DE10063738C2 - Process for the production of formylphenylboronic acids - Google Patents

Description

The invention relates to a process for the preparation of formylphenylboronic acids of the formula (I):

Ortho-, meta- and para-formylphenylboronic acids are versatile building blocks in organic synthesis and important intermediates in the synthesis of active ingredients in the agrochemical and pharmaceutical industries but above all, the compounds as enzyme stabilizers, inhibitors and bactericides are of high efficiency and importance tung.

Despite the high economic interest in this connection due to the applications mentioned only a few and expensive manufacturing methods are described in the literature.

Boronic acids are generally generated by the implementation of organometallic compounds (e.g. Grignard Compounds or lithium organyls) with boron trihalides or trialkyl borates. Due to the Re Activity of the formyl group against organometallic compounds is this procedure in the production of For mylphenylboronic acids only possible if the formyl group is protected beforehand. As raw materials p-Halogenbenzaldehyde are therefore to be used, for example acetalized and then to organometallic Reagent are implemented.

Noeth et al. ("Chem. Ber.", 1990, 1841-1843) convert p-bromobenzaldehyde to diethyl acetal, Grignardizing with magnesium shavings in tetrahydrofuran (THF) and obtained after reaction with tri-n-butylborate formylphenylbo ronic acid in a yield of 70%. The disadvantage of this synthesis is the high price of bromobenzaldehyde compared with chlorobenzaldehyde, the need for ultrasound activation in Grignard production and the use of expensive tributyl borates; In addition, complex cleaning procedures have to be carried out (including by the hydrolysis pro ducts 1-butanol).

Jendralla et al. ("Liebigs Ann.", 1995, 1253-1257) achieve by process improvements in the same Synthesis sequence after all an improvement to 78%; here too, however, the above-mentioned disadvantages remain changed exist.

Kobayashi et al. Achieve significantly better yields (up to 99%). by reacting the bromobenzaldehyde Diethylacetals with n-butyllithium and reaction with triisopropyl borate; against an economically interesting process However, the high prices of bromobenzaldehyde, triisopropyl borate and butyllithium speak here.

There was therefore a need to develop a process for the production of formylphenylboronic acids, that starts from commercially available and inexpensive starting compounds and the target products by Um setting with cheap boron compounds in good yields and high purities.

It was first found that the required Grignard compounds were made from different chlorobenzalde hyd-acetals by reaction with magnesium in various ethers by methods of the prior art are not are accessible.

In the unpublished German application DE-A 199 60 866 it was found that by addition of transition metal catalysts and simultaneous, mechanical activation of the magnesium Grignard verbin can be obtained in good yields. After reaction with trimethyl borate, the corresponding results formylphenylboronic acids in good yields. This is an economically very interesting one Manufacturing method, which, however, due to the required mechanical activation of the magnesium high In requires investments and places high demands on plant engineering. At the same time, the products contain traces of used transition metals in the ppm range, which depending on the application (pharmaceuticals, enzyme inhibitors) according to complex methods must be removed quantitatively.

The object of the present invention was therefore to produce a simple and economical process Provision of formylphenylboronic acids, starting from commercially available and inexpensive starting compounds to provide that without the use of transition metal catalysts and without high investment in plant construction. At the same time, the process should produce the products in the highest possible yields Deliver purity.

The inventive method solves this problem and relates to 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 subsequent implementation with a boron compound of the formula BY ₃ to give compounds of the formula (I):

wherein Y represents a straight-chain or branched C ₁ -C ₆ alkoxy or C ₁ -C ₅ dialkylamino group, halogen or a C ₁ - C ₆ alkylthio group,
R represents H, or a C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy radical.

The radical CHX ₂ is preferably an acetal of the formula (IV) or (V):

wherein R ¹ to R ^{4 are the} same or different and are hydrogen, C ₁ -C ₁₂ alkyl or phenyl, or R ¹ and R ² together or R ¹ and R ³ together a 5- or 6-membered, aliphatic or form aromatic ring;
or an oxazolidine of the formula (VI):

or an aminal of formula (VII):

wherein R ¹ to R ^{4 is} as defined above and R ⁵ and R 'are C ₁ -C ₆ alkyl or aryl.

Protected ortho-, meta- or para-chlorobenzaldehydes can be used as starting compounds of the formula (II) be set.

Although the lithium metal used according to the invention, based on its mass, is an expensive raw material, it is the price difference to magnesium, if you refer to the amount of substance used, is negligible. The Metal is used in the present process as a dispersion, powder, chips, sand, granules, pieces, bars or in other Form presented in a suitable solvent and reacted with the protected chlorobenzaldehyde.

Suitable, inert solvents are all those which, under the conditions according to the invention, do not contain Lit hium metal still react with the resulting lithiated aromatics, especially aliphatic or aromatic ethers, tertiary amines or hydrocarbons, such as. B. THF, diethyl ether, diisopropyl ether, di-n-butyl ether, toluene, cyclo hexane or dioxane or mixtures of the inert solvents in question.

The reaction of lithium metal with protected chlorobenzaldehydes is carried out at temperatures between -100 and + 35 ° C because the reaction is too slow at lower temperatures, at higher temperatures but temperatures to the resulting lithium aryls, for example the acetal, aminal or oxazolidine functionality grab and split. Preferred reaction temperatures are therefore in the range from -70 to + 10 ° C, especially before moves -55 to + 5 ° C.

The reaction of lithium with compounds of formula (II) is generally after 3 to 18 hours, ins special in 4 to 10 hours, completely expired, in some cases - depending on the nature of the used, protected chlorobenzaldehyde and the solvent used - the reaction is significantly slower, which means that poor time yields result. The rate of this reaction can be determined by the presence of or ganic redox catalysts such as biphenyl, naphthalene or other organic compounds increased significantly be, which quickly take up electrons from the Li metal and these quickly and efficiently on the C, Cl bond of the ge protected chlorobenzaldehyde. The redox catalysts are added in amounts between 0 and 5 mol% puts.

The molar ratio of lithium to the compound of the formula (II) is usually in the range from 1.9: 1 up to 8: 1; however, larger surpluses can also be used if this is the case, for. B. for apparatus reasons is advantageous, for. B. in pumping equipment.

The concentration of the lithium compound in the solvent can be between 0.5 and 50% by weight; be 5 to 35% by weight are preferred; particularly preferably 15 to 30% by weight. The protected chlorobenzaldehyde can either be dosed or (especially in the case of larger Li pieces) presented in full.

The reaction of the resulting lithium organyls of the formula (III) with the boron compounds becomes an ore high selectivities at low temperatures between +20 and -110 ° C, preferably between 0 and -80 ° C. The procedure can either be such that the boron compounds as liquids or solvents solutions to the solution of the lithium organyl or by adding the solution of the lithium organyl to the (given if necessary, dosed as a solution in hydrocarbons or ethers) submitted boron compound. Conveniently,  becomes a slight excess, in particular an excess in the range of 5 to 50%, of boron compound used.

Suitable boron compounds, for example boron halides, such as BBr ₃ , BF ₃ , BCl ₃ or boric acids, such as, for. B. trimethyl borate, triisopropyl borate or tributyl borate can be used; Mixed halo boric acid esters can also be used. Likewise, amines or thio compounds of boron can be used, for example tris (diethylamino) borane or tris (n-butylthio) borane.

After thawing the reaction mixtures to room temperature, there are various work-up methods suitable, for example hydrolysis by adding water, adjusting the pH to a slightly acidic range (2.5-6.5), distilling off the solvent, filtering and drying the product. It is for economic reasons of interest to get the solvent used in the lithiation in anhydrous form and this directly to use again in the lithiation, this can also from the reaction mixture with the simultaneous addition of a higher boiling solvent can be obtained by distillation; for example, diethyl ether by cyclohexane or THF to be replaced by toluene.

Before the formylphenylboronic acids are separated off from the reaction mixture, for example by filtration or centrifugation, water-soluble solvents, such as THF, should expediently e.g. B. abge by distillation are separated, since otherwise the solubility of the products in water is increased and the yields are reduced accordingly become. The pH of the hydrolysis mixture is initially in the alkaline range and is before the product is obtained or before distilling off water-soluble solvents to a value in the range from 7.5 to 1.0 in order to Ne benreactions, such as. B. Cannizzaro reactions; pH ranges between 6.0 and 3.0 are preferred; the particular pH of the free boronic acid is particularly preferred.

The filtration or centrifugation of the products is expediently carried out at temperatures in the range from -10 up to + 75 ° C.

The drying of the resulting formylphenylboronic acids must be un because of their sensitivity to oxidation ter protective gas and in a vacuum and at mild temperatures, preferably in the range of 20 to 80 ° C, performed become.

The product is obtained in constant purity under protective gas in a very pure form (<99%, HPLC a / a) and can be in can be used in most cases without further cleaning.

Purifications are required for special applications. B. by dissolving in sodium hydroxide solution 0-30 ° C, extraction with toluene or another hydrocarbon or ether and subsequent precipitation by Acidification can be made. Such, suitable purification methods are for example in the German described, not prepublished application DE-A 100 32 017.1.

The process according to the invention is to be illustrated by the following examples, without the invention limit to:

example 1

3.52 g of lithium chips and 180 g of THF are placed at -50 ° C. 53.6 g of 4-chlorobenzaldehyde diethylacetal are added dropwise in 90 min. After stirring for a further 2 hours, the mixture is cooled to -70 ° C. and at this temperature 31.2 g of trimethyl borate dissolved in 60 ml of THF were added dropwise in 15 min. Let the batch thaw overnight. At 0 ° C 250 g of water are added and the pH is adjusted to 4.5 with 26.5 g of HCl 36%. The water-moist THF is in the slight vacuum distilled off as completely as possible. The resulting suspension is cooled to 10 ° C and at 10 ° C aspirated. The product is washed with a little ice water and dried at 40 ° C in a gentle stream of nitrogen. The The yield of pure 4-formylphenylboronic acid is 35.8 g (95.6%).

Example 2

3.52 g of lithium chips and 180 g of THF are placed at -50 ° C. 46.1 g of 4-chlorobenzaldehyde ethylene glycol cetal are added dropwise in 90 min. After stirring for a further 4 h, the mixture is cooled to -70 ° C. and at this temperature 31.2 g of trimethyl borate dissolved in 60 ml of THF were added dropwise in 15 min. Let the batch thaw overnight. At 0 ° C 250 g of water are added and the pH is adjusted to 4.5 with 26.5 g of HCl 36%. The water-moist THF is in the slight vacuum distilled off as completely as possible. The resulting suspension is cooled to 10 ° C and at 10 ° C aspirated. The product is washed with a little ice water and dried at 40 ° C in a gentle stream of nitrogen. The Yield of pure 4-formylphenylboronic acid is 33.8 g (90.1%); the slightly lower yield than in the first expe riment is explained by the cleavage product glycol, which increases the solubility of the product in the aqueous phase.

Example 3

The lithium compound was prepared analogously to Example 1; however, a 1: 1 mixture of THF and toluene was used as the solvent in this case. The resulting Li compound was reacted with 1.2 equivalents of a commercial solution of BCl ₃ in toluene at -70 ° C. The yield of 4-formylphenyl boronic acid was 79% here.

Example 4

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

Example 5

The Li compound was prepared analogously to Example 2 in the solvent toluene with addition performed by 0.25% biphenyl; the stirring time had to be increased to 14 hours. Yield 83%.

Example 6

Starting from 3-chlorobenzaldehyde diethylacetal, analogously to Example 1, 3- in a yield of 91.5% Obtained formylphenylboronic acid.

Example 7

Starting from 2-chlorobenzaldehyde diethylacetal, analogously to Example 1, 2- in a yield of 83% Obtained formylphenylboronic acid.

Example 8

3.52 g of lithium chips and 180 g of THF are placed at -50 ° C. 53.7 g of 3-chlorobenzaldehyde-N, N'-dimethyl Ethylenediaminal (255 mmol) are added dropwise in 90 min. After stirring for a further 2 hours, the temperature is reduced to -50 ° C cools and 31.2 g of trimethyl borate dissolved in 60 ml of THF are added dropwise at this temperature in 15 min. Leave overnight thaw the approach. 290 g of water are added at 0 ° C. and the pH is adjusted to 3.9 with 36.9 g of 37% HCl. The water-moist THF is distilled off as completely as possible in a slight vacuum (at normal pressure to ensure complete To ensure splitting of the terminal). The resulting suspension is cooled to 10 ° C. and suction filtered at 10 ° C. The product is carefully washed with ice water and dried at 40 ° C in a gentle stream of nitrogen. The out Prey of pure 3-formylphenylboronic acid is 34.5 g (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 in an inert solvent to give compounds of the formula (III) and subsequent reaction with a boron compound of the formula BY ₃ Compounds of formula (I):
in which Y represents a straight-chain or branched C ₁ -C ₆ alkoxy group, C ₁ -C ₅ dialkylamino group, halogen or a C ₁ -C ₆ alkylthio group,
R represents H, a C ₁ -C ₅ alkyl or a C ₁ -C ₅ alkoxy radical.
The radical CHX ₂ is preferably an acetal of the formula (IV) or (V):
wherein R ¹ to R ^{4 are the} same or different and are hydrogen, C ₁ -C ₁₂ alkyl or phenyl, or R ¹ and R ² together or R ¹ and R ³ together a 5- or 6-membered, aliphatic or form aromatic ring,
or an oxazolidine of the formula (VI):
or an aminal of formula (VII):
wherein R ¹ to R ^{4 is} as defined above and R ⁵ and R 'are C ₁ -C ₆ alkyl or aryl. 2. The method of claim 1, wherein the ratio of lithium: compound of formula (II) in the range of 1.9: 1 to 8: 1. 3. The method according to at least one of the preceding claims, wherein the lithium in the form of dispersion NEN, powder, sand, chips, pieces or granules presented and with the protected chlorobenzaldehyde of the formula (II) is reacted. 4. The method according to at least one of the preceding claims, wherein the reaction of lithium with the protected chlorobenzaldehyde is carried out at a temperature in the range of -100 to + 35 ° C. 5. The method according to at least one of the preceding claims, wherein aliphatic as the inert solvent or aromatic ethers, tertiary amines or hydrocarbons can be used. 6. The method according to at least one of the preceding claims, wherein the implementation of compounds of Formula (II) is carried out with lithium in the presence of organic redox catalysts. 7. The method according to at least one of the preceding claims, wherein the reaction of the lithium organyls of the formula (III) with the boron compounds BY _{3 is carried out} at temperatures in the range from +20 to -110 ° C. 8. The method according to at least one of the preceding claims, wherein the boron compound with respect to the Lithium organyl is added in excess. 9. The method according to at least one of the preceding claims, wherein prior to separation of the formylphenylbo ronic acids of formula (I) water-soluble solvents are removed by distillation. 10. The method according to claim 9, wherein the pH is in the range before the solvents are distilled off is set from 7.5 to 1.0. 11. The method according to claim 9 and / or 10, wherein the formylphenylboronic acid of formula (I) at temperatures is separated from the reaction mixture in the range from -10 to + 75 ° C. by filtration or centrifugation. 12. The method according to at least one of the preceding claims, wherein the formylphenylboron obtained acids of the formula (I) are dried under protective gas, if appropriate in vacuo.