SK12142001A3 - Method for producing derivatives of biphenyl-2-carboxylic acid - Google Patents

Abstract

The invention relates to a method for producing biphenyl-2-carboxylic acid derivatives of formula (I), wherein R<1> and R<2> can have the meanings given in the description and in the claims. The inventive method is suitable for use on an industrial scale.

Description

Process for the preparation of biphenyl-2-carboxylic acid derivatives

Technical field

The invention relates to a process for the preparation of biphenyl-2-carboxylic acid derivatives which is suitable for use on an industrial scale.

BACKGROUND OF THE INVENTION

The biphenyl-2-carboxylic acids of the formula I are of great importance as intermediates in the preparation of pharmaceutically interesting active substances, in particular in the preparation of those pharmaceutical active substances which can be used as angiotensin II antagonists.

Methods for preparing biphenyl-2-carboxylic acids and derivatives I are known in the art. One of the prior art approaches is carried out according to the method described by von Meyers et al. (e.g. Tetrahedron (1985), 41, 837-860), which consists in combining aromatic Grignard compounds of formula II with optionally substituted (2-methoxyphenyl) -2-oxazoles of formula III according to Scheme 1, first yielding the corresponding (2-oxazolinyl) ) -2-Biphenyl derivatives of general IV.

Scheme 1

(IV)

d) • ·

R ^Ox -2Zvyšok this case is optionally substituted oxazolin-2-yl radical. The definition of the radicals R ^{@ 1} and R ^{@ 2} is given in the following description and in the claims. The saponification of oxazolines of formula IV is converted to the corresponding carboxylic acids of formula I. This saponification of a compound of formula IV can be carried out formally by two different reactions. Scheme 2 exemplifies these two reactions for the preparation of biphenyl-2-carboxylic acid starting from biphenyloxazoline unsubstituted at the oxazoline residue (ie, R ¹ and R ² are hydrogen; R ^Ox is oxazolin-2-yl).

Scheme 2

(Vb)

The saponification of oxazoline according to reaction conditions known in the art leads to the formation of aminoester Vb in a first step (Meyers et al., J. Org. Chem. (1974), 39, 2787-2793). The amino ester Vb can then be saponified to the carboxylic acid I in the second step of the reaction, for example, by boiling in a 10-25% sodium hydroxide solution.

However, it is desirable for the industrial scale preparation that the saponification be carried out in a single container. However, reliance on the method known in the prior art, when carried out on an industrial scale, has produced only unsatisfactory results. , • ·

It has been found that due to the low solubility of the solvent used in the prior art (e.g., aqueous hydrochloric acid solution according to EP 59983), the aminoester Vb partially precipitates upon its formation. A precipitate Vb is formed both on the mixer and on the walls of the reaction vessel. This results in the amino ester Vb gradually declining from the reaction solution and, due to its low solubility, is then unavailable for further reaction to the desired target compound I. A significant reduction in yield is due to product I being enclosed in the crystallized and regularly agglomerated aminoester Vb.

The above-mentioned disadvantages lead to increased consumption in the industrial preparation of compound I, since separation of the aminoester Vb must be carried out on the one hand in the processing and purification of the end product and on the other hand a separate synthesis step must be carried out to convert the precipitated aminoester Vb.

It is therefore an object and object of the present invention to provide a process applicable on an industrial scale for the preparation of biphenyl-2-carboxylic acid derivatives / homologs that overcome the drawbacks of the prior art method.

Surprisingly, it has been found that the drawbacks of the prior art process for the preparation of biphenyl-2-carboxylic acid derivatives can be overcome if the saponification of oxazoline IV is carried out with hydrochloric acid at elevated temperature under pressure in the presence of an inert organic solvent which does not mix with water.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention provides an industrial process for the preparation of biphenyl-2-carboxylic acid derivatives of the general formula I

HOOC

Ä _ // (I) ·· · · · · ·

-4 in which

R ¹ and R ² are the same or different and represent a hydrogen atom, C 1 -C 6 -alkyl, which may be optionally substituted by a halogen atom, C 1 -C 6 -alkoxy, C 1 -C 6 -acyl, C 1 -C 6 alkoxycarbonyl, COOH, phenyl, benzyl, halogen, hydroxy, nitro or amino, or in which

R ¹ and R ² together with adjacent carbon atoms of the phenyl ring form a saturated or unsaturated 5- or 6-membered carbocycle, which may be optionally substituted with C 1 -C ₄ -alkyl, halogen, COOH, phenyl or hydroxy;

wherein the (2-oxazolinyl) -2-biphenyl derivative of general formula IV

in which

R ¹ and R ² are as defined above, and

R ^Ox represents an oxazolin-2-yl radical which may be mono-, di-, triple or quadruple substituted by one or more of C1-C6-alkyl, which may be optionally substituted by halogen, hydroxy or C1-C4alkoxy, C1-C6 -alkoxy, phenyl, which may be optionally 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 and pressure in the presence of an inert organic solvent that is not mixed with water.

According to the invention, a process for the preparation of the biphenyl-2-carboxylic acid derivatives of the general formula I is preferred in which

R ¹ and R ² are the same or different and are hydrogen, C ₄ alkyl, which may be optionally substituted with fluoro, chloro or bromo, Ci-C ₄ -alkoxy, C _r C ₄ acyl, C ₄ - alkoxycarbonyl, COOH, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy, • ···

-5nitro or amino, or wherein R ¹ and R ² together with adjacent carbon atoms of the phenyl ring form an unsaturated 6-membered carbocycle which may be optionally substituted with C 1 -C 4 -alkyl, fluoro, chloro, bromo, COOH, phenyl or hydroxy;

wherein the (2-oxazolinyl) -2-biphenyl derivative of formula (IV) wherein R ¹ and R ² are as defined above, and

R ^Ox represents an oxazolin-2-yl radical which may be mono- or di-substituted by one or more of C 1 -C 4 -alkyl, which may be optionally substituted by fluorine, chlorine, bromine, hydroxy or C 1 -C 4 -alkoxy, C 1 -C 4 ₄ -alkoxy, phenyl which may be optionally substituted by Ci-C ₄ -alkyl, C ₄ -alkoxy, hydroxy, nitro or amino, benzyl or C -C ₄ -alkoxycarbonyl, is saponified with hydrochloric acid at elevated temperature and pressure in the presence of an inert organic solvent that is not mixed with water.

Particularly preferred is a process for the preparation of biphenyl-2-carboxylic acid derivatives of the general formula I in which:

R ¹ and R ² are the same or different and are hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, CF 3, methoxy, ethoxy, COOH, phenyl, benzyl, fluoro, chloro, bromo, hydroxy, nitro or amino, or wherein R ¹ and R ² together with adjacent carbon atoms of the phenyl ring form a fused phenyl ring which may be optionally substituted with methyl, ethyl, n-propyl, isopropyl, tert-butyl, fluorine, chlorine, bromine , COOH, phenyl or hydroxy, wherein the (2-oxazolinyl) -2-biphenyl derivative of the general Formula IV wherein R ¹ and R ² are as defined above, and

R ^Ox represents an oxazolin-2-yl radical which may optionally be mono- or di-substituted by one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxymethyl, hydroxymethyl, methoxy, ethoxy, phenyl which may be optionally substituted by methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy or hydroxy, benzyl, methoxycarbonyl or ethoxycarbonyl,

It is saponified with hydrochloric acid at elevated temperature under pressure in the presence of an inert organic solvent that is not mixed with water.

Furthermore, according to the invention, a process for the preparation of biphenyl-2-carboxylic acid derivatives of the general formula I in which:

R ¹ and R ² are the same or different and are hydrogen, methyl, CF ₃ , COOH, phenyl, fluoro or hydroxy, or wherein

R ¹ and R ² together with adjacent carbon atoms of the phenyl ring form a fused phenyl ring wherein the (2-oxazolinyl) -2-biphenyl derivative of the general formula IV, wherein R ¹ and R ² is as defined above, and

R ^Ox represents an oxazolin-2-yl radical which may be mono- or di-substituted by one or more of methyl, ethyl, methoxy, ethoxy, phenyl or benzyl, is saponified with hydrochloric acid at elevated temperature under pressure in the presence of an inert organic solvent, which does not mix with water.

Of particular interest is the process for the preparation of biphenyl-2-carboxylic acid derivatives of the general formula I in which:

R ¹ and R ² are the same or different and are hydrogen, methyl or CF ₃ in which the (2-oxazolinyl) -2-biphenyl derivative of the general formula IV, wherein R ¹ and R ² is as defined above, and

R ^Ox represents an oxazolin-2-yl radical, which may optionally be mono- or di-substituted by a methyl group, is saponified with hydrochloric acid at elevated temperature under pressure in the presence of an inert organic solvent which is not mixed with water.

According to the invention, the following method is particularly preferred. 0.08 to 0.8, preferably 0.15 to 0.5, more preferably about 0.2 L of water and 3.0 to 6, are placed in a reaction vessel of a suitable size per mole of oxazolin-2-yl-biphenyl of formula IV. 0 mol, even more preferably 3.5 to 5.0 mol, most preferably about 4.0 mol of hydrochloric acid. The addition of the above hydrochloric acid is preferably carried out in the form of aqueous solutions, particularly preferably in the form of a 36.5% aqueous solution, so that the final concentration of hydrochloric acid is 20 to 30%, more preferably about 24%.

• ·

After inerting with the shielding gas, preferably nitrogen, the reaction vessel is evacuated (approximately 50 mbar) and mixed with 0.05 to 0.2, preferably 0.08 to 0.15, per mole of the starting compound of formula IV, Aliphatic or aromatic hydrocarbons and aromatic hydrocarbons containing from 6 to 10 carbon atoms are preferred as inert organic solvents according to the invention. Toluene, xylene, chlorobenzene and methylcyclohexane are particularly useful in the present invention, methylcyclohexane being particularly preferred.

After addition of an inert organic solvent, the reaction solution is heated to 120 to 160 ° C, preferably to 130 to 150 ° C, more preferably to 140 to 145 ° C. Stirring is continued for a further 3 to 10 hours, more preferably for 4 to 8 hours, at constant temperature. The apparatus is then closed (at the plant, for example, by closing the valve), so that the above-mentioned heating of the reaction solution generates an internal pressure of 0.3 to 0.6 MPa (3 to 6 bar), preferably 0.4 to 0.5 MPa. up to 5 bar). Depending on the melting point of the solvents used, the temperature may be varied to achieve the above pressure. This provides a further advantage according to the invention that conventional apparatuses such as DIN-Enamel apparatuses (6 bar) can be used.

Subsequently, the reaction vessel is cooled to a temperature at which the apparatus has at most atmospheric pressure (20 to 50 ° C). The vacuum is optionally equalized with an inert gas. For working-up, the reaction mixture is mixed with a suitable solvent or solvent mixture to allow separation of the aqueous phase with hydrochloric acid without loss of product. Use of toluene, xylene or methylcyclohexane in mixtures with tetrahydrofuran is preferred. Particularly preferred is a mixture of toluene and tetrahydrofuran in a ratio of about 1: 1. 0.1 to 1 L of the above-mentioned organic solvent or solvent mixture is used per mole of the starting compound of the formula IV used. Preferably, 0.2 to 0.5 L of the above solvent or solvent mixture is used per mole of oxazoline IV used. Particularly preferably, 0.3 to 0.35 L of an organic solvent or solvent mixture is used per mole of oxazoline of formula IV.

• ·

-8Examples of embodiments of the invention

Example 1

265 kg of 4 ^, -methyl-2- (4,4-dimethyl-oxazolin-2-yl) biphenyl of ₁ 205 L of water and 400 kg of 36.5% hydrochloric acid are placed in a 1200 liter enamelled stirrer apparatus. After inertization with nitrogen, it is evacuated to about 50 mbar and then 102.5 L of methylcyclohexane is added. After closing the cap, the mixture is warmed to about 140 ° C over 1 hour and stirred at 140-145 ° C for a further 4 to 8 hours. In this case, the internal temperature is set at 4 to 5 bar. It is then cooled to 20-30 ° C, the pressure is brought to atmospheric pressure with nitrogen and 175 L of toluene and 150 L of THF are added. The aqueous lower phase is separated and the remaining upper phase is extracted first with 205 L and then with 103 L of water. A further 512 L of water and 80 kg of 45% sodium hydroxide solution were added to the upper phase, and the lower phase after weaning was discharged into another 1200 liter enamelled apparatus with stirrer. This operation was repeated with 103 L of water and 8.9 kg of 45% sodium hydroxide solution.

Approximately 103 L of the combined aqueous extracts were distilled off, and after cooling to 25 ° C, 205 L of water was added followed by 97 kg of 36.5% hydrochloric acid. The product is centrifuged, washed with water and dried.

Yield: 190 kg of 4'-methylbiphenyl-2-carboxylic acid (90%).

Example 2

251 kg of 2 (4,4-dimethyloxazolin-2-yl) biphenyl, 205 L of water and 400 kg of 36.5% hydrochloric acid are placed in a 1200 liter enamelled stirrer apparatus. After inertization with nitrogen, it is evacuated to about 50 mbar and then 102.5 L of methylcyclohexane is added. After closing the cap, the mixture is heated to about 140 ° C for about 1 hour and stirred for a further 4 to 8 hours at 140 to 145 ° C. An internal pressure of 4 to 5 bar is produced. It is then cooled to 20-30 ° C, the pressure is brought to atmospheric pressure with nitrogen and 175 L of toluene and 150 L of THF are added. The aqueous lower phase was separated and the remaining organic upper phase was extracted once more with 205 L and then with 103 L of water. A further 512 liters of water and 80 kg of 45% sodium hydroxide solution are added to the upper phase, and the lower phase is discharged into a further 1200 liter enamelled apparatus after being weaned.

-9 with stirrer. This operation was repeated with 103 L of water and 8.9 kg of 45% sodium hydroxide solution. From the combined aqueous extracts, 103 L was distilled off first, and after cooling to 25 ° C, 205 L of water was added followed by 97 kg of 36.5% hydrochloric acid. The product is centrifuged, washed with water and dried.

Yield: 180 kg of biphenyl-2-carboxylic acid (91%).

Comparative example

265 kg of 4'-methyl-2- (4,4-dimethyl-oxazolin-2-yl) biphenyl, 205 L of water and 400 kg of 36.5% hydrochloric acid are placed in a 1200 liter enamelled mixer. After inerting with nitrogen, evacuating to about 50 mbar and closing the cap, the contents of the apparatus are heated to about 140 ° C for about 1 hour and stirred for a further 4 to 8 hours at 140 to 145 ° C, forming an internal pressure from 0.4 MPa to 0.5 MPa (4 to 5 bar). It is then cooled to 20-30 ° C, the pressure is brought to atmospheric pressure with nitrogen and 175 L of toluene and 150 L of THF are added. The aqueous lower phase is added to the waste water and the remaining organic upper phase is extracted once more with 205 L and then with 103 L of water. A further 512 L of water and 80 kg of 45% sodium hydroxide solution were added to the upper phase and after lowering the lower phase was discharged to another 1200 liter enamelled apparatus with a mixer. This operation was repeated with 103 L of water and 8.9 kg of 45% sodium hydroxide solution. From the combined aqueous extracts, 103 L was distilled off first, and after cooling to 25 ° C, 205 L of water was added followed by 97 kg of 36.5% hydrochloric acid. The product is centrifuged, washed with water and dried.

Yield: 100 kg of 4'-methylbiphenyl-2-carboxylic acid (47%).

Claims (12)

PATENT CLAIMS A process for the preparation of biphenyl-2-carboxylic acid derivatives of the general formula I in which R ¹ and R ² are the same or different and represent a hydrogen atom, C 1 -C 6 -alkyl which may be optionally 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 carbocycle, which may be optionally substituted by a C 1 -C 4 -alkyl, halogen, COOH, phenyl or hydroxy group, characterized in that A (2-oxazolinyl) -2-biphenyl derivative of the general formula IV wherein R ¹ and R ² are as defined above, and R ^Ox represents an oxazolin-2-yl radical which may be singly, two, three or four times substituted with one or more C1-C6-alkyl radicals, which may be optionally substituted by halogen, hydroxy or C1-C4-alkoxy, C1-C6 -alkoxy, phenyl, which may be optionally substituted by C1-C4 - an alkyl, C 1 -C ₄ -alkoxy, hydroxy, nitro or amino group, benzyl, pyridyl or C 1 -C ₆ -alkoxycarbonyl is saponified with hydrochloric acid at a temperature of 120 to 160 ° C and a pressure of 0.3 MPa to 0, 6 MPa (3 to 6 bar) in the presence of an inert organic solvent which is not mixed with water. A method according to claim 1, characterized in that R ¹ and R ² are the same or different and represent a hydrogen atom, C 1 -C 4 -alkyl which may be optionally 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 , chloro, bromo, 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 carbocycle which may be optionally substituted with C 1 -C 4 -alkyl, fluoro, chloro, bromo, COOH, phenyl or hydroxy, and R ^Ox is oxazolin-2-yl radical which can be singly or doubly substituted by one or more of the radicals Cl-C ₄ -alkyl, which can optionally be substituted by fluorine, chlorine, bromine, hydroxy or C -C ₄ -alkoxy, C -C ₄ -alkoxy, phenyl, which may be optionally substituted by C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, hydroxy, nitro or amino, benzyl or C 1 -C ₄ -alkoxycarbonyl. A method according to claim 1 or 2, characterized in that R ¹ and R ² are the same or different and represent a hydrogen atom, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, CF 3, methoxy, ethoxy, COOH, phenyl, benzyl, fluoro, chloro, bromo, hydroxy, nitro or amino, or R ¹ and R ² together with adjacent carbon atoms of the phenyl ring form a fused phenyl ring which may be optionally substituted with methyl, ethyl, n-propyl, isopropyl, tert-butyl, fluoro, chloro, bromo, COOH, phenyl or hydroxy, and R ^Ox represents an oxazolin-2-yl radical which may optionally be mono- or di-substituted by one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxymethyl, hydroxymethyl, methoxy, ethoxy, phenyl , which • · ···· · · · I ► · · « 12 may be optionally substituted with methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy or hydroxy, benzyl, methoxycarbonyl or ethoxycarbonyl. Method according to any one of claims 1 to 3, characterized in that R ¹ and R ² are the same or different and are hydrogen, methyl, CF 3, COOH, phenyl, fluoro or hydroxy, or R ¹ and R ² together with adjacent carbon atoms of the phenyl ring form a fused phenyl ring, and R ^Ox represents an oxazolin-2-yl radical which may be mono- or di-substituted by one or more of methyl, ethyl, methoxy, ethoxy, phenyl or benzyl. A method according to any one of claims 1 to 4, characterized in that R ¹ and R ² are the same or different and are hydrogen, methyl or CF 3, and R ^Ox represents an oxazolin-2-yl radical which may optionally be mono- or di-substituted by a methyl group. Process according to any one of claims 1 to 5, characterized in that the saponification is carried out at a pressure of 4 to 5 bar. * Process according to any one of claims 1 to 6, characterized in that 3.0 to 6.0 mol of hydrochloric acid are used for saponification per mole of the starting compound of the general formula IV used. Process according to any one of claims 1 to 7, characterized in that 3.5 to 5.0 mol of hydrochloric acid are used for saponification per mole of the starting compound of the formula IV used. • · · · · ··· 139. The process according to any one of claims 1 to 8, characterized in that aliphatic or aromatic hydrocarbons or aromatic chlorinated hydrocarbons having 6 to 10 carbon atoms are used as the organic solvent. Process according to any one of claims 1 to 9, characterized in that aliphatic or aromatic hydrocarbons having 7 to 8 carbon atoms or chlorobenzene are used as the organic solvent. Process according to any one of claims 1 to 10, characterized in that toluene, xylene, chlorobenzene and methylcyclohexane are used as the organic solvent. Process according to any one of claims 1 to 11, characterized in that methylcyclohexane is used as the organic solvent. A process for preparing 4'-methylbiphenyl-2-carboxylic acid according to any one of claims 1 to 12.