TW201837047A - Process for the preparation of d-glufosinate or salts thereof using ephedrine - Google Patents

Abstract

The invention relates primarily to a process for the preparation of D-glufosinate or salts thereof using ephedrine, in particular to the preparation of D-glufosinate or salts thereof by (dynamic kinetic) racemate resolution. The invention furthermore relates to particular salts of glufosinate and ephedrine and to the use of ephedrine for the (dynamic kinetic) racemate resolution of D, L-glufosinate or salts thereof.

Description

 Method for preparing glufosinate or a salt thereof using ephedrine  

The present invention relates generally to a process for the preparation of D-glufosinate or a salt thereof using ephedrine, and more particularly to the preparation of D-glufosinate or a salt thereof by resolution of a (dynamic) racemate. The invention further relates to a special salt of glufosinate and ephedrine and to the use of ephedrine for the resolution of D,L- glufosinate or a salt thereof.

No. 4,168,963 describes various phosphorus-containing herbicidal active compounds, in particular phosphinothricin (2-amino-4-[hydroxy(methyl)phosphonium]butyric acid, 2-amino-4-[hydroxyl ( Methyl)phosphonium]butyric acid, D,L-(high alanine-4-yl)(methyl)phosphinic acid (D,L-Ia), common name: glufosinate or its salt In particular, ammonium salts (D, L-Ib) have reached commercial importance in the field of agrochemicals.

The preparation of intermediates for the synthesis of such phosphorus-containing herbicidal active compounds, in particular glufosinate, is described, for example, in U.S. Patent No. 4,521,348, U.S. Patent No. 4,599,207, and U.S. Patent No. 6,359,162.

These phosphorus-containing herbicidal active amino acid derivatives are significantly more effective than their L-forms (L-Ia or L-Ib), while the respective mirror-isomeric D forms are clearly less effective in killing grass (US 4,265,654).

Therefore, many processes for the preparation of L-(homoalanine-4-yl)(methyl)phosphinic acid (L-Ia) and its ammonium salt (L-Ib) have been developed, for example by enzymatic amine transfer ( For example, DE 3920570, DE 3 923 650, EP 0 249 188 or WO 2007/100101) or by means of asymmetric hydrogenation (eg EP 0238954, EP 1864989 or EP 2060578).

WO 03/072792 and WO 2005/005641 describe a process for the preparation of sterile plants, wherein the D- glufosinate mirror isomer is preferably used as a non-phytotoxic substance.

The preparation of D-glufosinate and/or its salts has been relatively investigated or described in the literature, i.e., improvements are desired.

Bull. Chim. Soc. Jap., 1983, 56, 3744-3747 describes the use of D-camphor-10-sulfonic acid as a salt-forming substance from D, L-phenyl in the presence of acetic acid and salicylaldehyde as a racemic agent. D-phenylglycine was prepared from glycine.

US 4,647,692 precipitates with (+)-3-bromocamphor-10-sulfonic acid in the presence of a ketone and an organic acid such as acetic acid, and the racemate resolves the amino acid 4-hydroxyphenylglycine or 3,4 - Dihydroxyphenylglycine. In the general form, this method is also recommended as racemate separation (D, L-Ia).

J. Org. Chem., 1983, 48, 843-846 describes the racemic D-amino acid in acetic acid or other organic carboxylic acids in the presence of a catalytic amount of an aliphatic or aromatic aldehyde.

No. 4,520,205 describes the separation of the mirror isomers of racemic 2,3-dihydroindole-2-carboxylic acid by means of ephedrine.

In US 5,767,309 or US 5,869,668 (corresponding to WO 95/23805), it is described that the racemate resolves D,L-(homoalanine-4-yl)(methyl)phosphinic acid (D,L-Ia) and The method of salt, which can be carried out at the industrial level, is described as being suitable for chiral quinine, cinchonine, cinchonidine or strychnine; on the other hand, (+)-3-bromo camphor-8- Sulfonic acid is not suitable.

From a methodological and/or economic point of view, the above process has one or more disadvantages, for example: - the necessary (heterocyclic) intermediate is not immediately available and/or using an organometallic agent; - several synthetic steps such as certain eneamines, And after the hydrogenation has been carried out, the necessary cleavage of the thiol group; - using certain amine precursors (such as by enzymatic methods), and their like deamination products are technically very difficult to separate (eg by microfiltration), which is accompanied by Increasing costs; operating solids, such as crystallization or precipitation or filtration-filtration, processing solids in a time-intensive and therefore expensive process step.

Therefore, the object is mainly to find a method for preparing D-glufosinate or a salt thereof, in particular to prepare D-glufosinate or a salt thereof by racemate resolution, which can be carried out even at an industrial grade, and the above-mentioned one or A number of shortcomings are advantageous from a methodological and/or economic perspective.

The subject matter of the invention is a process for preparing D-(homoalanine-4-yl)(methyl)phosphinic acid (D-acid) and/or a salt thereof, characterized in that it comprises the following stages: a) supply content of 20% by weight Or more L-(high alanine-4-yl)(methyl)phosphinic acid (L-acid) and/or its salt (high alanine-4-yl)(methyl)phosphinic acid and / or a salt thereof, each calculated based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid used, and b) the L-acid and/or its salt provided in the stage a) Reacting with ephedrine in water or in an aqueous/organic solvent mixture, furthermore, wherein one, more or all of the following stages c) to e) are carried out as appropriate: c) in the case of the preparation of a free D-acid, according to stage b Acidification of the resulting salt, or in the preparation of an additional salt different from that obtained according to stage b), exchange with an alkali salt, d) addition of one or more solvents, and/or e) separation including D- (high The phase of alanine-4-yl)(methyl)phosphinic acid (D-acid) and/or its salt.

No special techniques and purification operations are required according to the inventive method, such as the enzymatic amine transfer, but can be carried out in any conventional industrial chemical plant.

Compared to the method described in WO 95/23805, according to the essential differences of the inventive method and the engineering or economic advantages of the method, it is mainly that the solid treatment or filtration is absolutely unnecessary according to the inventive method, since it is not necessary to carry out crystallization, according to the invention The method is particularly suitable for continuous method control. The ephedrine used according to the method of the invention can be isolated after the end of the reaction, for example by means of extraction, and preferably after purification by distillation, again for the recycling of ephedrine according to the method of the invention. Furthermore, ephedrine is significantly less expensive than, for example, quinine, and is available in an amount necessary for industrial grade methods, i.e., in sufficient amounts.

The method according to the invention is preferably carried out in the following manner: using a content of 30% by weight or more, preferably 40% by weight or more, preferably 45% by weight or more, of L-(high alanine-4-yl) (A) a phosphinic acid (L-acid) and/or a salt thereof (high alanine-4-yl)(methyl)phosphinic acid and/or a salt thereof, each in stage a) (high alanine- 4-Base) (Methyl)phosphinic acid is used in total and calculated.

In an advantageous embodiment, the process according to the invention is carried out in the form of racemized L-(homoalanine-4-yl)(methyl)phosphinic acid (L-acid) and/or a salt thereof.

In a preferred embodiment, the racemic compound D, L-(homoalanine-4-yl)(methyl)phosphinic acid (D,L-acid) and/or its salt is used in the process according to the invention. The aldehyde is split in a manner.

Therefore, a preferred method according to the invention is characterized in that D,L-(homoalanine-4-yl)(methyl)phosphinic acid (D,L-acid) and/or a salt thereof are used in stage a).

According to the method of the invention, glufosinate (i.e., free 2-amino-4-[hydroxy(methyl)phosphonium]butyric acid) or glufosinate can be used, and in this case, sodium and disodium are preferred. , ammonium or diammonium salt.

According to the method of the invention, D-glufosinate is prepared using ephedrine, in which case (+)-ephedrine is preferred. However, other compounds similar in structure to ephedrine, such as the non-image isomer, pseudoephedrine [(+)-(1 S , 2 S )-2-methylamino-1-phenylpropan-1-ol; CAS No. 90-82-4], or other chiral bases such as ( S )-1-phenylethylamine, have proven to be unsuitable for completion in individual tests (see comparative examples below).

For the narrative and examples, if the designations " R " and " S " are given as the absolute configuration of the chiral center, this follows the RS nomenclature according to the Cahn-Ingold-Prelog rule.

According to the method of the invention, (-)-ephedrine [(1 R , 2 S )-2-methylamino-1-phenylpropan-1-ol; CAS No. 299-42-3] may be used, and it is also possible to use it. Salt or hydrate such as hemihydrate (CAS No. 50906-05-3), hydrochloride (CAS No. 50-98-6) or sulfate (CAS No. 134-72-5).

(+)-ephedrine has proven to be particularly suitable for the preparation of D-(homoalanine-4-yl)(methyl)phosphinic acid; therefore, according to the method of the invention it is preferred to use (+)-ephedrine [(1 S) , 2 R )-2-Methylamino-1-phenylpropan-1-ol; CAS No. 321-98-2], it is also possible to use its salt or hydrate, such as hemihydrate (CAS No. 144429-10 -7), hydrochloride (CAS No. 24221-86-1) or sulfate (CAS No. 188661-03-2).

In a preferred embodiment, the method according to the invention is therefore characterized by a reaction with (+)-ephedrine.

Preferably, the method according to the invention is carried out in the following manner: the total amount of ephedrine (preferably (+)-ephedrine) in the reaction is from 0.5 to 8 mol equivalents, preferably from 0.8 to 6 mol equivalents, preferably from 1 to 4 molar equivalents, each based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid.

Preferably, the process according to the invention is carried out in the following manner: the total amount of water in the reaction is from 0.01 to 7 mol equivalents, preferably from 0.05 to 6 mol equivalents, preferably from 0.1 to 5 mol equivalents, each time (high alanine-4 The base (meth)phosphinic acid is used in a total amount.

According to the method of the invention, it is preferred that the total amount of water in the reaction is from 0.25 to 5 mole equivalents, more preferably from 0.5 to 4 mole equivalents, most preferably from 1 to 3 mole equivalents, each time (high alanine-4-yl) The total amount of (methyl)phosphinic acid used is based.

Preferably, the process according to the invention is carried out in the following manner: no organic solvent (ie water only) or an aqueous/organic solvent mixture, ie a solvent mixture of water and one or more organic solvents, is used in the reaction, preferably selected from the group consisting of A group of aromatic hydrocarbons, aliphatic hydrocarbons, saturated cyclic hydrocarbons, aliphatic alcohols, decylamines, ethers, esters, ketones and aliphatic nitriles. In this case, it is preferred to give C ₆ -C ₉ aromatic hydrocarbons and fats. Group C ₅ -C ₁₀ hydrocarbons, saturated cyclic C ₅ -C ₈ hydrocarbons, aliphatic C ₂ -C ₆ alcohols, and C ₃ -C ₇ ketones.

According to the invention, it is preferred not to use an organic solvent (i.e., only water) or a solvent mixture of water and one or more organic solvents (i.e., an aqueous/organic solvent mixture) selected from the group consisting of toluene and methyl tert-butyl ether ( MTBE), xylene, cyclohexane, methylcyclohexane, n-hexane, n-heptane, THF (tetrahydrofuran), 2-methyltetrahydrofuran, DMF (dimethylformamide), DMAc (dimethyl b) Guanidine), propionitrile, butyronitrile, ethyl acetate and aliphatic alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, 2-butanol, tert-butanol and 4- Methyl-2-pentanol constitutes a group.

Preferably, according to the invention, no organic solvent (i.e., only water) or a solvent mixture of water and one or more organic solvents (i.e., an aqueous/organic solvent mixture) is used, and the organic solvent is selected from the group consisting of toluene, xylene, cyclohexane, Methylcyclohexane, n-hexane, n-heptane, n-butanol, n-propanol, isopropanol, ethanol, and 4-methyl-2-pentanol, tert-butanol, isobutanol, and 2-butane Alcohols form a group.

The process according to the invention is preferably carried out in the following manner: step b) is carried out at a temperature in the range from 40 to 150 ° C, preferably in the temperature range from 50 to 120 ° C, particularly preferably in the temperature range from 60 to 100 ° C.

The process according to the invention is preferably carried out in the following manner: the reaction takes place in the presence of a catalytically effective amount of aldehyde, which is preferably carried out according to the inventive process in the absence of addition of an organic acid.

The process according to the invention is preferably carried out in the following manner: in the presence of from 0.01 to 10 mol%, preferably from 0.05 to 5 mol%, particularly preferably from 0.1 to 2.5 mol% of the catalytically effective aldehyde, each time with (high alanine) The -4-yl)(methyl)phosphinic acid is used in a total amount.

Suitable catalytically effective aldehydes are in this connection aliphatic aldehydes such as heptaldehyde, aromatic aldehydes such as benzaldehyde, heteroaromatic aldehydes such as 2-pyridine aldehyde, or salicylaldehyde such as salicylaldehyde, 3,5-dichlorosauraldehyde, 3 , 5-dinitrofuranal, 2-hydroxypyridine-3-carbaldehyde, 4-hydroxypyridine-3-carbaldehyde or also 2-hydroxy-5-nitrobenzylaldehyde.

The invention proceeds better in the presence of a catalytically effective amount of a six-membered (hetero) aromatic aldehyde which exhibits an electron-based radical at the 3-position based on the aldehyde and/or on the 3- and/or 5-position of the aldehyde. And is further replaced as appropriate. The invention is preferably carried out in the presence of 3,5-dichlorosauraldehyde and/or 5-nitrosauraldehyde.

The above definition is preferably in the range of 0.01 to 10 mol%, preferably 0.05 to 5 mol%, particularly preferably 0.1 to 2.5 mol%, depending on the total amount of oleic acid used in the method of the invention. The second time is based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid used.

The above preferred, better or particularly good process conditions or parameters are preferably combined with each other in accordance with the inventive method.

Accordingly, it is subsequently mentioned that the process conditions or parameters according to the inventive method are better, better or particularly good, as such accomplishes the purpose in a better manner and is particularly advantageous from a process engineering and/or economic point of view.

In a preferred embodiment, the method according to the invention is characterized in that the reaction is carried out at 0.5 to 8 mole equivalents of ephedrine, preferably (+)-ephedrine, and the total amount of water in the reaction is 0.01 to 7 mole equivalents. The reaction is carried out in the presence of 0.01 to 10 mol% of a catalytically effective aldehyde, and the molar amount is based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid, and the reaction is based on temperature. The range is from 40 to 150 °C.

In a more specific embodiment, the method according to the invention is characterized in that the reaction is carried out with 0.8 to 6 moles equivalent of ephedrine, preferably (+)-ephedrine, and the total amount of water in the reaction is 0.05 to 6 mole equivalents. The reaction is carried out in the presence of 0.05 to 5 mol% of a catalytically effective aldehyde, each of which is based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid and the reaction is based on temperature. The range is from 40 to 150 °C.

In a more specific embodiment, the method according to the invention is characterized in that the reaction is carried out with 0.8 to 6 moles equivalent of ephedrine, preferably (+)-ephedrine, and the total amount of water in the reaction is 0.05 to 6 mole equivalents. The reaction is carried out in the presence of 0.05 to 5 mol% of a catalytically effective six-membered (hetero) aromatic aldehyde, and the molar amount of each is based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid. The reaction is carried out at a temperature ranging from 50 to 120 °C.

In a more specific embodiment, the method according to the invention is characterized in that the reaction is carried out at a ratio of 0.8 to 6 mole equivalents (+)-ephedrine, the total amount of water in the reaction is 0.05 to 6 mole equivalents, and the reaction is from 0.1 to 2.5. The molar % catalyzed effective in the presence of a six-membered (hetero) aromatic aldehyde, and the molar amount is based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid, and the reaction is based on The temperature range is from 50 to 120 °C.

In a more specific embodiment, the method according to the invention is characterized in that the reaction is carried out at a ratio of 0.8 to 6 mole equivalents (+)-ephedrine, the total amount of water in the reaction is from 0.1 to 5 moles, and the reaction is from 0.1 to 2.5. Mohr% catalytically effective in the presence of a six-membered (hetero) aromatic aldehyde, which exhibits a hydroxyl radical based on the 2-position of the aldehyde and/or based on the 3- and/or 5-position of the aldehyde, and optionally Further substituted, the molar amount numbers are each based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid, and the reaction is carried out at a temperature ranging from 60 to 100 °C.

In a particularly preferred embodiment, the method according to the invention is characterized in that the reaction is carried out in an amount of from 1 to 4 mole equivalents (+)-ephedrine, the total amount of water in the reaction is from 0.25 to 5 moles, and the reaction is from 0.1 to 2.5. Mohr% catalytically effective in the presence of a six-membered (hetero) aromatic aldehyde, which exhibits a hydroxyl radical based on the 2-position of the aldehyde and/or based on the 3- and/or 5-position of the aldehyde, and optionally Further substituted, the molar amount numbers are each based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid, and the reaction is carried out at a temperature ranging from 60 to 100 °C.

In a particularly preferred embodiment, the process according to the invention is characterized in that the reaction is carried out with 1 to 4 mole equivalents (+)-ephedrine, the total amount of water in the reaction is from 0.5 to 4 mole equivalents, and the reaction is from 0.1 to 2.5. In the presence of mol%3,5-dichlorosauraldehyde and/or 5-nitrosalaldehyde, the molar amount is the total amount of (high alanine-4-yl)(methyl)phosphinic acid. The reaction is carried out at a temperature ranging from 60 to 100 ° C.

According to the method of the invention, if a salt is exchanged with a base, the base is preferably selected from the group consisting of NH ₃ , NaOH or KOH or an aqueous solution of such a base, and stage c) is carried out.

In stage d), depending on the desired product form, an organic solvent or solvent mixture for the extraction of ephedrine (if not already present in the reaction mixture) may be additionally added as a reaction mixture for subsequent treatment.

In addition to the solvent (mixture) used in stage b) as appropriate, one or more organic solvents are used in stage d). In this connection, suitable organic solvents which are preferably used in stage d) are selected from the group consisting of toluene, methyl tertiary butyl ether (MTBE), xylene, cyclohexane, methylcyclohexane, n-hexane, n-heptane, THF (tetrahydrofuran), 2-methyltetrahydrofuran, DMF (dimethylformamide), DMAc (dimethylacetamide), propionitrile, butyronitrile, ethyl acetate and aliphatic alcohols such as methanol, ethanol, positive Propanol, isopropanol, n-butanol, isobutanol, 2-butanol, tert-butanol and/or 4-methyl-2-pentanol.

The method according to the invention is suitable for carrying out on a commercial scale, ie at the factory or industrial level. Preferably, in the method of the batch method according to the invention, 50 kg or more of glufosinate or glufosinate salt, preferably 100 kg or more, particularly preferably 250 kg or more is used.

Further, according to the method of the invention, it is also suitable to carry out in a continuous operation.

The method according to the invention is subsequently exemplified by the use of racemic ammonium phospholammonium phosphate (D, L-Ib) (including aqueous solutions) as starting material, preferably including the following process stages: Stage 1: Mixing racemic ammonium glufosinate (D) , L-Ib), ephedrine and water, and optionally organic solvent or solvent mixture, stage 2: removal of ammonia (NH ₃ ) and most water, stage 3: addition of a catalytically effective amount of aldehyde to the reaction, (Asymmetric enrichment) glufosinate ephedrine salt, stage 4: addition of aqueous ammonia or alkali metal hydroxide solution, and optionally organic solvent or solvent mixture, stage 5: extraction and separation of the product aqueous phase, stage 6: Reuse stage 1 (preferably re-distill) ephedrine.

In the stage 1, it is preferred to use 0.8 to 6 mole equivalents of ephedrine (preferably (+)-ephedrine), preferably 1 to 4 mole equivalents, each time (high alanine-4-yl) ( The total amount of methyl)phosphinic acid is based.

In stage 1, racemic ammonium glufosinate (D, L-Ib) can be used as an aqueous solution.

One or more organic solvents may be additionally used in Stage 1 as appropriate. In fact, any general organic solvent is possible, preferably toluene, methyl tertiary butyl ether (MTBE), xylene, cyclohexane, methylcyclohexane, n-hexane, n-heptane, THF (tetrahydrofuran), 2 -methyltetrahydrofuran, DMF (dimethylformamide), DMAc (dimethylacetamide), propionitrile, butyronitrile, ethyl acetate and aliphatic alcohols such as methanol, ethanol, n-propanol, isopropanol , n-butanol, isobutanol, 2-butanol, tert-butanol and/or 4-methyl-2-pentanol.

In this connection, one or more organic solvents, from 0 (zero) to virtually unlimited molar equivalents, may be based on (high alanine-4-yl)(methyl)phosphinic acid; however, 0 (zero) It is preferred to be 4 molar equivalents.

In Stage 2, ammonia and most of the water can be removed by being under partial vacuum and/or heating the mixture. In this connection, preferably less than 6 equivalents of water should remain in the residue, based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid used.

As already explained above, the total amount of water in the reaction is preferably up to 5 mole equivalents, more preferably up to 4 mole equivalents, most preferably 1 to 3 mole equivalents, each time (high alanine-4-yl) (methyl The total amount of phosphinic acid used is based.

Stage 3 is preferably carried out in the following manner: in the presence of from 0.01 to 10 mol%, preferably from 0.05 to 5 mol%, particularly preferably from 0.1 to 2.5 mol% of the catalytically effective aldehyde, each time (high alanine- 4-yl)(methyl)phosphinic acid is used in a total amount, and is preferably an aliphatic aldehyde such as heptaldehyde, an aromatic aldehyde such as benzaldehyde, a heteroaromatic aldehyde such as 2-pyridine aldehyde, or an anthranil such as Liu Aldehyde, 3,5-dichlorosalaldehyde, 3,5-dinitrosauraldehyde, 2-hydroxypyridine-3-carbaldehyde, 4-hydroxypyridine-3-carbaldehyde or also 2-hydroxy-5-nitrobenzylaldehyde .

Stage 3 is preferably carried out in the presence of a catalytically effective amount of a six-membered (hetero) aromatic aldehyde; in this connection, salicylaldehyde and also heteroaromatic aldolaldehyde are preferred; 3,5-dichlorosalaldehyde and/or 5 - Nitroxanal is particularly preferred.

The above definition is preferably in the range of 0.01 to 10 mol%, preferably 0.05 to 5 mol%, particularly preferably 0.1 to 2.5 mol%, depending on the total amount of oleic acid used in the method of the invention. The second time is based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid used.

As already mentioned above, the process is preferably carried out in the following manner: the reaction is carried out at a temperature in the range of 40 to 150 ° C, more preferably 50 to 120 ° C, particularly preferably in the temperature range of 60 to 100 ° C.

In stage 4, depending on the desired product form, an aqueous alkali metal hydroxide solution or an aqueous ammonia solution may be added as a reaction mixture for subsequent treatment. Further, if it is not already present in the reaction mixture, an organic solvent for extracting ephedrine such as toluene, ethyl acetate or MTBE may be additionally added.

After phase separation, the ephedrine present in the organic phase can be reused after distillation (in the same reaction), that is, the ephedrine can be recycled.

Alternatively, instead of a glufosinate salt (such as ammonium glufosinate), glufosinate, which is a free acid, can also be used in Stage 1. In this case, the above stage 2 method can be omitted.

The reaction time according to the inventive method depends inter alia on several parameters, such as the reaction temperature and the reactor size. Skilled people will choose the optimal response time in the most optimal way and the economy may achieve the desired result. The reaction time is regularly in the range of 8 to 72 hours, frequently in the range of 12 to 60 hours, and most in the range of 16 to 48 hours.

According to the method of the invention, it is preferably carried out in the following manner, and it is preferred to first advantageously prepare ephedrine (in this case, preferably (+)-ephedrine) and (high alanine-4-yl) (methyl) a mixture, salt or mixture of phosphonic acids, which is reacted in the stage a) with its L-acid and/or salt (preferably in the form of its D, L-acid or salt) to form its desired D-acid and / or before salt.

Similarly, a mixture of D-(high alanine-4-yl)(methyl)phosphinic acid, which is advantageously produced by the reaction of the ephedrine (preferably (+)-ephedrine) and the process according to the invention, is advantageously employed. , a salt or a mixture of salts.

Therefore, the present invention relates to a mixture, salt or salt mixture of ephedrine and (high alanine-4-yl)(methyl)phosphinic acid, (+)-ephedrine and (high alanine-4- Mixtures, salts or salt mixtures of (meth)phosphinic acids are preferred.

A preferred mixture according to the invention can be obtained, for example, by mixing (high alanine-4-yl)(methyl)phosphinic acid with ephedrine (in this case preferably (+)-ephedrine). Ephedrine (in this case, preferably (+)-ephedrine) molar amount is preferably in the range of 0.5 to 4, preferably in the range of 0.75 to 3, more preferably in the range of 1 to 2, each time Based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid used.

Obtaining a salt according to the invention or a salt mixture according to the invention may, for example, preferably have a temperature range of 10 to 100 ° C, preferably a temperature range of 20 to 80 ° C, of (high alanine-4-yl)(methyl)phosphinic acid It is dissolved in water with ephedrine (preferably (+)-ephedrine in this case), and then the solution obtained by this is evaporated, that is, water is removed from the solution. Ephedrine (in this case, preferably (+)-ephedrine) molar amount is preferably in the range of 0.5 to 4, preferably in the range of 0.75 to 3, more preferably in the range of 1 to 2, each time Based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid used. Thus, using a molar equivalent of D, L-(high alanine-4-yl)(methyl)phosphinic acid with a molar equivalent of ephedrine, for example, results in a corresponding ephedrine and D,L- (high alanine) 4-yl)(methyl)phosphinic acid (1:1 salt) using one molar equivalent of D, L-(high alanine-4-yl)(methyl)phosphinic acid and dimol equivalent Ephedrine can cause ephedrine and D,L-(high alanine-4-yl)(methyl)phosphinic acid (1:2 salt).

Preferably, according to the invention, a salt or mixture of salts selected from the group consisting of: (-)-ephedrine and D,L-(homoalanine-4-yl)(methyl)phosphinic acid (1:1) Salt), (-)-ephedrine and D-(high alanine-4-yl)(methyl)phosphinic acid (1:1 salt), (-)-ephedrine and L-(high alanine) 4-yl)(methyl)phosphinic acid (1:1 salt), (-)-ephedrine and D,L-(homoalanine-4-yl)(methyl)phosphinic acid (2: 1 salt), (-)-ephedrine and D-(high alanine-4-yl)(methyl)phosphinic acid (2:1 salt), (-)-ephedrine and L-(high propylamine Acid-4-yl)(methyl)phosphinic acid (2:1 salt), (+)-ephedrine and D,L-(high alanine-4-yl)(methyl)phosphinic acid (1 :1 salt), (+)-ephedrine and D-(high alanine-4-yl)(methyl)phosphinic acid (1:1 salt), (+)-ephedrine and L-(high Alanine-4-yl)(methyl)phosphinic acid (1:1 salt), (+)-ephedrine and D,L-(homoalanine-4-yl)(methyl)phosphinic acid ( 2:1 salt), (+)-ephedrine and D-(high alanine-4-yl)(methyl)phosphinic acid (2:1 salt), (+)-ephedrine and L-( High alanine-4-yl)(methyl)phosphinic acid (2:1 salt).

Preferred salts according to the invention or mixtures thereof are selected from the group consisting of (+)-ephedrine and D,L-(homoalanine-4-yl)(methyl)phosphinic acid (1:1 salt) ), (+)-ephedrine and L-(high alanine-4-yl)(methyl)phosphinic acid (1:1 salt), (+)-ephedrine and D,L-(homoamine Acid-4-yl)(methyl)phosphinic acid (2:1 salt), (+)-ephedrine and L-(high alanine-4-yl)(methyl)phosphinic acid (2:1) salt).

In a further aspect, the use of the invention for ephedrine is preferably (+)-ephedrine, -L-(high alanine-4-yl)(methyl)phosphinic acid (L-acid) and/or Or a salt thereof to be converted into a reaction of D-(homoalanine-4-yl)(methyl)phosphinic acid (D-acid) and/or a salt thereof, or a racemate for resolution, particularly for dynamic racemization D, L-(high alanine-4-yl)(methyl)phosphinic acid and/or a salt thereof.

In the following examples, the amounts and percentage numbers refer to the weight unless otherwise indicated.

The symbols ">" and "<" mean "greater than" and "less than" respectively.

Abbreviations used :

Rac- glufosinate = racemic glufosinate, corresponding to D,L-(high alanine-4-yl)(methyl)phosphinic acid (D,L-Ia)

D-Glufosinate = D-(high alanine-4-yl)(methyl)phosphinic acid (D-Ia)

L-Glufosinate = L-(high alanine-4-yl)(methyl)phosphinic acid (L-Ia)

Rpm = revolutions per minute

Ep = molar equivalent, based on glufosinate

Mol%=mol%, based on glufosinate

quant.NMR=Quantitative NMR Spectroscopy

L: D = L- glufosinate: D-glufosinate weight ratio

Calcd for...=calculated by

Example 1:

5 g of rac- glufosinate (1 eq, free acid) was added to 4.56 g of (-)-ephedrine (1 eq), 10.52 in a 100 ml multi-necked flask equipped with a precision stirrer and reflux condenser at 20 °C. g 1-PrOH and 1.17 g of water, then 0.53 g of 3,5-dichlorosalic acid were added, and the resulting mixture was stirred at 20 ° C for 16 hours.

The obtained suspension was filtered, and a sample of the filter residue was dissolved in 20% aqueous NaOH and washed with dichloromethane, followed by chiral HPLC: 23:77 L:D.

Example 2:

10 g of rac-glufosinate (free acid) was added to 22.8 g of (+)-ephedrine and 2 ml of water and 10 g of toluene in a Flexi-Lab reactor with an anchor stirrer at 85 °C. After 1 hour, 105 mg of 3,5-dichlorosauraldehyde was added and the mixture was stirred overnight. The formulation was cooled to an internal temperature of 70 ° C, and 50 ml of toluene and also 33.1 g of sodium hydroxide solution were added. The phases were separated at 70 ° C, in this way 41 g of aqueous phase were obtained (according to quant. NMR 28% glufosinate disodium; 93% yield; 25:75 L: D; according to quant. NMR ephedrine content < 0.1%) and - -22 g of organic phase after concentration (according to quant. NMR (+) - ephedrine: 96.3%; 93% recovery).

Comparative example : Example C1: Comparative Example with (+)-Pseudoephedrine

First, 25 g of rac- glufosinate (free acid) and 57 g of (+)- pseudoephedrine (solid) and 5 ml of water and 25.4 g of toluene were stirred in a Flexi-Lab reactor at 120 ° C until a homogeneous suspension was obtained. After the temperature was lowered to 85 ° C, 263 mg of 3,5-dichlorosauraldehyde was added, and the mixture was stirred at 85 ° C overnight. The formulation was cooled to an internal temperature of 70 ° C, and 100 ml of toluene and 23 ml of sodium hydroxide solution were added thereto. The phases were separated at 70 °C. According to chiral HPLC, the aqueous phase included sodium glufosinate (L: D 50: 50).

Example C2: Comparative Example with ( S )-1-Phenylethylamine

20 g of rac-glufosinate (free acid) was added to 53.5 g of ( S )-(-)-1-phenylethylamine and 4 ml of water in a Flexi-Lab reactor at 95 °C. After adding 0.21 g of 3,5-dichlorosauraldehyde, the mixture was stirred overnight at a jacket temperature of 95 ° C and 300 rpm. After 24 hours, the sample was measured by chiral HPLC: 49:51 L:D.

Preparation of ephedrine and (high alanine-4-yl) (methyl) phosphinic acid salt Standard procedure for the preparation of ephedrine salt (1:1 salt) 1:

In a round bottom flask, 8.5 g of glufosinate and 7.7 g of ephedrine were completely dissolved in water, followed by complete evaporation of the obtained solution. The residue was suspended in 50 ml of ethanol at 20 ° C and then completely evaporated again. In this way, a 1:1 salt was obtained as a colorless amorphous solid.

Standard procedure for the preparation of ephedrine salt (2:1 salt) 2:

In a round bottom flask, 8.5 g of glufosinate and 15.5 g of ephedrine were completely dissolved in water, followed by complete evaporation of the obtained solution. The residue was suspended in 50 ml of ethanol at 20 ° C and then completely evaporated again. In this way, a 2:1 salt was obtained as a colorless amorphous solid.

The salt obtained according to the invention was analyzed by means of nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS).

Embodiment S1:

Preparation of (-)-ephedrine and D-(high alanine-4-yl)(methyl)phosphinic acid salt from D-glufosinate and (-)-ephedrine according to the above standard procedure 1. 1:1 salt).

¹ H NMR (601.6 MHz, D ₂ O) δ=1.16 (d, 3H), 1.19 (CH ₃ -EtOH, ~35 mol%), 1.26 (d, 3H), 1.57-1.67 (m, 2H), 2.05- 2.12 (m, 2H), 2.79 (s, 3H), 3.55-3.58 (m, 1H), 3.64 - 3.68 (CH ₂ -EtOH, ~35 mol%), 3.78-3.80 (m, 1H), 5.14 (m, 1H), 7.42-7.51 (m, 5H).

¹³ C NMR (151.3 MHz, D ₂ O) δ = 12.6, 17.8 (q (d)), 19.65 (EtOH), 27.09 (d (d)), 29.92 (t (d)), 33.58, 58.1 (d ( d)), 60.30 (EtOH), 62.78, 74.40, 128.98, 131.33, 131.68, 141.30, 177.09.

³¹ P NMR (243.5 MHz, D ₂ O) δ = 42.89.

MS, TOF ES+ 182.05 (MH+, calcd for C5H13NO4P 182.06) ( glufosinate H+); MS, TOF ES+ 166.11 (MH+, calcd for C10H16NO 166.12) (ephedrine H+).

Embodiment S2:

Preparation of (-)-ephedrine and L-(high alanine-4-yl)(methyl)phosphinic acid salt from L-glufosinate and (-)-ephedrine according to the above standard procedure 1. 1:1 salt).

¹ H NMR (601.6 MHz, D ₂ O) δ = 1.15 (d, 3H), 1.19 (CH ₃ -EtOH, ~35 mol%), 1.26 (d, 3H), 1.57-1.67 (m, 2H), 2.03 2.11 (m, 2H), 2.76 (s, 3H), 3.52-3.56 (m, 1H), 3.64 - 3.68 (CH ₂ -EtOH, ~35 mol%), 3.76-3.77 (m, 1H), 5.11-5.12 ( m, 1H), 7.42 - 7.51 (m, 5H).

¹³ C NMR (151.3 MHz, D ₂ O) δ = 12.8, 17.79 (t(d)), 19.65 (EtOH), 27.27 (d(d)), 29.94 (t(d)), 33.63, 58.16 (d ( d)), 60.29 (EtOH), 62.75, 74.58, 129.00, 131.3, 131.67, 141.42, 177.45.

³¹ P NMR (243.5 MHz, D ₂ O) δ = 42.96.

MS, TOF ES+ 182.05 (MH+, calcd for C5H13NO4P 182.06); MS, TOF ES+ 166.12 (MH+, calcd for C10H16NO 166.12).

Embodiment S3:

Preparation of (-)-ephedrine and D,L-(high alanine-4-yl)(methyl)phosphinic acid from rac- glufosinate and (-)-ephedrine according to the above standard procedure 1. Salt (1:1 salt).

_{^{1 H NMR (601.6MHz, D 2}} O) δ = 1.16 (d, 3H), 1.19 (CH 3 -EtOH, ~ 35mol%), 1.26 (d, 3H), 1.58-1.68 (m, 2H), 2.05- 2.12 (m, 2H), 2.79 (s, 3H), 3.55-3.59 (m, 1H), 3.64 - 3.68 (CH ₂ -EtOH, ~35 mol%), 3.78-3.80 (m, 1H), 5.14 - 5.15 ( m, 1H), 7.42 - 7.51 (m, 5H).

¹³ C NMR D ₂ O (151.3 MHz) δ=12.6, 17.8 (q(d)), 19.65 (EtOH), 27.05 (d(d)), 29.91 (t(d)), 33.57, 58.09 (d(d) )), 60.30 (EtOH), 62.79, 74.35, 128.97, 131.33, 131.68, 141.28, 177.01.

³¹ P NMR D ₂ O (243.5 MHz) δ = 42.87.

MS, TOF ES+ 182.05 (MH+, calcd for C5H13NO4P 182.06); MS, TOF ES+ 166.11 (MH+, calcd for C10H16NO 166.12).

Embodiment S4:

Preparation of (-)-ephedrine and D-(high alanine-4-yl)(methyl)phosphinic acid salt from D-glufosinate and (-)-ephedrine according to the above standard procedure 2 ( 2:1 salt).

¹ H NMR (601.6 MHz, D ₂ O) δ=1.13 (d, 6H), 1.25 (d, 3H), 1.55-1.63 (m, 2H), 1.93-2.02 (m, 2H), 2.63 (s, 6H) ), 3.34 - 3.38 (m, 2H), 3.59 - 3.61 (m, 1H), 4.98 - 4.99 (m, 2H), 7.41 - 7.50 (m, 10H).

¹³ C NMR (151.3 MHz, D ₂ O) δ=13.81, 17.77 (q(d)), 28.51 (d(d)), 30.10 (t(d)), 33.97, 58.57 (d(d)), 62.53 , 75.74, 129.17, 131.17, 131.62, 142.16, 179.98.

³¹ P NMR (243.5 MHz, D ₂ O) δ = 43.49.

MS, TOF ES+ 182.04 (MH+, calcd for C5H13NO4P 182.06); MS, TOF ES+ 166.12 (MH+, calcd for C10H16NO 166.12).

Embodiment S5:

Preparation of (-)-ephedrine and L-(high alanine-4-yl)(methyl)phosphinic acid salt from L-glufosinate and (-)-ephedrine according to the above standard procedure 2 ( 2:1 salt).

¹ H NMR (601.6 MHz, D ₂ O) δ = 1.13 (d, 6H), 1.25 (d, 3H), 1.55-1.63 (m, 2H), 1.93-2.01 (m, 2H), 2.61 (s, 6H) ), 3.32-3.36 (m, 2H), 3.59-3.61 (m, 1H), 4.97 (m, 2H), 7.41-7.50 (m, 10H).

¹³ C NMR D ₂ O (151.3 MHz) δ=13.92, 17.77 (q(d)), 28.56 (d(d)), 30.11 (t(d)), 34.01, 58.59 (d(d)), 62.52, 75.87, 129.19, 131.17, 131.62, 142.23, 180.07.

³¹ P NMR D ₂ O (243.5 MHz) δ = 43.51.

MS, TOF ES+ 182.06 (MH+, calcd for C5H13NO4P 182.06); MS, TOF ES+ 166.12 (MH+, calcd for C10H16NO 166.12).

Embodiment S6:

Preparation of (-)-ephedrine and D,L-(high alanine-4-yl)(methyl)phosphinic acid from rac- glufosinate and (-)-ephedrine according to the above standard procedure 2 Salt (2:1 salt).

¹ H NMR (601.6MHz, D ₂ O) δ = 1.13 (d, 6H), 1.25 (d, 3H), 1.55-1.63 (m, 2H), 1.94-2.02 (m, 2H), 2.63 (s, 6H) ), 3.34 - 3.38 (m, 2H), 3.60 - 3.62 (m, 1H), 4.95 (m, 2H), 7.41 - 7.50 (m, 10H).

¹³ C NMR (151.3 MHz, D ₂ O) δ=13.82, 17.77 (q(d)), 28.49 (d(d)), 30.10 (t(d)), 33.98, 58.56 (d(d)), 62.53 , 75.75, 129.17, 131.18, 131.62, 142.16, 179.93.

³¹ P NMR (243.5 MHz, D ₂ O) δ = 43.48.

MS, TOF ES+ 182.05 (MH+, calcd for C5H13NO4P 182.06); MS, TOF ES+ 166.10 (MH+, calcd for C10H16NO 166.12).

Claims (15)

 A process for the preparation of D-(homoalanine-4-yl)(methyl)phosphinic acid (D-acid) and/or a salt thereof, characterized in that it comprises the following stages: a) supply content of 20% by weight or more a large amount of L-(high alanine-4-yl)(methyl)phosphinic acid (L-acid) and/or its salt (high alanine-4-yl)(methyl)phosphinic acid and/or The salt, each calculated based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid used, and b) provided in stage a) in water or in an aqueous/organic solvent mixture The L-acid and/or its salt is reacted with ephedrine, and furthermore, one, more or all of the following stages c) to e) are carried out as appropriate: c) in the case of preparing a free D-acid, according to stage b Acidification of the resulting salt, or in the preparation of an additional salt different from that obtained according to stage b), exchange with an alkali salt, d) addition of one or more solvents, and/or e) separation including D- (high The phase of alanine-4-yl)(methyl)phosphinic acid (D-acid) and/or its salt.    According to the method of claim 1, it is characterized in that L-(high alanine-4-yl)(methyl)phosphinic acid (L-acid) having a content of 30% by weight or more and/or a salt thereof is used (high) Alanine-4-yl)(methyl)phosphinic acid and/or its salt, each calculated based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid used in stage a) .    The method according to claim 1 or 2, characterized in that D, L-(homoalanine-4-yl)(methyl)phosphinic acid (D,L-acid) and/or a salt thereof is used in the stage a).    The method according to any one of claims 1 to 3, characterized in that the reaction is carried out with (+)-ephedrine.    The method according to any one of claims 1 to 4, characterized in that the total amount of ephedrine in the reaction is from 0.5 to 8 mol equivalents, preferably from 0.8 to 6 mol equivalents, preferably from 1 to 4 mol equivalents, each time Based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid.    The method according to any one of claims 1 to 5, characterized in that the total amount of water in the reaction is from 0.01 to 7 mol equivalents, preferably from 0.05 to 6 mol equivalents, preferably from 0.1 to 5 mol equivalents, each time ( The high alanine-4-yl)(methyl)phosphinic acid is used in a total amount.   The method according to any one of claims 1 to 6, characterized in that the phase c) is preferably carried out by salt exchange with a base selected from the group consisting of NH ₃ , NaOH or KOH or an aqueous solution of such a base.  The method according to any one of claims 1 to 7, characterized in that the organic solvent or a solvent mixture of water and one or more organic solvents is not used in the reaction, and the organic solvent is preferably selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons, and saturated rings. A group of hydrocarbons, aliphatic alcohols, decylamines, ethers, esters, ketones and aliphatic nitriles.    The method according to any one of claims 1 to 8, characterized in that the step b) is carried out at a temperature in the range of 40 to 150 ° C, preferably in the temperature range of 50 to 120 ° C, particularly preferably in the temperature range of 60 to 100 ° C.    The method according to any one of claims 1 to 9, characterized in that the reaction takes place in the presence of a catalytically effective amount of an aldehyde.    The method according to any one of claims 1 to 10, characterized in that the reaction takes place in the presence of 0.01 to 10 mol%, preferably 0.05 to 5 mol%, particularly preferably 0.1 to 2.5 mol% of the catalytically effective aldehyde, each time Based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid used.    A mixture, salt or mixture of ephedrine and (high alanine-4-yl)(methyl)phosphinic acid.    A salt or salt mixture according to claim 12, which is selected from the group consisting of: (-)-ephedrine and D,L-(homoalanine-4-yl)(methyl)phosphinic acid (1: 1 salt), (-)-ephedrine and D-(high alanine-4-yl)(methyl)phosphinic acid (1:1 salt), (-)-ephedrine and L-(high propylamine Acid-4-yl)(methyl)phosphinic acid (1:1 salt), (-)-ephedrine and D,L-(homoalanine-4-yl)(methyl)phosphinic acid (2 :1 salt), (-)-ephedrine and D-(high alanine-4-yl)(methyl)phosphinic acid (2:1 salt), (-)-ephedrine and L-(high Alanine-4-yl)(methyl)phosphinic acid (2:1 salt), (+)-ephedrine and D,L-(high alanine-4-yl)(methyl)phosphinic acid ( 1:1 salt), (+)-ephedrine and D-(high alanine-4-yl)(methyl)phosphinic acid (1:1 salt), (+)-ephedrine and L-( High alanine-4-yl)(methyl)phosphinic acid (1:1 salt), (+)-ephedrine and D,L-(homoalanine-4-yl)(methyl)phosphinic acid (2:1 salt), (+)-ephedrine and D-(high alanine-4-yl)(methyl)phosphinic acid (2:1 salt), (+)-ephedrine and L- (High alanine-4-yl)(methyl)phosphinic acid (2:1 salt).    A salt or mixture of salts according to claim 12 or 13, which is selected from the group consisting of: (+)-ephedrine and D,L-(homoalanine-4-yl)(methyl)phosphinic acid ( 1:1 salt), (+)-ephedrine and L-(high alanine-4-yl)(methyl)phosphinic acid (1:1 salt), (+)-ephedrine and D,L -(homoalanine-4-yl)(methyl)phosphinic acid (2:1 salt), (+)-ephedrine and L-(high alanine-4-yl)(methyl)phosphinic acid (2:1 salt).    Use of ephedrine for converting L-(high alanine-4-yl)(methyl)phosphinic acid (L-acid) and/or its salt to D-(homoalanine-4-yl Reaction of (meth)phosphinic acid (D-acid) and/or its salt, or - for racemate resolution D,L-(homoalanine-4-yl)(methyl)phosphinic acid And / or its salt.