Preparation method of optically active pydiflumetofen intermediate

Abstract

The invention discloses a preparation method of an optically active pydiflumetofen intermediate, which comprises the following specific operation processes: dissolving (+ / -)-O-methyl-N-[1-methyl-2-(2, 4, 6-trichlorophenyl)-ethyl]-hydroxylamine by using an organic solvent, adding into 100mM of PBS (Phosphate Buffer Solution) with pH (Potential of Hydrogen) of 7.5, then adding monoamine oxidase and a chemical reducing agent, continuously introducing oxygen, reacting for 2-3 hours at the temperature of 50-60 DEG C, and finally adding a catalyst, thereby obtaining the optically active pydiflumetofen intermediate. The preparation method comprises the following steps of: stirring and reacting until the reaction is complete, quenching the reaction solution by using a sodium hydroxide solution, filtering the reaction solution by using diatomite to remove the quenched precipitate, extracting the filtrate for three times by using an organic solvent, merging the extract liquor, washing with water, drying by using anhydrous Na2SO4, and concentrating under reduced pressure to obtain the (S)-O-methyl-N-[1-methyl-2-(2, 4, 6-trichlorophenyl)-ethyl]-hydroxylamine. The method has the advantages of being simple in operation process, low in cost, environmentally friendly, capable of saving energy and the like, deracemization of the high-concentration pydiflumetofen intermediate amine can be achieved, the yield is high, and the optical purity of the product is high.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical organic synthesis, and particularly relates to a method for preparing an optically active fluopicolide intermediate. Background Art

[0002] Fluopicolide is currently the only SDHI fungicide registered for the prevention and treatment of wheat fusarium head blight. Fluopicolide has a pyrazoleamide structure, a novel molecular structure, high fungicidal activity, broad spectrum, low toxicity, environmental safety, and long-lasting and stable efficacy. At the same time, this type of fungicide has a different mechanism of action from classic benzimidazole, triazole and methoxy acrylate pesticides, and is not prone to cross-resistance. It can be used as a substitute or alternating agent for the currently commonly used triazole fungicides, has good application potential, and is a new tool for wheat fusarium head blight resistance management.

[0003] According to research, more than 30% of pesticides on the market have asymmetric centers in their chemical structures, but so far less than 7% of chiral pesticides are marketed as single or enriched enantiomers. Currently, the fluopicolide preparations on the market are sold as an equal mixture of two enantiomers as shown in the following formula.

[0004]

[0005] The chemical name of the (S)-configuration is: 3-(difluoromethyl)-N-methoxy-1-methyl-N-[(1S)-1-methyl-2-(2,4,6-trichlorophenyl)ethyl]pyrazole-4-carboxamide; the chemical name of the (R)-configuration is: 3-(difluoromethyl)-N-methoxy-1-methyl-N-[(1R)-1-methyl-2-(2,4,6-trichlorophenyl)ethyl]pyrazole-4-carboxamide.

[0006] The efficacy and activity test showed that (S) has more significant fungicidal activity than (R). Therefore, the preparation of single (S)-configuration fluopicolide is one of the important methods to reduce the use of pesticides, improve the efficacy of pesticides, avoid resource waste, and reduce global environmental risks.

[0007] The (S)-configured fluopicolide finished product can be prepared by reacting (S)-configured O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine and 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl chloride. The reaction equation is as follows:

[0008]

[0009] Therefore, to synthesize the (S)-configuration fluopicolide hydroxylamide product, the (S)-configuration intermediate hydroxylamine must first be obtained.

[0010] The method for obtaining (S)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine reported in the current patent CN 105339352 B is:

[0011] In an inert solvent, under argon / nitrogen protection, chiral amino alcohol (-)-norephedrine is used to provide a chiral environment, and borane diethylaniline complex is used to reduce the oxime ether to prepare (S)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine. The reaction equation is as follows:

[0012]

[0013] The above process requires maintaining strict low temperature and vacuum conditions, using organic solvents and expensive chiral auxiliary agents, and has cumbersome steps and complex operations. Summary of the invention

[0014] In view of the above problems, the object of the present invention is to provide a method for preparing an optically active fluopicolide intermediate.

[0015] The present invention uses racemic O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine (hereinafter referred to as "hydroxylamine") compound (I) as a raw material, and uses monoamine oxidase (MAO-N) to selectively oxidize the (R) configuration in (±)-hydroxylamine to generate (2E)-1-(2,4,6-trichlorophenyl)-2-acetone-O-methyl oxime (compound (II)), and the (S) configuration of hydroxylamine (compound (III)) is completely retained. Compound (II) is then in situ reduced to racemic hydroxylamine (I) by chemical reduction, and deracemization of O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine is achieved through a biological oxidation-chemical reduction cycle, thereby preparing (S)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine with high yield and high optical purity.

[0016] The reaction equation is as follows:

[0017]

[0018] The specific technical solutions are as follows:

[0019] A method for preparing an optically active fluopicolide intermediate comprises the following steps:

[0020] 1) Deracemization:

[0021] After dissolving (±)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine in an organic solvent, the solution was added to a 100 mM PBS buffer solution at pH 7.5, and then monoamine oxidase and a chemical reducing agent were added. Oxygen was continuously introduced and the reaction was stirred until completion.

[0022] 2) Separation of compounds:

[0023] The reaction solution of step 1) is quenched with sodium hydroxide solution, and the reaction solution is filtered through diatomaceous earth to remove the precipitate after quenching. The filtrate is extracted three times with an organic solvent, the extracts are combined, washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain (S)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine.

[0024] Furthermore, the organic solvent in step 1) is dimethyl sulfoxide, methanol or ethanol, preferably methanol; the amount of the organic solvent added is 2-20% of the total reaction system volume, preferably 10%.

[0025] Furthermore, the concentration of (±)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine in the total reaction system in step 1) is 1.0 mM to 20.0 mM, preferably 10.0 mM.

[0026] Furthermore, in step 1), the enzyme activity value of monoamine oxidase is 50 U / g, and the mass ratio of the added amount of (±)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine to monoamine oxidase is 0.1:1-2; preferably 0.1:2. Furthermore, the chemical reducing agent in step 1) is palladium carbon-formate or borane ammonia complex, wherein the formate is ammonium formate, sodium formate or potassium formate, preferably palladium carbon-ammonium formate; when the chemical reducing agent is palladium carbon-formate, the reaction solution is filtered through diatomaceous earth to remove the precipitate after quenching, which is denatured protein and palladium carbon; when the chemical reducing agent is borane ammonia complex, the reaction solution is filtered through diatomaceous earth to remove the precipitate after quenching, which is denatured protein; palladium carbon is a black solid particle whose properties remain unchanged before and after the reaction, and is insoluble in water and organic solvents, and can be directly filtered out (the denatured protein can be adsorbed by diatomaceous earth and is also removed by filtration), and the formate and BH3-NH3 matched with palladium carbon belong to the category of inorganic salts and are both soluble in water, so they can only be separated by subsequent extraction.

[0027] Furthermore, in step 1), the stirring reaction temperature is 25-45° C., and the time is 12-24 hours, preferably 35° C., for 24 hours.

[0028] Furthermore, the organic solvent used for extraction in step 2) is dichloromethane, ethyl acetate or diethyl ether; preferably dichloromethane.

[0029] The beneficial effects of the present invention are:

[0030] The preparation method has the advantages of simple operation process, low cost, environmental friendliness, energy saving, etc., can achieve the deracemization of high-concentration fluopicolide intermediate amine, has high yield, and high product optical purity, is suitable for the batch preparation of specific chiral intermediate amines of fluopicolide, and saves costs for the subsequent industrial production and application of fluopicolide. DETAILED DESCRIPTION

[0031] The present invention is further described below in conjunction with embodiments, but the protection scope of the present invention is not limited thereto.

[0032] Example 1

[0033] 0.5 g (±)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine (I) was dissolved in 20 mL of methanol (10% v / v relative to the volume of the total reaction system), and then added to 180 mL of PBS (100 mM) buffer at pH 7.5. Then, 1.3 g of ammonium formate, 2 g of palladium carbon (Pd / C), and 5 g (50 U / g) of monoamine oxidase were added, and oxygen was continuously introduced, and stirring was continued at 30°C for 12 h.

[0034] The reaction solution was quenched with 10 mL of 1 M NaOH solution, filtered through diatomaceous earth to remove denatured protein and palladium carbon after quenching, and the filtrate was extracted three times with 30 mL of dichloromethane. The organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 0.41 g of (S)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine with a yield of 78.34%, a purity of 96.8%, and an ee of 94.7%.

[0035] Example 2

[0036] 0.5 g (±)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine (I) was dissolved in 20 mL of methanol (10% v / v relative to the volume of the total reaction system) and added to 180 mL of PBS (100 mM) buffer at pH 7.5. Then, 0.6 g of BH3-NH3 and 10 g (50 U / g) of monoamine oxidase were added and oxygen was continuously introduced. Stirring was continued at 30°C for 24 h.

[0037] The reaction solution was quenched with 10 mL of 1 M NaOH solution, filtered through diatomaceous earth to remove the denatured protein after quenching, and the filtrate was extracted three times with 30 mL of ethyl acetate. The organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 0.44 g of (S)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine with a yield of 83.73%, a purity of 96.6%, and an ee of 95.5%.

[0038] Example 3

[0039] 0.5 g (±)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine (I) was dissolved in 20 mL of dimethyl sulfoxide (10% v / v relative to the volume of the total reaction system), and then added to 180 mL of PBS (100 mM) buffer at pH 7.5. Then, 0.6 g of BH3-NH3 and 5 g (50 U / g) of monoamine oxidase were added, and oxygen was continuously introduced, and stirring was continued at 45°C for 12 h.

[0040] The reaction solution was quenched with 10 mL of 1 M NaOH solution, filtered through diatomaceous earth to remove the denatured protein after quenching, and the filtrate was extracted three times with 30 mL of dichloromethane. The organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 0.42 g of (S)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine with a yield of 78.79%, a purity of 96.7%, and an ee of 97.0%.

[0041] Example 4

[0042] 0.5 g (±)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine (I) was dissolved in 20 mL of ethanol (10% v / v relative to the volume of the total reaction system) and added to 180 mL of PBS (100 mM) buffer at pH 7.5. Then, 1.4 g of sodium formate, 2 g of palladium on carbon (Pd / C), and 10 g (50 U / g) of monoamine oxidase were added, and oxygen was continuously introduced, and stirring was continued at 35°C for 24 h.

[0043] The reaction solution was quenched with 10 mL of 1 M NaOH solution, filtered through diatomaceous earth to remove denatured protein and palladium carbon after quenching, and the filtrate was extracted three times with 30 mL of ether. The organic phases were combined, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain 0.46 g of (S)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine with a yield of 87.09%, a purity of 96.8%, and an ee of 97.8%.

Claims

1. A method for preparing an optically active fluopicolide intermediate, characterized in that: The steps include: 1) Deracemization: After dissolving (±)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine in an organic solvent, the solution was added to a 100 mM PBS buffer solution at pH 7.5, and then monoamine oxidase and a chemical reducing agent were added. Oxygen was continuously introduced and the reaction was stirred until completion. 2) Separation of compounds: The reaction solution of step 1) is quenched with sodium hydroxide solution, and the reaction solution is filtered through diatomaceous earth to remove the precipitate after quenching. The filtrate is extracted three times with an organic solvent, the extracts are combined, washed with water, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain (S)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine.

2. The method for preparing an optically active fluopicolide intermediate according to claim 1, characterized in that: The organic solvent in step 1) is dimethyl sulfoxide, methanol or ethanol, preferably methanol; The amount of organic solvent added is 2-20% of the total reaction system volume, preferably 10%.

3. The method for preparing an optically active fluopicolide intermediate according to claim 2, characterized in that: The concentration of (±)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine in the total reaction system in step 1) is 1.0 mM to 20.0 mM, preferably 10.0 mM.

4. The method for preparing an optically active fluopicolide intermediate according to claim 1, characterized in that: In step 1), the enzyme activity value of monoamine oxidase is 50 U / g, and the mass ratio of the added amount of (±)-O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine to monoamine oxidase is 0.1:1-2; preferably 0.1:

2.

5. The method for preparing an optically active fluopicolide intermediate according to claim 1, characterized in that: The chemical reducing agent in step 1) is palladium carbon-formate or borane ammonia complex, wherein the formate is ammonium formate, sodium formate or potassium formate, preferably palladium carbon-ammonium formate.

6. The method for preparing an optically active fluopicolide intermediate according to claim 1, characterized in that: The stirring reaction temperature in step 1) is 25-45°C for 12-24 hours, preferably 35°C for 24 hours.

7. The method for preparing an optically active fluopicolide intermediate according to claim 1, characterized in that: The organic solvent used for extraction in step 2) is dichloromethane, ethyl acetate or diethyl ether; dichloromethane is preferred.

Images