FI90995C - Process for the preparation of chiral compounds as pure optical isomers - Google Patents

Description

90995

PROCEDURE FOR THE PREPARATION OF CHIRAL COMPOUNDS AS PURE OPTICAL ISOMERS

The invention relates to a production process for the preparation of optical isomers of chiral compounds, in which a chiral and a non-chiral starting material are reacted with enzymes catalyzed by supercritical carbon dioxide as a reaction medium such that only one of the optical purity of the starting material.

A significant proportion (40%) of the drugs currently in use are in molecules with one or more chiral centers. Many of the pests used in agriculture and plant disease pesticides are also chiral compounds.

It is known that, in general, only one optical optical isomer, the enantiomer, of a chiral compound has the desired pharmacological or biological effect. However, for example, only about 12% of drugs are currently prepared as pure optical isomers. The main part is prepared and used as racemic mixtures.

The undesired enantiomer of the racemic mixture is often unaffected as a drug, can sometimes cause side effects and, in the worst case, can be toxic. It is obvious that the majority of chiral drugs and agrochemicals should be prepared and used as pure optical isomers. New legislation and the development of new, less expensive manufacturing technologies 25 bring obligations and opportunities, especially for the production of new, chiral drugs in pure optical isomers.

It is known to synthesize optically active compounds without enzymes using as intermediates, for example, intermediates prepared by asymmetric epoxidation. (Ex. K.B. Sharpless, Chemtech Nov. 1985, p. 682). The preparation of such chiral reagents is complex and very expensive. Overall, the process is expensive, which is part of the reason why drugs or agrochemicals are not produced more extensively as pure 2 enantiomers.

It is also known to prepare enantiomerically pure chiral compounds by separating the enantiomers of the racemic mixture by chromatographic methods (G. GCjbitz, Chromatography Vol. 30, No. 9/10, 1990, 555 * 564). Liquid chromatography using a mixture of organic solvents as eluent can be used. Several solid, chiral phases can be considered in liquid chromatography. However, there is no general-purpose chiral packaging material in the field of view, and it is thus necessary to develop its own method for each chiral separation. The liquid chromatographic production process requires the use of large amounts of organic solvents, which pose a fire hazard, occupational safety problems and environmental risks. In addition, there should be a small amount of solvent residue in the products. The desired optically pure product must be separated from the eluent by evaporation of the solvents. 15Solvents still need to be purified by distillation for reuse, which consumes a lot of energy.

It is also known to utilize the stereo- or enantiomeric specificity of enzymes to catalyze the synthesis of a particular enantiomer of a chiral compound in organic solvents (M. Schneider, Performance Chemicals, April 1989, 28-31). The organic solvents used in the process are flammable, toxic and the products must be recovered by distillation as in liquid chromatographic separation methods for the racemic mixture. The process also requires the treatment of large amounts of very dilute organic solutions.

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However, it is also known that many enzymes can catalyze reactions non-enantiospecifically even in a supercritical carbon dioxide environment (e.g., U.S. Pat. 4,925,790 and A. Marty et al., Biotechnology Letters, Vol 12, No. 1,1990,11-16). Supercritical carbon dioxide means carbon dioxide with a temperature higher than 30 than the critical temperature of carbon dioxide, ie higher than 32 ° C, and with a pressure higher than the corresponding critical pressure, i.e. greater than 72 bar. In this supercritical state, carbon dioxide can be used as a solvent for volatile or hydrophobic substances. Supercritical carbon dioxide is toxic, non-combustible and inexpensive

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3 90995 solvent. By using supercritical carbon dioxide as the reaction medium, occupational safety and emission problems as well as fire risks arising from the handling of large amounts of organic solvents can be avoided. A further advantage is that the recycling of carbon dioxide 5 for reuse consumes only a small part of the amount of energy required to recover organic solvents by distillation.

We have surprisingly found that some enzymes can selectively catalyze the reactions of the second enantiomer of chiral compounds in supercritical carbon dioxide. The finding makes possible a new process for the preparation of pure optical isomers of chiral compounds.

It is an object of the present invention to provide a new method for the preparation of optical isomers of chiral compounds which is more advantageous than previously known methods. The object of the invention is to provide a process in which, unlike the previous methods, carbon dioxide in the supercritical state is used as a medium in enzyme-catalyzed, enantioselective reactions.

Advantages of the process according to the invention include that a non-combustible, toxic and inexpensive solvent, carbon dioxide, is used in the dissolution of starting materials, as an intermediate in enzyme-catalyzed enantioselective reactions and possibly further in the fractionation of the reaction mixture and purification of products. A further advantage of the process is that the carbon dioxide forms an oxidation-protective atmosphere for the starting materials and the reaction products. Further advantages are the controllability of the solubility of the supercritical carbon dioxide. By this is meant that the ability of the supercritical carbon dioxide to dissolve hydrophobic substances strongly depends on its density. This property makes it possible to precipitate the reaction mixture from carbon dioxide simply by reducing the pressure of the carbon dioxide. In this way, the carbon dioxide is separated from the reaction mixture and can be recycled back to the dissolution of the starting materials with very low energy consumption. A further advantage of the process according to the invention is that the supercritical carbon dioxide has very good mass transfer properties compared to liquid solvents.

4 This property of carbon dioxide accelerates the dissolution of starting materials and promotes reactions limited by mass transfer. Another advantage of the method according to the invention is that the production process is practically completely closed.

5 There are no solvent releases, the generation of wastewater is very low, the process space is well protected from foreign microbial contamination and parts of the process can be easily sterilized if necessary. Carbon dioxide also does not leave harmful solvent residues in the products.

One preferred embodiment of the method according to the invention is the resolution of a racemic mixture of a chiral compound. In this application, the racemic mixture and the non-chiral reagent are contacted with the enzymes in supercritical carbon dioxide such that essentially only one enantiomer of the racemic mixture reacts. The resulting chiral reaction product is enantiomerically pure and differs from the racemic starting material physicochemically to such an extent that it can be separated from the reaction mixture by conventional methods such as extraction, crystallization or evaporation. If necessary, other optically pure isomers can be further prepared from the enantiomerically pure reaction product obtained by conventional chemical methods. One of the advantages of the process, compared with, for example, resolution with chiral reagents, is that in the process according to the invention, cheap, simple substances such as carboxylic acids or alcohols can be used instead of expensive chiral reagents.

25 The following examples illustrate some embodiments of the method.

Example 1 4.9 g of lipase 30 (EC 3.1.1.3) produced by the yeast Mucor m / e / ie / 'immobilized on an ion exchange resin was weighed into a 250 ml pressure vessel which was sealed and purged with atmospheric carbon dioxide. The pressure east i a was heated to 50 ° C and pumped with carbon dioxide so that the pressure inside the vessel rose to 150 bar. With carbon dioxide, the vessel was charged with 0.3 mL of water, 45 mmol of I: 90995 racemic ibuprofen, and 105 mmol of propanol, butanol, or amyl alcohol. The contents of the pressure vessel were agitated with a magnetic rod placed inside the vessel and rotated by a magnetic field passed through the bottom of the vessel.

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During the reaction, small samples were taken from the contents of the pressure vessel and analyzed by gas chromatography and liquid chromatography using chiral columns.

After the experiment, the contents of the pressure vessel were passed through a pressure relief valve to a vessel at 10 atmospheric pressure. Under reduced pressure, the components of the reaction mixture precipitated from carbon dioxide. They dripped and settled to the bottom of the collecting vessel. The supercritical carbon dioxide as the solvent in the reaction mixture gasified and escaped from the top of the collecting vessel.

According to the results of the analysis, the rate of esterification of the S-enantiomer of ibuprofen with these alcohols was about nine times the rate of esterification of the R-enantiomer of ibuprofen.

Reaction Enantiomeric _purity_ of S-ibuprofen ester 20 S, R-1buprofen + amyl alcohol 85% S, R-1buprofen + butyl alcohol 85% S, R-1buprofen + propyl alcohol 85% S, R-1bbrofen + ethyl alcohol 85%

Table 1. Enantiomeric purity of the propyl ester of S-ibuprofen formed in a lipase-catalyzed reaction between racemic ibuprofen and alcohols after 25% of racemic ibuprofen has reacted.

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Example 2 6

In the experimental set-up described in Example 1, the amount of water fed to the reactor with carbon dioxide was varied to find the optimum moisture for the reaction rate and enantioselectivity. Racemic ibuprofen and propanol were used as reaction starting materials. The results were as shown in Table 2.

According to the results, the preferred water content for the reaction rate is 0.35 to 1.3 10 ml of water / l of carbon dioxide. The enantiomeric purity of the resulting ester was not affected by water content.

15 S-ibuprofen ester

Carbon dioxide Reaction rate enantiomeric water content purity mmol / ml / l (kg lipase * h)% 0__6J__85.4 20 0.3__6JJ__84.5 0.35__6JJ__84.1 0.55__8J5__84.4 0.85__8Λ__84.4 1.3__416__83.6 25 1.75 3.5 85.3

Table 2. Effect of supercritical carbon dioxide water content on the conversion rate of racemic ibuprofen and the enantiomeric purity of the resulting chiral ester in the lipase-catalyzed 3Q esterification reaction of ibuprofen and propanol.

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Example 3.

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In the experimental setup described in Example 1, the effect of excess propanol on the reaction rate of ibuprofen and the enantiomeric purity of the resulting ester was varied to deliberately determine the content of non-chiral propanol reacting with racemic ibuprofen 5. The concentration of racemic ibuprofen in this series of experiments was 12 mmol / liter. The results are shown in Table 3.

In this series of experiments, a preferred excess of propanol in terms of reaction rate proved to be 3-16 mol propanol / mol ibuprofen. The enantiomeric purity of the resulting propyl ester of S-ibuprofen in excess propanol did not have a decisive effect.

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Propanol content Reaction rate Enantiomeric purity of S-ibuprofen propyl ester 20 mmol / l mmol / _ (kg enzyme * h) __% _ 30 5.6 82.9 40 9.8 83.5 60 9.6 83.5 80 10.8 84 25 110 10.4 82.6 210__9 ^ 2__80.1

Table 3. Effect of propanol content on the conversion rate of racemic ibuprofen and the enantiomeric purity of the resulting chiral S-ibuprofen ester in a lipase-catalyzed esterification reaction.

Example 4.

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In the experimental setup described in Example 1, the reaction temperature and pressure were varied. 5 Their effect on the rate of reaction between racemic ibuprofen and propanol and the enantiomeric purity of the resulting chiral S-ibuprofen propyl ester is shown in Table 4.

Temperature Pressure Reaction rate S-ibuprofen propyl ester 0 enantiomeric ___purity_ C__bar__mmol / (kg * h)% 50 250 7.9 83 50 150 11.7 83.5 50 110 22.1 82.6 15 36 150 7.3 83.8 42 150 10.7 82.3 62 150 9.2 83.7

Table 4. Effect of temperature and pressure on the rate of esterification of racemic ibuprofen and propanol in a lipase-catalyzed reaction.

Example 5.

In the experimental setup described in Example 1, 45 mmol of 2-octanol was used as the chiral, racemic starting material and 105 mmol of hexanoic acid as the non-chiral reagent. The rate of production of the resulting ester in the experiment was 12.5 mmol of ester per kg of lipase and per hour. The enantiomeric purity of the resulting R-2-octanol was 84% after 50% of the racemic 2-octanol had reacted.

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Example 6.

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In the experimental setup described in Example 1, 45 mmol of ibuprofen propyl ester was used as the chiral, racemic starting material and 105 mmol of amyl alcohol as the non-chiral reagent. The rate of the alcoholysis reaction was measured to be 17.5 mmol of ibuprofen amyl ester / (kg of lipase * h). The enantiomeric purity of the resulting S-ibuprofen amyl ester was 60% after 25% of the racemic starting material had reacted 10 15 20 25 30

Claims (3)

1: A process for the preparation of chiral compounds as optical isomers, characterized in that a) a compound belonging to the groups of carboxylic acids or esters and an alcohol reacting therewith, one of the reactive compounds being chiral and the other non-chiral, are dissolved in supercritical carbon dioxide, and a solution of the non-chiral compound in the supercritical carbon dioxide is contacted with an enzyme belonging to the lipase group (EC 3.1.1.3) produced by Mucor male yeast at a temperature of 35 to 70 ° C and a pressure of 80 to 250 bar, the supercritical carbon dioxide containing 0.4 to 1.5 ml. water per liter of carbon dioxide so that mainly only one stereoisomeric form of the chiral compound reacts with the non-chiral compound. Process according to Claim 1, characterized in that the chiral compound to be dissolved in the supercritical carbon dioxide forms a racemic mixture. Process according to Claim 1, characterized in that the chiral compound to be dissolved in the supercritical carbon dioxide is racemic ibuprofen. 90995