DE19603575A1 - Process for the production of optically active amines - Google Patents

Abstract

Specific optically active (S)-amines are obtained as follows: in a first stage, suitable racemic amines are allowed to react, in the presence of lipase from Candida antarctica and optionally in the presence of a diluting agent, with an ester; and in a second stage, the mixture obtained is separated.

Description

The present invention relates to a new process for the production of known, optically active amines, which are used as intermediates for the production of Pharmaceuticals and crop protection products can be used.

From DE-A 43 32 738 it is already known that optically active, primary and have secondary amines prepared by first adding racemic amine to Presence of a hydrolase with an ester in the acid part in the vicinity of the Carbonyl carbon atom has an electron-rich heteroatom, enantio selectively acylated, then the resulting mixture of optically active (S) -amine and separates optically active acylated (R) amine (= amide), thereby obtaining the (S) amine and optionally the other from the acylated (R) amine by amide cleavage Enantiomer wins. Lipases from Pseudomonas come as hydrolases, e.g. B. Amano P, or from Pseudomonas spec. DSM 8246 in question. The optical one The degree of purity of the enantiomers obtained is very high. Disadvantage of this However, the process is that the reaction in the enzymatic acylation is quite long times are required and work is carried out in a very dilute solution. That ver permanent (S) -enantiomer is only in after relatively long reaction times obtained sufficiently high optical yield. The achievable space-time yields therefore leave something to be desired for practical purposes. It is also unfavorable that in Relative to the substrate, relatively high amounts of enzyme are required. In addition, the enzyme has a very high activity, so that a considerable Effort for cleaning, concentration and processing necessary is. In addition, this mode of operation is only suitable for a discontinuous one Execution.

Furthermore, Chimia 48 570 (1994) shows that a few racemic Amines with ethyl acetate in the presence of lipase from Candida antarctica enantioselective to mixtures of (S) -amine and acetylated (R) -amine (= amide) react from which (S) -amine and acetylated (R) -amine can be isolated, the acetylated (R) amine being released by subsequent amide cleavage can be. A disadvantage of this method is that the reak is quite long tion times are required and, moreover, the yields are not always satisfactory are. The ratio of enzyme to substrate is also disadvantageous here  detention, so that an economic use of the method, especially one continuous implementation, are hardly possible.

It has now been found that optically active (S) amines of the formula

in the
R¹ and R² are different,
R¹ is methyl, ethyl or a radical of the formula (II)

-R³-X-R⁴ (II),

in which
R³ represents a C₁-C₁₀ alkylene radical or a C₂-C₁₀ alkenylene radical,
R⁴ is a C₁-C₁₀ alkyl radical, a C₆-C₁₀ aryl radical or a C₇-C₁₄ aralkyl radical and
X represents O, S or NR⁵ (with R⁵ = C₁-C₁₀ alkyl or phenyl) and
R² represents C₁-C₁₀ alkyl or optionally substituted C₆-C₁₄ aryl,
get when one

• a) in a first stage racemic amines of the formula in the
  R¹ and R² have the meanings given above,
  with esters of the formula in the
  R⁵ and R⁶ are identical or different and each represents optionally substituted C₁-C₂₀ alkyl or optionally substituted C₆-C₁₀ aryl,
  in the presence of lipase from Candida antarctica and optionally in the presence of a diluent and
• b) in a second stage the mixture obtained containing (S) -amine of the formula (IS) and acylated (R) -amine of the formula in the
  R¹, R² and R⁵ have the meanings given above,

separates.

(R) -amines are those optically active compounds of the formula (I) and (IV-R) to understand the asymmetrically substituted carbon atom (R) configuration. Accordingly, among (S) amines are those to understand optically active compounds of the formula (I) and (I-S) which are based on the Chira center have the (S) configuration. In the formulas for (R) - and (S) amines are the asymmetrically substituted carbon atoms with * featured.  

As substituents for alkyl and aryl radicals come, for. B. up to 3 of the same or ver various substituents from the group comprising C₁-C₆-alkyl, C₁-C₆-alkoxy, Halogen, nitro and cyano residues in question. For those substituted with alkyl radicals Alkyl residues are branched alkyl residues.

In formulas (I), (IS), and (IV-R), R1 and R2 are different from each other, wherein
R¹ is preferably methyl, ethyl or a radical of the formula (III) in which R³ is a methylene or ethylene radical, R⁴ is a methyl, ethyl, phenyl or benzyl radical and X is O and
R² is preferably C₁-C₄ alkyl.

In the formulas (I), (I-S) and (IV-R) R 1 very particularly preferably represent -CH₂-O-CH₃ and R² for methyl.

In the formulas (III) and (IV-R) R⁵ is preferably from one to optionally C₁-C₆-alkyl substituted twice by C₁-C₄-alkyl or for optionally one up to twice by C₁-C₄-alkyl, C₁-C₄-alkoxy, chlorine, bromine, nitro and / or Cyano substituted phenyl. R⁵ particularly preferably stands for unsubstituted C₁-C₄ alkyl. In formula (III) R⁶ is independent of R⁵ preferably and in particular ders preferred for one of the radicals that are preferred at R⁵ and especially before trains are specified. R⁵ very particularly preferably stand for methyl and R⁶ for Ethyl.

It is extremely surprising to see that optically active amines Formula (I-S) according to the inventive method in high yield and very have good optical purity. Due to the known state of the Technology could not be expected that the special use lipase from Candida antarctica a higher enantioselectivity and a faster reaction in the reaction between the respective amine and each because ester causes than those previously used in corresponding processes Enzyme systems.

The method according to the invention has a number of advantages. So enabled it is the production of a large number of optically active amines in high yield  prey and excellent optical purity. It is also favorable that at relative high substrate concentration can be worked, the reaction times are short are and a continuous way of working is possible. It is also advantageous that the required biocatalyst is available in large quantities and also at elevated temperature is stable. The biocatalyst can be in relation to the substrate be used in a relatively small amount. Finally, the through also prepares implementation and isolation of the desired substances none Difficulties.

The racemi required as starting materials for the process according to the invention The amines of the formula (I) are known or can be prepared according to known methods Create methods. The esters of the formula (III) required are also known or can be produced according to methods known per se. The required lipase can be used both natively and in immobilized form. Possible Immobilizations include the use of lipase in microencapsulated Form or bound to an organic or inorganic carrier material. As Backing materials come e.g. B. diatomaceous earth, ion exchangers, zeolites, poly saccharides, polyamides and polystyrene resins in question, in particular Celite® and Lewatit® types. For example, lipase from Candida antarctica in is suitable Form of the commercially available product Novozym® 435.

A wide variety of possible diluents are used organic solvents in question, especially ethers such as Diethyl ether or methyl tert-butyl ether (= MTBE). You can also without additive a special diluent. Then it is useful to have one Use excess of the ester of formula (III).

Based on one mole of racemic amine of the formula (I), for example Use 0.5 to 20 mol of an ester of the formula (III). When working without additional diluent, this amount of ester is preferably 1 to 10 mol, in particular 1 to 5 mol. When working with the addition of a ver this amount of ester is preferably 1 to 7 mol, in particular the other at 1 to 4 mol.

The method according to the invention can, for example, at temperatures in the loading range from 0 to 90 ° C, in particular 10 to 60 ° C. Usually  one works at atmospheric pressure, optionally under an inert gas, for. B. Nitrogen.

If the process according to the invention is carried out batchwise, one z. B. proceed in such a way that the respective racemic amine of the formula (I), the respective ester of formula (III), optionally a diluent and Lipase from Candida antarctica combines in any order and that resulting mixture at the respective reaction temperature until reached of the desired turnover. The amount of lipase based on the racemi cal amine of formula (I) can be varied within wide limits. At for example, 0.1 to 10% by weight of immobilized lipase, e.g. B. Novozym® 435, based on the racemic amine of formula (I), use or appropriate amount of native lipase. This amount is preferably 0.5 to 8% by weight of immobilized lipase or the corresponding amount of native lipase.

If the process according to the invention is carried out continuously, one can e.g. B. proceed so that a mixture containing a racemic amine Formula (I), an ester of formula (III) and optionally a diluent at reaction temperature via immobilized lipase from Candida antarctica. In relation to the racemic amine of formula (I), the lipase z. B. be used in an amount that is required to meet a particular to obtain the desired conversion of the racemic amine of the formula (I). Of the Desired conversion of the racemic amine of formula (I) depends on desired enantiomeric excess in the (S) -amine of formula (I-S) produced or the desired enantiomeric excess in the acylated available (R) amine of formula (IV-R). For example, you can at least 0.000001 g immobilized lipase, e.g. B. Novozym® 435, per g of racemic amine of the formula (I) or use an appropriate amount of native lipase. Preferably is this amount 0.0001 to 0.1 g of immobilized lipase or an equivalent Amount of native lipase.

When working up after the reaction of the racemic amine of the formula (I) with the mixture of the formula (III) present, it is discounted Nuclear work first required to separate the lipase, which in can be accomplished for example by filtration. So separated lipase can be used again for the next approach. Such a return The lipase can be repeated several times. That after the separation  the mixture present in the lipase corresponds to that in the continuous mode of operation obtained mixture. It contains that from the (R) form of the racemic amine Formula (I) obtained acylated (R) -amine of formula (IV-R), the desired one (S) -amine of the formula (I-S), the alcohol formed from the ester used, optionally unreacted (R) -amine of formula (I), possibly not unreacted esters of formula (III) and optionally diluents.

The desired (S) -amine of the formula (I-S) can be separated off, for example by distillation or extraction. Distillation is preferred.

The residue remaining after this separation can be discarded or opened can be used in any way. For example, you can see what it contains Isolate acylated (R) -amine of formula (IV), e.g. B. by distillation, and it as win such or after its isolation from the acylated (R) amine Formula (IV) split off the acyl group in a manner known per se and so that the prepared (S) -amine of the formula (I-S) corresponding (R) -amine or racemize the acylated (R) -amine obtained and after removal of the Use the acyl group again in the process according to the invention.

The amines of the formula (I-S) which can be prepared by the process according to the invention are valuable intermediates for the manufacture of pharmaceuticals or Active ingredients with insecticidal, fungicidal or herbicidal properties. In particular They are suitable for the preparation of herbicidally active N-thienylchloroacet amides (see e.g. EP-A 296 463 and EP-A 210 320).

Examples example 1

1 g of immobilized Candida antarctica lipase (Novozym® 435) in 50 ml MTBE suspended and mixed with 10 g (±) -2-amino-1-methoxypropane and 38.8 g of ethyl acetate were added. After stirring at 30 ° C. for 22 hours, the Response canceled. With a yield of 40%, the ee value for (S) -2-amino-1-methoxypropane over 96 (GC).

Example 2

In a glass tube heated to 40 ° C, 22 cm long and 1 cm inside knife, which was sealed with a frit at the bottom, 3.77 g were immobilized Candida antarctica lipase (Novozym® 435) filled into MTBE as a suspension. The bed volume was 17 ml. A solution of 10 g was then poured over the frit (±) -2-Amino-1-methoxypropane in 100 ml MTBE and 38.8 g ethyl acetate with a Pumped in rate of 10 ml / h. There was a constant turnover of 94%, based on racemate, a. The ee value for the (S) -2-amino-1-methoxypropane was over 97% (GC).

Example 3

From the reaction mixture obtained in Example 1, the immobilized Candida antarctica lipase separated by filtration and the filtrate by distillation worked up. At normal pressure, ethyl acetate, ethanol and MTBE initially worked over, then at 84 to 90 ° C (S) -2-amino-1-methoxypropane and finally at 13 mbar and 105 to 110 ° C (R) -N-acetyl-2-amino-1-methoxypropane.

Example 4

The procedure was as in Example 1, but not fresh immobilized antarctica lipase used, but the one according to Example 3 had been recovered. The yield and the ee value for (S) -2-amino-1- methoxypropane were as in Example 1.

Claims (11)

1. Process for the preparation of optically active (S) amines of the formula in the
R¹ and R² are different,
R¹ is methyl, ethyl or a radical of the formula (II) -R³-X-R⁴ (II), in which
R³ represents a C₁-C₁₀ alkylene radical or a C₂-C₁₀ alkenylene radical,
R⁴ is a C₁-C₁₀ alkyl radical, a C₆-C₁₀ aryl radical or a C₇-C₁₄ aralkyl radical and
X represents O, S or NR⁵ (with R⁵ = C₁-C₁₀ alkyl or phenyl) and
R² represents C₁-C₁₀ alkyl or optionally substituted C₆-C₁₄ aryl,
characterized in that one

• a) in a first stage racemic amines of the formula in the
  R¹ and R² have the meanings given above,
  with esters of the formula in the
  R⁵ and R⁶ are the same or different and each represents optionally substituted C₁-C₂₀ alkyl or optionally substituted C st-C₁₀ aryl,
  in the presence of lipase from Candida antarctica and, if appropriate, in the presence of a diluent and
• b) in a second stage the mixture obtained containing (S) -amine of the formula (IS) and acylated (R) -amine of the formula in the
  R¹, R² and R⁵ have the meanings given above,

separates. 2. The method according to claim 1, characterized in that in the formulas (I), (I-S) and (IV-R) R1 and R2 are different from each other and R1 is Is methyl, ethyl or a radical of formula (III), in which R³ is one Methylene or ethylene radical, R⁴ for a methyl, ethyl or phenyl radical and X is O and R² is C₁-C₄ alkyl.   3. The method according to claims 1 and 2, characterized in that in the Formulas (III) and (IV-R) R⁵ for optionally once or twice C₁-C₄-alkyl substituted C₁-C₆-alkyl or optionally with C₁-C₄ alkyl, C₁-C₄ alkoxy, chlorine, bromine, nitro and / or cyano substi tuiert phenyl and in formula (III) R⁶ independently of R⁵ one of the previously specified meanings for R⁵ fulfilled. 4. The method according to claims 1 to 3, characterized in that in the Formulas R¹ for -CH₂-O-CH₃, R² for methyl and R⁵ and R⁶ independently stand for each other for unsubstituted C₁-C₄ alkyl. 5. The method according to claims 1 to 4, characterized in that one in Presence of an organic solvent works. 6. The method according to claims 1 to 5, characterized in that 0.5 to 20 moles of an ester of formula (III) per mole of racemic amine Formula (I) is used. 7. The method according to claims 1 to 6, characterized in that it at 0 to 90 ° C. 8. The method according to claims 1 to 7, characterized in that one discontinuous procedure 0.1 to 10 wt .-% immobilized lipase Candida antarctica (based on amine) and with continuous driving at least 0.000001 g immobilized Candida antarctica lipase per g racemic amine of formula (I) is used. 9. The method according to claims 1 to 8, characterized in that the Separation of the (S) -amine produced by distillation. 10. The method according to claims 1 to 9, characterized in that one after separation of the (S) -amine produced, the also obtained acylated (R) -amine isolated and if necessary therefrom by cleavage of the Acyl group is the (R) -amine corresponding to the (S) -amine produced wins.