HK1078876B - Method for producing formylphenylboronic acids - Google Patents

Description

Process for preparing formylphenylboronic acids

The invention relates to a method for producing formylphenylboronic acids of formula (I).

Ortho-, meta-, para-formylphenylboronic acids are important intermediates in organic synthesis for the synthesis of diverse base structures and also in the agrochemical and pharmaceutical industry for the synthesis of active substances, but above all as compounds which are important, highly effective enzyme stabilizers, enzyme inhibitors and fungicides.

Although these compounds are of great economic interest owing to the abovementioned applications, only a few and costly processes are available in the literature.

Boric acid is typically prepared from a metal organic compound, such as a Grignard-Verbindungen or organolithium compound, with a boron trihalide or a trialkyl borate. Depending on the reactivity of the formyl group towards the organometallic compound, the above-described process is only possible in the preparation of formylphenylboronic acids if the formyl group is previously protected accordingly. Thus, p-halogenobenzaldehydes are used as starting materials, which are, for example, acetalized and subsequently converted into organometallic reagents.

Noeth et al (chem. Ber.1990, 1841-1843) convert p-bromobenzaldehyde into diethylacetal, Grignard it with magnesium chips in Tetrahydrofuran (THF), and obtain formylphenylboronic acid in 70% yield after reaction with tri-n-butyl borate. The disadvantages of this synthesis method are that bromobenzaldehyde is expensive compared to chlorobenzaldehyde, and the necessity of using ultrasonic excitation and the use of expensive tributyl borate in the Grignard (Grignard) preparation process; in addition, costly purification steps (in which the product 1-butanol is hydrogenated) are carried out.

Jendrella et al (Liebigs Ann.1995, 1253-1257) improved the same synthetic procedure to 78% by process modification, but the above-mentioned disadvantages remained unaddressed.

Kobayashi et al showed a significant increase in yield (up to 99%) by reacting n-butyllithium with bromobenzaldehyde-diethylacetal and tripropyl borate. However, the expensive price of bromobenzaldehyde, tripropyl borate and butyllithium makes this process economically unattractive.

It is therefore desirable to develop further processes for preparing formylphenylboronic acids using readily available and inexpensive starting compounds by conversion of inexpensive boron compounds to give the end products in high yields and high purity.

It was first established that the desired Grignard compound is obtained from different chlorobenzaldehyde-acetals by reaction with magnesium in different ethers, which is not possible according to the prior art methods.

It is described in the yet unpublished German application DE-A-19960866 that it is possible to obtain very high yields of Grignard compounds by adding a transition metal catalyst and simultaneously activating the magnesium mechanically (mecanische Aktivaerung). The corresponding formylphenylboronic acid is obtained in very high yields after reaction with trimethyl borate. This involves a very economically advantageous production process which, however, requires high investment and high requirements for plant construction, depending on the mechanical activation of magnesium. At the same time, the products also contain traces of the transition metals used in the ppm range, which have to be removed quantitatively in an expensive manner depending on the application (pharmaceutical, enzyme inhibitors).

The object of the present invention was therefore to provide a simple and economical process for preparing formylphenylboronic acid, based on commercially available and inexpensive starting compounds, which does not use transition metal catalysts and does not require high investment in plant construction. At the same time the process should provide a product of as high yield and purity as possible.

This object is achieved according to the invention BY a process which involves preparing formylphenylboronic acids of the general formula (I) BY reacting protected chlorobenzaldehydes of the general formula (II) with lithium metal in an inert solvent to give compounds of the formula (III) and subsequently reacting them with a compound of the formula BY₃To give a compound of the general formula (I)

Wherein Y represents a linear or branched C₁-C₆-alkoxy, C₁-C₅Dialkylamino, halogen or C₁-C₆An alkylthio group, R represents H, C₁-C₅-alkyl or C₁-C₅-alkoxy groups. Radical CHX₂Preferred are acetals of the formula (IV) or (V)

Wherein R is¹To R⁴Identically or differently hydrogen, C₁-C₁₂-alkyl or-phenyl, or R¹And R²Together or R¹And R³Together form a 5-or 6-membered aliphatic or aromatic ring; or an oxazolidine of formula (VI)

Or aminals of the formula (VII)

Wherein R is¹To R⁴As defined above, and R⁵And R' represents C₁-C₆-alkyl or-aryl.

Protected o-, m-or p-chlorobenzaldehydes can be used as starting compounds of the formula (II).

Although the metallic lithium used according to the present invention is an expensive raw material in terms of mass, such a price difference is relatively slight in comparison with magnesium in consideration of the amount of the used material. In the present invention, the metal is added in the form of dispersion, powder, chips, gravel, granules, blocks, strips or other forms to a suitable solvent and allowed to react with the protected benzaldehyde chloride. Suitable inert solvents are all those which react neither with metallic lithium nor with the lithiated aromatic substance formed under the reaction conditions according to the invention, in particular aliphatic or aromatic ethers, tertiary amines or hydrocarbons, such as THF, diethyl ether, diisopropyl ether, di-n-butyl ether, toluene, cyclohexane or dioxane, or mixtures of the inert solvents in question.

The reaction of lithium metal and protected chlorobenzaldehyde is carried out at a temperature in the range of-100 ℃ to +35 ℃ because the reaction proceeds very slowly at low temperatures, but the aryl lithium formed at higher temperatures, for example, attacks and cleaves acetal, aminal or oxazolidine functional groups. The preferred reaction temperature range is therefore from-70 to +10 ℃ and particularly preferably from-55 ℃ to +5 ℃.

The reaction of lithium with the compounds of the formula (II) is generally complete after 3 to 18 hours, in particular after 4 to 10 hours. In some cases, depending on the nature of the protected chlorobenzaldehyde and the solvent used, respectively, which are used, the reaction proceeds significantly more slowly, with the result that the time yield is unfavourable. The rate of progress of the reaction can be significantly increased by the presence of an organic redox catalyst, such as biphenyl, naphthalene, or other organic compound, which rapidly absorbs electrons from the lithium metal and rapidly and efficiently adds to the C, Cl bond of the protected chlorobenzaldehyde. The redox catalyst is used in an amount of between 0 and 5 mol%.

The molar ratio of lithium to the compound of the formula (II) is generally in the range from 1.9: 1 to 8: 1, but it is of course also possible to use a large excess if, for example, it is advantageous for plant reasons, such as in a circulation pump plant.

The concentration of the lithium compound in the solvent can be between 0.5 and 50 wt.%, preferably between 5 and 35 wt.%, particularly preferably between 15 and 30 wt.%. The protected chlorobenzaldehyde can be metered in or, in the case of larger lithium blocks, can be added completely beforehand.

The reaction of the resulting organolithium of the formula (III) with boron compounds is carried out at low temperatures in the range from +20 to-110 ℃ and preferably in the range from 0 to-80 ℃ for the purpose of high selectivity. The method of metering the boron compound into the organolithium solution in the form of a liquid or a solution, or metering the organolithium solution into the boron compound (which may be a hydrocarbon or ether solution, if desired) may be employed. A slight excess, in particular an excess of 5 to 50%, of boron compound is purposefully used.

Suitable boron compounds are, for example, boron halides, such as BBr₃、BF₃、BCl₃Or borates, such as trimethyl borate, triisopropyl borate or tributyl borate, it being likewise possible to use mixed haloborates. It is also possible to use boron amines or thio compounds, such as tris (diethylamino) boron or tris (n-butylthio) boron.

The reaction mixture is suitable for various working-up methods after melting to room temperature, for example hydrolysis with water, adjustment of the pH in the slightly acidic range (2.5-6.5), removal of the solvent by distillation, filtration and drying of the product. If the solvent for lithiation is to be obtained in anhydrous form and used directly for the lithiation reaction for economic reasons, it can be distilled off from the reaction mixture with simultaneous addition of a high-boiling solvent, for example cyclohexane instead of diethyl ether and toluene instead of THF.

Prior to isolation of the formylphenylboronic acid from the reaction mixture, for example by filtration or centrifugation, the water-soluble solvent, for example THF, should be removed by a suitable, for example distillation operation, otherwise the solubility of the product in water would increase and the yield would be correspondingly reduced. The pH of the hydrolysis mixture is initially in the alkaline range and is adjusted to a value in the range from 7.5 to 1.0 before the product is obtained and before the water-soluble solvent is distilled off, in order to avoid side reactions, such as the Cannizzaro reaction. The preferred pH range is between 6.0 and 3.0, with individual levels of free boric acid being particularly preferred.

The filtration or centrifugation of the product is suitably carried out at a temperature in the range of-10 to +75 ℃.

The drying of the formylphenylboronic acid produced, on account of its oxygen sensitivity, must be carried out gently under vacuum in a protective gas atmosphere, preferably at from 20 to 80 ℃.

The continuous preparation under protective gas gives a very pure product (> 99%, HPLC a/a) and in most cases can be used subsequently without further purification.

Purification is required for specific applications. For example, it can be dissolved in caustic soda solution at 0-30 ℃ and extracted with toluene or another hydrocarbon or ether, followed by precipitation by acidification. Such a purification process is described, for example, in the unpublished German application DE-A-10032017.1.

The process according to the invention is illustrated by the following examples, without restricting the invention thereto.

Example 1

3.52g of lithium chips and 180g of THF at-50 ℃ were prepared. 53.6g of 4-chlorobenzaldehyde-diethyl acetal was added dropwise thereto over 90 min. After subsequent stirring for 2 hours, it is cooled to-70 ℃ and 31.2g of trimethyl borate dissolved in 60ml of THF are added dropwise at this temperature for 15 min. The material was melted overnight. 250g of water were added at 0 ℃ and the pH was adjusted to 4.5 with 26.5g of 36% HCl. The hygroscopic THF is distilled off as completely as possible under slight vacuum. The resulting suspension was cooled to 10 ℃ and suction filtered at 10 ℃. The product was washed with a small amount of ice water and dried at 40 ℃ in a weak stream of nitrogen. The yield of pure 4-formylphenylboronic acid was 35.8g (95.6%).

Example 2

4.3g of lithium chips were prepared, 0.03g of biphenyl and 450g of THF were added at-50 ℃. 53.6g of 4-chlorobenzaldehyde-ethylene glycol acetal was added dropwise thereto over 90 minutes. After subsequent stirring for 7 hours, it was cooled to-60 ℃ and 32.2g of trimethyl borate dissolved in 30ml of THF were added dropwise at this temperature for 30 min. The material was melted overnight. 250g of water were added at 0 ℃ and the pH was adjusted to 4.5 with 26.5g of 36% HCl. The hygroscopic THF is distilled off as completely as possible under slight vacuum. The resulting suspension was cooled to 10 ℃ and suction filtered at 10 ℃. The product was washed with a small amount of ice water and dried at 40 ℃ in a weak stream of nitrogen. The yield of pure 4-formylphenylboronic acid was 33.8g (90.1%), which was slightly less than in the first experiment because the cleavage product, ethylene glycol, increased the solubility of the product in the aqueous phase.

Example 3

The preparation of the lithium compound is carried out analogously to example 1, but in this case a 1: 1 mixture of THF and toluene is used as solvent. The resulting lithium compound was reacted with 1.2 equivalents of commercial BCl in toluene at-70 deg.C₃The solution is reacted. The yield of 4-formylphenylboronic acid here was 79%.

Example 4

Example 2 was repeated with the addition of 0.2 mol% of biphenyl, wherein the stirring time could be reduced to 2 hours. The yield here was 89%.

Example 5

The preparation of the lithium compound is carried out analogously to example 2 with the addition of 0.25% of biphenyl in the solvent toluene, after which the stirring time has to be extended to 14 hours. The yield was 83%.

Example 6

3-formylphenylboronic acid is obtained in a yield of 91.5% in a similar manner to example 1, starting from 3-chlorobenzaldehyde-diethylacetal.

Example 7

Starting from 2-chlorobenzaldehyde-diethylacetal, in a manner analogous to example 1, 2-formylphenylboronic acid is obtained in a yield of 83%.

Example 8

3.52g of lithium chips and 180g of THF at-50 ℃ were prepared. 53.7g of 3-chlorobenzaldehyde-N, N' -dimethylethylenediamine (255mmol) were added dropwise over 90 min. After subsequent stirring for 2 hours, it was cooled to-50 ℃ and 31.2g of trimethyl borate dissolved in 60ml of THF were added dropwise at this temperature over 15 min. The material was melted overnight. 290g of water were added at 0 ℃ and the pH was adjusted to 3.9 with 36.9g of 37% HCl. The hygroscopic THF is distilled off as completely as possible under slight vacuum (under atmospheric pressure, in order to ensure complete cleavage of the acetal). The resulting suspension was cooled to 10 ℃ and filtered with suction at 10 ℃. The product was washed carefully with a small amount of ice water and dried at 40 ℃ in a weak stream of nitrogen. The yield of pure 3-formylphenylboronic acid was 34.5g (92.1%).

Claims (12)

1. A process for the preparation of formylphenylboronic acids of the general formula (I) BY reacting protected chlorobenzaldehydes of the general formula (II) with lithium metal in an inert solvent to give compounds of the formula (III) and subsequently reacting them with a compound of the formula BY₃To give a compound of the general formula (I)

Wherein Y represents a linear or branched C₁-C₆-alkoxy, C₁-C₅Dialkylamino, halogen or C₁-C₆Alkylthio groups, R representing H, C₁-C₅-alkyl or C₁-C₅Alkoxy, radical CHX₂Is an acetal of formula (IV) or (V)

Wherein R is¹To R⁴The same or different represent hydrogen, C₁-C₁₂-alkyl or phenyl, or R¹And R²Together or R¹And R³Together form a 5-or 6-membered aliphatic or aromatic ring; or an oxazolidine of formula (VI)

Or aminals of the formula (VII)

Wherein R is¹To R⁴As defined above, and R⁵And R' represents C₁-C₆-alkyl or aryl.

2. The process according to claim 1, wherein the molar ratio of lithium to compound of formula (II) is in the range from 1.9: 1 to 8: 1.

3. A process according to claim 1 or 2, wherein lithium is in the form of a dispersion, powder, crumb, gravel, block or granule and is reacted with the protected chlorinated benzaldehyde of formula (II).

4. A process according to claim 1 or 2, wherein the reaction of lithium with the protected chlorobenzaldehyde is carried out at a temperature in the range of-100 ℃ to +35 ℃.

5. The process according to claim 1 or 2, wherein aliphatic or aromatic ethers, tertiary amines or hydrocarbons are used as inert solvents.

6. A process according to claim 1 or 2, wherein the reaction of the compound of formula (II) with lithium is carried out in the presence of an organic redox catalyst.

7. The process according to claim 1 or 2, wherein the organolithium of formula (III) is reacted with a boron compound BY₃The reaction of (a) is carried out in the range of +20 to-110 ℃.

8. The process according to claim 1 or 2, wherein an excess of boron compound is used with respect to the organolithium.

9. The process according to claim 1, wherein the water-soluble solvent is distilled off before the isolation of the formylphenylboronic acid of the formula (I).

10. The process according to claim 9, wherein the pH is adjusted to the range of 7.5 to 1.0 before distilling off the solvent.

11. The process according to claim 9 or 10, wherein the formylphenylboronic acid of the formula (I) is isolated from the reaction mixture by filtration or centrifugation at a temperature in the range from-10 ℃ to +75 ℃.

12. The process according to claim 1 or 2, wherein the formylphenylboronic acid of the formula (I) obtained is dried under protective gas in vacuo.