TW201831500A - Process for the preparation of l-glufosinate or salts thereof using ephedrine - Google Patents

Abstract

The invention relates primarily to a process for the preparation of L-glufosinate or salts thereof using ephedrine, in particular to the preparation of L-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 L-glufosinate or a salt thereof using ephedrine  

The present invention relates generally to a process for the preparation of L-glufosinate or a salt thereof using ephedrine, in particular for the preparation of L-glufosinate or a salt thereof by (dynamic kinetics) racemate resolution. The invention also relates to specific salts of glufosinate and ephedrine and to the use of ephedrine for the (dynamic kinetics) racemate 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-(homoalanine-4-yl)(methyl)phosphinic acid (D,L-Ia), common name: glufosinate or its salt, especially It is the ammonium salt (D, L-Ib) that has been of commercial importance in the field of agrochemicals.

Processes for the manufacture of intermediates for the synthesis of such phosphorus-containing herbicidal active compounds, in particular glufosinate, have been described, for example, in US 4,521,348, US 4,599, 207 and US 6,359,162 B1.

The phosphorus-containing herbicidal active amino acid derivatives are mainly effective in their L-forms (L-Ia or L-Ib), and the corresponding mirror-isomerized D-forms are clearly less effective in weeding (US 4,265,654).

Therefore, a process for producing L-(homoalanine-4-yl)(methyl)phosphinic acid (L-Ia) and its ammonium salt (L-Ib) has been developed.

Form L can be obtained by enzymatic amino transfer as described, for example, in DE 39 20 570, DE 3 923 650, EP 0 249 188 or WO 2007/100101.

In CN103275896, in order to prepare an L-form of high optical purity, a strain of Bacillus cereus is used .

Furthermore, processes for the preparation of L-forms by asymmetric hydrogenation are known, for example from P0238954, EP1864989 or EP2060578.

Bull. Chim. Soc. Jap., 1983, 56, 3744-3747 describes the use of D-camphor-10-sulfonic acid as a salt former in the presence of acetic acid and salicylaldehyde as a racemate. , L-phenylglycine to prepare D-phenylglycine.

No. 4,647,692 describes the precipitation of amino acid 4-hydroxyphenylglycine or 3,4- by the use of (+)-3-bromocamphor-10-sulfonic acid in the presence of a ketone and an organic acid such as acetic acid. Racemate analysis of dihydroxyphenylglycine. In the general form, this method is also recommended for the racemate separation of (D, L-Ia).

J. Org. Chem., 1983, 48, 843-846 describes the racemization of D-amino acids 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 a process for the separation of racemic isomers of 2,3-dihydroindole-2-carboxylic acid by ephedrine.

In US 5,767,309 or US 5,869,668 (corresponding to WO 95/23805), it is described that D,L-(high alanine-4-yl)(methyl)phosphinic acid (D,L-Ia) can be carried out on an industrial scale or Its salt, in which the palmitic quinine, cinchonine, cinchonidine or brucine is described as suitable; on the other hand, The use of (+)-3-bromocamphor-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, such that: - the necessary (heterocyclic) intermediate is not readily available and/or using an organometallic agent, - the number of synthetic steps, for example , such as certain enelenamines, and the necessary thiol cleavage after hydrogenation, using specific amine donors (such as with enzyme methods), which are technically very difficult to separate (eg borrow By microfiltration), which is associated with increased costs; - solids operations such as crystallization or precipitation or filtration-filtration and treatment of solids are time intensive and are therefore an expensive process step.

Therefore, the object is mainly to find a process for preparing L-glufosinate or a salt thereof, in particular to prepare L-glufosinate or a salt thereof by racemization, which can be carried out even on an industrial scale. This method can substantially avoid one or more of the above disadvantages and is advantageous from a methodological and/or economic point of view.

The subject of the invention is a process for the preparation of L-(homoalanin-4-yl)(methyl)phosphinic acid (L-acid) and/or a salt thereof, characterized in that the process comprises the following stages: a Providing (high alanine-4-yl) with 20% by weight or more of D-(high alanine-4-yl)(methyl)phosphinic acid (D-acid) and/or its salt content (methyl)phosphinic acid and a salt thereof, each of which is based on the total amount of the high alanine-4-yl (methyl)phosphinic acid used and calculated, and b) provided in step a) The D-acid and/or its salt is reacted with ephedrine in water or in an aqueous/organic solvent mixture, wherein, optionally, one, more or all of the following steps c) to e) are carried out: c) in the case where the free L-acid is prepared, neutralized with the acid of the salt obtained according to stage b), or, in the case of another salt other than the salt obtained according to step b), Alkali salt exchange, d) addition of one or more organic solvents, and/or e) separation of L-(high alanine-4-yl)(methyl)phosphinic acid (L-acid) and/or its salt The phase.

The process according to the invention does not require special techniques and purification operations, such as, for example, those necessary for enzymatic amine transfer, but can be carried out in any conventional industrial chemical plant.

In contrast to the method described in WO 95/23805, the fundamental differences and methodological or economic advantages of the method according to the invention are mainly in that, in this respect, no one has to operate the solid or must be filtered in the method according to the invention, Since no crystallization is required, the method according to the invention is particularly suitable for continuous process control. The ephedrine used in the process according to the invention may be used in the process according to the invention, i.e. ephedra, after the end of the reaction, for example by extraction, and preferably after purification by distillation. It is recyclable. Furthermore, ephedrine is significantly less expensive than one example of quinine and can achieve the desired amount, i.e., a sufficient portion, for use in an industrial scale process.

The process according to the invention preferably employs D-(high alanine-4-yl) having 30% by weight or more, preferably 40% by weight or more, preferably 45% by weight or more. Methyl)phosphinic acid (D-acid) and/or its salt content (high alanine-4-yl (methyl) phosphinic acid and/or its salt, each step in step a) The total amount of (high alanine-4-yl (methyl) phosphinic acid used was used as a basis and calculation.

In an advantageous embodiment, the process according to the invention is racemized in such a way that D-(homoalanine-4-yl)(methyl)phosphinic acid (D-acid) and/or its salt is racemized. get on.

In a preferred embodiment, the process according to the invention is such that the racemic compound D,L-(homoalanine-4-yl)(methyl)phosphinic acid (D,L-acid) and/or Or a salt thereof is used in the form of racemate analysis.

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

In the process according to the invention, glufosinate (i.e., free 2-amino-4-[hydroxy(methyl)phosphonium]butyric acid) or glufosinate can be used, in this case, preferably. It is a sodium salt, a disodium salt, an ammonium salt or a diammonium salt.

In the process according to the invention, ephedrine, in this regard, preferably (-)-ephedrine is used to prepare L-glufosinate. However, other compounds structurally similar to ephedrine, such as the non-mirromeric enantiomerically pseudoephedrine [(+)-(1 S , 2 S )-2-methylamino-1-phenylpropane -1-Alcohol); CAS No. 90-82-4] or other palmitic bases, for example, ( S )-1-phenethylamine has proven to be unsuitable for this purpose in a separate test (see The following comparative examples).

In the case where the names " R " and " S " are given to the absolute configuration of the palm center in the context of the description and the examples, the RS nomenclature according to the Cahn-Ingold-Prelog rule is followed.

The method according to the present invention can be carried out using (+)-ephedrine [(1 S , 2 R )-2-methylamino-1-phenylpropan-1-ol; CAS No. 321-98-2], also It is possible to use salts or hydrates thereof, such as hemihydrate (CAS No. 144429-10-7), hydrochloride (CAS No. 24221-86-1) or sulfate (CAS No. 188661-03-2).

(-)-ephedrine has proven to be particularly suitable for the preparation of L-(homoalanine-4-yl)(methyl)phosphinic acid; accordingly, the method according to the invention is preferably (-)-hemp Flavin [(1 R , 2 S )-2-methylamino-1-phenylpropan-1-ol; CAS No. 299-42-3], it is also possible to use its salt or hydrate, for example, hemihydrate (CAS No. 50906-05-3), hydrochloride (CAS No. 50-98-6) or sulfate (CAS No. 134-72-5).

In a preferred embodiment, the method according to the invention is accordingly characterized in that the reaction is carried out with (-)-ephedrine.

The method according to the present invention is preferably such that 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, more preferably. This is carried out in a 1 to 4 molar equivalent basis, based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid.

The process according to the invention is preferably from 0.01 to 7 mole equivalents, preferably from 0.05 to 6 mole equivalents, preferably from 0.1 to 5 moles equivalents, of the total amount of water in the reaction, each time (high propylamine) The total amount of acid-4-yl)(methyl)phosphinic acid is based on the total amount.

Further preferred is a method according to the invention, each time based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid, wherein the total amount of water in the reaction is from 0.25 to 5 moles. The ear equivalent is more preferably from 0.5 to 4 mole equivalents and most preferably from 1 to 3 mole equivalents.

The process according to the invention preferably does not use an organic solvent (i.e., only water) or an aqueous/organic solvent mixture, i.e., a solvent mixture of water and one or more organic solvents, preferably organic solvents are preferred. The group consisting of aromatic hydrocarbons, aliphatic hydrocarbons, saturated cyclic hydrocarbons, aliphatic alcohols, decylamines, ethers, esters, ketones and aliphatic nitriles is selected, but in this case, C ₆ is preferred. a -C ₉ aromatic hydrocarbon, an aliphatic C ₅ -C ₁₀ hydrocarbon, a saturated cyclic C ₅ -C ₈ hydrocarbon, an aliphatic C ₂ -C ₆ alcohol, and a C ₃ -C ₇ ketone.

Preferably, according to the present invention, no organic solvent (i.e., only water) or a solvent mixture of water and one or more organic solvents (i.e., aqueous/organic solvent mixture) is used, and the organic solvent is selected from the following Group: toluene, methyl tertiary butyl ether (MTBE), xylene, cyclohexane, methylcyclohexane, n-hexane, n-heptane, THF (tetrahydrofuran), 2-methyltetrahydrofuran, DMF ( Dimethylformamide), DMAc (dimethylacetamide), acetonitrile, butyronitrile, ethyl acetate and aliphatic alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutyl Alcohol, 2-butanol, tertiary butanol and 4-methyl-2-pentanol.

More preferably, according to the present invention, no organic solvent (i.e., only water alone) or a solvent mixture of water and one or more organic solvents (i.e., an aqueous/organic solvent mixture) is used, which are selected from the following Group consisting of: toluene, xylene, cyclohexane, methylcyclohexane, n-hexane, n-heptane, n-butanol, n-propanol, isopropanol, ethanol, 4-methyl-2-pentanol , tertiary butanol, isobutanol and 2-butanol.

The process according to the invention is preferably carried out in step b) at a temperature in the range from 40 to 150 ° C, preferably in the range of from 50 to 120 ° C and especially preferably in the range from 60 to 100 ° C. The way it is carried out.

The process according to the invention is preferably carried out in such a way that the reaction takes place in the presence of a catalytically effective amount of aldehyde, in which case the process according to the invention is preferably carried out without the addition of an organic acid.

The process according to the invention is preferably carried out in such a way that the reaction takes place 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 a catalytically effective aldehyde, Each time based on the total serving amount of (high alanine-4-yl)(methyl)phosphinic acid used.

In this regard, suitable catalytically effective aldehydes are aliphatic aldehydes such as heptaldehyde, aromatic aldehydes such as benzaldehyde, heteroaromatic aldehydes such as 2-pyridinecarboxaldehyde, or salicylaldehyde, such as salicylaldehyde, 3. 5-Dichlorosalicylaldehyde, 3,5-dinitrosalicylaldehyde, 2-hydroxypyridine-3-carbaldehyde, 4-hydroxypyridine-3-carbaldehyde or 2-hydroxy-5-nitrobenzaldehyde.

More preferably, the process is carried out in the presence of a catalytically effective amount of a six membered (hetero) aromatic aldehyde which exhibits a hydroxyl group at position 2 relative to the aldehyde group and/or The electron withdrawing group is exhibited at a position 3- and/or 5-position relative to the aldehyde group, and is optionally further substituted. The process is preferably carried out in the presence of 3,5-dichlorosalicylaldehyde and/or 5-nitrosalicylaldehyde.

The total molar amount of the six-membered (hetero) aromatic aldehyde used in the above method according to the present invention is preferably from 0.01 to 10 mol%, preferably from 0.05 to 5 mol%, and particularly preferably between Within the range of 0.1 to 2.5 mol%, each time based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid used.

The above preferred, more preferred or especially preferred process conditions or parameters are preferably combined with one another each time in the process according to the invention.

Correspondingly, the method conditions or parameters of the method according to the invention mentioned later are preferred, better or especially preferred, since the objects are achieved in a preferred manner and are derived from method engineering or economics. This is especially advantageous from a point of view.

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

In a more preferred embodiment, the process according to the invention is characterized in that the reaction is carried out with 0.8 to 6 molar equivalents of (-)-ephedrine, the total amount of water in the reaction being 0.05 to 6 molar equivalents, the reaction is carried out in the presence of 0.05 to 5 mol% of a catalytically effective aldehyde, each molar amount of which is based on (high alanine-4-yl)(methyl)phosphinic acid The total serving amount is based on the basis, and the reaction is carried out at a temperature in the range of 40 to 150 °C.

In a more preferred embodiment, the process according to the invention is characterized in that the reaction is carried out with 0.8 to 6 molar equivalents of (-)-ephedrine, the total amount of water in the reaction being 0.05 to 6 molar equivalents, the reaction is carried out in the presence of 0.05 to 5 mol% of a catalytically effective six-membered (hetero) aromatic aldehyde, each molar amount of the number is (high alanine-4-yl) The total amount of (methyl)phosphinic acid is used as a reference, and the reaction is carried out at a temperature in the range of 50 to 120 °C.

In a more preferred embodiment, the process according to the invention is characterized in that the reaction is carried out with 0.8 to 6 molar equivalents of (-)-ephedrine, the total amount of water in the reaction being 0.05 to 6 molar equivalents, the reaction is carried out in the presence of 0.1 to 2.5 mol% of a catalytically effective six-membered (hetero) aromatic aldehyde, each molar amount of the number is (high alanine-4-yl) The total amount of (methyl)phosphinic acid is used as a reference, and the reaction is carried out at a temperature in the range of 50 to 120 °C.

In a more preferred embodiment, the process according to the invention is characterized in that the reaction is carried out with 0.8 to 6 molar equivalents of (-)-ephedrine, the total amount of water in the reaction being from 0.1 to 5 molar equivalents, the reaction being carried out in the presence of 0.1 to 2.5 mol% of a catalytically effective six-membered (hetero) aromatic aldehyde in the form of 2- with respect to the aldehyde group The position of the number exhibits a hydroxyl group and/or exhibits a pull electron group at a position 3- and/or 5-position relative to the aldehyde group, and is optionally further substituted, each time the number of moles is digital (high alanine- The total amount of 4-yl)(methyl)phosphinic acid is based on the basis, and the reaction is carried out at a temperature in the range of 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 from 1 to 4 mole equivalents of (-)-ephedrine, the total amount of water in the reaction being 0.25 Up to 5 molar equivalents, the reaction is carried out in the presence of 0.1 to 2.5 mole % of a catalytically effective six-membered (hetero) aromatic aldehyde which exhibits a hydroxyl group at position 2 relative to the aldehyde group and/or The electron withdrawing group is exhibited at a position 3- and/or 5-position relative to the aldehyde group, and is optionally further substituted, each molar amount of the number is (high alanine-4-yl) (methyl) The total amount of phosphinic acid is based on the basis, and the reaction is carried out at a temperature in the range of 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 of (-)-ephedrine, the total amount of water in the reaction being 0.5 Up to 4 molar equivalents, the reaction is carried out in the presence of 0.1 to 2.5 mol% of 3,5-dichlorosalicylaldehyde and/or 5-nitrosalicylaldehyde, each molar amount of The total amount of (high alanine-4-yl)(methyl)phosphinic acid is based on the basis, and the reaction is carried out at a temperature in the range of from 60 to 100 °C.

In the process according to the present invention, if a salt exchange occurs with a base proceeds to step C), selected from the group consisting of the base line is preferably formed of the following: an aqueous solution of NH _3, NaOH or KOH, or such a base.

In step d), depending on the desired product form, if not present in the reaction mixture, an organic solvent or solvent mixture for the extraction of ephedrine may be additionally added to treat the reaction mixture.

Preferably, one or more organic solvents are used in stage d) in addition to the solvent (mixture) optionally used in stage b). In this regard, suitable organic solvents preferred for stage d) are selected from the group consisting of methyl tertiary butyl ether (MTBE), xylene, cyclohexane, methylcyclohexane, and hexa Alkane, n-heptane, THF (tetrahydrofuran), 2-methyltetrahydrofuran, DMF (dimethylformamide), DMAc (dimethylacetamide), acetonitrile, butyronitrile, ethyl acetate and aliphatic alcohol, For example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, 2-butanol, tertiary butanol and/or 4-methyl-2-pentanol.

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

The method according to the invention is also suitable for carrying out in a continuous operation.

The process according to the invention is subsequently illustrated by the example of (including) an aqueous solution of racemic ammonium phospholammonium (D,L-Ib) as a starting material, and preferably comprises the following process steps: Stage 1: Mixing racemic grass Ammonium phospholammonium (D, L-Ib), ephedrine and water, and optionally organic solvent or solvent mixture, stage 2: removal of ammonia (NH ₃ ) and most of the water, stage 3: addition of a catalytically effective amount of aldehyde and reaction Giving (mirrorically enriched) 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 aqueous product phase Stage 6: Reuse (preferably re-distill) the ephedrine in Stage 1.

In 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 The base is based on the total amount of (methyl)phosphinic acid.

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

Optionally, one or more organic solvents may be additionally used in Stage 1. In fact, any common 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), acetonitrile, butyronitrile, ethyl acetate and aliphatic alcohols such as methanol, ethanol, positive Propanol, isopropanol, n-butanol, isobutanol, 2-butanol, tertiary butanol and/or 4-methyl-2-pentanol.

In this regard, based on (high alanine-4-yl)(methyl)phosphinic acid, 0 (zero) to almost unlimited molar equivalents of organic solvent or solvent can be used; however, 0 (zero) A molar equivalent of 4 moles is preferred.

In Stage 2, ammonia and most of the water can be removed by laying on a partial vacuum and/or heating the mixture. In this regard, 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 and most preferably from 1 to 3 mole equivalents, each time used (high The total amount of alanine-4-yl)(methyl)phosphinic acid is based on the total amount.

Stage 3 is preferably carried out in such a manner that the reaction is carried out in the presence of from 0.01 to 10 mol%, preferably from 0.05 to 5 mol% and especially preferably from 0.1 to 2.5 mol% of a catalytically effective aldehyde. The sub-system is based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid used, and is preferably an aliphatic aldehyde such as heptanal, an aromatic aldehyde such as benzaldehyde or a heteroaromatic aldehyde. , for example, 2-pyridinecarboxaldehyde, or also salicylaldehyde, for example, such as salicylaldehyde, 3,5-dichlorosalicylaldehyde, 3,5-dinitrosalicylaldehyde, 2-hydroxypyridine-3-carbaldehyde , 4-hydroxypyridine-3-carbaldehyde or also 2-hydroxy-5-nitrobenzaldehyde.

Stage 3 is preferably carried out in the presence of a catalytically effective amount of a six-membered (hetero) aromatic aldehyde; in this respect, salicylaldehyde and heteroaromatic hydroxy formaldehyde are preferred; 3,5-dichlorosalicylide Aldehydes and/or 5-nitroso salicylaldehyde are especially preferred.

The total molar amount of the six-membered (hetero) aromatic aldehyde used in the above method according to the present invention is preferably from 0.01 to 10 mol%, preferably from 0.05 to 5 mol%, and particularly preferably between Within the range of 0.1 to 2.5 mol%, each time based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid used.

As described above, the process is preferably carried out in such a manner that the reaction is carried out at a temperature in the range of from 40 to 150 ° C, more preferably from 50 to 120 ° C, particularly preferably in the range of from 60 to 100 ° C.

In stage 4, depending on the desired product form, an aqueous alkali metal hydroxide solution or aqueous ammonia solution is added to treat the reaction mixture. Further, if it is not present in the reaction mixture, an organic solvent for ephedrine extraction, for example, for example, toluene, ethyl acetate or MTBE may be additionally added.

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

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

The reaction time of the process according to the invention depends inter alia on several parameters, such as the reaction temperature and the reactor size. Those skilled in the art will select the most desirable reaction time in such a way that it is possible to achieve the desired result economically in an optimal manner. The reaction time is usually in the range of 8 to 72 hours, often in the range of 12 to 60 hours, and most is in the range of 16 to 48 hours.

The process according to the invention can be carried out in the following manner, and advantageously, the D-acid and/or its salt provided in step a), preferably in the form of D, L-acid or a salt thereof, The reaction is preceded by the preparation of the desired L-acid and/or its salt, first preparing ephedrine (in this case, preferably (-)-ephedrine) and (high alanine-4-yl) (methyl) a mixture, salt or mixture of salts of phosphinic acid.

Similarly, ephedrine (preferably (-)-ephedrine) and L-(high alanine-4-yl)(methyl)phosphinic acid produced by the reaction according to the method of the present invention Mixtures of acids, salts or salts are advantageous.

Accordingly, the present invention also relates to mixtures, salts or mixtures of ephedrine and (high alanine-4-yl)(methyl)phosphinic acid, (-)-ephedrine and (high alanine-4-yl) ( Mixtures of methyl)phosphinic acids, salts or mixtures of salts 4-methyl)(methyl)phosphinic acid are preferred.

Preferred mixtures according to the invention may, for example, be (-)-ephedrine by (p-alanine-4-yl)(methyl)phosphinic acid and ephedrine. Mix together to get. Ephedrine, in this case, preferably the molar amount of (-)-ephedrine 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 amount of the molar amount of (high alanine-4-yl)(methyl)phosphinic acid used.

The salt according to the invention or the mixture of salts according to the invention may, for example, be (high propylamine) by a temperature preferably in the range of from 10 to 100 ° C, preferably in the range of from 20 to 80 ° C Acid-4-yl)(methyl)phosphinic acid and ephedrine, in this case preferably (-)-ephedrine, dissolved in water, and then evaporating the solution thus obtained, ie, removing from the solution Water to get. Ephedrine, in this case, preferably the molar amount of (-)-ephedrine, in this case, 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 Within the range of 2, each time based on the molar amount of (high alanine-4-yl)(methyl)phosphinic acid used. Thus, a molar equivalent of D,L-(high alanine-4-yl)(methyl)phosphinic acid is produced with a molar equivalent of (-)-ephedrine, for example, corresponding ( -) - ephedrine and D, L-(high alanine-4-yl)(methyl)phosphinic acid (1:1 salt), while using one molar equivalent of D,L-(high alanine-4- (meth)phosphinic acid with two molar equivalents of (-)-ephedrine can produce corresponding (-)-ephedrine and D,L-(high alanine-4-yl)(methyl) times Phosphonic acid (2:1 salt).

According to the invention, preference is given to mixtures of salts or 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-(high alanine-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)phosphinium Acid (1:1 salt), (+)-ephedrine and D,L-(high alanine-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-(high alanine-4 -yl)(methyl)phosphinic acid (2:1 salt), (-)-ephedrine and L-(homoalanine-4-yl)(methyl)phosphinic acid (2:1 salt).

In another aspect, the invention relates to the use of ephedrine, preferably (-)-ephedrine, for the use of D-(high alanine-4-yl)(methyl)phosphinic acid (D- Conversion of an acid) and/or a salt thereof to L-(high alanine-4-yl)(methyl)phosphinic acid (L-acid) and/or a salt thereof, or - for D, L- (high Racemate resolution of alanine-4-yl)(methyl)phosphinic acid and/or its salts, especially for dynamic kinetic racemate resolution.

Example:

In the following examples, the parts by weight and percentage refer to the weight unless otherwise indicated.

The symbols ">" and "<" indicate "greater than" and "less than", respectively.

Abbreviation used: rac- glufosinate = racemic glufosinate, equivalent 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

Eq = molar equivalent, based on glufosinate

Molar%=mol%, based on glufosinate

quant.NMR=Quantitative NMR Spectroscopy

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

Calcd for=calculation

Example 1:

20 g of D-glufosinate (1 eq, free acid, L: D < 1:99) and 73 g of (-)-ephedrine (4 eq) with 6 ml of water (3 eq) in Flexi with anchor stir bar The -Lab reactor was stirred at 300 rpm and heated to a jacket temperature of 95 °C. After 1 hour, 211 mg of 3,5-dichlorosalicylaldehyde (1 mol%) was added to the mixture and stirred overnight. After 20 hours, the sample was treated with NaOH and toluene (89:11 L:D). After 24 hours, the formulation was allowed to cool to an internal temperature of 75 ° C, followed by the addition of 53 ml of 20% NaOH. The phases were separated at 50 ° C: aqueous phase (80.65 g quant. NMR: 27.9% glufosinate disodium; 94% yield; 89:11 L:D). The organic phase was evaporated (74.3 g quant. NMR: 96.1% ephedrine; quantitative recovery).

Example 2:

In a 100 ml multi-necked flask equipped with a precision bearing stirrer and a reflux condenser, 5 g of racemic (rac)- glufosinate (1 eq, free acid) was added to 11.4 g of (-) at 85 °C. Ephedrine (2.5 eq), 5 g of toluene and 0.16 g of water were added followed by 0.053 g of 3,5-dichlorosalicylaldehyde, and the resulting mixture was stirred at 85 ° C for 16 hours. The suspension sample was then dissolved in 20% aqueous NaOH, washed with dichloromethane and then detected by palm chromatography: 92:8 L:D.

Example 3:

In a 100 ml multi-necked flask equipped with a precision bearing stirrer and a reflux condenser, 5 g of racemic-glufosinate (1 eq, free acid) was added to 11.4 g of (-)-ephedrine at 85 °C. (2.5 eq), 5 g of toluene and 0.66 g of water, followed by the addition of 0.053 g of 3,5-dichlorosalicylaldehyde, and the resulting mixture was stirred at 85 ° C for 16 hours. The suspension sample was then dissolved in 20% aqueous NaOH, washed with dichloromethane and then detected by palm HPLC: 91:9 L:D.

Example 4:

In a 100 ml multi-necked flask equipped with a precision bearing stirrer and a reflux condenser, 5 g of racemic-glufosinate (1 eq, free acid) was added to 9.1 g of (-)-ephedrine at 75 °C. (2 eq), 5.2 g of 1-BuOH and 0.52 g of water, followed by the addition of 0.053 g of 3,5-dichlorosalicylaldehyde, and the resulting mixture was stirred at 75 ° C for 16 hours. The suspension sample was then dissolved in 20% aqueous NaOH, washed with dichloromethane and then detected by palm chromatography: 77:23 L:D.

Example 5:

40 g of a 50% aqueous solution of racemic-glufosinate ammonium was treated with 73 g of (-)-ephedrine and evaporated on a rotary evaporator at 60 ° C with 20 mbar. The residue was dissolved in 100 ml of toluene and then heated to a jacket temperature of 95 ° C in a Flexi-Lab reactor with an anchor stirrer and stirred at 300 rpm. 211 mg of 3,5-dichlorosalicylaldehyde was added and the mixture was stirred overnight. After 44 hours, the formulation was cooled to an internal temperature of 75 ° C and treated with 53 ml of 20% NaOH. The phases were separated at 50 ° C: aqueous phase (81.4 g HPLC: 85:15 L:D; quant. NMR: 24.7% glufosinate disodium; 81% yield). The organic phase was evaporated (67.3 g quant. NMR: 97.1% ephedrine; 92% recovered).

Example 6

In a 100 ml multi-necked flask equipped with a precision bearing stirrer and a reflux condenser, 5 g of racemic-glufosinate (1 eq, free acid) was added to 9.1 g of (-)-ephedrine at 75 °C. (2 eq), 4.3 g of ethanol and 0.47 g of water, followed by the addition of 0.053 g of 3,5-dichlorosalicylaldehyde, and the resulting mixture was stirred at 75 ° C for 16 hours. The suspension sample was then dissolved in 20% aqueous NaOH, washed with dichloromethane and then detected by palm chromatography: 77:23 L:D.

Example 7

In a 100 ml multi-necked flask equipped with a precision bearing stirrer and a reflux condenser, 5 g of racemic-glufosinate (1 eq, free acid) was added to 9.1 g of (-)-ephedrine at 75 °C. (2 eq), 3.69 g of 4-methyl-2-pentanol and 0.41 g of water, followed by the addition of 0.053 g of 3,5-dichlorosalicylaldehyde, and the resulting mixture was stirred at 75 ° C for 16 hours. The suspension sample was then dissolved in 20% aqueous NaOH, washed with dichloromethane and then detected by palm chromatography: 68:31 L:D.

Example 8

In a 100 ml multi-necked flask equipped with a precision bearing stirrer and a reflux condenser, 5 g of racemic-glufosinate (1 eq, free acid) was added to 9.1 g of (-)-ephedrine at 75 °C. (2 eq), 3.69 g of tert- BuOH and 0.41 g of water, followed by the addition of 0.053 g of 3,5-dichlorosalicylaldehyde, and the resulting mixture was stirred at 75 ° C for 16 hours. The suspension sample was then dissolved in 20% aqueous NaOH, washed with dichloromethane and then detected by palm chromatography: 84:16 L:D.

Example 9

In a 100 ml multi-necked flask equipped with a precision bearing stirrer and a reflux condenser, 5 g of racemic-glufosinate (1 eq, free acid) was added to 9.1 g of (-)-ephedrine at 75 °C. (2 eq), 2.9 g of 2-BuOH (isobutanol) and 0.3 g of water, followed by the addition of 0.053 g of 3,5-dichlorosalicylaldehyde, and the resulting mixture was stirred at 75 ° C for 16 hours. The suspension sample was then dissolved in 20% aqueous NaOH, washed with dichloromethane and then detected by palm chromatography: 87:13 L:D.

Example 10:

In a Flexi-Lab reactor with a jacket temperature of 95 ° C, 20 g of racemic- glufosinate (1 eq, free acid) was added to 73 g of (-)-ephedrine (4 eq) with 2 ml of water at 300 rpm. Stir. After 1 hour, 211 mg of 3,5-dichlorosalicylaldehyde (1 mol%) was added to the mixture and stirred overnight. After 24 hours, the formulation was cooled to an internal temperature of 75 ° C and 53 ml of 20% NaOH was added. The phases were separated at 50 ° C: aqueous phase (78.5 g quant. NMR: 29.2% glufosinate disodium; 92% yield; 86:14 L: D); the organic phase was evaporated (74.95 g quant. NMR: 92.4% ephedrine; >95% recovery).

Example 11

40 g of a 50% aqueous solution of racemic-glufosinate ammonium was treated with 61 g of (-)-ephedrine and evaporated at 60 ° C under a vacuum of 5 mbar. The residue, which was a liquid at 60 ° C and a total weight of 81 g, was then heated in a Flexi-Lab reactor with an anchor stirrer to a jacket temperature of 95 ° C and stirred at 300 rpm. 177 mg of 3,5-dichlorosalicylaldehyde was added and the resulting mixture was stirred overnight. After 48 hours, the preparation was cooled to an internal temperature of 75 ° C and treated with 21 ml of a 25% aqueous ammonia solution and 100 ml of toluene. After separation of the phases at 50 ° C, an aqueous phase (33 g, 55.4% glyphosate, according to quant. NMR; 91% yield; 85:15 L:D) and evaporated organic phase (60.4 g, 88) was obtained. % ephedrine content, according to quant. NMR).

Example 12

3 g of racemic-glufosinate (free acid) was placed in 9.6 g of (-)-ephedrine and 0.3 in a 100 ml multi-necked flask equipped with a precision bearing stirrer and a reflux condenser at a bath temperature of 95 °C. In ml water, 5 mol% benzaldehyde was subsequently added. The mixture was stirred at 95 ° C overnight and after 24 hours, the sample was detected by palm chromatography: 57:43 L:D.

Example 13

3 g of racemic-glufosinate (free acid) was placed in 9.6 g of (-)-ephedrine and 0.3 in a 100 ml multi-necked flask equipped with a precision bearing stirrer and a reflux condenser at a bath temperature of 95 °C. In ml water, 5 mol% n-heptanal was subsequently added. The mixture was stirred at 95 ° C overnight and after 24 hours, the sample was detected by palm chromatography: 58:42 L:D.

Example 14

In a Flexi-Lab reactor with an anchor stirrer, 20 g of racemic-glufosinate (free acid) was added to 73 g of (-)-ephedrine and 2 ml of water at a jacket temperature of 95 °C. After 1 hour, 134 mg of salicylaldehyde was added and the mixture was stirred. After 24 h, the sample was measured by palm HPLC: 60:40 L:D. After 76 h, another sample was detected by palm HPLC: 72:28 L:D.

Example 15

In a 100 ml multi-necked flask equipped with a precision bearing stirrer and a reflux condenser, 5 g of rac-glufosinate (free acid) was added to 16 g of (-)-ephedrine and 0.5 g of water at 90 °C. After one hour, 46 mg of 2-hydroxy-5-nitrobenzaldehyde was added, and the mixture was stirred at 90 ° C overnight. After 24 hours, the sample was taken out and dissolved in 1 M sodium hydroxide solution and 3 ml of dichloromethane, and the aqueous phase was detected by palm chromatography: 88:12 L:D.

Example 16:

In a Flexi-Lab reactor with an anchor stirrer, 20 g of racemic-glufosinate (free acid) was added to 73 g of (-)-ephedrine and 4 ml of water at a jacket temperature of 95 °C. After 1 hour, 234 mg of 3,5-dinitrosalicylaldehyde was added and the mixture was stirred at 95 °C. After 24 hours, the sample was detected by palm HPLC: 58:42 L:D.

Example 17

7.5 g of D-glufosinate (free acid) and 17.8 g of L-glufosinate ammonium and 84 g of (-)-ephedrine (re-distilled; 96.4% according to quant. NMR) were completely dissolved in water, It was then evaporated (total 131.4 mmol of glufosinate and 3.70 eq of (-)-ephedrine). The liquid residue at 60 ° C was transferred to a Flexi-Lab reactor. The water content of 8.22% was determined from the sample of this mixture. The palm HPLC of this sample showed 70:30 L:D. At a jacket temperature of 85 ° C, 263 mg of 3,5-dichlorosalicylaldehyde (1.05 mol%) was added and the mixture was stirred overnight. The formulation was then cooled to an internal temperature of 70 ° C, then 75 ml of toluene and 82 g of sodium hydroxide solution (20%) were added thereto. After phase separation, 105.6 g of glufosinate disodium (94:6 L:D; 24.8% pure aqueous solution according to quant. NMR; 89% yield) and 85.6 g of (-) from the evaporated organic phase were obtained. - Ephedrine (quantitative recovery).

Example 18

25 g of racemic-glufosinate (1 eq, free acid) and 23.2 g of (-)-ephedrine (1 eq) were dissolved in 200 ml of water at 60 ° C and then evaporated to dryness. Transferring the formed salts of (-)-ephedrine and D,L-(homoalanine-4-yl)(methyl)phosphinic acid (1:1 salt) to a Flexi-Lab reaction with an anchor stir bar And treated with 44 ml of toluene and 527 mg of 3,5-dichlorosalicylaldehyde. In order to increase the stirrability of the mixture, the latter was heated to 95 ° C and an additional 23.2 g of (-)-ephedrine was added at this temperature, and the resulting mixture was stirred at a jacket temperature of 95 ° C overnight. After 16 hours, the sample was detected by palm HPLC: 67:33 L:D.

Example 19

4.1 g of racemic-glufosinate (1 eq, free acid) and 3.74 g of D-(+)-ephedrine (1 eq) were placed at .95 g water (2.5 eq) and 8.6 g positive at 20 °C. In propanol. 432 mg of 3,5-dichlorosalicylaldehyde (10 mol%) was added and the resulting mixture was stirred overnight. The suspension was filtered and the sample was measured by palm chromatography (57:43 L:D).

Example 20

25 g of racemic-glufosinate (1 eq, free acid) and 57.3 g of (-)-ephedrine (99.5%; 2.5 eq), 25.4 g of toluene (2 eq) and 5 g of water (2 eq) The anchored stirrer in a Flexi-Lab reactor was stirred at 300 rpm and heated to a jacket temperature of 85 °C. After 1 hour, 264 mg of 3,5-dichlorosalicylaldehyde (1 mol%) was added and the mixture was stirred at 85 ° C overnight. After 16 hours, the formulation was cooled to an internal temperature of 55 ° C, treated with 65 g of toluene, and then 70.5 g of a 10% aqueous ammonia solution. The phases were separated at 55 ° C: 94.5 g of aqueous phase were obtained (quant. NMR: 29.7% glyphosate ammonium; 94% yield; 95:5 L: D). The organic phase was evaporated (59.3 g quant. NMR: 95.2% ephedrine; 99% recovered).

 Comparative example:   Example C1: Comparative Example, (+)- pseudoephedrine

25 g of racemic-glufosinate (free acid) was first stirred at 120 ° C and 57 g of (+)-pseudoephedrine (solid) with 5 ml of water and 25.4 g of toluene in a Flexi-Lab reactor until A homogeneous suspension. After the temperature was lowered to 85 ° C, 263 mg of 3,5-dichlorosalicylaldehyde was added and the mixture was stirred at 85 ° C overnight. The preparation 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: the aqueous phase contained, according to palm HPLC, sodium glufosinate (L: D 50: 50).

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

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

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

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

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

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

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

Embodiment S1:

The salts of (-)-ephedrine and D-(homoalanine-4-yl)(methyl)phosphinic acid (1:1 salt) are based on the above criteria by D-glufosinate and (-)-ephedrine. Process 1 was prepared.

¹ H NMR (601.6 MHz, D ₂ O) δ=1.16 (d, 3H), 1.19 (CH ₃ -EtOH, ~35 Mole %), 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:

The salt of (-)-ephedrine and L-(homoalanine-4-yl)(methyl)phosphinic acid (1:1 salt) is based on the above criteria by L-glufosinate and (-)-ephedrine Process 1 was prepared.

¹ H NMR (601.6 MHz, D ₂ O) δ = 1.15 (d, 3H), 1.19 (CH ₃ -EtOH, ~35 Mole %), 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 C 5 H 13 NO 4 P 182.06); MS, TOF ES + 166.12 (MH +, calcd for C10H16NO 166.12).

Embodiment S3:

The salts of (-)-ephedrine and D,L-(homoalanine-4-yl)(methyl)phosphinic acid (1:1 salt) are based on rac- glufosinate and (-)-ephedrine Prepared in the above standard procedure 1.

¹ H NMR (601.6 MHz, D ₂ O) δ=1.16 (d, 3H), 1.19 (CH ₃ -EtOH, ~35 Mole %), 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:

The salts of (-)-ephedrine and D-(homoalanine-4-yl)(methyl)phosphinic acid (2:1 salt) are based on the above criteria by D-glufosinate and (-)-ephedrine. Process 2 was prepared.

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:

The salts of (-)-ephedrine and L-(homoalanine-4-yl)(methyl)phosphinic acid (2:1 salt) are based on the above criteria by L-glufosinate and (-)-ephedrine. Process 2 was prepared.

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:

The salts of (-)-ephedrine and D,L-(homoalanine-4-yl)(methyl)phosphinic acid (2:1 salt) are from racemic-glufosinate and (-)-ephedra Prepared according to the above standard procedure 2.

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 L-(homoalanine-4-yl)(methyl)phosphinic acid (L-acid) and/or a salt thereof, characterized in that the process comprises the following stages: a) providing with 20 % by weight or more of D-(high alanine-4-yl)(methyl)phosphinic acid (D-acid) and/or its salt content (hyperalanine-4-yl) (methyl) times Phosphonic acid and/or its salt, each time based on the total amount of the high alanine-4-yl (methyl)phosphinic acid used and calculated, and b) the D-acid provided in step a) And/or its salt is reacted with ephedrine in water or in an aqueous/organic solvent mixture, wherein, optionally, one, more or all of the following steps c) to e) are carried out: c) in the free In the case where the L-acid is prepared, the acid is neutralized with the salt obtained according to stage b), or, in the case of another salt other than the salt obtained according to step b), the salt exchange is carried out with a base. , d) adding one or more organic solvents, and/or e) isolating the phase comprising L-(homoalanine-4-yl)(methyl)phosphinic acid (L-acid) and/or a salt thereof.    The method of claim 1, which is characterized in that a D-(high alanine-4-yl)(methyl)phosphinic acid (D-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 a salt thereof, each used in step a) (the total amount of high alanine-4-yl (methyl) phosphinic acid is Benchmarks and calculations.    The method of claim 1 or 2, characterized in that in stage a), D,L-(homoalanine-4-yl)(methyl)phosphinic acid (D,L-acid) and/or Or its salt.    The method of any one of claims 1 to 3, characterized in that the reaction is carried out with (-)-ephedrine.    The method of any one of claims 1 to 4, characterized in that each time the ephedrine in the reaction is based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid The total amount is from 0.5 to 8 mole equivalents, preferably from 0.8 to 6 mole equivalents, preferably from 1 to 4 mole equivalents.    The method of any one of claims 1 to 5, characterized in that the total amount of water in the reaction is based on the total amount of (high alanine-4-yl)(methyl)phosphinic acid each time. It is 0.01 to 7 mole equivalents, preferably 0.05 to 6 mole equivalents, preferably 0.1 to 5 mole equivalents.   The method of any one of claims 1 to 6, characterized in that step c) is carried out, the salt exchange being carried out with a base preferably selected from the group consisting of NH ₃ , NaOH or KOH or the bases Aqueous solution.  The method according to any one of claims 1 to 7, characterized in that in the reaction, no organic solvent or a solvent mixture of water and one or more organic solvents is used, and the organic solvents are preferably selected from the following Groups formed: aromatic hydrocarbons, aliphatic hydrocarbons, saturated cyclic hydrocarbons, aliphatic alcohols, decylamines, ethers, esters, ketones, and aliphatic nitriles.    The method of any one of claims 1 to 8, characterized in that step b) is at a temperature in the range of from 40 to 150 ° C, preferably in the range of from 50 to 120 ° C and particularly preferably from 60 to The temperature is in the range of 100 ° C.    The method of any one of claims 1 to 9, characterized in that the reaction occurs in the presence of a catalytically effective amount of an aldehyde.    The method of any one of claims 1 to 10, characterized in that the reaction is in the range 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. Occurs in the presence of each of 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 mixture of salts or salts of claim 12 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- (meth)phosphinic acid (1:1 salt), (-)-ephedrine and D,L-(high alanine-4-yl)(methyl)phosphinic acid (2:1 salt), ( -) - ephedrine and D-(homoalanine-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-(high alanine-4-yl)(methyl)phosphinic acid (2:1 salt), (+)-ephedrine and D-(high propylamine Acid-4-yl)(methyl)phosphinic acid (2:1 salt), (+)-ephedrine and L-(high alanine-4-yl)(methyl)phosphinic acid (2:1 salt) .    A mixture of salts or salts of claim 12 or 13 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-(high propylamine Acid-4-yl)(methyl)phosphinic acid (2:1 salt), (-)-ephedrine and L-(high alanine-4-yl)(methyl)phosphinic acid (2:1 salt) .    Use of ephedrine, preferably (-)-ephedrine, for the use of D-(high alanine-4-yl)(methyl)phosphinic acid (D-acid) and/or a salt thereof Conversion to L-(high alanine-4-yl)(methyl)phosphinic acid (L-acid) and/or its salt, or - for D,L-(homoalanine-4-yl) Analysis of the racemate of (methyl)phosphinic acid and/or its salt.