Methods for preparing l-glufosinate

Patent metadata

Field	Value
Publication number	US-2024182502-A1
Application number	US-202218284108-A
Country	US
Kind code	A1
Filing date	Mar 30, 2022
Priority date	Apr 1, 2021
Publication date	Jun 6, 2024
Grant date	—

Abstract

Methods for the production of L-glufosinate (also known as phosphinothricin or (S)-2-amino-4-(hydroxy(methyl)phosphonoyl)butanoic acid) ammonium salt are provided. The methods comprise a refined multi-step process. The first step involves the oxidative deamination of D-glufosinate to PPO (2-oxo-4-(hydroxy(methyl)phosphinoyl)butyric acid). The second step involves the specific amination of PPO to L-glufosinate, using an amine group from one or more amine donors. The third step involves the enrichment of the desired enantiomer in the yield by conversion of the obtained side product to the desired final product as well. By addition of the third refinement step, the proportion of the D-glufosinate present in a mixture of L-glufosinate and D-glufosinate can substantially be converted to the desired L-glufosinate ammonium salt.

First claim

1 . A method for obtaining L-glufosinate ammonium salt of formula L-(1) from a L-glufosinate C 1 —C 6 -alkylammonium salt of formula L-(2),

wherein R 1 and R 2 in formula L-(2) are selected independently from one another from hydrogen, methyl, ethyl, propyl, butyl, or pentyl; and
which method comprises:
Step 1: adding Ca(OH) 2 to an aqueous solution of a L-glufosinate C 1 -C 6 -alkylammonium salt L-(2), whereby the L-glufosinate C 1 -C 6 -alkylammonium salt (L-2) reacts to the L-glufosinate calcium salt L-(3), and the thereby released low boiling C 1 -C 6 -alkylamine is removed by distillation;
Step 2: adding (NH 4 ) 2 SO 4 to the remaining aqueous solution of the calcium salt of L-glufosinate L-(3), whereby the calcium ion of the L-glufosinate L-(3) calcium is replaced by the ammonium ion of the ammonium sulfate, and the precipitated calcium sulfate (gypsum) is removed by filtration.
Step 3: isolating the desired ammonium salt L-(1) by removal of water from the clear filtrate.

2 . The method according to claim 1 , wherein the L-glufosinate-alkylammonium salt of formula L-(2) is obtained by deracemization of glufosinate-ammonium of formula DL-(1) in a two-step process,

wherein in a first step an oxidative deamination of D-glufosinate to PPO (2-oxo-4-(hydroxy(methyl)phosphinoyl)butyric acid) is carried out with a D-amino acid oxidase (DAAO) enzyme, and
in a second step the PPO is aminated to a L-glufosinate C 1 -C 6 -alkylammonium salt of formula L-(2) by a transaminase (TA) enzyme using an amine group from one or more amine donors.

3 . The method according to claim 2 , wherein the L-glufosinate C 1 -C 6 -alkylammonium salt of formula L-(2) is obtained in the second step by reaction with the transaminase (TA) enzyme in the presence of an amine donor, which is an aliphatic secondary C 1 -C 6 -alkylamine selected from the group consisting of ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, amylamine, sec-pentylamine, n-hexylamine, and sec-hexylamine.

4 . The method according to claim 2 , wherein the amine donor is a secondary aliphatic C 1 -C 6 -alkylamine selected from isopropylamine or sec-butylamine.

5 . The method according to claim 1 , wherein the C 1 -C 6 -alkylammonium ion in the L-glufosinate C 1 -C 6 -alkylammonium salt of formula L-(2) is isopropylamine ammonium or sec-butylamine ammonium.

6 . The method according to claim 2 , wherein the DAAO enzyme is selected from an enzyme from Rhodosporidium toruloides (UniProt P80324), Trigonopsis variabilis (UniProt Q99042), Neolentinus lepideus (KZT28066.1), Trichoderma reesei (XP_006968548.1), or Trichosporon oleaginosus (KLT40252.1).

7 . The method according to claim 2 , wherein the DAAO enzyme is a mutant DAAO.

8 . The method according to claim 6 , wherein the mutant DAAO is a mutant DAAO based on the sequence from Rhodosporidium toruloides.

9 . The method according to claim 2 , wherein the TA enzyme is a S-selective ω-transaminase enzyme selected from the group consisting of Arthrobacter sp., Bacillus megaterium, Klebsiella pneumoniae JS2F (S), Bacillus thuringiensis JS64 (S), V. fluvialis JS17 (S), Pseudomonas sp. KNK425 (S), Alcaligenes denitrificans Y2k-2 (S), Mesorhizobium sp. LUK (S), Bacillus megaterium SC6394 (S), Moraxella lacunata WZ34 (S), Janibacter terrae DSM13953 (S), Pseudomonas cichorii DSM 50259 (S), Pseudomonas fluorescens ATCC49838 (S), Pseudomonas fluorescens KNK08-18 (S) , Pseudomonas sp. ACC (S), Pseudomonas putida NBRC14164 (S), Bacillus halotolerans (S), Bacillus subtilis subsp. stercoris (S), Bacillus subtilis subsp. inaquosorum (S), Bacillus endophyticus (S), Rhizobium radiobacter (S), Chromobacterium violaceum DSM30191 (S), Pseudomonas aeruginosa (S) Ingram et al. (2007), Arthrobacter citreus (S), Caulobacter crescentus (S), Rhodobacter sphaeroides (S), Paracoccus denitrificans (S), Polaromonas sp. JS666 (S), Ochrobactrum anthropi (S), Acinetobacter baumannii (S), Acetobacter pasteurianus (S), Burkholderia vietnamensis (S), Halomonas elongata (S), Burkholderia graminis (S), Thermomicrobium roseum (S), Sphaerobacter thermophilus (S), Geobacillus thermodenitrificans (S), Bacillus megaterium (S), Bacillus mycoides (S), Halomonas sp. CSM-2 (S), , Rhodospirillaceae bacterium (S), Labrenzia sp. LAB (S), Afipia sp. P52-10 (S), Oceanibaculum indicum (S), Ilumatobacter coccineus (S), Variovorax sp. KK3 (S), Paraburkholderia caribensis (S), Hydrogenophaga palleronii (S), Solirubrobacter soli (S), Kineosporia sp. R_H_3 (S), Roseomonas deserti (S), Sinorhizobium meliloti (S), Bosea lupine (S), Bosea vaviloviae (S), Pseudacidovorax intermedius (S), Burkholderia sp. UYPR1.413 (S), ), Escherichia coli K12 (S), Pseudomonas putida (S), Pseudomonas fluorescens (S), Pseudomonas chlororaphis (S), , Silicibacter pomeroyi (S), Rhodobacter sphaeroides KD131 (S), Ruegeria sp. TM1040 (S), Mesorhizobium loti MAFF30399 (S), and Bacillus anthracis (S).

10 . The method according to claim 2 , wherein the TA enzyme is a mutant ω-transaminase based on the sequence from Arthrobacter sp. or from Bacillus megaterium.

11 . A method for obtaining L-glufosinate ammonium salt of formula L-(1) by deracemization of glufosinate-ammonium of formula DL-(1), wherein
in a starting step an oxidative deamination of D-glufosinate to PPO (2-oxo-4-(hydroxy(methyl)phosphinoyl)butyric acid) is carried out with a D-amino acid oxidase (DAAO) enzyme, and in a following step the PPO is aminated to a L-glufosinate C 1 -C 6 -alkylammonium salt of formula L-(2) by a transaminase (TA) enzyme using an amine group from an amine donor selected from the group consisting of ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, amylamine, sec-pentylamine, n-hexylamine, and sec-hexylamine,

wherein R 1 and R 2 in formula L-(2) are selected independently from one another from methyl, ethyl, propyl, butyl, or pentyl, and
in a further following step Ca(OH) 2 is added to the aqueous solution of L-glufosinate C 1 -C 6 -alkylammonium salt of formula L-(2), whereby it reacts to L-glufosinate calcium salt of formula L-(3), and the released low-boiling C 1 -C 6 -alkylamine is removed by distillation:

and
in a further following step (NH 4 ) 2 SO 4 is added to the remaining aqueous solution of the calcium salt of L-glufosinate of formula L-(3), whereby the calcium ion of the L-glufosinate calcium salt of formula L-(3) is replaced by the ammonium ion of the ammonium sulfate, and the precipitated calcium sulfate (gypsum) is removed by filtration:

and wherein
in a final step the desired L-glufosinate ammonium salt of formula L-(1) is obtained by removal of water from the clear filtrate.

12 . The method of claim 11 , wherein the all method steps are performed consecutively as one-pot-process in a single container.

13 . The method of claim 11 , wherein the individual method steps are performed consecutively as multi-pot-process in separate containers.

14 . A met

Assignees

• Basf Se

Inventors

• Ditrich Klaus
• Escribano Cuesta Ana

Classifications

• C07F9/301 Primary

  Acyclic saturated acids which can have further substituents on alkyl · CPC title

• C12P41/006

  by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures · CPC title

• C12P13/04 Primary

  Alpha- or beta- amino acids {(other amino acids C12P13/005)} · CPC title

• C12P41/002

  by oxidation/reduction reactions · CPC title

• C07C51/412

  by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part · CPC title