WO1997028271A1

WO1997028271A1 - Method of producing optically active amines

Info

Publication number: WO1997028271A1
Application number: PCT/EP1997/000239
Authority: WO
Inventors: Claus Dreisbach; Uwe Stelzer
Original assignee: Bayer Aktiengesellschaft
Priority date: 1996-02-01
Filing date: 1997-01-20
Publication date: 1997-08-07
Also published as: JP2000504224A; EP0877815A1; KR19990082197A; CA2244917A1; DE19603575A1

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

Process for the production of optically active amines

The present invention relates to a new process for the preparation of known, optically active amines which are used as intermediates for the preparation of

Pharmaceuticals and crop protection products can be used

From DE-A 4 332 738 it is already known that optically active, primary and secondary amines can be prepared by first enantio racemic amine in the presence of a hydrolase with an ester which has an electron-rich heteroatom in the acid part in the vicinity of the carbonyl carbon atom - selectively acylated, then separating the resulting mixture of optically active (S) amine and optically active acylated (R) amine (= amide), thereby obtaining the (S) amine and optionally from the acylated (R) amine Amide cleavage that wins other enantiomers Lipases from Pseudomonas, for example Amano P, or from Pseudomonas spec DSM 8246 can be used as hydrolases. The optical

The degree of purity of the enantiomers obtained is very high. However, a disadvantage of this process is that quite long reaction times are required in the case of the enzymatic acylation and the reaction is carried out in a very dilute solution. The remaining (S) -enantiomer is only removed after a relatively long reaction time - Obtain a sufficiently high optical yield The achievable space-time yields therefore leave something to be desired for practical purposes. It is also unfavorable that relatively high amounts of enzyme are required with respect to the substrate. Otherwise, the enzyme has a very high activity, so that a considerable effort for cleaning, concentrating and working up is necessary. In addition, this method of operation is only suitable for a discontinuous one

execution

Furthermore, from Chimia 48, 570 (1994) it emerges that a few racemic amines with ethyl acetate in the presence of lipase from Candida antarctica react enantioselectively to form mixtures of (S) -amine and acetylated (R) -amine (= amide), from which (S) -Amιn and acetylated (R) -Amιn can be isolated, the acetylated (R) -amine can be released by subsequent amide cleavage. It is disadvantageous about this method that quite long reaction times are again required and also the Yields are not always satisfactory. The ratio of enzyme to substrate is also disadvantageous here. liable, so that an economical use of the method, in particular also a continuous implementation, are hardly possible.

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

in the

R ¹ and R ^{2 are} different,

R ^{1 represents} methyl, ethyl or a radical of the formula (II)

-R ³ -XR ⁴ (II),

in which

R ³ is a C ^ C- _Q alkylene radical or a C ₂ -C, ₀ - AI may learn keny,

R ^{4 is} a C _j -C _Q alkyl radical, a C ₆ -C ₁₀ aryl radical or a C ₇ -C ₁₄ aralkyl radical and

X represents O, S or NR ⁵ (with R ⁵ = C, -C _{] 0} alkyl or phenyl) and

R ^{2 represents} C - C ₁₀ alkyl or optionally substituted C ₆ -C _{] 4} aryl,

get when one

a) in a first stage racemic amines of the formula

in the R ¹ and R ^{2 have} the meanings given above,

with esters of the formula

O

(HI),

-C - OR in the

R ⁵ and R ⁶ are the same or different and each represents optionally substituted C - ₂₀ alkyl or optionally substituted C ₆ _{-C] 0} aryl are C and R ⁵ additionally also be hydrogen,

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) -Amιn of formula (I-S), and acylated (R) -Amιn of formula

NH - C - R (IV-R),

R ¹ - CH - R ²

in the

R .1 ^J , R- and R have the meanings given above,

separates

(R) amines are to be understood as those optically active compounds of the formulas (I) and (IV-R) which have the (R) configuration on the asymmetrically substituted carbon atom. Accordingly, (S) amines are those optically active compounds of the To understand formulas (I) and (IS) which have the (S) configuration at the chirate center In the formulas for (R) - and (S) amines, the asymmetrically substituted carbon atom is identified by *.

Suitable substituents for alkyl and aryl radicals are, for example, up to 3 identical or different substituents from the group comprising C ₁ -C ₆ -alkyl, C - C ₆ -alkoxy, halogen, nitro and cyano radicals substituted with alkyl radicals

Alkyl residues are branched alkyl residues

In formulas (I), (IS), and (IV-R), R ¹ and R ^{2 are} different from each other, wherein

R ¹ preferably represents methyl, ethyl or a radical of the formula (III) in which R ^{3 represents} a methylene or ethylene radical, R ^{4 represents} a methyl, ethyl,

Phenyl or benzyl and X are O and

R ² preferably represents C _r C ₄ alkyl

In the formulas (I), (IS) and (IV-R), R ¹ very particularly preferably represents -CH ₂ -O-CH ₃ and R ^{2 represents} methyl

In the formulas (III) and (IV-R), R ⁵ preferably represents C 1 -C ₆ -alkyl which is optionally substituted once or twice by C ₄ -C ₄ -alkyl or optionally em 2 to 2 times by C-C _4- alkyl, C _] -C ₄ -alkoxy, chlorine, bromine, nitro and / or cyano-substituted phenyl. R ⁵ particularly preferably represents unsubstituted C _r C ₄ -alkyl. In formula (III), R ^{6 is} preferably and independently of R ⁵ particularly preferably represents one of the radicals set forth in Trains t R ⁵ as preferred and particularly bevor¬ most preferably, R ⁵ is methyl and R ⁶ is ethyl

It is to be regarded as extremely surprising that optically active amines of the formula (I-S) can be prepared in high yield and very good optical purity by the process according to the invention on the basis of the known state of the art

Technically, it could not be expected that the special use of lipase from Candida antarctica causes a higher enantioselectivity and a faster reaction in the reaction between the respective amine and the respective ester than the enzyme systems previously used in corresponding processes The method according to the invention has a number of advantages. It enables the production of a large number of optically active amines with high yield and excellent optical purity. It is also favorable that it is possible to work with a relatively high substrate concentration, the reaction times are short and continuous operation is possible. It is also advantageous that the required biocatalyst is available in large quantities and is stable even at elevated temperatures. The biocatalyst can be used in a relatively small amount in relation to the substrate. Finally, the implementation of the reaction and the isolation of the desired substances also pose no difficulties.

The racemic amines of the formula (I) required as starting materials for the process according to the invention are known or can be prepared by methods known per se. The esters of the formula (III) required are likewise known or can be prepared by methods known per se. The required lipase can be used both natively and in immobilized form. Possible

Immobilizations are, for example, the use of lipase in microencapsulated form or bound to an organic or inorganic carrier material. Support materials include, for example, diatomaceous earth, ion exchangers, zeolites, polysaccharides, polyamides and polystyrene resins, 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 organic solvents come into consideration as optional diluents, in particular ethers such as diethyl ether or methyl tert-butyl ether (= MTBE). You can also work without adding a special diluent. It is expedient to use an excess of the ester of the formula (III).

Based on one mol of racemic amine of the formula (I), for example 0.5 to 20 mol of an ester of the formula (III) can be used. When working without an 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 diluent, this 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 temperatures in the range from 0 to 90 ° C., in particular from 10 to 60 ° C. Usually one works at atmospheric pressure, optionally under an inert gas, for example nitrogen.

If the process according to the invention is carried out batchwise, for example, the procedure can be such that the respective racemic amine of the formula (I), the respective ester of the formula (III), if appropriate a diluent and lipase from Candida antarctica are combined in any order and the resulting mixture at the respective reaction temperature until the desired conversion is reached. The amount of lipase based on the racemic amine of the formula (I) can be varied within wide limits. For example, 0.1 to 40% by weight of immobilized lipase, eg B use Novozym ^® 435, based on the racemic amine of the formula (I), or a corresponding amount of native lipase. This amount is preferably 0.5 to 30% by weight of immobilized lipase or the corresponding amount of native lipase

When the process according to the invention is carried out continuously, it is possible, for example, to proceed so that a mixture comprising a racemic amine of the formula (I), an ester of the formula (III) and, if appropriate, a diluent is passed from the Candida antarctica via immobilized lipase at reaction temperature Ratio to the racemic amine of the formula (I), the lipase, for example, can be used in an amount which is required to obtain a specific desired conversion of the racemic amine of the formula (I). The desired conversion of the racemic amine of the formula (I) is directed after the desired enantiomeric excess in the prepared (S) -Amιn of formula (IS) or the desired enantiomeric excess in the available acylated

(R) -amine of the formula (IV-R) For example, one can at least 0.000001 grams of immobilized lipase, for example Novozym ^® 435, per g of racemic amine of the formula (I) or a corresponding amount of native lipase used preferably amounts to this quantity 0 , 00001 to 0.1 g of immobilized lipase or a corresponding amount of native lipase

When working up the mixture present after the reaction of the racemic amine of the formula (I) with the ester of the formula (III), it is first necessary, in the case of a batchwise procedure, to separate the lipase, which can be accomplished, for example, by filtration Lipase can be used again for the next approach. Such a return of the lipase can be repeated several times. The mixture present after the lipase has been separated off corresponds to the mixture obtained in the continuous procedure. It contains the acylated (R) -amine of the formula (IV-R) obtained from the (R) form of the racemic amine of the formula (I), the desired one

(S) -amine of formula (I-S), the alcohol formed from the ester used, optionally unreacted (R) -amine of formula (I), optionally unreacted ester of formula (III) and optionally diluent

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 used in any way. For example, the acylated (R) -amine of formula (IV) contained therein can be isolated, for example by distillation, and obtained as such or after its isolation from the acylated (R) -amine of formula (IV) in a manner known per se split off the acyl group and thus obtain the (R) -amine corresponding to the (S) -amine of formula (IS) prepared or racemize the acylated (R) -amine obtained and reuse it in the process according to the invention after removal of the acyl group

The amines of the formula (I-S) which can be prepared by the process according to the invention are valuable intermediates for the preparation of pharmaceuticals or of

Active ingredients with insecticidal, fungicidal or herbicidal properties are particularly suitable for the preparation of herbicidally active N-thienylchloroacetamides (see, for example, EP-A 296 463 and EP-A 210 320)

Examples

example 1

1 g of immobilized Candida antarctica lipase (Novozym ^® 435) was suspended in 50 ml of MTBE and 10 g of (+) - 2-amino-l-methoxypropane were added and 38.8 g of ethyl acetate were added. After stirring for 22 hours at 30 ° C. the

Response canceled. With a yield of 40%, the ee value for (S) -2-amino-1-m eth oxypropane was over 96% (GC)

Example 2

3.77 g were immobilized in a glass tube of 22 cm long and 1 cm inside diameter heated to 40 ° C., which was closed at the bottom with a frit

Candida antarctica lipase (Novozym ^® 435) filled in suspension in MTBE. The bed volume was 17 ml. A solution of 10 g (±) -2-amino-l-methoxypropane in 100 ml MTBE and 38.8 g ethyl acetate was then added to the frit pumped in at a rate of 10 ml / h There was a constant conversion of 60%, based on racemate, The ee value for the (S) -2-amino-l-methoxypropane was over 97% (GC)

Example 3

The immobilized Candida antarctica lipase was separated by filtration from the reaction mixture obtained according to Example 1 and the filtrate was worked up by distillation. At normal pressure, first ethyl acetate, ethanol and MTBE passed over, then at 99 ° C. (S) -2-amino-1-methoxypropane and finally at 13 mbar and 105 to 1 10 ° C (R) -N-acetyl-2-amino-l-methoxypropane

Example 4

The procedure was as in Example 1, but not fresh immobilized antarctica lipase was used, but rather that which had been recovered according to Example 3. The yield and the ee value for (S) -2-amino-1-methoxypropane were as in Example 1 Example 5

3 g of immobilized Candida antarctica lipase (Novozym ^® 435) were suspended in 100 ml of MTBE and 10 g (±) -2-amino-l-benzyloxypropane and 20.8 g of ethyl acetate were added. The mixture was stirred at 40 ° C. and interrupted after 50% conversion. The reaction solution was filtered and distilled through a column

3.5 g (S) -2-amino-1-benzyloxypropane (bp. = 73 ° C. at 1.8 mbar) were obtained with an ee of 95%.

Example 6

3 g of immobilized Candida antarctica lipase (Novozym ^® 435) were suspended in 100 ml of MTBE and with 10 g (±) -2-amino-1-benzyl oxybutane and 19.3 g

Ethyl acetate added. The mixture was stirred at 40 ° C. and interrupted after 50% conversion. The reaction solution was filtered and distilled through a column. 3.5 g of (S) -2-amino-1-benzyl oxypropane (bp. = 1 1 1 ⁰ C-1 13 ° C at 7.6 mbar) were obtained with an ee of 95%.

Claims

1. Process for the preparation of optically active (S) amines of the formula

*

in the

R ¹ and R ^{2 are} different,

R ^{1 represents} methyl, ethyl or a radical of the formula (II)

-R ³ -XR ⁴ (II),

in which

R ^{3 represents} a CpC- _Q alkylene radical or a C, -C _{] 0} -alkenylene radical,

R ^{4 is} a C - C _{] 0} alkyl radical, a C ₆ -C _{] 0} aryl radical or a C ₇ -C _{) 4} aralkyl radical and

X represents O, S or NR ⁵ (with R ⁵ - C, -C _{] 0} -alkyl or phenyl) and

R ^{2 represents} C _r C ₁₀ alkyl or optionally substituted C ₆ -C _{] 4} aryl,

characterized in that one

a) in a first stage racemic amines of the formula

NH ₂ R - CH -R in the

R ¹ and R ^{2 have} the meanings given above,

with esters of the formula

O

II (HI),

-C - OR ^c

in the

R ⁵ and R ⁶ are the same or different and each if appropriate substituted C - C ₂₀ alkyl or optionally sub¬ stituiertes C ₆ _{-C] 0} aryl, and R ⁵ may additionally denote also hydrogen,

in the presence of lipase from Candida antarctica and, if appropriate, in the presence of a diluent and

b) in a second step the mixture obtained containing (S) -amine of the formula (I-S) and acylated (R) -amine of the formula

O

H 5 NH -C - R (IV-R),

R - CH - R

in the

R ¹ , R ² and R ^{5 have} the meanings given above,

separates

A method according to claim 1, characterized in that in the formulas

(I), (IS) and (IV-R) R ¹ and R ^{2 are} different from one another and R ^{1 is} methyl, ethyl or a radical of the formula (III) in which R ^{3 is} one Methylene or ethylene radical, R ^{4 is} a methyl, ethyl or phenyl radical and X is O and R ^{2 is} C _r C ₄ alkyl.

3. A process according to claims 1 and 2, characterized in that in the formulas (III) and (IV-R) R ⁵ is optionally substituted once or twice by C _r C ₄ alkyl-substituted C _j -CG alkyl or optionally With

C, -C ₄ alkyl, C _r C ₄ alkoxy, chlorine, bromine, nitro and / or cyano substituted phenyl and in formula (III) R ⁶ independently of R ^{5 has} one of the meanings given for R ⁵ .

4. Process according to Claims 1 to 3, characterized in that in the formulas R ¹ for -CH ₂ -O-CH ₃ , R ² for methyl and R ⁵ and R ⁶ independently of one another represent unsubstituted C - C ₄ alkyl

5 Process according to claims 1 to 4, characterized in that in

Presence of an organic solvent works.

6. Process according to Claims 1 to 5, characterized in that 0.5 to 20 mol of an ester of the formula (III) per mol of the racemic amine

Formula (I) is used.

7. Process according to Claims 1 to 6, characterized in that it is carried out at 0 to 90 ° C.

8. Process according to Claims 1 to 7, characterized in that 0.1 to 10% by weight of immobilized lipase is used in a batchwise procedure

Candida antarctica (based on amine) and at least 0.000001 g immobilized lipase from Candida antarctica per g racemic amine of the formula (I) is used in the case of continuous driving.

9. The method according to claims 1 to 8, characterized in that one carries out the separation of the (S) -amine produced by distillation.

10. The method according to claims 1 to 9, characterized in that, after the separation of the (S) -amine produced, the acylated (R) -amine also obtained and optionally isolated therefrom by cleavage of the Acyl group wins the (R) -amine corresponding to the (S) -amine produced.