C
4
-alkyl, fluorine, chlorine, bromine, COOH, phenyl or hydroxy;
characterised in that a (2-oxazolinyl)-2-biphenyl derivative of general formula (IV),
wherein
R
1
and R
2
are as hereinbefore defined and
R
Ox
denotes an oxazolin-2-yl group, which may optionally be mono- or disubstituted by one or more of the groups C
1
-C
4
-alkyl, which may optionally be substituted by fluorine, chlorine, bromine, hydroxy or C
1
-C
4
-alkoxy, C
1
-C
4
-alkoxy, phenyl, which may optionally be substituted by C
1
-C
4
-alkyl, C
1
-C
4
-alkoxy, hydroxy, nitro or amino, benzyl or C
1
-C
4
-alkoxycarbonyl,
is saponified with hydrochloric acid at elevated temperature under pressure, in the presence of an inert organic solvent which is immiscible with water.
Particularly preferred is a process for preparing biphenyl-2-carboxylic acid derivatives of general formula (I), wherein
R
1
and R
2
which may be identical or different, denote hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, CF
3
, methoxy, ethoxy, COOH, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, nitro or amino, or wherein
R
1
and R
2
together with adjacent carbon atoms of the phenyl ring form an anellated phenyl ring which may optionally be substituted by methyl, ethyl, n-propyl, isopropyl, tert.-butyl, fluorine, chlorine, bromine, COOH, phenyl or hydroxy,
characterised in that a (2-oxazolinyl)-2-biphenyl derivative of general formula (IV)
wherein
R
1
and R
2
are as hereinbefore defined and
R
Ox
denotes an oxazolin-2-yl group, which may optionally be mono- or disubstituted by one or more of the groups methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert.-butyl, methoxymethyl, hydroxymethyl, methoxy or ethoxy, or phenyl, which may optionally be substituted by methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert.-butyl, methoxy, ethoxy or hydroxy, or benzyl, methoxycarbonyl or ethoxycarbonyl,
is saponified with hydrochloric acid at elevated temperature under pressure, in the presence of an inert organic solvent which is immiscible with water.
Also of importance
Schneider Heinrich
Schneider Margarete
Boehringer Ingelheim Pharma KG
Forohar Farhad
Killos Paul J.
Raymond R. P.
Schneider Margarete
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