HRP20010616A2 - Method for producing derivatives of biphenyl-2-carboxylic acid - Google Patents

Description

The invention relates to a process for the production of biphenyl-2-carboxylic acid derivatives of the formula (I)

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which can be applied in a technical scale, whereby R1 and R2 can have the meaning specified in the description and in the patent claims.

Background of the invention

Biphenyl-2-carboxylic acids of formula (I) are important as intermediates in the production of pharmaceutically interesting active substances, especially in the production of pharmaceutical active substances that can be used as angiotensin-IL antagonists.

Processes for the production of biphenyl-2-carboxylic acids and their derivatives (I) are known from the state of the art. One, important for the background of the invention, procedure is carried out by connecting an aromatic Grignard compound (II) with an optionally substituted (2-methoxyphenyl)-2-oxazoline (III) according to scheme 1, which was described by Meyers et al. (eg in Tetrahedron (1985), vol. 41, 837-860), whereby the corresponding (2-oxazolinyl)-2-biphenyl derivative (IV) is first obtained.

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Scheme 1:

In this case, the residue R0x represents an optionally substituted oxazolin-2-yl residue. The definition of residues R1 and R2 is given in the later part of the description as well as in the patent claims. Saponification of oxazoline (IV) leads to a corresponding chemical change in the corresponding carboxylic acid of formula (I). This saponification of compound (IV) can, formally considered, be carried out in two reactionally different ways. Scheme 2 shows these ways of carrying out the reaction, using the example of the production of biphenyl-2-carboxylic acid, starting from biphenyl-oxazoline unsubstituted on the oxazoline residue (ie R1 and R2 = hydrogen; R0x = oxazolin-2-yl).

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Scheme 2:

Saponification of oxazoline, according to reaction conditions known from the state of the art, in the first step leads to the formation of amino ester (Vb) (Meyers et al., J. Org. Chem. (1974) Vol. 39, 2787-2793). The amino ester (Vb) can then, in the second reaction stage, for example by boiling for several hours in 10-25% sodium alkali, saponified into carboxylic acid (I).

For the production process on a large technical scale, it is preferable to carry out the saponification process as a one-pot process. However, when starting from a process known from the state of the art, acid saponification is carried out in one vessel (eg according to EP59983), it only leads to unsatisfactory results on a large technical scale.

It was observed that due to the low solubility in the solvent used according to the state of the art (eg aqueous hydrochloric acid according to EP 59983), the amino ester (Vb) is partially excreted after its formation. A deposit (Vb) forms on the mixer as well as on the walls of the reaction vessel. This leads to the fact that the amino ester (Vb) is successively extracted from the reaction solution and, due to its low solubility, it is practically no longer available for further reaction for the desired target compound (I). A large decrease in utilization occurs due to the inclusion of product (I) in the crystallized and actually coagulated amino ester (Vb).

The aforementioned disadvantages lead to increased costs in the industrial production of compound (1), because within the processing and cleaning of the final product, the separation of the amino ester (Vb) must be carried out, and due to the conversion of the secreted amino ester (Vb) into the final product, it must also be carried out a separate synthesis step.

Therefore, the aim and task of the proposed invention is to provide a process for the production of derivatives/homologues of biphenyl-2-carboxylic acid that can be applied in industrial production and in which the shortcomings that appear in the process known from the state of the art are overcome.

Description of the invention in detail

It was surprisingly found that the defects that appear in the production process for biphenyl-2-carboxylic acid derivatives known from the state of the art can be avoided if the saponification of oxazoline (IV) is carried out with hydrochloric acid at elevated temperature, under pressure and in the presence of an inert organic solvent which does not mix with water.

The proposed invention therefore relates to a process that can be applied on an industrial scale for the production of biphenyl-2-carboxylic acid derivatives of the general formula (I)

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where

R1 and R2, the same or different, represent hydrogen, C1-C6-alkyl, which can be substituted with halogen, C1-C6-alkoxy, C1-C6-acyl, C1-C6-alkoxycarbonyl, COOH, phenyl, benzyl, halogen, hydroxy, nitro or amino, or in which

R1 and R2 together with the adjacent carbon atoms of the phenyl ring form a saturated or unsaturated 5- or 6-membered carbocycle which can be substituted with C1-C4-alkyl, halogen, COOH, phenyl or hydroxy if necessary; which is indicated by the fact that the (2-oxazolinyl)-2-biphenyl derivative of the general formula (IV)

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where

R1 and R2 have the above meaning and

R0x represents an oxazolin-2-yl residue, which is, if necessary, singly, doubly, triply or quadruply substituted with one or more C1-C6-alkyl residues, which can be substituted with halogen, hydroxy or with C1-C4-alkoxy, C1 -C6-Alkoxy, phenyl which, if necessary, can be substituted with C1-C4-alkyl, C1-C4-Alkoxy, hydroxy, nitro or amino, benzyl, pyridyl or C1-C6-Alkoxycarbonyl, saponified with hydrochloric acid at elevated temperature under pressure and in the presence of an inert, water-immiscible organic solvent.

According to the invention, preference is given to the process for the production of biphenyl-2-carboxylic acid derivatives of the general formula (I), in which

R1 and R2, the same or different, represent hydrogen, C1-C4-alkyl, which can be substituted with fluorine, chlorine or bromine, if necessary, C1-C4-alkoxy, C1-C4-acyl, C1-C4-alkoxycarbonyl, COOH, phenyl, benzyl, fluoro, chloro, bromo, hydroxy, nitro or amino, or in which

R1 and R2, together with the adjacent carbon atoms of the phenyl ring, form an unsaturated 6-membered carbocycle, which, if necessary, can be substituted with C1-C4-alkyl, fluorine, chlorine, bromine, COOH, phenyl or hydroxy; which is indicated by the fact that the (2-oxazolinyl)-2-biphenyl derivative of the general formula (IV) in which

R1 and R2 have the above meaning, i

R0x represents an oxazolin-2-yl radical, which can be singly or doubly substituted with one or more C1-C4-alkyl radicals, which can be optionally substituted with fluorine, chlorine, bromine, hydroxy or with C1-C4-alkoxy . under pressure and in the presence of an inert organic solvent that does not mix with water.

According to the invention, a special advantage is given to the process for the production of biphenyl-2-carboxylic acid derivatives of the general formula (I), in which

R1 and R2, the same or different, represent hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, CF3, methoxy, ethoxy, COOH, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy , nitro or amino, or in which

R1 and R2 together with the adjacent carbon atoms of the phenyl ring form an annelized phenyl ring which, if necessary, can be substituted with methyl, ethyl, n-propyl, iso-propyl, tert-butyl, fluorine, chlorine, chromium, COOH, phenyl or with hydroxy,

which is indicated by the fact that the (2-oxazolinyl)-2-biphenyl derivative of the general formula (IV) in which

R1 and R2 have the above meaning, i

R0x represents an oxazolin-2-yl residue, which can be singly or doubly substituted as needed with one or more residues from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, methoxymethyl, hydroxymethyl , methoxy, ethoxy, phenyl, which can be substituted with methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, methoxy, ethoxy or with hydroxy, benzyl, methoxycarbonyl or ethoxycarbonyl, saponified with salt acid at elevated temperature, under pressure and in the presence of an inert organic solvent that does not mix with water.

Furthermore, according to the invention, a process for the production of biphenyl-2-carboxylic acid derivatives of the general formula (I) is significant, in which

R1 and R2, the same or different, represent hydrogen, methyl, CF3, COOH, phenyl, fluorine or hydroxy, or in which

R1 and R2 together with the adjacent carbon atoms of the phenyl ring form an fused phenyl ring, which is indicated by the fact that the (2-oxazolinyl)-2-biphenyl derivative of the general formula (IV), in which

R1 and R2 have the above meaning, i

R0x represents an oxazolin-2-yl residue, which, as necessary, is singly or doubly substituted with one or more residues from the group consisting of methyl, ethyl, methoxy, ethoxy, phenyl or benzyl, saponified with hydrochloric acid at elevated temperature, under pressure and in the presence an inert organic solvent that does not mix with water.

Special significance is given to the process for the production of biphenyl-2-carboxylic acid derivatives of the general formula (I), in which

R1 and R2, the same or different, represent hydrogen, methyl or CF3, which is indicated by the fact that the (2-Oxazolinyl)-2-biphenyl derivative of the general formula (IV), in which

R1 and R2 have the aforementioned meaning and

R0x represents an oxazolin-2-yl residue, which can be singly or doubly substituted with methyl if necessary, saponified with hydrochloric acid at elevated temperature, under pressure and in the presence of an inert organic solvent that does not mix with water.

According to the invention, a particularly advantageous form and method of execution is carried out as follows. 0.08-0.8, preferably 0.15-0.5, especially preferably approx. 0.2 l of water and 3.0-6.0 moles, preferably 3.5-5.0 moles, especially preferably approx. 4.0 moles of hydrochloric acid per mole of oxazolin-2-yl-biphenyl (IV). Preferably, the aforementioned hydrochloric acid is added in the form of an aqueous solution, especially preferably in the form of a 36.5% aqueous solution, so that a hydrochloric acid concentration of 20 - 30% is obtained, especially preferably of approx. 24%.

After creating an inert atmosphere with a protective gas, preferably with nitrogen, the reaction vessel is evacuated (at approx. 50 mbar) and per mole of the starting compound (IV) used is mixed with 0.05-0.2, preferably 0.08-0, 15, especially the front with approx. 0.1 l of inert organic solvent. As inert organic solvents according to the invention, aliphatic or aromatic hydrocarbons and aromatic hydrogen chlorides having 6-10 C-atoms come into consideration. Aliphatic or aromatic hydrocarbons having 7-8 carbon atoms are preferred. Solvents that can be used according to the invention are preferably toluene, xylene, chlorobenzene and methylcyclohexane. Particular preference is given to methyl-cyclohexane.

After the addition of an inert organic solvent, the reaction solution is heated to a temperature in the range of 120-160°C, preferably 130-150°C, especially preferably 140-145°C. At a constant temperature, it is stirred for a further 3-10 hours, preferably 4-8 hours. At the same time, the apparatus is closed (in operation, for example by closing the steam valve), so that a pressure of 3-6 bar (= bar overpressure), preferably 4-5 bar, is established inside the apparatus by means of the previously mentioned heating of the reaction solution. Depending on the boiling point of the solvent used, the temperature can be changed, which establishes the internal pressure mentioned above. Thus, according to the invention, the advantage is obtained that conventional devices can be used, such as for example DIN enameled devices (pressure level of 6 bar).

Then the reaction vessel is cooled to the temperature at which the apparatus has maximum atmospheric pressure (20 50°C). If necessary, the pressure is equalized using an inert gas. For workup, the reaction mixture is mixed with a suitable solvent or with a mixture of solvents that allows separation of the aqueous phase of hydrochloric acid without loss of product. It is advantageous to use toluene, xylene or methylcyclohexane in a mixture with tetrahydrofuran. A mixture of toluene and tetrahydrofuran in a ratio of approximately 1:1 is particularly advantageous. Between 0.1-1 l of the above-mentioned organic solvent or solvent mixture is placed per mole of the starting compound (IV) used. Preferably, 0.2-0.5 l of the aforementioned organic solvent or mixture of solvents is used per mole of oxazoline (IV) used. It is particularly preferred to use approx. 0.3-0.35 l of organic solvent or mixture of solvents per mole of oxazoline (IV) used.

The aqueous lower phase is then separated and the remaining upper phase is extracted with water several more times, preferably 2-3 times, especially preferably 2 times. The amount of water used for rinsing according to the invention for one extraction is in the range of 0.05-0.5 l per mole of oxazoline (IV) used. Preferably, for one stage of extraction, 0.1-0.2 l of water is used per mole of the starting compound (IV) used.

The organic upper phase washed in this way is then made alkaline. For this purpose, according to the invention, aqueous solutions of hydroxides of alkali or alkaline earth metals can be used. Lithium, sodium or potassium hydroxide is preferably used. 0.7-1 mol of base is used per mol of starting compound (IV), preferably 0.8-0.9 mol of base.

After phase separation, the lower phase is discharged into another reaction vessel. The residual upper phase is then again subjected to the above-mentioned leaching. At the same time, according to the invention, only approx. 10% mass/mass of the colic base used in the first stage of alkalization. After separating the lower phase again, the combined aqueous extracts are freed from the solvent collected by washing by distillation. Per mole of the starting compound (IV) used, it distils approximately 0.05-0.5 l of water, preferably between 0.07 and 0.2 l, especially preferably approx. 0.1 l of water. When it cools down to a temperature below 40°C, preferably to a temperature in the range of 20-30°C, especially preferably to 25°C, 0.1-0.5 l is added per mole of starting compound used, preferably approx. 0.2 l of water and then acidified with 1-5 moles, preferably 2-4 moles, especially preferably approx. 3.5 moles of hydrochloric acid.

The secreted product is separated by centrifugation, washed with water and dried.

The following examples serve to illustrate the implementation of the synthesis procedure according to the invention for the production of biphenyl-2-carboxylic acid derivatives of the general formula (I). They are understood only as possible examples of the presented process and the invention is not limited to their content.

Example 1

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 l enameled mixer. The atmosphere is then made inert with nitrogen and evacuated to approx. 50 mbar and then 102.5 l of methylcyclohexane are added. The steam valve is closed and in about 1 hour it heats up to approx. 140°C and mixed for another 4 to 8 hours at 140 - 145°C. In doing so, an internal pressure of 4-5 bar is established. After that, it is cooled to 20 - 30°C, the nitrogen pressure is adjusted to atmospheric pressure and 175 l of toluene and 150 l of THF are added. The aqueous lower phase is separated and the residual organic phase is extracted once again with 205 l and then with 103 l of water. A further 512 l of water and 80 kg of 45% sodium lye are added to the upper phase, and after separation, the lower phase is discharged into another enameled mixer of 1200 1. This procedure is repeated with 103 l of water and 8.9 kg of 45%- tne sodium alkali.

From the combined aqueous extracts, approx. 103 l, and when it cools down to 25°C, add 205 l of water and then 97 kg of 36.5% hydrochloric acid. The product is separated by centrifugation, 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 l enameled mixer. The atmosphere is made inert with nitrogen and then evacuated to approx. 50 mbar and then another 102.5 l of methylcyclohexane is added. When the steam valve is closed, it heats up in about 1 hour to approx. 140°C and mixed for a further 4 to 8 hours at 140-145°C. In doing so, an internal pressure of 4-5 bar is established. It is then cooled to 20 - 30°C, adjusted to atmospheric pressure with nitrogen and 175 l of toluene and 150 l of THF are added. The aqueous phase is separated and the remaining organic phase is extracted once again with 205 l and then with 103 l of water. A further 512 l of water and 80 kg of 45% sodium lye are added to the upper phase, and when the lower phase is separated, it is dropped into another enameled mixer of 1200 1. This procedure is repeated with 103 l of water and 8.9 kg of 45% -tne sodium lye. From the combined aqueous extracts, approx. 103 l, and when it cools down to 25°C, add 205 l of water and then 97 kg of 36.5% hydrochloric acid. The product is separated by centrifugation, 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 l enameled mixer. The atmosphere is made inert with nitrogen, then evacuated to approx. 50 mbar and the fuel flap closes. After that, for about 1 hour, the inside of the device heats up to approx. 140°C and mixed for a further 4 to 8 hours at 140-145°C, during which an internal pressure of 4-5 bar is established. After that, it is cooled to 20 - 30°C, adjusted to atmospheric pressure with nitrogen and 175 l of toluene and 150 l of THF are added. The lower aqueous phase is added to the waste water, and the remaining organic upper phase is extracted once again with 205 l and then with 103 l of water. A further 512 l of water and 80 kg of 45% caustic soda are added to the upper phase and the lower phase is separated and discharged into another enameled mixer of 1200 l. This procedure is repeated with 103 l of water and 8.9 kg of 45% caustic soda alkalis. From the combined water extracts, he first distills approx. 103 l, and when it cools down to 25°C, add 205 l of water and then 97 kg of 36.5% hydrochloric acid. The product is separated by centrifugation, washed with water and dried.

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

Claims (13)

1. Process for the production of biphenyl-2-carboxylic acid derivatives of the general formula (I) [image] where R1 and R2, the same or different, represent hydrogen, C1-C6-alkyl, which can be substituted with halogen if necessary, C1-C6-alkoxy, C1-C6-acyl, C1-C6-alkoxy carbonyl, COOH, phenyl, benzyl , halogen, hydroxy, nitro or amino, or in which R1 and R2, together with the adjacent carbon atoms of the phenyl ring, form a saturated or unsaturated 5- or 6-membered carbocycle which, if necessary, can be substituted with C1-C4-alkyl, halogen, COOH, phenyl or with hydroxy, indicated that (2 -oxazolinyl)-2-biphenyl derivative of general formula (IV) [image] where R1 and R2 have the aforementioned meaning and R0x represents an oxazolin-2-yl residue, which is, if necessary, singly, double, triple or quadruple substituted with one or more C1-C6-alkyl residues, which can be substituted with halogen, hydroxy or with C1-C4-Alkoxy, C1-C6-Alkoxy, phenyl which can optionally be substituted with C1-C4-Alkyl, C1-C4-Alkoxy, hydroxy, nitro or amino, benzyl, pyridyl or C1-C6-Alkoxycarbonyl, saponifies with hydrochloric acid at a temperature of 120-160CC and under a pressure of 3-6 bar, in the presence of an inert organic solvent that does not mix with water. 2. The method according to claim 1, characterized in that R1 and R2, the same or different, represent hydrogen, C1-C4-alkyl, which can be substituted with fluorine, chlorine or bromine if necessary, C1-C4-alkoxy, C1-C4-acyl, C1-C4-alkoxycarbonyl, COOH , phenyl, benzyl, fluoro, chloro, bromo, hydroxy, nitro or amino, or yes R1 and R2 together with the adjacent carbon atoms of the phenyl ring form an unsaturated 6-membered carbocycle, which can be substituted with C1-C4-alkyl, fluorine, chlorine, bromine, COOH, phenyl or hydroxy, and R0x represents an oxazolin-2-yl radical, which can be singly or doubly substituted with one or more C1-C4-alkyl radicals, which can be optionally substituted with fluorine, chlorine, bromine, hydroxy or with C1-C4-alkoxy , C1-C4-Alkoxy, phenyl, which may optionally be substituted with C1-C4-alkyl, C1-C4-Alkoxy, hydroxy, nitro or amino, benzyl or C1-C4-Alkoxycarbonyl. 3. The procedure according to claim 1 or 2, characterized in that R1 and R2, the same or different, represent hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, CF3, methoxy, ethoxy, COOH, phenyl, benzyl, fluorine, chlorine, bromine, hydroxy , nitro or amino, or yes R1 and R2 together with the adjacent carbon atoms of the phenyl ring form an annelized phenyl ring which, if necessary, can be substituted with methyl, ethyl, n-propyl, iso-propyl, tert-butyl, fluorine, chlorine, chromium, COOH, phenyl or with hydroxy, and R0x represents an oxazolin-2-yl residue, which can be singly or doubly substituted as needed with one or more residues from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, methoxymethyl, hydroxymethyl , methoxy, ethoxy, phenyl, which may optionally be substituted with methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, methoxy, ethoxy or with hydroxy, benzyl, methoxycarbonyl or ethoxycarbonyl. 4. The method according to any of claims 1 to 3, characterized in that R1 and R2, the same or different, represent hydrogen, methyl, CF3, COOH, phenyl, fluorine or hydroxy, or that R1 and R2 together with the neighboring carbon atoms of the phenyl ring form an annelated phenyl ring, and R0x represents an oxazolin-2-yl radical, which is, if necessary, singly or doubly substituted with one or more radicals from the group consisting of methyl, ethyl, methoxy, ethoxy, phenyl or benzyl. 5. The method according to any of claims 1 to 4, characterized in that R1 and R2, the same or different, represent hydrogen, methyl or CF3, and R0x represents an oxazolin-2-yl residue, which can be singly or doubly substituted with methyl as needed. 6. The process according to any of claims 1 to 5, characterized in that the saponification is carried out under a pressure of 4-5 bar. 7. The process according to any of claims 1 to 6, characterized in that 3.0-6.0 moles of hydrochloric acid are used for saponification per mole of the starting compound of the general formula (IV) used. 8. The process according to any of claims 1 to 7, characterized in that 3.5-5.0 moles of hydrochloric acid are used for saponification per mole of the starting compound of the general formula (IV) used. 9. The method according to any of claims 1 to 8, characterized in that an aliphatic or aromatic hydrocarbon having 6-10 carbon atoms is used as an organic solvent. 10. The method according to any of claims 1 to 9, characterized in that an aliphatic or aromatic hydrocarbon having 7-8 carbon atoms or chlorobenzene is used as an organic solvent. 11. The method according to any of claims 1 to 10, characterized in that toluene, xylene, chlorobenzene and methylcyclohexane are used as organic solvents. 12. The method according to any of claims 1 to 11, characterized in that chlorobenzene is used as an organic solvent. 13. A process for the production of 4'-methylbiphenyl-2-carboxylic acid, characterized in that it is in accordance with any claim 1 bis 12.