KR100671084B1 - Process for preparing [l]- or [d]-homoalanin-4-yl-(methyl)phosphinic acid and its salts by racemic resolution - Google Patents

Abstract

Compounds of the invention are obtained by racemate separation of D, L-homoalanin-4-yl (methyl) phosphinic acid via precipitation of one of the diastereomeric salts using a chiral base such as quinine or cinconine. If precipitation of diastereomeric salts occurs with racemization of unwanted enantiomers in the presence of (hetero) aromatic aldehydes, modified racemate separation can increase the yield of the desired enantiomers. The racemization method is also suitable for structurally different optically active amino acids.

Description

Method for preparing [L]-or [D] -homoalanin-4-yl- (methyl) phosphinic acid and salts thereof by racemate separation {PROCESS FOR PREPARING [L]-OR [D] -HOMOALANIN-4-YL- (METHYL) PHOSPHINIC ACID AND ITS SALTS BY RACEMIC RESOLUTION}

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[DL] -homoalanin-4-yl (methyl) phosphinic acid (DL-Ia) and its ammonium salt (DL-Ib) are amino acid derivatives with herbicidal activity (DE-A-27 17 440). The amino acid derivatives are L-form (L-Ia or L-Ib) active, whereas the related enantiomeric D forms are practically inactive (DE-A-2856260):

[Formula 1]

In order to use purely active substances, special processes have been developed for preparing [L] -homoalanin-4-yl (methyl) phosphinic acid and its salts.

According to DE-A-3 920 570 and DE-A-3 923 650, Form L can be obtained by enzymatic transamination. However, the workup of the transamination solution is very technology intensive; It also produces a large amount of salt.

According to EP-A-224 880, likewise pure form L, in several stages, starts from [D] -valine and becomes [R] -3-isopropyl-2,5-dialkoxy-3,6-di as main reaction. Obtained using ethanethiomer-selective alkylation of hydropyrazine; The difficulty in obtaining heterocyclic intermediates and the need for the use of organometallic agents is disadvantageous for industrial scale applications. Form L is also obtained by asymmetric hydrogenation of N-substituted 2-amino-4-[(methyl) (hydroxy) phosphino] butenoic acid (EP-A-238954).

It is also possible to prepare (L-Ia) starting from L-vinylglycine or (substituted) L-4-vinyl-1,3-oxazolidin-5-one, and methanephosphonose monoesters ( EP-A-546566 and 346658); Obtaining chiral precursors is not easy.

Moreover, methods using methanephosphonose diesters are known (EP-A-508298 and EP-A-530506); The required phosphorus component is not readily available in large quantities, which impedes the performance of the process on a large scale.

The separation of the racemic mixture [DL-Ia] into pure enantiomers by virtue of a "classic" precipitation method using the solubility difference of diastereomeric salts has not been disclosed to date. For structurally different amino acids, several methods have been disclosed in which racemates can be separated using chiral compounds as diastereomeric salts. In this connection, methods of combining the precipitation of diastereomeric salts of the desired enantiomers with the racemization of unwanted enantiomers are of particular interest.

See, eg, Bull. Chim. Soc. Jap. 56 (1983) 3744-3747, and [D] -phenylglycine from [DL] -phenylglycine using [d] -camphor-10-sulfonic acid as the salt former in the presence of acetic acid and salicyaldehyde as racemic agents. A process for preparing phenylglycine in 68% yield and 95.9% optical purity is disclosed.

Shiraiwa et al., Chem. Lett. 1990, 233] discloses N-methyl- [D] -2-phenylglycine from N-methyl- [DL] -2-phenylglycine using [1] -camphorsulfonic acid in butanoic acid without the addition of aldehydes or ketones. A method of preparing is disclosed. In this case the salt of D-amino acid precipitates, while the L-amino acid racemics. Subsequently triethylamine is used to liberate the D-amino acid from the diastereomeric salt in 71-77% yield.

US-A-4 647 692 discloses amino acids 4-hydroxyphenylglycine and 3,4- by precipitating with (+)-3-bromocamphor-10-sulfonic acid in the presence of organic acids such as acetic acid and ketones. Disclosed is a racemate separation of dihydroxyphenylglycine. This method is also recommended as a general form for the racemate separation of DL-Ia.

Regardless of the precipitation method which combines racemate separation and racemization of unwanted enantiomers, publications describing only racemization methods are known:

J. Org. Chem. 48 (1983) 843-846 relates to the racemization of D-amino acids in acetic acid or other organic carboxylic acids in the presence of catalytic amounts of aliphatic or aromatic aldehydes.

US-A-3213106 discloses the racemization of optically active amino acids in water without the addition of strong bases or strong acids at temperatures between 150 and 250 ° C; Furthermore, according to JP-42-13445, the amino acids can be racemized in water by metal ion catalysis in the presence of aliphatic aldehydes. The latter racemization method has the disadvantage that the amino acids are partially degraded at the mentioned temperatures or the conversion rate is too slow.

It has proved infeasible to apply the above-mentioned precipitation method to the separation of [DL] -homoalanin-4-yl (methyl) phosphonic acid using d- or l-camphorsulfonic acid or derivatives thereof. For example, it is not possible to separate the diastereomeric salts of [L] -homoalanin-4-yl (methyl) -phosphinic acid and [d] -3-bromocamphor-10-sulfonic acid (Control A). Self-explanatory from) and B) (see "Control").

It is therefore an object of the present invention to find a racemate separation method that can be performed on an industrial scale and substantially eliminates the above mentioned disadvantages.

The present invention

a) reacting [DL] -homo-alanine-4-yl (methyl) phosphinic acid (DL acid) or a salt thereof with a chiral base,

b) a salt of [D] -homoalanin-4-yl (methyl) phosphinic acid (D acid) or a salt of [L] -homoalanin-4-yl (methyl) phosphinic acid (L acid), respectively, L From the resulting mixture solution of D acid or diastereomeric salts of L acid and chiral base in an aqueous or aqueous-organic solvent that dissolves better than the salt of acid or D acid, the salt of L acid and chiral base or D acid and chiral base Crystallizing the salt (racemate separation) and

c) neutralizing the resulting salt with an acid when free L acid or D acid is to be prepared, or carrying out metathesis if a salt other than that obtained according to b) is to be prepared.

[L] -homoalanin-4-yl (methyl) phosphinic acid (L acid) and salts thereof from racemic [DL] -homoalanin-4-yl (methyl) phosphinic acid (DL acid) or salts thereof, or [ D] -homoalanin-4-yl (methyl) phosphinic acid (D acid) and salts thereof.

The process according to the invention for preparing [L] -homoalanine-4-yl (methyl) phosphonic acid and salts thereof is carried out using chiral bases, preferably alkaloid bases such as quinine, cinconidine and brucin . It is particularly advantageous to use quinine.

The enantiomers of the chiral bases such as quinidine and synconin are suitable for the preparation of [D] -homoalanin-4-yl (methyl) phosphinic acid.

Because of the greater economic importance for L acid, the following describes the process route for the preparation of L acid. This method can be used similarly for the preparation of D acids by using enantiomeric chiral bases.

To reduce the solubility of the [L] type diastereomeric salts relative to solubility in pure aqueous solutions, for example, a solvent mixture consisting of water and an organic solvent that is water miscible at the particular mixing ratio employed can be used. Suitable mixing partners for the aqueous-organic solvent mixture include, for example, alcohols such as methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, secondary-butanol and t-butanol; Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and N-methylpyrrolidone; And organic solvents selected from the group consisting of combinations of these solvents. It is also possible to use relatively small amounts of solvent, ie highly concentrated solutions, in order to use water as the sole solvent.

The use of i-propanol or t-butanol in combination with water has proved to be particularly advantageous.

The optimum temperature for crystallization varies depending on the chiral base, solvent, salt concentration, amount of chiral base, and crystallization rate. As a rule, it is advantageous to carry out the crystallization at a temperature of 0 to 100 ° C., preferably 0 to 85 ° C., in particular 15 to 75 ° C. Suitable and preferred solvent mixtures are water and alcohols, for example t-butanol and water, for example 20:80 to 90:10, preferably 50:50 to 85:15, in particular 70:30 to 85:15 Or isopropanol and water, for example from 20:80 to 90:10, preferably from 50:50 to 90:10, in particular from 70:30 to 85:15. Crystallization is carried out at temperatures of 0 to 85 ° C., in particular 15 to 75 ° C., with preference being given to the latter proportions.

Separation of the acid (L-Ia) from the diastereomeric salt, which is a crystal, can occur by neutralization with organic or inorganic acids, in some cases in a suitable solvent, similarly to conventional methods. Metathesis to another salt can be carried out by reaction with an excess of inorganic base containing the desired cation, or if an optionally substituted ammonium salt of (L-Ia) has to be prepared, e.g. For example, by an amine base). The preparation of ammonium salt (L-Ib) which can be satisfactorily used as a herbicide is preferably by metathesis with ammonia. The reaction with ammonia can be carried out by dissolving the crystals in a suitable solvent such as, for example, methanol and passing it through ammonia or by adding an aqueous solution of ammonia in a solvent such as, for example, excess methanol, to form an ammonium salt (L-Ib ) May be carried out by precipitation. The mother liquor containing the chiral base can then be returned to the next batch.

In a preferred process of the process according to the invention, the chiral base and the unwanted D isomer (D-Ia) or salts thereof, for example the salt of the chiral base and (D-Ia), are racemized and the resulting racemic compound ( DL-Ia) or salts thereof can be used for the racemate separation according to the invention.

In principle, a method suitable for the racemization of (D-Ia) is a method that can racemize other amino acids. See, eg, already mentioned above in Bull. Chim. Soc. Jap. 56 (1983) 3744-3747; Chem. Lett. 1990 (233) and [J. Org. Chem. 48 (1983) 843-846 disclose catalysis of racemization of optically active amino acids by aldehydes in organic acids.

Racemization may occur separately or with racemate separation:

a) The aforementioned processes are suitable for separating the crystallized salt of the L isomer and then carrying out the racemization of the D isomer. (See Example C in the “Control” section below). However, in addition to the additional process steps in the case of additional racemization, known processes usually have the disadvantage that the racemization must take place, for example, in the presence of an acid. The addition of organic acids is quite technically disadvantageous for the process when the known process is applied to the racemization of chiral base salts and D isomer salts produced according to the invention in the mother liquor of the crystallization step. Because of the means for adding the acid, for example the exchange of solvents, the racemization solution cannot be returned directly to the next crystallization batch without changing the crystallization conditions.

b) Furthermore, if the racemization of the D isomer takes place in the same reaction mixture simultaneously with the crystallization of the L isomer salt and the chiral base salt, the known racemization methods can no longer be applied or can be carried out industrially. None (obvious from subsequent control example D). The diastereomeric salts of (D-Ia) and chiral bases can be racemized slowly in acetic acid in the presence of salicylic aldehyde in the case of quinine (control C), but the diastereo of (L-Ia) in acetic acid medium It is impossible to crystallize the mercury salt (Control D).

The organic acid added in the known racemization process must be removed in the preferably combined crystallization process according to the invention for the reasons mentioned above. Racemization in the presence of known aldehydes generally does not occur without acid addition, ie the racemization is carried out with aldehydes in a neutral or weak base or a much weaker acidic aqueous medium to carry out.

Surprisingly, the experiments of the present invention show that racemization occurs even in such media when using some aldehydes.

Thus, the invention also relates to hydroxyl groups in position 2 for aldehyde groups and to electron-withdrawing radicals in positions 3 or 5 for aldehyde groups, for example NO ₂ , CN, CF ₃ and SO ₃ H, in particular Optically active amino acids, preferably (D) comprising reacting optically active amino acids in an aqueous or aqueous-organic medium in the presence of a 6-membered (hetero) aromatic aldehyde having NO ₂ and optionally substituted further A novel method for racemization of the amino acids of -Ia) and derivatives thereof.

Racemization according to the invention takes place without the addition of inorganic or organic acids. Preference is given to racemization at neutral or weakly basic or weakly acidic media, for example at pH 4-9, in particular at pH 5-8.

The racemization is usually carried out at temperatures of 0 to 120 ° C., preferably 30 to 85 ° C., in particular 35 to 75 ° C., depending on the reactivity of the aldehyde.

Preferred aldehydes for racemization are salicylsaldehyde activated by an electron-withdrawing radical at the 3 or 5 position on the phenyl ring, for example a nitro group, optionally substituted further. For example, 5-nitrosalicylaldehyde or 3,5-dinitrosalicylaldehyde.

Also, for example, similar heteroaromatic aldehydes may be used instead of aromatic aldehydes. In this connection it is also possible to use pyridinealdehydes, for example pyridoxal, which may be immobilized on inorganic or organic supports depending on the substitution pattern.

Suitable amino acids are usually optically active amino acids and salts thereof, such as D- or L-alanine, substituted D- or L-alanine, substituted glycine, for example phenylglycine or hydroxyphenylglycine, and D Or amino acid derivatives such as L-leucine, and (D- or L-Ia).

The amount of aldehyde used can be varied within a wide range and can be easily optimized by preliminary experiments. Preference is given to using aldehydes in less than stoichiometric amounts, in particular in catalytic amounts, based on amino acids or salts thereof. In general, the amount of specific aldehydes ranges from 0.01 to 0.1 moles per mole of amino acid or salt thereof used. If very small amounts of aldehyde are used, the conversion takes place too slowly for practical purposes. The use of excess aldehyde may impair the subsequent processability of the mixture and also appears to be of little significance from an economic point of view.

A particularly advantageous aspect of the racemization according to the invention is that it can be carried out at significantly lower temperatures than expected. The conversion can take place not only at temperatures of 80-150 ° C. when used in strong acid media, but also at temperatures below 80 ° C., preferably 35-75 ° C., in particular 40-70 ° C. In contrast to the conventional methods mentioned, this low temperature for the racemate separation of (DL-Ia) with a chiral base indicates that the crystallization of the salt of (L-Ia) and the chiral base is in one mixture (D -Ia) allows simultaneous occurrence of the racemization of the salt.

Various possible methods for carrying out racemate separation according to the invention and racemization of the acid (D-Ia) or salts thereof according to the invention are described below.

One possible method contains, after crystallization in step b) of the process according to the invention, the mother liquor (essentially the residue of the diastereomeric salt of (D-Ia) and the diastereomeric salt of (L-Ia)). ) Is heated in the presence of one of the aldehydes and subjected to racemization at a temperature of from 0 to 120 ° C, preferably from 30 to 85 ° C, in particular from 35 to 75 ° C. The salts of racemized amino acids and chiral bases can then be returned directly to the next crystallization batch, without post-treatment and solvent change.

Processes (modification method 1) combined as a batch process or continuous process for producing ammonium heat (L-Ib) starting from ammonium salts (DL-Ib) are, for example,

(1) In a solvent mixture of water and an organic solvent that dissolves ammonium [DL] -homoalanin-4-yl (methyl) phosphinate, the ammonium [DL] -homoalanin-4-yl (methyl) phosphinate is chiral React with base, remove free ammonia, then

(2) The diastereomeric salt of [L] -homoalanin-4-yl (methyl) phosphinic acid and chiral base at a temperature of 0 to 85 ° C is crystallized from a solvent mixture of water and an organic solvent, for example Isolate this by suction filtration and subsequently

(3) the mother liquor that produced the crystals (essentially containing the residues of other diastereomeric salts of [D] -amino acids and diastereomeric salts of [L] -amino acids) in the presence of (hetero) aromatic aldehydes, After heating at a temperature of 20-120 ° C. and racemization, the resulting solution is sent to the next crystallization batch (2),

(4) reacting a diastereomeric salt of [L] -homoalanin-4-yl (methyl) phosphonic acid and chiral base from step (2) in a mixture of water and an organic solvent, or the organic solvent itself, When the ammonium [L] -homoalanin-4-yl (methyl) phosphinate (L-Ib) precipitates, the precipitated ammonium salt (L-Ib) is isolated, for example by suction filtration, and the mother liquor (Essentially containing a chiral base) to the next batch of step (1).

In order to optimize the combined process, it is important to adjust the temperature to suit the particular process step. In step (1) a temperature of 20 to 100 ° C. is advantageous, while step (2) is advantageously carried out at 0 to 85 ° C., preferably 15 to 75 ° C. The temperature of step (3) should be suitable for the reactivity of the aldehyde. The process according to step (4) may preferably be carried out at 0 to 60 ° C.

Another particularly preferred method which is particularly preferred is to carry out racemization in the same stage as the crystallization of the diastereomeric salt of (L-Ia). Wherein the crystallization conditions for solvent and temperature are exactly the same as for racemization; This limits the choice of racemization process and, in the case of racemization with the above-mentioned aldehydes, also limits the selection of possible aldehydes. As already mentioned above, the combined process cannot be carried out using conventional processes in the presence of acids and aldehydes, but using the process of the invention for racemization using certain aldehydes without the addition of acids. Can be done.

A unique variant of the combined process is a mixture of D acid and a diastereomeric salt of L acid and chiral base, dissolved in an aqueous or aqueous-organic solvent that dissolves the salt of D acid better than the salt of L acid, the presence of aldehydes. Under reaction at a temperature of 0 to 85 ° C., preferably 30 to 85 ° C. (fixed at a temperature low enough for the salts of L acid and chiral base to crystallize simultaneously).

In principle, the preferred combined process (racemate separation and racemization) can convert (DL-Ia) to 100% (L-Ia). For the preferred method, the abovementioned 6-membered (hetero) aromatic aldehydes and chiral bases having a hydroxyl group at position 2 relative to the aldehyde group and an electron-withdrawing radical at position 3 or 5 relative to the aldehyde group Suitable and mentioned bases and aldehydes are particularly preferred.

As a batch or continuous process for the preparation of ammonium salts (L-Ib) starting from ammonium salts (DL-Ib), the preferred combined process (modification method 2) is for example

(1 ') In a solvent mixture of water and an organic solvent that dissolves ammonium [DL] -homoalanin-4-yl (methyl) phosphinate, ammonium [DL] -homoalanin-4-yl (methyl) phosphinate React with the chiral base, remove the ammonia, then

(2 ') react with aromatic aldehydes in the presence of a solvent mixture of water and an organic solvent at a temperature of from 0 to 85 ° C., preferably from 30 to 85 ° C., and at the same time [L] -homoalanine-4-yl (methyl) force The diastereomeric salts of the finic acid and chiral base are crystallized and the crystals are isolated, for example by suction filtration, and the mother liquor is added to step 2 'of the next batch,

(3 ') a diastereomeric salt of [L] -homoalanin-4-yl (methyl) phosphinic acid and chiral base from step (2') in a mixture of water and an organic solvent or in the organic solvent itself with ammonia The precipitated ammonium [L] -homoalanin-4-yl (methyl) phosphinate is further filtered under inhalation and the mother liquor (which essentially contains a chiral base) is returned to step (1 ') of the next batch. It includes.

In order for the process to be successful, it is important to adjust the temperature to the specific process step. Process steps (1 ') and (3') substantially correspond to process steps (1) and (4) of the above-mentioned combined process (modification method 1). The process step according to step (1 ′) is advantageously carried out at a temperature of 20 to 100 ° C., while the process according to step (2 ′) allows the diastereomeric salts of (L-Ia) to crystallize but which is undesirable (D The racemization of -Ia) is advantageously carried out at a temperature which still occurs fast enough. The temperature of step 3 'is advantageously carried out at 0 to 60 ° C.

Schematic comparisons of variant methods 1 and 2 take the example of racemate separation of (L-Ib), reducing the process steps of variant method 2 (see Table 1):

TABLE 1

Individual process steps can be carried out batchwise or continuously. It is desirable to return the mother liquor resulting from the use to a completed process with low yield loss.

Suitable solvents for the abovementioned process steps are those already mentioned for the crystallization step. An advantageous process is to use the same solvent system in all process steps. However, sometimes it is also meaningful to change the nature of the solvent system by adding only another solvent to the solvent from the preceding step.

In the following examples, amounts and percentage results are by weight unless otherwise indicated. "L salt", "D salt" and "D, L salt" mean salts of (L-Ia), (D-Ia) and (D, L-Ia) and chiral base, respectively.

Example 1

1.1

39.6 g (0.2) of 99.8% pure ammonium [DL] -homoalanin-4-yl- (methyl) phosphinate and 65.5 g (0.2 mol) of (-) quinine (purity: 99%) were heated in 210.8 g of water Reflux. Subsequently 22.6 g of aqueous ammonia are removed under reduced pressure of 100 mbar. At 70 ° C., 766.4 g of tert-butanol and then 3.38 g (0.02 mol) of 5-nitrosalicylaldehyde were added, and the clear solution was added [L] -homoalanine-4-yl (methyl) -phosphinic acid / quinine salt. Sieve at 50 ℃. Diastereomeric L salt precipitates slowly at 48 degrees C or less. The mixture is allowed to reach room temperature over 6 hours, the solid is suction filtered, washed with a small amount of tert-butanol / water (80:20) and dried at 60 ° C. under vacuum. This gives 41.0 g of [L] -homoalanin-4-yl (methyl) -phosphinic acid / quinine salt with a purity of L salt: D salt ratio of 98.7: 1.3.

1.2

The mother liquor from Example 11 was refluxed for 9 hours (sample measurement L: D = 50.6: 49.4) and another 0.2 mole batch at 79 ° C. similar to Example 1.1 (the amount used was about 0.319 moles of [DL] salt) Add to Crystallization takes place and 97.3 g of [L] -homoalanine-4-yl (methyl) -phosphinic acid / quinine salt having a purity of 99.5: 0.5 ratio of L salt: D salt is obtained, corresponding to 60% of theory. do. The mother liquor can in turn be added to another batch. The crystals were dissolved in 97.3 g of methanol and 27.8 g (0.29 mol) of ammonia methanol solution (17.7% concentration) was added; The formed crystals are then filtered. 36.2 g of ammonium [L] -homoalanin-4-yl (methyl) -phosphinate having an optical purity of L: D ratio of 99.5: 0.5 is obtained. This corresponds to an isolated yield of 57.0% of theory based on 0.319 moles of DL salt. The mother liquor from these crystals (essentially containing (-) quinine) is added to another batch.

Example 2

99.8% pure ammonium [DL] -homoalanin-4-yl- (methyl) phosphinate (0.2 mol) 39.6 g (0.2 mol) and (-) quinine (purity: 99%) 65.5 g (0.2 mol) Heated in 210.8 g; Subsequently 24.0 g of aqueous ammonia are removed under reduced pressure of 100 mbar. At 70 ° C., 766.4 g of tert-butanol and then 4.3 g (0.02 mol) of 3,5-dinitrosalicylaldehyde are added, the mixture is cooled to 50 ° C. and the clear solution is [L] -homoalanine-4 Seeding with-(methyl) -phosphinic acid / quinine salt. The mixture is stirred for 9-10 hours, during which time the L salt precipitates slowly. The mixture is allowed to reach room temperature over 6 hours, the solid is suction filtered, washed with tert-butanol / water (80:20) and dried at 60 ° C. under vacuum. This gives 86.5 g of [L] -homoalanin-4-yl (methyl) -phosphinic acid / quinine salt in purity of 99.5: 0.5 ratio of L salt: D salt. This corresponds to 85.1% yield of theory. The mother liquor is added to another batch at 70 ° C. The crystals were dissolved in 86.5 g of methanol and 24.7 g (0.258 mol) of ammonia methanol solution (177% concentration) were added; The formed crystals are then filtered. 32.2 g of ammonium [L] -homoalanin-4-yl (methyl) -phosphinate having an L: D optical purity of 99.0: 1.0 are obtained. This corresponds to an isolated yield of 80.5% of theory. Mother liquor (essentially containing (-) quinine) is added to another batch.

Example 3

3,5 g (0.019 mol) of ammonium [DL] -homoalanin-4-yl- (methyl) phosphinate and 6.2 g (0.019 mol) of (-) quinine are dissolved in 18.2 g of water at 50 ° C. and hot acetone Add 27.4 g. Clear solution is obtained at 50 ° C. While seeding the clear solution with [L] -homoalanin-4-yl (methyl) -phosphinic acid / quinine salt, it is cooled slowly and crystallization takes place. The solid is suction filtered at 20 ° C., washed with a small amount of acetone and the filter mass is dried at 60 ° C. under vacuum. An enantiomeric ratio of 99.8: 0.2 affords 4.0 g of [L] -homoalanin-4-yl (methyl) -phosphinic acid / quinine salt containing L-amino acid and D-amino acid portions. This is 83.3% yield of theory based on the amount of use of the L form and corresponds to 41.7% yield of theory based on the D, L mixture used.

Example 4

3.5 g (0.019 mol) of ammonium [DL] -homoalanin-4-yl- (methyl) phosphinate and 6.2 g (0.019 mol) of (-) quinine are dissolved in 18,2 g of water at 50 ° C. and hot isopropanol Add 103.1 g. Clear solution is obtained at 50 ° C. The clear solution is cooled slowly while seeding with [L] -homoalanin-4-yl (methyl) -phosphinic acid / quinine salt and crystallization takes place. The solid is suction filtered at 20 ° C., washed with a small amount of acetone and the filter mass is dried at 60 ° C. under vacuum. 4.2 g of [L] -homoalanin-4-yl (methyl) -phosphinic acid / quinine salt containing L-amino acid portion and D-amino acid portion of the enantiomer ratio of 99.8: 0.2 are obtained. This is 86.3% yield of theory based on the usage of the L form and corresponds to 43.2% yield of theory based on the D, L mixture used.

Example 5

[D] -homoalanine-4-yl (methyl) -phosphinic acid (D: L = 99.5: 0.5) 1.1 g (0.006 mol), quinine 2.0 g (0.006 mol) and 3,5-dinitrosalicylaldehyde 0.13 g (0.0006 mol) is dissolved in 5.2 g of water and 23.0 g of tert-butanol and stirred at 40 ° C. for 23 h. An enantiomeric ratio of 50.2: 49.8 affords the [DL] -homoalanin-4-yl (methyl) -phosphinic / quinine salt containing the D-amino acid moiety and the L-amino acid moiety.

Example 6

0.8 g of [L] -tert-leucine (purity: 99%, 0.006 mol), 2.0 g (0.006 mol) of quinine, and 0.13 g (0.0006 mol) of 3,5-dinitrosalicylaldehyde were added to 5.2 g and 3 Dissolve in 23.0 g of rapid-butanol and stir at 50 ° C. for 24 hours. An enantiomeric ratio of 50.9: 49.1 affords [DL] -tert-leucine containing the D-amino acid moiety and the L-amino acid moiety.

Example 7

3.44 g of [DL] -homoalanin-4-yl (methyl) phosphinic acid and 5.6 g (0.019 mol) of cinconine are dissolved in 27 ml of water at 50 ° C. and 243 g of tert-butanol are added at high temperature. The solution is seeded with [D] -homoalanin-4-yl- (methyl) phosphinic acid and cooled slowly at room temperature. 4.5 g of [D] -homoalanin-4-yl- (methyl) phosphinic acid / cinconin salt having enantiomeric purity of D: L = 96.7: 3.3 is obtained. This corresponds to 96.2% isolated yield of theory.

Control

A) 2.7 g (0.015 mol) of [DL] -homoalanin-4-yl (methyl) phosphinic acid in 10 g of demineralized water at 75 ° C. at 90 g of tert-butanol, ammonium (+)-3-bromocamphor-8 Add 5.0 g (0.015 mol) of sulfonate and maintain a temperature of 75 ° C. The mixture is heated to reflux for 1 hour and then allowed to slowly reach room temperature. The precipitated crystals are suction filtered, washed and dried at 50 ° C. under vacuum. 4.8 g of a salt of homoalanine-4-yl (methyl) phosphinic acid / (+)-3-bromocamphor-8-sulfonic acid having a diastereomer content of L: D = 50: 50 are obtained.

B) 3.0 g (0.015 mol) of ammonium [DL] -homoalanin-4-yl (methyl) -phosphinate, 5.0 g (0.015 mol) of ammonium (+)-3-bromocamphor-8-sulfonate is demineralized Dissolve 10 g at 75 ° C. and at this temperature, 135 g of tert-butanol are added. 1.53 g (0.015 mol) of H ₂ SO ₄ (96% concentration) are added and the mixture is cooled slowly. 3.5 g of a salt of homoalanine-4-yl (methyl) phosphinic acid / (+)-3-bromocamphor-8-sulfonic acid having a diastereomer content of L: D = 50.1: 49.9 are obtained.

C) 2.9 g (0.0057 mol) of [D] -homoalanin-4-yl (methyl) phosphinic acid / quinine salt (purity of salt D: L salt = 99.8: 0.2), 0.07 g of salicylaldehyde, 6.2 g of acetic acid and water 0.02 g is stirred at 50 ° C. for 8 hours. The solution obtained in this way contains a racemic salt with a diastereomeric ratio of L salt: D salt = 49.8: 50.2.

D) 6.2 g of quinine, 3.44 g of [DL] -homalanine-4-yl (methyl) phosphinic acid in 20 ml of acetic acid and 80 ml of methyl isobutyl ketone are heated and slowly cooled to room temperature. During this, 3.1 g of [DL] salt with a diastereomeric ratio of L: D = 49.6: 50.4 is crystallized.

Claims (17)

a) Reaction of [DL] -homoalanin-4-yl (methyl) phosphinic acid (DL acid) or a salt thereof with a chiral alkaloid base selected from the group consisting of quinine, cinconine, quinidine, cinconidine and brucin Steps, b) [D] -homoalanin-4-yl (methyl) phosphinic acid (D acid) salt or [L] -homoalanin-4-yl (methyl) phosphinic acid (L acid) salt is a salt of L acid, respectively In an aqueous or aqueous-organic solvent that dissolves better than a salt of D acid, crystallizing the salt of L acid or D acid and the chiral alkaloid base from a mixture solution of the resulting D acid or L acid and diastereomeric salts of the chiral alkaloid base. Step (separation of the racemic compound) and c) neutralizing the resulting salt with an acid when preparing a free L acid or D acid, or performing metathesis when preparing a salt other than that obtained according to step b) above, From racemic [DL] -homoalanin-4-yl (methyl) phosphinic acid or salts thereof, [L] -homoalanin-4-yl (methyl) phosphinic acid and salts thereof of formula (I): or [D] -homo Process for preparing Alanine-4-yl (methyl) phosphinic acid and salts thereof: Formula 1 The method of claim 1, Process for preparing L acid or salts thereof. The method of claim 2, Method of using quinine as chiral alkaloid base. The method of claim 2 or 3, As a solvent, a method of using a solvent mixture of water and an organic solvent selected from the group consisting of alcohols and ketones. The method of claim 4, wherein Using water and isopropane or a solvent mixture of tert-butanol as solvent. The method according to any one of claims 1 to 3, Step b) is carried out at a temperature of from 0 to 100 ° C. The method according to any one of claims 1 to 3, D isomerization of D isomer (D-Ia) or a salt thereof and the resulting racemic compound (DL-Ia) used for racemate separation. The method of claim 7, wherein In the presence of a 6-membered (hetero) aromatic aldehyde having an electron-withdrawing radical at position 2 relative to the aldehyde group and position 3 or 5 relative to the aldehyde group and optionally further substituted, A process for reacting the D isomer (D-Ia) in an aqueous or aqueous-organic medium without the addition of an organic acid. The method of claim 8, And wherein the (hetero) aromatic aldehyde is 5-nitrosalicylaldehyde or 3,5-dinitrosalicylaldehyde. The method of claim 7, wherein The racemization is carried out at a temperature of 0 to 120 ℃. The method of claim 8, A mixture of the D acid and the diastereomer salt of L acid and chiral alkaloid base dissolved in an aqueous or aqueous-organic solvent in which the salt of D acid is more soluble than the salt of L acid is obtained at a temperature of 0 to 85 ° C. in the presence of aldehyde (L At a temperature set low enough to simultaneously crystallize the salt of the acid and the chiral alkaloid base. [L]-or [D] -homoalanine-4-yl (methyl) phosphinic acid and a salt of a chiral alkaloid base selected from the group consisting of quinine, cinconine, quinidine, cinconidine and brucin. Salts of [L] -homoalanin-4-yl (methyl) phosphinic acid (L acid) with quinine. The method of claim 12, And a salt wherein the chiral alkaloid base is quinine, cinconidine or brucin. The method of claim 12, A salt wherein the chiral alkaloid base is quinine. The method of claim 12, The salt wherein the chiral alkaloid base is cicononidine. The method of claim 12, A salt wherein the chiral alkaloid base is brucin.