KR19990082197A - Method for preparing optically active amines - Google Patents

Abstract

Certain optically active (S) -amines of the present invention are obtained by reacting a racemic amine suitable in the first step with an ester in the presence of a lipase from Candida antarctica and optionally in the presence of a diluent, It is prepared by separating.

Description

Method for preparing optically active amines

The present invention relates to novel processes for the preparation of known optically active amines which can be used as intermediates in the manufacture of pharmaceuticals and crop protection agents.

The preparation of optically active primary and secondary amines has already been disclosed in German Patent Publication No. 4 332 738, which comprises, firstly, a racemic amine with an ester having an electron-rich heteroatom in the acid residue adjacent to the carbonyl carbon, React in the presence of a hydrolase to enantioselectively acylate, and then split the resulting mixture of optically active (S) -amines and optically active acylated (R) -amines (= amides) accordingly ( S) -amines can be obtained and optionally prepared by decomposing amides from acylated (R) -amines to obtain the remaining enantiomers. Suitable hydrolases are Pseudomonas, for example Amano P, or lipases from Pseudomonas species DSM 8246. The optical purity grade of the enantiomers obtained by this method is quite high. However, the method has the disadvantage that a fairly long reaction time is required when carrying out enzymatic acylation, and that the reaction is carried out in a considerably diluted solution. Only when reacting for a relatively long time, the (S) -enantiomer is obtained which has a sufficiently high optical activity yield. Thus, the space-time yield that can be achieved is actually somewhat different from what is desired. In addition, there is a disadvantage that a relatively large amount of enzyme is required compared to the substrate. In addition, the activity of this enzyme is so high that a significant amount of cost is required for purification, concentration and processing. In addition, the process is only suitable for batch processes.

In addition, some racemic amines react enantioselectively with ethyl acetate in the presence of lipases from Candida antarctica, resulting in (S) -amines and acetylated (R) -amines (= amides). It is possible to provide a mixture, from which both (S) -amine and acetylated (R) -amine can be separated, followed by decomposition of the amide to liberate the acetylated (R) -amine. Chimia 48 , 570 (1994). The disadvantage of this method is that the reaction time is very long and the yield is not always satisfactory. In addition, there is also a disadvantage in the enzyme-substrate ratio, so it is almost impossible to use the process economically, especially in a batch process.

In the present invention,

a) In a first step, the racemic amine of formula (I) is reacted with an ester of formula (III) in the presence of Candida antarctica lipase, and optionally a diluent,

b) in a second step, by dividing the resulting mixture comprising (S) -amine of formula (I-S) and acylated (R) -amine of formula (IV-R)

It was found that optically active (S) -amines of the formula (I-S) can be obtained.

[In the above formula,

R ¹ and R ² are different,

R ¹ is methyl, ethyl or a group of formula (II)

R ² represents C ₁ -C ₁₀ -alkyl or optionally substituted C ₆ -C ₁₄ -aryl]

-R ³ -XR ⁴

[In the above formula,

R ³ represents a C ₁ -C ₁₀ -alkylene group or a C ₂ -C ₁₀ -alkenylene group,

R ⁴ represents a C ₁ -C ₁₀ -alkyl group, a C ₆ -C ₁₀ -aryl group or a C ₇ -C ₁₄ -aralkyl group,

X represents O, S or NR ⁵ , wherein R ⁵ is C ₁ -C ₁₀ -alkyl or phenyl]

[In the above formula,

R ¹ and R ² have the aforementioned meanings]

[In the above formula,

R ⁵ and R ⁶ are the same or different and in each case represent optionally substituted C ₁ -C ₂₀ -alkyl or optionally substituted C ₆ -C ₁₀ -aryl, R ⁵ may further represent hydrogen;

[In the above formula,

R ¹ , R ² and R ⁵ have the meanings mentioned above.

(R) -amine is used to mean an optically active compound of formula (I) and formula (IV-R) having an (R) -configuration at an asymmetrically substituted carbon atom. Similarly, (S) -amine is used to mean optically active compounds of formula (I) and formula (I-S) having a (S) -configuration at the chiral center. In the formulas for (R)-and (S) -amines, asymmetrically substituted carbons are indicated by * in each case.

Suitable substituents for alkyl and aryl groups, for example C ₁ -C ₆ - alkyl, C ₁ -C ₆ - alkoxy, and other substituents or equal to three of the group from consisting of halogen, nitro and cyano. Alkyl groups substituted with alkyl groups are branched chain alkyl groups.

In formulas (I), (IS) and (IV-R), R ¹ and R ² are different,

R ^{1 preferably} represents methyl, ethyl or a group of formula (II), wherein R ³ represents a methylene or ethylene group, R ⁴ represents a methyl, ethyl, phenyl or benzyl group, X represents O,

It is preferable that R ² represents C ₁ -C ₄ -alkyl.

In the formulas (I), (IS) and (IV-R), it is particularly preferred that R ¹ is —CH ₂ —O—CH ₃ and R ² represents methyl.

In formulas (III) and (IV-R), R ⁵ represents C ₁ -C ₆ -alkyl optionally substituted mono to C ₁ -C ₄ -alkyl, or C ₁ -C ₄ -alkyl, C Preference is given to phenyl optionally mono- or di-substituted with _1- C ₄ -alkoxy, chlorine, bromine, nitro and / or cyano. It is particularly preferred that R ⁵ represents unsubstituted C ₁ -C ₄ -alkyl. In formula (III), R ⁵ R ⁶ are different from Independently, preferred for R ⁵ represents one of the groups mentioned as preferred or particularly preferred that in the above or are particularly preferred. It is particularly preferable that R ⁵ represents methyl and R ⁶ represents ethyl.

No doubt it will be surprising that the optically active amines of the formula (I-S) can be produced by the process of the invention in high yield and very good optical purity. This could not be expected from the known prior art that certain uses of Candida antarctica lipase when reacting certain amines and certain esters result in higher enantioselectivity and higher reaction rates than enzyme systems conventionally used in the same method. Because.

The method according to the invention has several advantages. For example, the process of the present invention allows the production of large amounts of optically active amines in high yield and excellent optical purity. In addition, the method of the present invention has the advantage that the reaction can be carried out at a relatively high material concentration, the reaction time is short, and a continuous process is possible. Another advantage is the fact that a large amount of the necessary biocatalyst can be obtained, which is stable even at elevated temperatures. For the substrate, relatively small amounts of biocatalysts can be used. As a result, the reaction can be carried out without any difficulty and the desired material can be separated.

The racemic amines of formula (I) which are required as starting materials for the process according to the invention are known or can be prepared according to known processes. Likewise required esters of formula (III) are also known or can be prepared according to known methods. Necessary lipases can be used either in their natural state or in immobilized form. Possible immobilization methods are, for example, the use of lipases in microencapsulated or combined form with organic or inorganic support materials. Examples of suitable support materials are diatomaceous earth, ion exchangers, zeolites, polysaccharides, polyamides and polystyrene resins, in particular the Celite (trade name) and Lewatit (trade name) types. Examples of suitable lipases are Candida antarctica lipases in the form of commercially available Novozym 435 (tradename).

Suitable diluents optionally used include a wide variety of organic solvents, in particular ethers (eg diethyl ether or methyl tert-butyl ether (= MTBE)). It is also possible to carry out the reaction without a specific diluent. It is convenient to use an excess of ester of formula (III).

For example, it is possible to use from 0.5 to 20 mol of ester of formula (III) per mol of racemic amine of formula (I). When the reaction is carried out without adding a diluent, the amount of ester is preferably 1 to 10 mol, in particular 1 to 5 mol. When the reaction is carried out by adding a diluent, the amount of ester is preferably 1 to 7 mol, in particular 1 to 4 mol.

The process according to the invention can be carried out, for example, at a temperature in the range from 0 to 90 ° C, in particular from 10 to 60 ° C. The process is generally carried out under atmospheric pressure and in some cases under an inert gas, for example nitrogen.

When the process according to the invention is carried out batchwise, for example, certain racemic amines of formula (I), certain esters of formula (III), optionally diluents and candida anthrutica lipase, in the desired sequence Can be combined accordingly and the resulting mixture can be carried out by stirring at a certain reaction temperature until the desired conversion is achieved. Based on the racemic amine of formula (I), the amount of lipase is variable in a wide range. For example, based on the racemic amine of formula (I), an immobilized lipase, for example 0.1-40% by weight of Novozyme 435 (trade name), or a corresponding amount of natural lipase can be used. Preference is given to 0.5-30% by weight of immobilized lipase or a corresponding amount of natural lipase.

When the process according to the invention is carried out continuously, for example, a mixture comprising racemic amine of formula (I), ester of formula (III) and optionally a diluent is immobilized at the reaction temperature at the candida antarctica This can be done by passing through lipase. Here, the lipase can be used in proportion to the racemic amine of formula (I), for example in an amount necessary to obtain a specific desired conversion of the racemic amine of formula (I). The desired amount of conversion of the racemic amine of formula (I) is the desired excess of the enantiomer in the resulting (S) -amine of formula (IS), or the acylated (R) of formula (IV-R) produced. Depending on the intended excess of the enantiomer in the amine. For example, at least 0.000001 g of an immobilized lipase (eg Novozym 435; trade name) or a corresponding amount of natural lipase can be used per gram of racemic amine of formula (I). Preference is given to 0.000001 to 0.1 g of immobilized lipase or a corresponding amount of natural lipase.

When treating the resulting mixture after reacting the racemic amine of formula (I) with the ester of formula (III), the lipase must first be separated in the case of a batch process, for example by filtration. Thus, the separated lipase can be reused in subsequent batches. In this way, lipase can be recycled repeatedly. The resulting mixture after removal of the lipase corresponds to the mixture obtained when carried out in a continuous process. This mixture contains acylated (R) -amines of formula (IV-R) obtained from the R form of racemic amines of formula (I), the desired (S) -amines of formula (IS), esters used Alcohols formed, optionally unreacted (R) -amines of formula (I), optionally unreacted esters of formula (III), and optionally diluents.

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

The residue remaining after the separation step can be discarded or used as needed. For example, the acylated (R) -amines of the formula (IV) contained in the residue can be obtained as is, for example by separation by distillation, or the acylated (R) -amines of the formula (IV) After separation, the acyl group is removed in a known manner to obtain (R) -amines corresponding to the (S) -amines of formula (IS) prepared, or acylated (R) contained in the residue. After amines are racemized to remove acyl groups, they can be reused in the process according to the invention.

Amines of formula (I-S) that can be prepared by the process according to the invention are useful as intermediates in the manufacture of pharmaceuticals or active compounds with pesticidal, fungicidal or herbicidal power. This compound is particularly suitable for the preparation of N-thienylchloroacetamides having herbicidal activity (see, eg, EP 296 463 and 210 210).

<Example 1>

1 g of immobilized Candida antarctica lipase (Novozym 435; trade name) is suspended in 50 ml of MTBE, the suspension is treated with 10 g of (±) -2-amino-1-methoxypropane and 38.8 g of ethyl acetate are added. It was. After the mixture was stirred at 30 ° C. for 22 hours, the reaction was stopped. At a yield of 40%, the ee value for (S) -2-amino-1-methoxypropane exceeded 96% (GC).

<Example 2>

3.77 g of immobilized Candida antarctica lipase (Novozym 435; tradename) was introduced in a suspension form in MTBE in a glass tube (22 cm long, 1 cm internal diameter) heated at 40 ° C. with a bottom covered with frit. The bed volume reached 17 ml. Then a solution of 10 g of (±) -2-amino-1-methoxypropane and 38.8 g of ethyl acetate in 100 mL of MTBE was pumped through the frit at a rate of 10 mL per hour. Based on the racemate, a constant conversion of 60% was achieved. The ee value for (S) -2-amino-1-methoxypropane was greater than 97% (GC).

<Example 3>

Immobilized Candida antarctica lipase was separated from the reaction mixture obtained according to Example 1 by filtration and the filtrate was distilled off. Ethyl acetate, ethanol and MTBE were first distilled under atmospheric pressure, followed by (S) -2-amino-1-methoxypropane at 99 ° C., finally at 13 mbar and (R) -N-acetyl at 105 to 110 ° C. -2-amino-1-methoxypropane was distilled off.

<Example 4>

The lipase recovered according to Example 3 was the same as the method of Example 1, except that the lipase recovered in place of the unused immobilized antarctica lipase was used. The yield and ee value for (S) -2-amino-1-methoxypropane are the same as in Example 1.

<Example 5>

3 g of immobilized Candida antarctica lipase (Novozym 435; trade name) was suspended in 100 ml of MTBE, and the suspension was treated with 10 g of (±) -2-amino-1-benzyloxypropane and 20.8 g of ethyl acetate. The mixture was stirred at 40 ° C and stopped after the conversion reached 50%. The reaction solution was filtered over a column and distilled off. This gave 3.5 g of (S) -2-amino-1-benzyloxypropane (73 ° C. at boiling point = 1.8 mbar) with ee.

<Example 6>

3 g of immobilized Candida antarctica lipase (Novozym 435; trade name) was suspended in 100 ml of MTBE, and the suspension was treated with 10 g of (±) -2-amino-1-benzyloxybutane and 19.3 g of ethyl acetate. The mixture was stirred at 40 ° C and stopped after the conversion reached 50%. The reaction solution was filtered over a column and distilled off. This gave ee 95% of (S) -2-amino-1-benzyloxypropane (111-113 ° C. at boiling point = 7.6 mbar).

Claims (10)

a) in a first step, the racemic amine of formula (I) is reacted with an ester of formula (III) in the presence of Candida antarctica lipase, and optionally a diluent, b) in a second step, dividing the resulting mixture comprising (S) -amine of formula (I-S) and acylated (R) -amine of formula (IV-R) A process for producing an optically active (S) -amine of the formula (I-S) below. <Formula (I-S)> [In the above formula, R ¹ and R ² are different, R ¹ is methyl, ethyl or a group of formula (II) R ² represents C ₁ -C ₁₀ -alkyl or optionally substituted C ₆ -C ₁₄ -aryl] <Formula (II)> -R ³ -XR ⁴ [In the above formula, R ³ represents a C ₁ -C ₁₀ -alkylene group or a C ₂ -C ₁₀ -alkenylene group, R ⁴ represents a C ₁ -C ₁₀ -alkyl group, a C ₆ -C ₁₀ -aryl group or a C ₇ -C ₁₄ -aralkyl group, X represents O, S or NR ⁵ , wherein R ⁵ is C ₁ -C ₁₀ -alkyl or phenyl] <Formula (I)> [In the above formula, R ¹ and R ² have the aforementioned meanings] <Formula (III)> [In the above formula, R ⁵ and R ⁶ are the same or different and in each case represent optionally substituted C ₁ -C ₂₀ -alkyl or optionally substituted C ₆ -C ₁₀ -aryl, R ⁵ may further represent hydrogen; <Formula (IV-R)> [In the above formula, R ¹ , R ² and R ⁵ have the meanings mentioned above. The compound of claim 1, wherein in formulas (I), (IS) and (IV-R), R ¹ and R ² are different from each other, and R ¹ is methyl, ethyl or formula (II) (wherein R ³ is A methylene or ethylene group, R ⁴ represents a methyl, ethyl or phenyl group, X represents O) and R ² represents C ₁ -C ₄ -alkyl. 3. The compound of claim 1, wherein in formulas (III) and (IV-R), R ⁵ represents C ₁ -C ₆ -alkyl optionally substituted or substituted with C ₁ -C ₄ -alkyl , or C ₁ -C ₄ - alkyl, C ₁ -C ₄ - alkoxy, chlorine, bromine, nitro and (or) represents a substituted phenyl, optionally cyano, R ⁵ different from R ⁶ independently represent in the general formula (III), Characterized by satisfying one of the groups mentioned for R ⁵ . 4. The compound of claim 1, wherein in formulas R ¹ represents —CH ₂ —O—CH ₃ , R ² represents methyl, and R ⁵ and R ⁶ are independently unsubstituted. Characterized by C ₁ -C ₄ -alkyl. The process according to any one of claims 1 to 4, wherein the reaction is carried out in the presence of an organic solvent. The process according to any one of claims 1 to 5, characterized in that 0.5 to 20 mol of ester of formula (III) is used per mol of racemic amine of formula (I). The process according to claim 1, wherein the reaction is carried out at 0 to 90 ° C. 8. 8. The immobilized candida anthrutic lipase (based on the amine) according to any one of claims 1 to 7, wherein the reaction is carried out batchwise per gram of racemic amine of formula (I). The weight percent is characterized by using at least 0.000001 g of immobilized Candida antarctica lipase when the reaction is carried out continuously. The method according to any one of claims 1 to 8, characterized in that the (S) -amine prepared above is separated by distillation. 10. The method according to any one of claims 1 to 9, after separating the prepared (S) -amine, the acylated (R) -amine obtained together is also separated, and optionally, the prepared (S) A process characterized in that the (R) -amine corresponding to the amine is obtained by removing the acyl group from the acylated (R) -amine.