A kind of synthesis method of metamifop
By condensing 2,6-dichlorobenzoxazole with hydroquinol, forming an intermediate and amidating it with 2-fluoro-N-methylaniline, the waste gas and wastewater in the existing oxazolamylamide synthesis process are solved. and the problem of low yield, the high-efficiency and environmentally friendly large-scale production of oxazole amide has been achieved.
Patent Information
- Application Number
- CN202411097211.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-12
- Publication Date
- 2024-12-24
- Estimated Expiration
- 2044-08-12
AI Technical Summary
The existing oxazole chloramylamine synthesis process produces a large amount of waste gas and wastewater, with low reaction yields and cannot achieve large-scale industrial production.
Condensation with hydroquinol was performed using 2,6-dichlorobenzooxazole and hydroquinol to form 4-[(6-chloro-1,3-benzooxazole-2-yl)oxy]phenol, and then with p-toluenesulfonate The acid chloride reaction forms intermediate A, which is then amidated with 2-fluoro-N-methylaniline and D-lactic acid methyl ester, and finally condenses in a weak alkali anhydrous system to obtain oxazolamylamine.
This method uses common reagents, with high single-step yield and low pollution, meeting the needs of large-scale production.
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Figure CN118638073B_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of organic molecule synthesis, and in particular to a method for synthesizing metamifop. Background Art
[0002] Metamifloxacin (Metamifop) CAS number is 256412-89-2, molecular formula is C 23 H 18 ClFN2O4, molecular weight 440.8, oxadiazine is an aryloxyphenoxypropionate (AOPP) herbicide, as an acetyl-CoA carboxylase inhibitor, mainly used in crops such as rice.
[0003] The chemical name of oxadiazol is (R)-2-{(4-chloro-1,3-benzoxazol-2-yloxy)phenoxy}-2'-fluoro-N-methylpropanamide, and its English chemical name is (2R)-2-{4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenoxy}-N-(2-fluorophenyl)-N-methylpropanamide.
[0004] At present, the synthesis process of oxadiazine mainly comprises the following steps: first chlorinating the raw material (R)-2-(4-((6-chlorobenzoxazole)oxy)phenoxypropionic acid, and then reacting it with N-methyl-2-fluoroaniline under the action of an acid-binding agent to obtain oxadiazine. The chlorination step of this method will produce a large amount of waste gas or waste water. Another method is to produce oxadiazine by one-step dehydration of the raw materials (R)-2-(4-((6-chlorobenzoxazole)oxy)phenoxypropionic acid and N-methyl-o-fluoroaniline. This method uses triphenylphosphine, which is costly and produces phosphorus-containing waste water, which is unfriendly to the environment and has a low reaction yield. The raw material (R)-2-(4-((6-chlorobenzoxazole)oxy)phenoxy-N-(2-fluorophenyl)propionamide undergoes a nucleophilic substitution reaction with iodomethane in the presence of a strong base reagent to obtain oxadiazine. The reagent NaH used in this method is too dangerous. At the same time, iodomethane is highly toxic and expensive, and large-scale industrial production cannot be achieved. Summary of the invention
[0005] The object of the present invention is to provide a method for synthesizing metamifop to solve the problems raised in the above background technology that a large amount of waste gas and waste water will be generated, the reaction yield is low and large-scale industrial production cannot be achieved.
[0006] To achieve the above object, the present invention provides the following technical solution: a method for synthesizing oxadiazine, the method comprising the following steps:
[0007] S1. Add 2,6-dichlorobenzoxazole, the first solvent and the acid-binding agent to hydroquinone, add dilute acid to adjust the acidity after substitution condensation reaction, and stir to obtain 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol;
[0008] S2. 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol, a second solvent, and p-toluenesulfonyl chloride are added to react to obtain intermediate A;
[0009] S3. 2-fluoro-N-methylaniline, a third solvent, a catalyst, and then D-methyl lactate are added to obtain intermediate B after amidation reaction;
[0010] S4. Add the intermediate A, (R)-N-(2-fluorophenyl)-2-hydroxy-N-methylpropionamide, the fourth solvent, and the acid binding agent to obtain oxadiazine after condensation reaction.
[0011] Preferably, the endpoint of the condensation reaction in S1 is when HPLC detects that the reaction of 2,6-dichlorobenzoxazole is complete.
[0012] Preferably, the acid binding agent in S1 is any one of trimethylamine, triethylamine, tripropylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or morpholine, and the first solvent in S1 is any one of dichloroethane, dichloromethane, chloroform, carbon tetrachloride, o-dichlorobenzene or toluene.
[0013] Preferably, the equivalent ratio of 2,6-dichlorobenzoxazole, hydroquinone and acid-binding agent in S1 is 1:1.05-1.3:1.05-2, and the dilute acid added to S1 is any one of dilute hydrochloric acid or dilute sulfuric acid.
[0014] Preferably, the second solvent in S2 is any one of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, o-dichlorobenzene, toluene or xylene, and the intermediate A in S2 is 4-(6-chlorobenzoxazole-2-hydroxy)-4'-methylbenzenesulfonate benzene.
[0015] Preferably, the equivalent ratio of 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol to p-toluenesulfonyl chloride in S2 is 1:1.05-1.3.
[0016] Preferably, the third solvent in S3 is any one of dichloromethane, dichloroethane, chloroform, methanol and ethanol, and the catalyst in S3 is any one of triethylamine, morpholine, trimethylamine or tripropylamine.
[0017] Preferably, the equivalent ratio of 2-fluoro-N-methylaniline, D-methyl lactate and catalyst in S3 is 1:1.0-1.4:0.1-0.5, and the intermediate B in S3 is (R)-N-(2-fluorophenyl)-2-hydroxy-N-methylpropionamide.
[0018] Preferably, the equivalent ratio of the intermediate A, (R)-N-(2-fluorophenyl)-2-hydroxy-N-methylpropionamide and the acid binding agent in S4 is 1:0.95-1.15:1.05-1.3.
[0019] Preferably, the acid binding agent in S4 is any one of trimethylamine, triethylamine, tripropylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or morpholine, and the fourth solvent in S4 is any one of dichloromethane, dichloroethane, chloroform or toluene.
[0020] Compared with the prior art, the invention has the following beneficial effects: the synthesis method of oxadiazine is:
[0021] 2,6-dichlorobenzoxazole is used as a raw material, which is first condensed with hydroquinone to generate 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol, which is then reacted with p-toluenesulfonyl chloride to form an intermediate A, which is amidated with D-methyl lactate and 2-fluoro-N-methylaniline to obtain an intermediate B: (R)-N-(2-fluorophenyl)-2-hydroxy-N-methylpropionamide, and finally the intermediate A and the intermediate B: (R)-N-(2-fluorophenyl)-2-hydroxy-N-methylpropionamide are condensed in a weak base anhydrous system to obtain oxadiazine. The reagents used in the invention are common reagents, have high single-step yield, and are less polluting, thus meeting the needs of large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Figure 1 This is a schematic diagram of the preparation process route of the present invention;
[0023] Figure 2 For Example 6 of the present invention 1 HNMR spectrum. DETAILED DESCRIPTION
[0024] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0025] See also Figure 1-Figure 2 The present invention provides a technical solution: a method for synthesizing oxadiazine, the method comprising the following steps:
[0026] Step 1. Add 2,6-dichlorobenzoxazole, a first solvent and an acid-binding agent to hydroquinone, add dilute acid to adjust the acidity and stir after substitution condensation reaction to obtain 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol, the end point of the condensation reaction is that the reaction of 2,6-dichlorobenzoxazole is complete as detected by HPLC, the acid-binding agent is any one of trimethylamine, triethylamine, tripropylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or morpholine, the first solvent in S1 is any one of dichloroethane, dichloromethane, chloroform, carbon tetrachloride, o-dichlorobenzene or toluene, the equivalent ratio of 2,6-dichlorobenzoxazole, hydroquinone and acid-binding agent is 1:1.05-1.3:1.05-2, and the dilute acid added to S1 is any one of dilute hydrochloric acid or dilute sulfuric acid;
[0027] Step 2. Add p-toluenesulfonyl chloride to 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol and a second solvent to obtain 4-(6-chlorobenzoxazol-2-hydroxy)-4'-methylbenzenesulfonate benzene, wherein the second solvent is any one of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, o-dichlorobenzene, toluene or xylene, and the equivalent ratio of 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol to p-toluenesulfonyl chloride is 1:1.05-1.3;
[0028] Step 3. Add 2-fluoro-N-methylaniline, a third solvent, and a catalyst to methyl D-lactate, and obtain (R)-N-(2-fluorophenyl)-2-hydroxy-N-methylpropionamide after amidation reaction. The third solvent is any one of dichloromethane, dichloroethane, chloroform, methanol and ethanol. The catalyst in S3 is any one of triethylamine, morpholine, trimethylamine or tripropylamine. The equivalent ratio of 2-fluoro-N-methylaniline, methyl D-lactate and the catalyst is 1:1.0-1.4:0.1-0.5.
[0029] Step 4. Add 4-(6-chlorobenzoxazole-2-hydroxy)-4'-methylbenzenesulfonate benzene and (R)-N-(2-fluorophenyl)-2-hydroxy-N-methylpropionamide, a fourth solvent, and an acid binding agent to obtain oxadiazine after condensation reaction. The equivalent ratio of 4-(6-chlorobenzoxazole-2-hydroxy)-4'-methylbenzenesulfonate benzene, (R)-N-(2-fluorophenyl)-2-hydroxy-N-methylpropionamide and the acid binding agent is 1:0.95-1.15:1.05-1.3, and the acid binding agent is any one of trimethylamine, triethylamine, tripropylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or morpholine. In S4, the fourth solvent is any one of dichloromethane, dichloroethane, chloroform or toluene.
[0030] Specifically, step 1: add 2,6-dichlorobenzoxazole, a first solvent and an acid binding agent into a reaction bottle, control the temperature to 0-60°C and keep warm, dropwise add the first solvent solution of hydroquinone, control the reaction temperature to 10-80°C after the dropwise addition, take a sample and HPLC to detect whether the reaction of 2,6-dichlorobenzoxazole is complete and the substitution condensation reaction is complete; cool, dropwise add dilute acid to adjust the pH to 2-5, separate the liquids, dry the organic phase, filter, and concentrate to obtain 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol.
[0031] Specifically, step 2: add the 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol and the second solvent in the previous step to the reaction bottle, control the temperature at -5 to 50°C, add p-toluenesulfonyl chloride in batches, and after the addition is completed, control the reaction temperature at -5 to 70°C, and control the temperature to react completely. The end point of the reaction is HPLC detection of 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol reaction is complete, add water for washing, separate the liquids, dry the organic phase, filter, and concentrate to obtain intermediate A.
[0032] Specifically, step 3: add 2-fluoro-N-methylaniline and the third solvent, a catalyst into a reaction bottle, control the temperature at 10-60°C, add D-methyl lactate dropwise, and reflux at 20-70°C after the addition is complete. HPLC detects 2-fluoro-N-methylaniline, adds water for washing, separates the liquids, dries, and concentrates under reduced pressure to obtain intermediate B.
[0033] Example 1: This example is a specific implementation example of preparing 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol.
[0034] The basic process of this embodiment is step 1 of the technical solution of the present invention during specific implementation.
[0035] Some specific parameters of this embodiment are as follows:
[0036] A 1000 ml reaction bottle was used, which was equipped with a mechanical stirrer, a reflux condenser, a thermometer and a constant pressure dropping funnel.
[0037] In a 1000ml four-necked bottle, 300g of dichloromethane, 94g (0.50mol, 1.00eq) of 2,6-dichlorobenzoxazole and 65.7g (0.65mol, 1.30eq) of triethylamine were added dropwise under stirring. The dichloromethane solution of hydroquinone, wherein 60.5g (0.55mol, 1.1eq) of hydroquinone, was added dropwise. The dropping temperature was controlled to be <42°C. After the dropping was completed, the oil bath was heated to reflux 40-42°C, and the reaction was kept warm for 4 hours. The HPLC analysis of the reaction of 2,6-dichlorobenzoxazole showed that the reaction was complete. The solution was cooled, 1mol / L dilute hydrochloric acid was added, the pH was adjusted to 2-3, the liquid was separated, dried, filtered, and concentrated to obtain 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol: 128.3g, with a yield of 98.1% (theoretical weight 130.8g).
[0038] Example 2: This example is another specific implementation example of preparing 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol.
[0039] The basic process of this embodiment is step 1 of the technical solution of the present invention during specific implementation.
[0040] Some specific parameters of this embodiment are as follows:
[0041] A 1000 ml reactor was used, which was equipped with a mechanical stirrer, a reflux condenser, a thermometer and a constant pressure dropping funnel.
[0042] In a 1000ml four-necked bottle, 200g of chloroform, 94g (0.50mol, 1.00eq) of 2,6-dichlorobenzoxazole and 63.0g (0.75mol, 1.50eq) of sodium bicarbonate were added dropwise under stirring. The chloroform solution of hydroquinone, wherein 57.8g (0.55mol, 1.05eq) of hydroquinone, was added dropwise. The dropping temperature was controlled at 30-35°C. After the dropping was completed, the oil bath was heated to reflux at 60-65°C. The reaction was kept warm for 1 hour. The HPLC analysis of the reaction of 2,6-dichlorobenzoxazole showed that the reaction was complete. The mixture was cooled, 1mol / L dilute sulfuric acid was added, the pH was adjusted to 3, the liquid was separated, dried, filtered, and concentrated to obtain 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol: 126.3g, with a yield of 96.6% (theoretical weight 130.8g).
[0043] Example 3: This example is a specific implementation example for preparing intermediate A.
[0044] The basic process of this embodiment is step 2 of the technical solution of the present invention during specific implementation.
[0045] Some specific parameters of this embodiment are as follows:
[0046] A 2000 ml reaction bottle was used, which was equipped with a mechanical stirrer, a reflux condenser, a thermometer and a solid addition funnel.
[0047] In a 2000ml four-necked bottle, add 700g toluene and 130.8g (0.5mol, 1.0eq) of 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol. Stir and cool to -5-0°C. Add p-toluenesulfonyl chloride in batches: 104.9g (0.55mol, 1.1eq). React at 0-5°C for 3 hours. Take a sample and HPLC to detect that the reaction of 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol is complete. Add 300g of water, separate the liquids, dry, filter, and concentrate the organic phase to obtain 200.1g of intermediate A with a yield of 96.2% (theoretical weight is 207.9g).
[0048] Example 4: This example is another specific implementation example for preparing intermediate A.
[0049] The basic process of this embodiment is step 2 of the technical solution of the present invention during specific implementation.
[0050] Some specific parameters of this embodiment are as follows:
[0051] A 2000 ml reaction bottle was used, which was equipped with a mechanical stirrer, a reflux condenser, a thermometer and a solid addition funnel.
[0052] In a 2000ml four-necked bottle, 800g of dichloromethane and 130.8g (0.5mol, 1.0eq) of 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol were added. The mixture was stirred and cooled to between -10°C and -5°C. 102.0g (0.535mol, 1.07eq) of p-toluenesulfonyl chloride were added in batches. The mixture was reacted at 0-10°C for 1 hour. Samples were taken and HPLC was used to detect whether the reaction of 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol was complete. 400g of water was added. The mixture was separated, dried, filtered, and the organic phase was concentrated to obtain 198.5g of intermediate A with a yield of 95.5% (theoretical weight was 207.9g).
[0053] Example 5: This example is a specific implementation example for preparing (R)-N-(2-fluorophenyl)-2-hydroxy-N-methylpropionamide.
[0054] The basic process of this embodiment is step 3 of the technical solution of the present invention during specific implementation.
[0055] Some specific parameters of this embodiment are as follows:
[0056] A 1000 ml reaction bottle was used, which was equipped with a mechanical stirrer, a reflux condenser, a thermometer and a solid addition funnel.
[0057] In a 1000ml four-necked bottle, 400g of dichloromethane, 62.6g (0.5mol, 1.0eq) of 2-fluoro-N-methylaniline and 15.2g (0.15mol, 0.3eq) of triethylamine were added dropwise at a temperature of 20-35°C. After addition, 57.3g (0.55mol, 1.1eq) of D-methyl lactate were added dropwise. After the addition was completed, the mixture was refluxed for 2hr. After sampling, HPLC was performed to detect the complete reaction of 2-fluoro-N-methylaniline. The mixture was cooled, 200g of water was added, the mixture was separated, dried, filtered, and the organic phase was concentrated to obtain a crude product of (R)-N-(2-fluorophenyl)-2-hydroxy-N-methylpropionamide. The crude product was recrystallized from ethanol to obtain 93.7g of (R)-N-(2-fluorophenyl)-2-hydroxy-N-methylpropionamide with a yield of 95.1% (theoretical weight is 98.6g).
[0058] Example 6: This example is a specific implementation example for preparing oxadiazine.
[0059] The basic process of this embodiment is step 4 of the technical solution of the present invention during specific implementation.
[0060] Some specific parameters of this embodiment are as follows:
[0061] A 1000 ml reaction bottle was used, which was equipped with a mechanical stirrer, a reflux condenser, a thermometer and a solid addition funnel.
[0062] In a 1000ml four-necked bottle, add 400g of dichloromethane, 59.2g (0.3mol, 1.0eq) of (R)-N-(2-fluorophenyl)-2-hydroxy-N-methylpropionamide, and 36.4g (0.60mol, 1.2eq) of triethylamine. Control the temperature at 20-35°C, add intermediate A: 124.8g (0.30mol, 1.0eq) in batches, and heat under reflux for 10 hours. Take a sample and HPLC to detect whether the reaction of intermediate A is complete. Cool down, add 300g of 0.5N hydrochloric acid, stir and separate the liquids. Dry the organic phase, filter it with suction, and concentrate the organic phase to obtain 115.1g of oxadiazine, with a yield of 87% (theoretical weight is 132.3g). Figure 2 As shown: 1 HNMR (400MHz, CDCl3), δ=6.6~7.3 (M, 11H, Ph), 2.8 (s, 3H, -CH3), 1.6 (S, 3H, -CH3).
[0063] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.
Claims
1. A method for synthesizing metamifop, characterized in that: The synthesis method comprises the following steps: S1. Add 2,6-dichlorobenzoxazole, the first solvent and the acid-binding agent to hydroquinone, add dilute acid to adjust the acidity and stir after substitution condensation reaction to obtain 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol; the equivalent ratio of 2,6-dichlorobenzoxazole, hydroquinone and the acid-binding agent in S1 is 1:1.05-1.3:1.05-2; S2. Add p-toluenesulfonyl chloride to 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol and the second solvent to obtain an intermediate A; the intermediate A in S2 is 4-(6-chlorobenzoxazol-2-hydroxy)-4'-methylbenzenesulfonate benzene; the equivalent ratio of 4-[(6-chloro-1,3-benzoxazol-2-yl)oxy]phenol to p-toluenesulfonyl chloride in S2 is 1:1.05-1.3; S3. Add 2-fluoro-N-methylaniline, a third solvent, and a catalyst to methyl D-lactate, and obtain an intermediate B after amidation reaction; the equivalent ratio of 2-fluoro-N-methylaniline, methyl D-lactate, and the catalyst in S3 is 1:1.0-1.4:0.1-0.5, and the intermediate B in S3 is (R)-N-(2-fluorophenyl)-2-hydroxy-N-methylpropionamide; S4. Add the intermediate A and (R)-N-(2-fluorophenyl)-2-hydroxy-N-methylpropionamide to the fourth solvent and the acid binding agent, and obtain oxadiazine after condensation reaction; the equivalent ratio of the intermediate A, (R)-N-(2-fluorophenyl)-2-hydroxy-N-methylpropionamide and the acid binding agent in S4 is 1:0.95-1.15:1.05-1.
3.
2. The method for synthesizing metamifop according to claim 1, characterized in that: The endpoint of the condensation reaction in S1 is when HPLC detects that the reaction of 2,6-dichlorobenzoxazole is complete.
3. The method for synthesizing metamifop according to claim 1, characterized in that: The acid binding agent in S1 is any one of trimethylamine, triethylamine, tripropylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or morpholine, and the first solvent in S1 is any one of dichloroethane, dichloromethane, chloroform, carbon tetrachloride, o-dichlorobenzene or toluene.
4. The method for synthesizing metamifop according to claim 1, characterized in that: The dilute acid added in S1 is any one of dilute hydrochloric acid or dilute sulfuric acid.
5. The method for synthesizing metamifop according to claim 1, characterized in that: The second solvent in S2 is any one of dichloromethane, dichloroethane, chloroform, carbon tetrachloride, o-dichlorobenzene, toluene or xylene.
6. The method for synthesizing metamifop according to claim 1, characterized in that: The third solvent in S3 is any one of dichloromethane, dichloroethane, chloroform, methanol and ethanol, and the catalyst in S3 is any one of triethylamine, morpholine, trimethylamine or tripropylamine.
7. The method for synthesizing metamifop according to claim 1, characterized in that: The acid binding agent in S4 is any one of trimethylamine, triethylamine, tripropylamine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or morpholine, and the fourth solvent in S4 is any one of dichloromethane, dichloroethane, chloroform or toluene.