CN114555612A

CN114555612A - Method for preparing L-glufosinate-ammonium intermediate

Info

Publication number: CN114555612A
Application number: CN202180006007.2A
Authority: CN
Inventors: 刘永江; 周磊; 曾伟; 徐敏; 程柯; 尹英遂
Original assignee: Lier Chemical Co Ltd; Guangan Lier Chemical Co Ltd
Current assignee: Lier Chemical Co Ltd; Guangan Lier Chemical Co Ltd
Priority date: 2020-01-13
Filing date: 2021-01-13
Publication date: 2022-05-27
Also published as: WO2021143712A1

Abstract

The invention relates to a method for preparing an L-glufosinate-ammonium intermediate.

Description

Method for preparing L-glufosinate-ammonium intermediate

Technical Field

Background

Glufosinate is an important herbicide.

Disclosure of Invention

The present invention provides a process for the preparation of a compound of formula (I) or a salt thereof,

the method comprises the following steps:

reacting a compound of formula (II)

With a compound of the formula (III),

preferably, an enantiomerically pure compound of formula (II) is reacted with a compound of formula (III),

wherein:

Hal ¹is halogen;

PG is hydrogen;

z is OX or OY;

R ₁is C₁-C ₁₆Alkyl, cyclohexyl, cyclopentyl or phenyl, wherein each radical may be substituted by hydrogen, C₁-C ₆Alkyl radical, C₁-C ₆Alkoxy or dialkylamino radicals (e.g. -N (C)₁-C ₆Alkyl radical)₂Group) substitution;

R ₂is C₁-C ₈Alkyl radical, C₁-C ₈An ether group or a phenyl group;

x and Y are each independently an alkyl, alkenyl or aryl group; preferably, X and Y are each independently C₁-C ₆Alkyl radical, C₂-C ₆Alkenyl or C₆-C ₁₀An aromatic group;

the chiral carbon atom is labeled; preferably, the compound of formula (I) is enantiomerically pure.

Further, the aforementioned R₂Is C₁-C ₆Alkyl, preferably C₁-C ₄Alkyl, more preferably ethyl.

Further, the aforementioned R₁Is phenyl or C₁-C ₆Alkyl, preferably C₁-C ₄Alkyl, more preferably methyl.

Further, the aforementioned X and Y are each independently C₁-C ₆Alkyl, preferably C₁-C ₄More preferably, X and Y are both ethyl.

Further, the aforementioned R₁Is methyl, X is ethyl and Y is ethyl.

Further, the aforementioned enantiomeric ratio is 50.5: 49.5 to 99.5: 0.5 of (L): (D) -enantiomer or (D): (L) -enantiomer.

Further, the aforementioned enantiomeric ratio is 50.5: 49.5 to 99.5: 0.5 of (L): (D) -enantiomer.

In some embodiments, Hal¹Is a chlorine atom.

In some embodiments, R₂Is ethyl.

In some embodiments, X and Y are both ethyl, and Z is-O-ethyl.

The reaction can take place at room temperature, the reaction temperature can be 20-200 ℃, and in view of the reaction efficiency, the reaction temperature is preferably 50-150 ℃, 90-140 ℃ or 100-150 ℃. If the temperature is too low, the reaction rate is too slow, and if the temperature is too high, byproducts are generated.

The aforementioned reaction can be carried out under solvent-free conditions or in an inert solvent. The addition of the solvent can reduce the generation of impurities and prolong the reaction time. The inert solvent can be selected from one or more of benzene solvents, amide solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, sulfone or sulfoxide solvents, ether solvents or ester solvents; preferably, the inert solvent is selected from one or more of benzene solvents, amide solvents, halogenated hydrocarbon solvents, ether solvents and ester solvents.

In a specific embodiment, the inert solvent may be selected from one or more of chlorobenzene, trimethylbenzene, 1, 4-dioxane, 1, 2-dichloroethane, dimethyl sulfoxide, N-methylpyrrolidone (N-methylpyrrolidone), N-dimethylformamide, petroleum ether, N-heptane, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, ethyl acetate, and butyl acetate. The solvent has certain influence on the reaction effect, and preferably comprises benzene, chlorobenzene, trimethylbenzene, 1, 4-dioxane, 1, 2-dichloroethane, dimethyl sulfoxide, N-methylpyrrolidone and N, N-dimethylformamide.

Preferably, the reaction solvent is an ether solvent or a benzene solvent other than toluene; most preferably, the reaction solvent is chlorobenzene, trimethylbenzene or 1, 4-dioxane.

The molar ratio of the compound of formula (II) to the compound of formula (III) is 1: 1 to 10, preferably 1: 1.3 to 3, more preferably 1: 1.3 to 2.

The reaction time (i.e., the time required for complete reaction of the starting materials) can vary widely and can range from 0.5 to 48 hours, for example from 5 to 25 hours, depending on the temperature, operating conditions and batch size.

In some embodiments, an additive is further added to the reaction system to increase the reaction rate and reduce the time required for the reaction to complete, preferably, elemental iodine, BHT (2, 6-di-tert-butyl-p-cresol), halide salts (e.g., sodium iodide, sodium bromide, TBAB (tetrabutylammonium bromide), TBAI (tetrabutylammonium iodide)), or combinations thereof.

In a preferred embodiment, the reaction of the compound of formula (II) with the compound of formula (III) is carried out without the addition of an additional base.

The invention also provides a method for preparing L-glufosinate-ammonium, which comprises the following steps:

the compound of formula (Ia) is prepared according to the method described above,

hydrolyzing the obtained compound of formula (Ia) under acidic conditions to obtain L-glufosinate-ammonium;

wherein PG, Z and R₂As defined above.

In some embodiments, the acidic conditions are achieved by the addition of hydrochloric acid.

The invention also provides a compound of formula (I) or a salt, enantiomer or mixture of enantiomers in any proportion thereof,

wherein PG, Z and R₁And R₂As defined above; preferably, PG is hydrogen; z is-O-ethyl; r₁Is methyl; and R is₂Is ethyl;

chiral carbon atoms are labeled;

preferably, the compound of formula (I) is compound 2:

in some embodiments, the present invention provides a method of preparing compound 2, comprising the step of reacting compound 1 with MDEP:

preferably, the molar ratio of the compound 1 to the MDEP is 1: 1-10, preferably 1: 1.3-3, more preferably 1: 1.3-2;

preferably, the reaction temperature is 20-200 ℃, more preferably 50-150 ℃, 90-140 ℃ or 100-150 ℃;

preferably, the reaction solvent is chlorobenzene, trimethylbenzene or 1, 4-dioxane;

preferably, the reaction is carried out in the presence of an additive, preferably elemental iodine, BHT, halogenated salts (e.g., sodium iodide, sodium bromide, TBAB, TBAI), or combinations thereof;

preferably, the reaction time is 0.5 to 48 hours, such as 5 to 25 hours or 5 to 10 hours.

The process of the present invention can effectively maintain the ee value of the starting material (i.e. maintain the stereoconfiguration of the chiral carbon atom in the compound of formula (II)) by selecting appropriate reaction conditions, so that the prepared product of a specific configuration (e.g. the L-enantiomer of the compound of formula (I) (e.g. compound 2 and L-glufosinate obtained by hydrolysis thereof) or the D-enantiomer of the compound of formula (I)) also has a good enantiomeric excess percentage (% ee) (e.g.% ee is greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%).

Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

The term "amino protecting group" refers to a group that can be attached to a nitrogen atom on an amino group to protect the amino group from reaction and which can be easily removed in a subsequent reaction. Suitable amino protecting groups include, but are not limited to, the following:

a carbamate group of the formula-C (O) O-R, wherein R is, for example, methyl, ethyl, tert-butyl, benzyl, phenethyl, CH₂＝CH-CH ₂-, etc.; amide groups of the formula-c (o) -R ', wherein R' is, for example, methyl, ethyl, phenyl, trifluoromethyl, and the like; formula-SO₂The group of N-sulfonyl derivatives of-R ', wherein R' is, for example, tolyl, phenyl, trifluoromethyl, 2, 5, 7, 8-pentamethylchroman-6-yl-, 2, 3, 6-trimethyl-4-methoxybenzene, and the like.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group including, for example, straight and branched chain groups of 1 to 18, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Alkyl groups having 1 to 6 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be halogen, nitro, sulfonyl, etheroxy, etherthio, ester, thioester, or cyano.

The term "alkenyl" refers to an alkyl group as defined above containing at least two carbon atoms and at least one carbon-carbon double bond. Such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent may be halogen, nitro, sulfonyl, etheroxy, etherthio, ester, thioester, or cyano.

The term "ether" refers to an-O-alkyl group, wherein the alkyl group is as defined above.

The term "aryl" refers to a group having at least one aromatic ring structure. The aryl group is preferably a phenyl group or a benzyl group. Phenyl and benzyl groups may be substituted or unsubstituted.

C ₁-C ₄Alkyl groups are linear or branched, saturated hydrocarbon chains containing from 1 to 4 carbon atoms. It may beMethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl groups.

As used herein, the term "halogen" includes fluorine, chlorine, bromine and iodine.

Brief description of the drawings

FIG. 1 is a gas chromatogram of the reaction solution after the completion of the first step reaction in example 7, in which the peak of the chromatogram with a retention time of 1 to 5min represents the compound and the solvent after MDEP deterioration, the peak of the chromatogram with a retention time of 6.2min represents compound 1, and the peak of the chromatogram with a retention time of 9.7min represents compound 2.

Detailed Description

Example 1

L-homoserine lactone hydrochloride (ee value 99%, 137.56g/mol, 0.073mol) was weighed into a reaction vessel 10g, and 50mL of ethanol (46.07g/mol, 0.886mol, 0.816g/mL) was added, wherein the molar ratio of homoserine lactone hydrochloride to ethanol was 1: 12.1. The temperature of the system is reduced to 10 ℃, 21.7g of thionyl chloride (118.97g/mol, 0.182mol) is slowly added dropwise, and the molar ratio of L-homoserine lactone hydrochloride to thionyl chloride is 1: 2.5. The temperature of the system is maintained at 10 ℃, and the stirring reaction is carried out for 30 min. Gradually heating to 35 ℃, stirring for reaction for 20h, continuously generating bubbles in the process, monitoring the reaction progress by using LC-MS, and stopping the reaction. The temperature of the system is reduced to room temperature, the residual thionyl chloride and ethanol are removed by reduced pressure distillation, the solid residue is beaten with 30mL of a mixed solvent of n-hexane and ethyl acetate (the volume ratio of the n-hexane to the ethyl acetate is 2: 1), filtered and dried to obtain 13.69g of chloro-homoserine ethyl ester hydrochloride (202.08g/mol, 0.0657mol), the HPLC purity is 97%, and the yield is 90% calculated based on the amount of the reactant L-homoserine lactone hydrochloride.

Reacting the solid of the chloro-homoserine ethyl ester hydrochloride with a saturated sodium carbonate solution, adjusting the pH of the system to 7-8, adding ethyl acetate for extraction, and extracting for 3 times in total, wherein the dosage of the ethyl acetate in the 3-time extraction process is 30mL, 10mL and 10mL respectively. The organic phase was collected and concentrated to give 10.30g of the target compound, chloroserine ethyl ester (165.62g/mol, 0.0591mol) as an oil, with an HPLC purity of 95% and an ee value of 99%, in a yield of 90% based on the intermediate chloroserine ethyl ester hydrochloride.

MS(ESI)：m/z[M+H] ⁺Calculated C6H13ClNO 2: 166.06, respectively; measured value: 166.0.

¹H NMR(CDCl ₃，400MHz)δ：4.04(q，J＝7.1Hz，2H)，3.65-3.50(m，2H)，3.48(dd，J＝9.0，4.7Hz，1H)，2.05(dddd，J＝14.7，8.5，6.4，4.6Hz，1H)，1.87-1.64(m，3H)，1.13(t，J＝7.2Hz，3H).

¹³C NMR(CDCl ₃，100MHz)δ：175.3，61.0，51.6，41.5，37.0，14.1.

example 2

The first step is as follows:

diethyl Methylphosphonite (MDEP) (65.9g, 484.8mmol, 2.0eq), compound 1(40.0g, 242.4mmol, 1.0eq) and chlorobenzene (81.9g, 727.2mmol, 3.0eq) were added to a three-necked flask, respectively, under nitrogen, and the mixture was stirred to warm to 140 ℃ for 6h, and the solvent and excess diethyl methylphosphonite were distilled off under reduced pressure to give compound 2, which was directly reacted in the next step.

In addition, a small amount of crude compound 2 was purified and characterized by mass spectrometry and nmr spectroscopy, with the following characterization data:

MS(ESI)：m/z[M+H] ⁺calcd for C9H21NO 4P: 238.11, respectively; measured value: 238.1.

¹H NMR(DMSO-d ₆，400MHz)δ：4.10(qd，J＝7.1，3.0Hz，2H)，3.96-3.85 (m，2H)，3.46(brs，2H)，3.41(ddd，J＝7.0，4.9，2.1Hz，1H)，1.85-1.67(m，3H)，1.67-1.58(m，1H)，1.37(d，J＝13.7Hz，3H)，1.20(td，J＝7.1，4.6Hz，6H).

¹³C NMR(DMSO-d ₆，100MHz)δ：174.5，60.3，59.3，59.2，54.0，53.9，26.8，25.6，24.7，16.5，16.5，14.1，13.8，13.8，12.9，12.9.

³¹P NMR(DMSO-d ₆，160MHz)δ：53.88.

the second step is that:

compound 2(1.0eq, 100% from the first reaction yield) and 36% HCl (294.9mL, 3432.6mmol, 14.0eq) were added to a three-necked flask and heated under reflux until the reaction was complete. The enantiomeric excess percentage of L-glufosinate-ammonium in the reaction solution after the reaction was completed was measured to be 85% ee. The solvent in the reaction solution was evaporated to dryness, then 95% ethanol (200mL) and water (20mL) were added and refluxed until the product was completely dissolved, cooled to crystallize, filtered, and dried to obtain L-glufosinate (white crystals, 26.2g, separation yield of two steps 60%, enantiomeric excess percentage of purified L-glufosinate was 97% ee).

MS(ESI)：m/z[M+H] ⁺Calcd for C5H13NO 4P: 182.05, respectively; measured value: 182.1.

¹H NMR(D ₂O，400MHz)δ：4.08(t，J＝6.2Hz，1H)，2.11(dddd，J＝14.6，11.0，8.7，6.0Hz，2H)，1.99-1.73(m，2H)，1.44(d，J＝14.2Hz，3H).

¹³C NMR(D ₂O，100MHz)δ：171.0，52.8，52.6，25.5，24.6，22.6，22.5，13.9，13.0.

³¹P NMR(D ₂O，160MHz)δ：53.8.

examples 3 to 11 and comparative example 1

Examples 3-11 and comparative example 1 were completed according to the procedure described in example 2 (wherein the reaction conditions of the first step (i.e., the equivalent weight of the reactants, the reaction temperature, the reaction time, the additives, the reaction solvent, etc. in the first step) are shown in the following table, and the reaction conditions of the second step are substantially the same as in example 2). The isolated yield of the final reaction product (i.e., calculated on the amount of L-glufosinate obtained by further hydrolysis of compound 2) and the enantiomeric excess percentage of L-glufosinate in the reaction solution at the completion of the second reaction step are shown in the following table.

The reaction solution obtained after the completion of the first reaction step in example 7 was subjected to gas chromatography, and the chromatogram was as shown in fig. 1. Figure 1 shows that compound 1 is converted to compound 2 with higher conversion.

As can be seen from the above experimental results, the time required for completing the first reaction step does not exceed 20 hours. In particular, when 1, 4-dioxane was used as the reaction solvent, 20 hours were required for completion of the first reaction step (example 7); the time required to complete the first reaction step can be significantly reduced to about 6 hours when additives of TBAB, BHT or a combination thereof are added to the 1, 4-dioxane (examples 8-9).

Further, from the results of comparative example 1, it can be seen that when toluene was used as the first-step reaction solvent, the enantiomeric excess percentage of L-glufosinate-ammonium in the reaction liquid at the time of completion of the second-step reaction was 15% ee. Surprisingly, when trimethylbenzene, chlorobenzene or 1, 4-dioxane is used as the first-step reaction solvent, the enantiomeric excess percentage of L-glufosinate-ammonium in the reaction solution at the completion of the second-step reaction is more than 50%.

Various modifications of the invention in addition to those described herein will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including all patents, patent applications, journal articles, books, and any other publications, cited in this application is hereby incorporated by reference in its entirety.

Claims

A process for the preparation of a compound of formula (I) or a salt thereof,

characterized in that the method comprises the following steps:

reacting a compound of formula (II)

With a compound of the formula (III),

preferably, an enantiomerically pure compound of formula (II) is reacted with a compound of formula (III),

wherein:

Hal ¹is halogen;

PG is hydrogen;

z is OX or OY;

R ₁is C₁-C ₁₆Alkyl, cyclohexyl, cyclopentyl or phenyl, wherein each radical may be substituted by hydrogen, C₁-C ₆Alkyl radical, C₁-C ₆Alkoxy or dialkylamino substitution;

R ₂is C₁-C ₈Alkyl radical, C₁-C ₈An ether group or a phenyl group;

x and Y are each independently an alkyl, alkenyl or aryl group;

chiral carbon atoms are labeled; preferably, the compound of formula (I) is enantiomerically pure.
The method of claim 1, wherein: the R is₂Is C₁-C ₆Alkyl, preferably C₁-C ₄An alkyl group.
The method according to claim 1 or 2, characterized in that: the R is₁Is phenyl or C₁-C ₆Alkyl, preferably C₁-C ₄Alkyl, more preferably methyl.
A method according to any one of claims 1-3, characterized in that: x and Y are each independently C₁-C ₆Alkyl, preferably C₁-C ₄An alkyl group.
The method of claim 4, wherein: the R is₁Is methyl, X is ethyl and Y is ethyl.
The method according to any one of claims 1 to 5, wherein: the compound of formula (I) has a ratio of two enantiomers of (L) to (D) -enantiomer or (D) to (L) -enantiomer of 50.5: 49.5 to 99.5: 0.5.
The method according to any one of claims 1-6, wherein: the enantiomeric ratio is 50.5: 49.5 to 99.5: 0.5 of (L): (D) -enantiomer.
The method according to any one of claims 1 to 7, wherein: the reaction temperature is 20-200 ℃, preferably 50-150 ℃ or 90-140 ℃.
The method according to any one of claims 1-8, wherein: the reaction is carried out under solvent-free conditions or in an inert solvent.
The method according to any one of claims 1-9, wherein: the inert solvent is selected from one or more of benzene solvents, amide solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, sulfone or sulfoxide solvents, ether solvents or ester solvents; preferably, the inert solvent is selected from one or more of benzene solvents, amide solvents, halogenated hydrocarbon solvents, ether solvents and ester solvents.
The method according to claim 10, wherein the inert solvent is selected from one or more of chlorobenzene, trimethylbenzene, 1, 4-dioxane, 1, 2-dichloroethane, dimethyl sulfoxide, N-dimethylformamide, petroleum ether, N-heptane, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, ethyl acetate, and butyl acetate; preferably, the inert solvent is chlorobenzene, trimethylbenzene or 1, 4-dioxane.
The method according to any one of claims 1-11, wherein: the molar ratio of the compound of the formula (II) to the compound of the formula (III) is 1: 1-10, preferably 1: 1.3-3, and more preferably 1: 1.3-2.
The process of any one of claims 1 to 12, wherein an additive is further added to the reaction system, wherein the additive is preferably elemental iodine, BHT, a halide salt (e.g., sodium iodide, sodium bromide, TBAB, TBAI), or a combination thereof.
A method for preparing L-glufosinate-ammonium, characterized by: the method comprises the following steps:

a compound of formula (Ia) prepared according to the process of any one of claims 1-13,

hydrolyzing the obtained compound of formula (Ia) under acidic conditions to obtain L-glufosinate-ammonium;

wherein PG, Z and R₂As defined in any one of claims 1 to 13.
A compound of formula (I) or a salt, enantiomer or mixture of enantiomers in any ratio thereof,

wherein PG, Z and R₁And R₂As defined in any one of claims 1 to 13;

chiral carbon atoms are labeled.
A process for the preparation of compound 2 comprising the step of reacting compound 1 with MDEP:

preferably, the molar ratio of the compound 1 to the MDEP is 1: 1-10, preferably 1: 1.3-3, more preferably 1: 1.3-2;

preferably, the reaction temperature is 20-200 ℃, more preferably 50-150 ℃, 90-140 ℃ or 100-150 ℃;

preferably, the reaction solvent is chlorobenzene, trimethylbenzene or 1, 4-dioxane;

preferably, the reaction is carried out in the presence of an additive, preferably elemental iodine, BHT, halogenated salts (e.g., sodium iodide, sodium bromide, TBAB, TBAI), or combinations thereof.