Process for the preparation of a pesticide intermediate

Abstract

The present application relates to a kind of preparation method of pesticide intermediate.The pesticide intermediate is oxime ether.In existing production process, dimethyl sulfate, halogenated methane and other methylating reagents are used.However, these reagents are highly toxic, harmful to the health of employees, and also cause adverse effects on the ecological environment.The present application opens up a green synthesis process, and uses low-toxic methylating reagents to complete methylation.In esterification reaction, a new esterification method is used, and highly toxic or dangerous materials such as dimethyl sulfate, concentrated sulfuric acid or hydrogen chloride gas are abandoned, which have great environmental impact.The method is healthy and environmentally friendly, safe to operate, reduces environmental pollution and lowers production costs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of fine chemical industry, and relates to a preparation method of a pesticide intermediate, i.e., an oxime ether. BACKGROUND

[0002] The oxime ether is a key intermediate for synthesizing a plurality of pesticides such as trifloxystrobin, enestrobin, kresoxim-methyl, trifloxystrobin and kresoxim-methyl. The structural formula is formula (I):

[0003]

[0004] There are many synthesis routes for the oxime ether I, and a relatively competitive route is to use o-methylphenylacetonitrile as a raw material, to obtain the target product oxime ether I through oximation, methylation, hydrolysis and esterification. The route map is as follows,

[0005]

[0006] In the existing technology, dimethyl sulfate is used as a raw material in methylation, and dimethyl sulfate is highly toxic, which seriously affects the health of employees and poses a threat to the ecological environment. In the esterification reaction, concentrated sulfuric acid is usually used to catalyze esterification, or hydrogen chloride gas is introduced for esterification. Both concentrated sulfuric acid and hydrogen chloride gas seriously corrode production equipment and pollute the environment. Moreover, hydrogen chloride gas has a high safety risk in transportation and use, and it is inconvenient to measure during operation, which causes many inconveniences to production and leads to an increase in production cost.

[0007] WO2013144924 discloses an esterification method of compound V, in which chlorosulfoxide is added dropwise into a methanol solution to achieve the esterification target, but a large amount of sulfur dioxide is generated in the reaction process, polluting the environment.

[0008] WO2017085747 discloses a method for esterifying compound V with triphosgene and methanol as esterification reagents to prepare oxime ether I. The method has the following disadvantages: (1) the temperature is as high as 40-50℃ when triphosgene is added, and at this temperature, the triphosgene is easy to aggregate and suddenly burst, causing a violent reaction, a large amount of phosgene is generated in a short time, and the toxic gas overflows, resulting in a safety accident and an environmental disaster. (2) the reaction needs to be carried out at 60℃ for more than 10 hours in the later stage, and under high-temperature conditions, phosgene leakage accidents are easy to occur, and the energy consumption is high, the cost is high, and the method is not conducive to large-scale production.

[0009] Therefore, there is an urgent need to develop an economic, safe and environmentally friendly preparation process. SUMMARY

[0010] In view of the above-mentioned disadvantages, the present application provides a more environmentally friendly and efficient preparation method of oxime ether.

[0011] The oxime ether according to the present application refers to (E)-2-(methoxyimino)-2-methylphenylacetic acid methyl ester, and the preparation method thereof comprises the following steps:

[0012]

[0013] esterification: esterification of compound V (O-methyl-o-methylphenylacetic acid ketoxime) with methanol in the presence of an activating agent to synthesize an ester, and purification to obtain the oxime ether I; the activating agent is selected from one or more than two of activating agent A or activating agent combination B or a mixture of A and B, the activating agent A is selected from acetyl chloride, chloroacetyl chloride, dichloroacetyl chloride, trichloroacetyl chloride, propionyl chloride, phosgene, acetyl bromide, bromoacetyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, phosphorus oxybromide, oxalyl chloride, oxalyl chloride monomethyl ester, oxalyl chloride monoethyl ester, methyl chloroformate, dimethylaminformyl chloride, trifluoroacetyl chloride, benzoyl chloride, 4-pyridinecarboxyl chloride, 2-pyridinecarboxyl chloride; the activating agent combination B comprises: one or two of the activating agent BI of diphosgene and triphosgene, and one or more than two of the catalyst BII selected from trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline, N,N-dipropylaniline, trimethylamine hydrohalide, triethylamine hydrohalide, tripropylamine hydrohalide, tributylamine hydrohalide, diisopropylethylamine hydrohalide, pyridine hydrohalide, 2-methylpyridine hydrohalide, 3-methylpyridine hydrohalide, 4-methylpyridine hydrohalide, 2,6-dimethylpyridine hydrohalide, 4-dimethylaminopyridine hydrohalide, N,N-dimethylaniline hydrohalide, N,N-diethylaniline hydrohalide, N,N-dipropylaniline hydrohalide, N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylformamide, N-morpholine.

[0014] In one embodiment, the amount of methanol is more than 1 times, preferably more than 5 times, more preferably more than 10 times the molar amount of compound V.

[0015] In one embodiment, the reaction can be carried out in methanol as solvent, and additional inert solvent can also be added. The additional inert solvent is selected from one or more of n-pentane, cyclopentane, n-hexane, cyclohexane, methylcyclohexane, petroleum ether, benzene, toluene, xylene, chlorobenzene, dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate, amyl propionate, acetone, butanone, cyclopentanone, cyclohexanone, diethyl ether, propyl ether, isopropyl ether, butyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, dimethyl sulfoxide (DMSO), acetonitrile, N-methyl pyrrolidone (NMP), and sulfolane.

[0016] In one embodiment, the method comprises: dissolving compound V in methanol and optionally inert solvent, cooling to below 20°C, adding activating agent A, reacting at -40°C to 100°C, and purifying to obtain oxime ether I.

[0017] Preferably, the amount of activating agent A is 1.0 to 5.0 times the molar amount of compound V, preferably 1.5 to 2.5 times.

[0018] Preferably, the activating agent A is selected from one or more of acetyl chloride, oxalyl chloride, and propionyl chloride.

[0019] Preferably, the cooling is to -30°C to 5°C, more preferably -20°C to 0°C.

[0020] Preferably, the reaction is at 20°C to 50°C, more preferably at 25°C to 35°C, and still more preferably at room temperature.

[0021] Preferably, the reaction time is 1 to 48 hours, preferably 12 to 36 hours, and more preferably 18 to 24 hours.

[0022] In one embodiment, the method comprises: dissolving compound V and catalyst BII in methanol and optionally inert solvent, controlling the temperature to below 40°C, adding activating agent BI, reacting at 0°C to 60°C, and purifying to obtain oxime ether I.

[0023] Preferably, the amount of activating agent BI is 0.3 to 2.0 times the molar amount of compound V, preferably 0.5 to 1.5 times.

[0024] Preferably, the activating agent BI is selected from one or more of diphosgene, triphosgene, or a mixture of diphosgene and triphosgene.

[0025] Preferably, the amount of catalyst BII is 0.05 to 0.5 times, preferably 0.1 to 0.2 times the molar amount of compound V.

[0026] Preferably, catalyst BII is selected from one or more of triethylamine, pyridine and N,N-dimethylformamide.

[0027] Preferably, the temperature is controlled to -50°C to 25°C, preferably -40°C to 20°C, more preferably -40°C to 10°C, and even more preferably -40°C to 0°C. Then the reaction is carried out at 0°C to 30°C, more preferably at room temperature.

[0028] Preferably, after the addition of activating agent BI, the mixture is incubated for 1 to 3 hours.

[0029] Preferably, the reaction time is 1 to 72 hours, preferably 12 to 48 hours.

[0030] Preferably, the temperature is controlled to 20 to 35°C, preferably 20 to 25°C, and the reaction is incubated at this temperature for 12 to 48 hours after the addition of activating agent BI.

[0031] In one embodiment, the method comprises: dissolving compound V, activating agent A and catalyst BII in methanol and optionally an inert solvent, cooling to below 20°C, adding activating agent BI, and reacting at -40°C to 100°C to obtain oxime ether I.

[0032] Preferably, the temperature is controlled to -20°C to 0°C, more preferably -10°C to 0°C.

[0033] Preferably, the reaction is carried out at 0°C to 30°C, more preferably at room temperature.

[0034] Preferably, the reaction time is 1 to 72 hours, preferably 12 to 48 hours.

[0035] Preferably, the purification according to the present application comprises concentration to dryness after the reaction is completed, followed by recrystallization from a methanol aqueous solution. The methanol content of the methanol aqueous solution is 10% to 90%, preferably 80% to 90%.

[0036] In one preferred embodiment, the method according to the present application can further comprise:

[0037]

[0038] Hydrolysis: Compound IV is hydrolyzed to obtain compound V (O-methyl-o-methylphenylacetic ketoxime).

[0039] The hydrolysis method is known in the art, for example, it can be carried out in the presence of an acid or a base.

[0040] Preferably, the hydrolysis is carried out in the presence of a base selected from one or more of sodium hydroxide, potassium hydroxide.

[0041] Preferably, the hydrolysis is carried out in alcohol and water, the alcohol being selected from one or more of n-propanol, n-butanol. The volume ratio of alcohol to water is 1:2-5.

[0042] Methylation: In one preferred embodiment, the method of the present application can further comprise:

[0043]

[0044] Compound III is methylated with dimethyl carbonate (DMC) or trimethyl phosphate (TMP) as the methylating agent to obtain compound IV (2-(2-methylphenyl)-2-methoxyiminoacetonitrile);

[0045] wherein M is selected from one of H, Li, Na, K, Ca.

[0046] In one embodiment, the amount of dimethyl carbonate (DMC) and trimethyl phosphate (TMP) is 3-100 times, preferably 5-30 times, more preferably 5-15 times the molar amount of compound III.

[0047] In one embodiment, when M is H, compound III is methylated with dimethyl carbonate (DMC) as the methylating agent, and one or more of organic bases DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN (1,5-diazabicyclo[4.3.0]non-5-ene), 4-DMAP (4-dimethylaminopyridine) as the catalyst; or inorganic base and phase transfer catalyst (PTC) composition as the catalyst.

[0048] Preferably, the amount of organic base is 0.5-5 times, preferably 1-2 times the molar amount of compound III.

[0049] Preferably, when inorganic base and phase transfer catalyst (PTC) composition are used as the catalyst, the inorganic base includes, but is not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, etc., preferably one or more of sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate. The amount of inorganic base is 0.3-2 times, preferably 0.5-1.2 times the molar amount of compound III.

[0050] Preferably, the phase transfer catalyst (PTC) includes, but is not limited to, tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), benzyltriethylammonium chloride (BTEAC), dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, hexadecyltrimethylammonium chloride, methyltrioctylammonium chloride (TOMAC), tetrabutylammonium hydrogen sulfate, polyethylene glycol, etc. Preferably, one or more of tetrabutylammonium bromide (TBAB), benzyltriethylammonium chloride (BTEAC), methyltrioctylammonium chloride (TOMAC), and polyethylene glycol is used. The polyethylene glycol is preferably PEG400 or PEG600. The amount of the phase transfer catalyst (PTC) is preferably 0.01 to 0.3 times, more preferably 0.03 to 0.1 times, the molar amount of compound III.

[0051] Preferably, when M is selected from one of Li, Na, K, and Ca, compound III is methylated with dimethyl carbonate (DMC) as the methylating agent and a phase transfer catalyst (PTC) as the catalyst.

[0052] Preferably, the phase transfer catalyst (PTC) is as described above. Specifically, the phase transfer catalyst (PTC) includes, but is not limited to, tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB), benzyltriethylammonium chloride (BTEAC), dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, hexadecyltrimethylammonium chloride, methyltrioctylammonium chloride (TOMAC), tetrabutylammonium hydrogen sulfate, polyethylene glycol, etc. Preferably, one or more of tetrabutylammonium bromide (TBAB), benzyltriethylammonium chloride (BTEAC), methyltrioctylammonium chloride (TOMAC), and polyethylene glycol is used. The polyethylene glycol is preferably PEG400 or PEG600. The amount of the phase transfer catalyst (PTC) is preferably 0.01 to 0.3 times, more preferably 0.05 to 0.1 times, the molar amount of compound III.

[0053] In the present application, dimethyl carbonate can be used as both the methylating agent and the reaction solvent, i.e., no additional solvent is needed for the reaction. The reaction temperature is preferably 0 to 180°C, more preferably 60 to 100°C, and even more preferably at the reflux temperature.

[0054] Preferably, when M is H, compound III is methylated with trimethyl phosphate as the methylating agent and an inorganic base as the catalyst. The reaction solvent is one or more of DMF (N,N-dimethylformamide), acetonitrile, acetone, DMSO (dimethyl sulfoxide), sulfolane, NMP (N-methyl pyrrolidone), or the reaction is carried out directly using trimethyl phosphate as the solvent. The inorganic base includes, but is not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, cesium carbonate, sodium carbonate, etc., and preferably one or more of potassium hydroxide, calcium hydroxide, potassium carbonate, and cesium carbonate. The amount of inorganic base used is 0.2 to 2.0 times, and preferably 0.5 to 1.2 times, the molar amount of compound III. The reaction temperature is 0 to 180°C, preferably 60 to 100°C, and more preferably 70 to 90°C.

[0055] Preferably, when M is selected from one of Li, Na, K, and Ca, compound III is methylated with trimethyl phosphate as the methylating agent. The reaction solvent is one or more of DMF (N,N-dimethylformamide), acetonitrile, acetone, DMSO (dimethyl sulfoxide), sulfolane, NMP (N-methyl pyrrolidone), or the reaction is carried out directly using trimethyl phosphate as the solvent. The reaction temperature is 0 to 180°C, preferably 60 to 100°C, and more preferably 70 to 90°C.

[0056] In the present application, the methylation and hydrolysis can be carried out "one-pot", and the hydrolysis reaction can be carried out directly after the methylation without purification.

[0057] Thus, in one embodiment, the method of the present application can comprise: adding compound III to dimethyl carbonate (DMC) or trimethyl phosphate (TMP), optionally adding the catalyst and / or the reaction solvent described above, carrying out the methylation reaction described above, concentrating the reaction to dryness; adding the alcohol and water, and the base described above, carrying out the hydrolysis reaction; washing the reaction with a water-immiscible organic solvent after the reaction, and then acidifying the aqueous phase, separating the phases, optionally extracting the aqueous phase again, washing the combined organic phase, and concentrating to dryness to obtain compound V.

[0058] Preferably, the water-immiscible organic solvent is selected from one or more of n-pentane, cyclopentane, n-hexane, cyclohexane, methylcyclohexane, petroleum ether, benzene, toluene, xylene, chlorobenzene, dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, 1,1-dichloroethane, 1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isopropyl acetate, isobutyl acetate, amyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate, amyl propionate, diethyl ether, dipropyl ether, isopropyl ether, dibutyl ether, methyl tert-butyl ether, and cyclopentyl methyl ether.

[0059] In a preferred embodiment, the method of the present application further comprises:

[0060]

[0061] oximation: using compound II (o-methylphenylacetonitrile) as raw material, oximation to obtain compound III;

[0062] wherein M is H, Li, Na, K, Ca.

[0063] The oximation method is known in the art, for example, the oximation agent can be n-butyl nitrite, and the reaction is carried out in the presence of an inorganic base, and optionally acidified to obtain.

[0064] Preferably, the inorganic base is an alkali containing lithium, sodium, potassium, calcium, preferably a hydroxide or carbonate or bicarbonate of lithium, sodium, potassium, calcium, for example lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.

[0065] After oximation, acidification to obtain compound II with M as H; without acidification to obtain compound III with M as Li, Na, K, Ca.

[0066] Therefore, in an embodiment of the present application, the preparation method of the present application comprises:

[0067]

[0068] oximation: using compound II (o-methylphenylacetonitrile) as raw material, oximation to obtain compound III (2-methyl-α-cyanophenylhydroxylamine or a salt thereof); methylation of compound III using dimethyl carbonate (DMC) or trimethyl phosphate (TMP) as a methylating agent to obtain compound IV (2-(2-methylphenyl)-2-methoxyiminodiacetonitrile), and further hydrolysis to obtain compound V (O-methyl-o-methylphenylacetonitrile oxime); esterification of compound V with methanol in the presence of an activating agent to synthesize an ester, and purification to obtain oxime ether I;

[0069] wherein M is H, Li, Na, K, Ca.

[0070] Preferably, the conditions of each step are as described above.

[0071] Advantages

[0072] In view of the shortcomings of the prior art method, the present application selects dimethyl carbonate or trimethyl phosphate as raw material in methylation, and the reaction process is safe and environmentally friendly. In the esterification reaction, the environmentally harmful raw materials such as concentrated sulfuric acid, hydrogen chloride gas and thionyl chloride are abandoned, and acetyl chloride, propionyl chloride, oxalyl chloride, oxalyl chloride monoester, dialkylamino formyl chloride and the like are selected as the activating agent, which is safe and convenient in production. In particular, the method of the present application can also select phosgene in esterification. Since phosgene is toxic, triphosgene and bis-phosgene, which are commonly used in chemical industry, can also be selected. Bis-phosgene and triphosgene can be decomposed to obtain phosgene. Compared with WO2017085747, the innovation of the method of the present application lies in that phosgene is directly used, or bis-phosgene or triphosgene is selected to obtain phosgene by decomposition, and a catalyst is added during the decomposition, so that the reaction temperature can be reduced when compound V is esterified to obtain compound I, and efficient esterification can be achieved at a low temperature of-40℃. At low temperature, the phosgene produced by the decomposition of bis-phosgene and triphosgene is in liquid state, which reduces the possibility of gas evaporation and overflow from the source, and reduces the risk, so that the reaction is safe and controllable. On the other hand, after adding the catalyst, the decomposition of triphosgene and bis-phosgene is stable, orderly and controllable, and the phenomenon of sudden burst does not occur. By reducing the temperature of triphosgene and bis-phosgene, slowly adding triphosgene and bis-phosgene or passing in phosgene, and finally naturally warming up to room temperature for reaction (without reaching the temperature of more than 40℃ required by WO2017085747), the purpose of esterification of compound V can be achieved, and the oxime ether I is obtained, realizing the yield of more than 90% and the purity of more than 98%. The process of the present application is safe and controllable, meets the green and environmental protection requirements, and has the advantages of simple operation steps, good safety, low energy consumption, short period and suitability for large-scale production. DETAILED DESCRIPTION

[0073] In order to better understand the present application, some embodiments will be further described below, but not further limit the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all the embodiments. Based on the embodiments of the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0074] The experimental methods in the following examples are conventional methods, unless otherwise specified. If the specific technology or condition is not specified in the examples, it is carried out according to the technology or condition described in the literature in the art, or according to the product manual.

[0075] Example 1. Synthesis of compound III (M=H)

[0076] Sodium hydroxide 4.8 grams was mixed with 30 ml of methanol, stirred and dissolved, then 13.17 grams (0.1 mole) of o-methylphenylacetonitrile was added in one portion, 12 grams of n-butyl nitrite was added dropwise at below 20°C, and the reaction was allowed to proceed at room temperature for about 5 hours. After the raw material was consumed, the reaction was concentrated, acidified with hydrochloric acid to pH 3-4, and 16.14 grams of a white solid was obtained, with a yield of 99.5%.

[0077] Example 2. Synthesis of metal salts of compound III (III, M = Li, Na, K, Ca)

[0078] Lithium hydroxide 2.4 grams (0.1 mole) was mixed with 20 ml of methanol, and a 50 ml methanol solution of compound III 16.2 grams (0.1 mole) was added dropwise while stirring. After the dropwise addition was completed, the mixture was stirred for half an hour, and then concentrated to dryness. The resulting solid was dried at 50°C to obtain a lithium salt of III, 16.8 grams, with a yield of 100%.

[0079] A sodium salt of compound III was obtained in the same manner (yield 99.5%), a potassium salt (yield 99.8%), and a calcium salt (yield 99.2%)

[0080] Example 3. Synthesis of compound V

[0081] 16 grams of compound III (M = H), 100 ml of dimethyl carbonate, 16 grams of DBU, reflux for 12 hours, cool to room temperature, add hydrochloric acid to adjust pH 3-4, separate, recover DBU from the aqueous phase. Concentrate the organic phase to dryness, add 60 ml of methanol, 100 ml of water, and 7.5 grams of sodium hydroxide, and reflux for 20 hours. Concentrate to dryness, dissolve in 200 ml of dichloromethane and 100 ml of water, acidify to pH 2-3, separate, extract the aqueous phase with 50 ml of dichloromethane, combine the organic phases, wash with brine, and concentrate to dryness to obtain a yellowish viscous liquid which solidifies upon standing to obtain 17.1 grams of V with a yield of 95%. The content is 96.2%.

[0082] Example 4. Synthesis of compound V

[0083] 16 grams of compound III (M = H), 100 ml of dimethyl carbonate, 13 grams of 4-DMAP, reflux for 18 hours, cool to room temperature, add hydrochloric acid to adjust pH 2-3, separate, recover DMAP from the aqueous phase. Concentrate the organic phase to dryness, add 40 ml of n-butanol, 50 ml of water, and 9 grams of sodium hydroxide, and reflux for 8 hours. Concentrate to dryness under reduced pressure, add 100 ml of ethyl acetate and 100 ml of water, and acidify to pH 2. Extract the aqueous phase with 100 ml of ethyl acetate once, combine the organic phases, wash with brine, and concentrate to dryness to obtain a yellowish viscous liquid which solidifies upon standing to obtain 17.6 grams of V with a yield of 98.3%. The content is 97.2%.

[0084] Example 5. Synthesis of compound V

[0085] 16 g of compound III (M = H), dimethyl carbonate 100 ml, potassium carbonate 7 g, 1.2 g of TOMAC, reflux for 10 hours, cool to room temperature, filter off the potassium carbonate, concentrate to dryness, add 60 ml of ethanol, 100 ml of water, 10 g of sodium hydroxide, reflux for 20 hours, concentrate to dryness, add 50 ml of dichloroethane, 100 ml of water, dissolve, separate, add 200 ml of dichloroethane to the aqueous phase, acidify to pH 2-3, separate, extract the aqueous phase with 50 ml of dichloroethane, combine the organic phases, wash with brine, concentrate to dryness, obtain a yellowish viscous liquid, let it solidify, obtain 17.0 g of V, 95% yield. Content 96.2%.

[0086] Example 6. Synthesis of compound V

[0087] 16 g of compound III (M = H), dimethyl carbonate 100 ml, potassium carbonate 7 g, 1.2 g of TOMAC, reflux for 10 hours, cool to room temperature, filter off the potassium carbonate, concentrate to dryness, add 60 ml of ethanol, 100 ml of water, 10 g of sodium hydroxide, reflux for 20 hours, concentrate to dryness, add 50 ml of dichloroethane, 100 ml of water, dissolve, separate, add 200 ml of dichloroethane to the aqueous phase, acidify to pH 2-3, separate, extract the aqueous phase with 50 ml of dichloroethane, combine the organic phases, wash with brine, concentrate to dryness, obtain a yellowish viscous liquid, let it solidify, obtain 17.0 g of V, 95% yield. Content 96.2%.

[0088] Example 7. Synthesis of compound V

[0089] 19.8 g of potassium oxime (III, M = K), dimethyl carbonate 100 ml, 4 g of TOMAC, reflux for 10 hours, cool to room temperature, concentrate to dryness, obtain a viscous liquid, add 20 ml of n-butanol, 60 ml of water, 8.8 g of sodium hydroxide, reflux for 8 hours, concentrate to dryness, add 150 ml of water, 50 ml of isopropyl acetate, stir to dissolve, separate, add 200 ml of dichloroethane to the aqueous phase, acidify to pH 2, separate, extract the aqueous phase with 50 ml of dichloroethane, combine the organic phases, wash with brine, concentrate to dryness, obtain a yellowish viscous liquid, let it solidify, obtain 17.0 g of V, 95% yield. Content 97.8%.

[0090] Example 8. Synthesis of compound V

[0091] 16.6 g of the sodium salt of the oxime (III, M = Na), dimethyl carbonate 100 ml, 3 g of TBAB, reflux for 13 hours, cooling to room temperature, concentration to dryness, addition of n-propanol 25 ml, water 80 ml, sodium hydroxide 8.5 g, reflux for 12 hours, concentration to dryness, addition of water 150 ml, toluene 50 ml, stirring dissolution, separation, addition of 200 ml of dichloroethane to the aqueous phase, acidification to pH 2, separation, extraction of the aqueous phase with 50 ml of dichloroethane, combination of the organic phases, washing with brine, concentration to dryness, obtaining of a yellowish viscous liquid, setting solidification, obtaining of 16.5 g of V with a yield of 92.2%. Content 97.3%.

[0092] Example 9. Synthesis of compound V

[0093] 18.2 g of the sodium salt of the oxime (III, M = Na), dimethyl carbonate 100 ml, 3.3 g of BTEAC, reflux for 11 hours, cooling to room temperature, concentration to dryness, obtaining of a viscous liquid, addition of n-propanol 25 ml, water 80 ml, sodium hydroxide 9.5 g, reflux for 12 hours, concentration to dryness, addition of water 150 ml, toluene 50 ml, stirring dissolution, separation, addition of 200 ml of dichloroethane to the aqueous phase, acidification to pH 2, separation, extraction of the aqueous phase with 50 ml of dichloroethane, combination of the organic phases, washing with brine, concentration to dryness, obtaining of a yellowish viscous liquid, setting solidification, obtaining of 17.3 g of V with a yield of 96.6%. Content 97.5%.

[0094] Example 10. Synthesis of compound V

[0095] 18.2 g of the sodium salt of the oxime (III, M = Na), trimethyl phosphate 100 ml, 75°C for 10 hours, concentration to dryness under reduced pressure, obtaining of a viscous liquid, addition of n-butanol 20 ml, water 80 ml, sodium hydroxide 7 g, reflux for 12 hours, concentration to dryness, addition of water 150 ml, dichloroethane 50 ml, stirring dissolution, separation, addition of 200 ml of dichloroethane to the aqueous phase, acidification to pH 2, separation, extraction of the aqueous phase with 50 ml of dichloroethane, combination of the organic phases, washing with brine, concentration to dryness, obtaining of a yellowish viscous liquid, setting solidification, obtaining of 17.5 g of V with a yield of 97.8%. Content 99.1%.

[0096] Example 11. Synthesis of compound V

[0097] 19.8 g of potassium oxime (III, M = K), trimethyl phosphate 100 ml, 80°C for 8 hours, concentrated to dryness under reduced pressure, add n-butanol 20 ml, water 80 ml, sodium hydroxide 8.8 g, reflux for 11 hours, concentrated to dryness, add water 150 ml, dichloroethane 50 ml, stir to dissolve, separate, add 200 ml of dichloroethane to the aqueous phase, acidify to pH 2, separate, extract the aqueous phase with 50 ml of dichloroethane, combine the organic phases, wash with brine, concentrate to dryness, obtain a yellowish viscous liquid, let it solidify, obtain 17.6 g of V, 98.3% yield. Content 99.5%.

[0098] Example 12. Synthesis of compound V

[0099] 19.3 g of calcium oxime (III, M = Ca), trimethyl phosphate 100 ml, 85°C for 7 hours, concentrated to dryness under reduced pressure, obtain a viscous liquid, add n-butanol 20 ml, water 80 ml, sodium hydroxide 7.9 g, reflux for 11 hours, concentrated to dryness, add water 150 ml, dichloromethane 50 ml, stir to dissolve, separate, add 200 ml of dichloroethane to the aqueous phase, acidify to pH 2, separate, extract the aqueous phase with 50 ml of dichloroethane, combine the organic phases, wash with brine, concentrate to dryness, obtain a yellowish viscous liquid, let it solidify, obtain 17.6 g of V, 98.3% yield. Content 99.6%.

[0100] Example 13. Synthesis of compound V

[0101] 19.8 g of potassium oxime (III, M = K), trimethyl phosphate 100 ml, 25°C for 60 hours, concentrated to dryness under reduced pressure, obtain a viscous liquid, add n-butanol 20 ml, water 80 ml, sodium hydroxide 10.2 g, reflux for 11 hours, concentrated to dryness, add water 150 ml, dichloroethane 50 ml, stir to dissolve, separate, add 200 ml of dichloroethane to the aqueous phase, acidify to pH 2, separate, extract the aqueous phase with 50 ml of dichloroethane, combine the organic phases, wash with brine, concentrate to dryness, obtain a yellowish viscous liquid, let it solidify, obtain 17.7 g of V, 98.9% yield. Content 99.5%.

[0102] Example 14. Synthesis of compound V

[0103] 16 g of the oxime (III, M = H), trimethyl phosphate 100 ml, potassium carbonate 13.8 g, 90°C for 6 hours, concentrated to dryness under reduced pressure, add n-butanol 20 ml, water 80 ml, sodium hydroxide 9.2 g, reflux for 11 hours, concentrated to dryness, add water 150 ml, dichloromethane 50 ml, stir to dissolve, separate, add 200 ml of ethyl acetate to the aqueous phase, acidify to pH 2, separate, extract the aqueous phase with 50 ml of ethyl acetate, combine the organic phases, wash with brine, concentrated to dryness, obtain a yellowish viscous liquid, solidify by standing, obtain 17.3 g of V, 96.6% yield. Content 99.5%.

[0104] Example 15. Synthesis of compound V

[0105] 16 g of the oxime (III, M = H), trimethyl phosphate 100 ml, potassium carbonate 13.8 g, 90°C for 6 hours, concentrated to dryness under reduced pressure, add n-butanol 20 ml, water 80 ml, sodium hydroxide 9.2 g, reflux for 11 hours, concentrated to dryness, add water 150 ml, dichloromethane 50 ml, stir to dissolve, separate, add 200 ml of ethyl acetate to the aqueous phase, acidify to pH 2, separate, extract the aqueous phase with 50 ml of ethyl acetate, combine the organic phases, wash with brine, concentrated to dryness, obtain a yellowish viscous liquid, solidify by standing, obtain 17.3 g of V, 96.6% yield. Content 99.5%.

[0106] Example 16. Synthesis of compound V

[0107] 16 g of the oxime (III, M = H), trimethyl phosphate 100 ml, potassium carbonate 13.8 g, 90°C for 6 hours, concentrated to dryness under reduced pressure, add n-butanol 20 ml, water 80 ml, sodium hydroxide 9.2 g, reflux for 11 hours, concentrated to dryness, add water 150 ml, dichloromethane 50 ml, stir to dissolve, separate, add 200 ml of ethyl acetate to the aqueous phase, acidify to pH 2, separate, extract the aqueous phase with 50 ml of ethyl acetate, combine the organic phases, wash with brine, concentrated to dryness, obtain a yellowish viscous liquid, solidify by standing, obtain 17.3 g of V, 96.6% yield. Content 99.5%.

[0108] Example 17. Synthesis of compound V

[0109] 16 g of the oxime (III, M = H), trimethyl phosphate 20 ml, acetone 100 ml, calcium hydroxide 3.8 g, reflux for 20 hours, concentrated to dryness under reduced pressure, add n-butanol 20 ml, water 70 ml, sodium hydroxide 8.5 g, reflux for 12 hours, concentrated to dryness, add water 150 ml, dichloromethane 50 ml, stir to dissolve, separate, add 200 ml of dimethyl carbonate to the aqueous phase, acidify to pH 2, separate, extract the aqueous phase with 50 ml of dimethyl carbonate, combine the organic phases, wash with brine, concentrated to dryness, obtain a yellowish viscous liquid, solidify by standing, obtain 15.8 g of V, 88.3% yield. Content 99.1%.

[0110] Example 18. Synthesis of oxime ether I

[0111] Compound V (19.3 g), methanol 100 ml, cool to -10 °C, add acetyl chloride 0.2 mol dropwise, after dropwise addition, react at room temperature for 24 hours, concentrated to dryness, recrystallized with 80% methanol aqueous solution, obtain white solid, dry at 50 °C, 18.6 g, yield 90%, E-oxime ether content 99.1%.

[0112] Example 19. Synthesis of oxime ether I

[0113] Compound V (19.3 g), methanol 200 ml, cool to -20 °C, add oxalyl chloride 0.15 mol dropwise, after dropwise addition, react at room temperature for 24 hours, concentrated to dryness, recrystallized with 80% methanol aqueous solution, obtain white solid, dry at 50 °C, 18.8 g, yield 90.7%, E-oxime ether content 99.4%.

[0114] Example 20. Synthesis of oxime ether I

[0115] Compound V (19.3 g), methanol 100 ml, dichloromethane 100 ml, cool to -5 °C, add oxalyl chloride monomethyl ester 0.3 mol dropwise, after dropwise addition, react at room temperature for 30 hours, concentrated to dryness, recrystallized with 70% methanol aqueous solution, obtain white solid, dry at 50 °C, 17.8 g, yield 85.9%, E-oxime ether content 98.3%.

[0116] Example 21. Synthesis of oxime ether I

[0117] Compound V (19.3 g), methanol 10 ml, dichloroethane 100 ml, cool to -5 °C, add propionyl chloride 0.3 mol dropwise, after dropwise addition, react at room temperature for 24 hours, concentrated to dryness, recrystallized with 80% methanol aqueous solution, obtain white solid, dry at 50 °C, 18.8 g, yield 90.7%, E-oxime ether content 99.3%.

[0118] Example 22. Synthesis of oxime ether I

[0119] Compound V (19.3 grams), methanol 200 ml, cool to -20°C, pass carbonyl chloride 0.15 mol, after passing, keep 2 hours, slowly warm to room temperature, react 24 hours, concentrate to dry, recrystallize with 80% methanol solution, get white solid, 50°C dry, 19.3 grams, yield 93.1%, E-oxime ether content 99.3%.

[0120] Example 23 Synthesis of oxime ether I

[0121] Compound V (19.3 grams), methanol 200 ml, pyridine 2 ml, cool to -40°C, add triphosgene 0.1 mol in batches, after adding, keep 2 hours, slowly warm to room temperature, react 18 hours, concentrate to dry, recrystallize with 80% methanol solution, get white solid, 50°C dry, 19.5 grams, yield 94%, E-oxime ether content 99.4%.

[0122] Example 24 Synthesis of oxime ether I

[0123] Compound V (19.3 grams), methanol 150 ml, pyridine hydrochloride 2 grams, cool to 0°C, add triphosgene 0.1 mol in batches, after adding, keep 2 hours, slowly warm to room temperature, react 18 hours, concentrate to dry, recrystallize with 80% methanol solution, get white solid, 50°C dry, 19.3 grams, yield 93.1%, E-oxime ether content 99.6%.

[0124] Example 25 Synthesis of oxime ether I

[0125] Compound V (19.3 grams), methanol 200 ml, DMF 2 ml, cool to -30°C, drop bis-carbonyl chloride 0.1 mol, after dropping, keep 2 hours, slowly warm to room temperature, react 24 hours, concentrate to dry, recrystallize with 80% methanol solution, get white solid, 50°C dry, 19.2 grams, yield 92.7%, E-oxime ether content 99.5%.

[0126] Example 26 Synthesis of oxime ether I

[0127] Compound V (19.3 grams), methanol 80 ml, tetrahydrofuran 100 ml, pyridine 2 ml, control temperature 5-10°C, drop 0.2 mol bis-carbonyl chloride, after adding, room temperature react 15 hours, concentrate to dry, recrystallize with 80% methanol solution, get white solid, 50°C dry, 18.9 grams, yield 91%, E-oxime ether content 98.5%.

[0128] Example 27 Synthesis of oxime ether I

[0129] Compound V (19.3 grams), methanol 160 ml, temperature control -5 to 0°C, drop 0.5 mol 2-pyridinecarbonyl chloride, stir for 10 minutes, after adding, room temperature reaction 18 hours, concentrated to dry, recrystallized with 80% methanol solution, white solid, 50°C drying, 19 grams, yield 91.7%, E-oxime ether content 98.3%

[0130] Example 28 Synthesis of oxime ether I

[0131] Compound V (19.3 grams), methanol 50 ml, toluene 50 ml, acetonitrile 50 ml, 2 ml DMF, temperature control -5 to 0°C, 0.08 mol triphosgene is added slowly in batches, room temperature reaction 24 hours, concentrated to dry, recrystallized with 80% methanol solution, white solid, 50°C drying, 19.0 grams, yield 91.7%, E-oxime ether content 98.6%.

[0132] Example 29 Synthesis of oxime ether I

[0133] Compound V (19.3 grams), methanol 150 ml, temperature control -5 to 0°C, 0.2 mol chloroacetyl chloride is added slowly in batches, 0-5°C for 2 hours, room temperature reaction 20 hours, concentrated to dry, recrystallized with 80% methanol solution, white solid, 50°C drying, 19.0 grams, yield 91.7%, E-oxime ether content 98.6%.

[0134] Example 30 Synthesis of oxime ether I

[0135] Compound V (19.3 grams), methanol 180 ml, temperature control -5 to 0°C, drop 0.25 mol trichloroacetyl chloride, after adding, room temperature reaction 20 hours, concentrated to dry, recrystallized with 80% methanol solution, white solid, 50°C drying, 18.9 grams, yield 91%, E-oxime ether content 98.5%.

[0136] Example 31 Synthesis of oxime ether I

[0137] Compound V (19.3 grams), methanol 120 ml, temperature control -10 to -5°C, drop 0.08 mol phosphorus trichloride, after adding, room temperature reaction 18 hours, concentrated to dry, recrystallized with 80% methanol solution, white solid, 50°C drying, 18.9 grams, yield 91%, E-oxime ether content 98.4%.

[0138] Example 32 Synthesis of oxime ether I

[0139] Compound V (19.3 g), methanol 150 ml, temperature control -5 to 0 °C, drop 0.07 mol phosphorus pentachloride solution in dichloromethane, after drop, keep temperature 2 hours, then room temperature stirring 16 hours, concentrated to dry, recrystallized with 80% methanol solution, obtained white solid, 50 °C drying, 19.3 g, yield 93.1%, E-oxime ether content 99.2%.

[0140] Example 33 Synthesis of oxime ether I

[0141] Compound V (19.3 g), methanol 160 ml, pyridine 2 ml, temperature control -5 to 0 °C, drop 0.005 mol methyl chloroformate, stirring 10 minutes, then slowly add 0.1 mol triphosgene, after adding, room temperature reaction 20 hours, concentrated to dry, recrystallized with 80% methanol solution, obtained white solid, 50 °C drying, 18.9 g, yield 91%, E-oxime ether content 98.8%.

[0142] Example 34 Synthesis of oxime ether I

[0143] Compound V (19.3 g), methanol 150 ml, pyridine 2 ml, temperature control -5 to 0 °C, drop 0.05 mol dimethylamine carbamoyl chloride, stirring 10 minutes, then slowly add 0.1 mol triphosgene, after adding, room temperature reaction 20 hours, concentrated to dry, recrystallized with 80% methanol solution, obtained white solid, 50 °C drying, 19 g, yield 91.7%, E-oxime ether content 98.4%.

[0144] Example 35 Synthesis of oxime ether I

[0145] Compound V (19.3 g), methanol 150 ml, temperature control -5 to 0 °C, drop 0.3 mol trifluoroacetyl chloride, stirring 10 minutes, after adding, room temperature reaction 24 hours, concentrated to dry, recrystallized with 70% methanol solution, obtained white solid, 50 °C drying, 18.9 g, yield 91%, E-oxime ether content 98.3%.

[0146] Example 36 Synthesis of oxime ether I

[0147] Compound V (19.3 g), methanol 180 ml, temperature control -5 to 0 °C, drop 0.3 mol benzoyl chloride, after adding, 35 °C reaction 24 hours, concentrated to dry, recrystallized with 80% methanol solution, obtained white solid, 50 °C drying, 19 g, yield 91.7%, E-oxime ether content 98.4%.

[0148] Example 37 Synthesis of oxime ether I

[0149] Compound V (19.3 grams), methanol 160 ml, temperature control -5-0°C, drop 0.5 mol 4-pyridine carboxyl chloride, stir for 10 minutes, after adding, room temperature reaction 18 hours, concentrated to dry, recrystallized with 80% methanol aqueous solution, obtained white solid, 50°C drying, 18.9 grams, yield 91%, E-oxime ether content 98.8%

[0150] Example 38 Synthesis of oxime ether I

[0151] Compound V (19.3 grams), methanol 200 ml, pyridine 2 ml, temperature control 35°C, batch addition of 0.1 mol triphosgene, incubation reaction 18 hours, concentrated to dry, recrystallized with 80% methanol aqueous solution, obtained white solid, 50°C drying, 17.2 grams, yield 82.9%, E-oxime ether content 98.2%.

[0152] The above is only the preferred embodiment of the present application, it should be noted that for the ordinary skilled in the art, without departing from the method of the present application, can also make a number of improvements and supplements, these improvements and supplements should also be considered as the protection scope of the present application.

Claims

1. A method for preparing an oxime ether, comprising: esterification: esterifying compound V with methanol in the presence of an activating agent to synthesize an ester, and purifying to obtain the oxime ether I; the activating agent is selected from activating agent A, and the activating agent A is selected from one or more than two of acetyl chloride, chloroacetyl chloride, dichloroacetyl chloride, trichloroacetyl chloride, propionyl chloride, phosgene, oxalyl chloride, oxalyl chloride monomethyl ester, trifluoroacetyl chloride, benzoyl chloride, 4-pyridine carboxyl chloride, and 2-pyridine carboxyl chloride; the method comprises: dissolving compound V in methanol and optionally an inert solvent, cooling to below 20℃, adding activating agent A, reacting at room temperature, and purifying to obtain the oxime ether I; the amount of activating agent A is 1.0-5.0 times the molar amount of compound V.

2. The production method according to claim 1, characterized by, The amount of methanol is more than 1 times the molar amount of compound V; the reaction uses methanol as the solvent.

3. The preparation method according to claim 1, characterized in that, The amount of activating agent A is 1.5-2.5 times the molar amount of compound V.

4. The production method according to claim 1, characterized by, The method further comprises: hydrolysis: hydrolyzing compound IV to obtain compound V.

5. The preparation method according to claim 1, characterized in that, The method further comprises: methylating compound III with dimethyl carbonate or trimethyl phosphate as the methylating agent to obtain compound IV; wherein M is selected from H, Li, Na, and K. 6.The method according to claim 5, characterized in that, when M is H, methylating compound III with dimethyl carbonate as the methylating agent, and using one or more than two of organic bases DBU, DBN, and 4-DMAP as the catalyst; or using a combination of inorganic bases and phase transfer catalysts as the catalyst; or when M is selected from Li, Na, and K, methylating compound III with dimethyl carbonate as the methylating agent, and using a phase transfer catalyst as the catalyst; or when M is H, methylating compound III with trimethyl phosphate as the methylating agent, and using an inorganic base as the catalyst; or when M is selected from Li, Na, and K, methylating compound III with trimethyl phosphate as the methylating agent.

7. The production method according to claim 5 or 6, characterized by, The methylating and hydrolyzing are carried out in “one pot”, and the hydrolyzing is directly carried out after the methylating without purification.

8. The production method according to claim 5 or 6, characterized by, adding compound III to dimethyl carbonate or trimethyl phosphate, optionally adding a catalyst and / or a reaction solvent, carrying out the methylating reaction, concentrating to dryness after the reaction, adding an alcohol and water, and a base, carrying out the hydrolyzing reaction, first washing with a water-immiscible organic solvent after the reaction, then adding a water-immiscible organic solvent to the aqueous phase, acidifying, separating the phases, optionally extracting the aqueous phase again, washing the combined organic phase, and concentrating to dryness to obtain compound V.

9. The production method according to claim 5 or 6, characterized by, The method further comprises: oximizing compound II to obtain compound III; wherein M is H, Li, Na, and K.

10. The method of claim 1, wherein, The method comprises: oximizing compound II to obtain compound III; methylating compound III with dimethyl carbonate or trimethyl phosphate as the methylating agent to obtain compound IV, and further hydrolyzing to obtain compound V; esterifying compound V with methanol in the presence of an activating agent to synthesize an ester, and purifying to obtain the oxime ether I; wherein M is H, Li, Na, and K.

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