Synthesis method of efficient (R)-(2-(4-((6-chlorobenzoxazole-2-yl) oxy) phenoxy) propionyl) glycine ethyl ester

Abstract

The invention discloses a synthetic method of efficient (R)-(2-(4-((6-chlorobenzoxazole-2-yl) oxy) phenoxy) propionyl) glycine ethyl ester. (R)-2-(4-((6-chlorobenzoxazole-2-yl) oxy) phenoxy) propionic acid, methylsulfonyl chloride and glycine ethyl ester hydrochloride are used as raw materials, and high-yield and high-purity (R)-(2-(4-((6-chlorobenzoxazole-2-yl) oxy) phenoxy) propionyl) glycine ethyl ester is obtained by a one-pot method under the catalysis of an acid-binding agent. The method is a one-pot reaction method, has the advantages of simple process, mild reaction conditions, convenience in operation, no need of dangerous reagent thionyl chloride, phosgene and other raw materials, few three wastes, safe and environment-friendly operation process, relatively cheap and easily available raw materials, low reaction cost and suitability for industrial production, and is a green process route.

Description

Technical Field

[0001] This invention relates to the field of pesticide technology, specifically to a method for synthesizing highly efficient (R)-(2-(4-((6-chlorobenzoxazol-2-yl)oxy)phenoxy)propionyl)glycine ethyl ester. Background Technology

[0002] (R)-(2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionyl)glycine ethyl ester is a class of aryloxyphenoxypropionate herbicides (patent number: CN105801513A). With increasing herbicide resistance, this herbicide can effectively replace currently available herbicides of this class, such as oxazolidinone and cyhalofop-butyl. Besides rice paddies, this herbicide shows promise for weed control in other crops and lawns, making it a highly promising herbicide. Patent CN105801513A also reports the synthesis process of this herbicide: The intermediate (R)-2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionic acid (I) is obtained by reacting the raw material (R)-2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionyl chloride with thionyl chloride; then, the intermediate (R)-2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionyl chloride undergoes a substitution reaction with glycine ethyl ester hydrochloride in the presence of triethylamine to obtain the herbicide. The reaction equation is as follows:

[0003]

[0004] This method requires two steps, has a low overall yield of only about 85%, and requires the use of acyl chloride reagents, which generates a large amount of waste gas. Furthermore, the reaction must be carried out at reflux temperature, increasing energy consumption.

[0005] To better achieve industrial-scale production, we developed a method to obtain high-yield, high-purity (R)-(2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionic acid, methanesulfonyl chloride, and glycine ethyl ester hydrochloride in one step under the catalysis of an acid-binding agent. Summary of the Invention

[0006] The purpose of this invention is to overcome the problems existing in the prior art and provide an efficient method for synthesizing (R)-(2-(4-((6-chlorobenzoxazol-2-yl)oxy)phenoxy)propionyl)glycine ethyl ester.

[0007] The technical solution of the present invention to solve the above-mentioned technical problems is as follows:

[0008] A highly efficient method for synthesizing (R)-(2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionyl)glycine ethyl ester is disclosed. The method uses (R)-2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionic acid, methanesulfonyl chloride, and glycine ethyl ester hydrochloride as raw materials. Under the action of a solvent and an acid-binding agent, an amidation reaction is performed to synthesize (R)-(2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionyl)glycine ethyl ester in a one-pot synthesis. The reaction equation for the synthesis method is as follows:

[0009]

[0010] Preferably, the solvent is an organic solvent.

[0011] Preferably, the organic solvent is one or a mixture of dichloromethane, dichloroethane, tetrahydrofuran, toluene, acetonitrile, DMF, NMP, and chloroform.

[0012] Preferably, the acid-binding agent is one or a mixture of triethylamine, DIPEA, pyridine, 2,6-dimethylpyridine, 3,5-dimethylpyridine, 3-methylpyridine, potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate.

[0013] Preferably, the molar ratio of (R)-2-(4-((6-chlorobenzoxazol-2-yl)oxy)phenoxy)propionic acid to the acid-binding agent is 1:2-10.

[0014] Preferably, the molar ratio of (R)-2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionic acid to the acid-binding agent is 1:3-6.

[0015] Preferably, the molar ratio of (R)-2-(4-((6-chlorobenzoxazol-2-yl)oxy)phenoxy)propionic acid to methanesulfonyl chloride is 1:1.1-3.

[0016] Preferably, the molar ratio of (R)-2-(4-((6-chlorobenzoxazol-2-yl)oxy)phenoxy)propionic acid and glycine ethyl ester hydrochloride is 1:1.1-2.

[0017] In this invention, if there is a conflict between the Chinese name and the structural formula of a compound, the structural formula shall prevail, unless the structural formula is obviously incorrect.

[0018] The beneficial effects of this invention are as follows: This invention is a one-pot reaction, with a simple process, mild reaction conditions, and convenient operation. It does not require the use of hazardous reagents such as thionyl chloride and phosgene, resulting in less waste, a safe and environmentally friendly operation, and relatively inexpensive and readily available raw materials. The reaction cost is low, making it suitable for industrial production. It is a green process route with good prospects for industrialization. Detailed Implementation

[0019] The present invention is illustrated below with reference to examples, but is not intended to limit the invention. Any simple substitutions or modifications made to the present invention by those skilled in the art are within the scope of the technical solutions protected by this invention.

[0020] Example 1:

[0021] In a reaction flask equipped with a mechanical stirrer and a thermometer, glycine ethyl ester hydrochloride (16.7 g, 0.12 mol), triethylamine (35.4 g, 0.35 mol), and 100 g of dichloromethane were added sequentially. The mixture was stirred at 20-25°C for 3 hours. Then, (R)-2-(4-((6-chlorobenzoxazol-2-yl)oxy)phenoxy)propionic acid (33.4 g, 0.1 mol) was added to the system. A solution of methanesulfonyl chloride (16.0 g, 0.14 mol) in dichloromethane (20 g) was added dropwise using a constant-pressure dropping funnel, while maintaining the internal temperature at 20-25°C. The addition was completed. After stirring for another 2 hours, the reaction was analyzed by HPLC. The normalized area of ​​the liquid phase of (R)-2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionic acid was less than 0.5%, which was qualified. After adding 150g of water and stirring for 30 minutes, the product was directly centrifuged to obtain wet product of (R)-2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionyl)glycine ethyl ester. After drying, 38.5g of (R)-2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionyl)glycine ethyl ester was obtained. The purity of the liquid phase was 97.3%, and the yield was 92.2%.

[0022] 1 H NMR (400MHz, DMSO-d6) δ8.59(t,J=6.0Hz,1H),7.83(d,J=2.0Hz,1H),7.50(d,J=8.4Hz,1H),7.44(d,J=9.0Hz,2H),7.35(dd,J=8.4,2.0Hz,1 H),7.05(d,J=9.0Hz,2H),4.80(q,J=6.6Hz,1H),4.09(q,J=7.0Hz,2H),3.86(d,J=6.0Hz,2H),1.48(d,J=6.6Hz,3H),1.17(t,J=7.0Hz,3H).

[0023] Example 2:

[0024] In a reaction flask equipped with a mechanical stirrer and a thermometer, glycine ethyl ester hydrochloride (16.7 g, 0.12 mol), 3-methylpyridine (37.3 g, 0.4 mol), and 40 g of dichloromethane were added sequentially. The mixture was stirred at 30-35 degrees Celsius for 3 hours. Then, (R)-2-(4-((6-chlorobenzoxazol-2-yl)oxy)phenoxy)propionic acid (33.4 g, 0.1 mol) was added to the system. A solution of methanesulfonyl chloride (16.0 g, 0.14 mol) in toluene (80 g) was added dropwise using a constant-pressure dropping funnel, while maintaining the internal temperature at 30-35 degrees Celsius. After the addition was complete... After stirring for another 2 hours, the reaction was analyzed by HPLC. The normalized area of ​​the liquid phase of (R)-2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionic acid was less than 0.5%, which was qualified. After that, 150g of water was added and stirred for 30 minutes. After centrifugation, wet product of (R)-2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionyl)glycine ethyl ester was obtained. After drying, 37.6g of (R)-2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionyl)glycine ethyl ester was obtained. The purity of liquid phase was 97.5% and the yield was 90.0%.

[0025] Example 3:

[0026] In a reaction flask equipped with a mechanical stirrer and a thermometer, glycine ethyl ester hydrochloride (27.9 g, 0.2 mol), sodium bicarbonate (50.4 g, 0.6 mol), and dichloromethane (150 g) were added sequentially. The mixture was stirred at 35-40°C for 3 hours. The system was then cooled to 10-15°C, and (R)-2-(4-((6-chlorobenzoxazol-2-yl)oxy)phenoxy)propionic acid (33.4 g, 0.1 mol) was added. Then, a solution of methanesulfonyl chloride (22.9 g, 0.2 mol) in acetonitrile (40 g) was added dropwise using a constant-pressure dropping funnel, while maintaining the internal temperature at 10-15°C. After the addition was complete and stirring continued for 2 hours, the reaction was analyzed by HPLC. The normalized area of ​​the liquid phase of (R)-2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionic acid was less than 0.5%, which was qualified. After that, 200g of water was added and stirred for 30 minutes. After centrifugation, wet product of (R)-2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionyl)glycine ethyl ester was obtained. After drying, 37.7g of (R)-2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionyl)glycine ethyl ester was obtained. The purity of liquid phase was 95.3% and the yield was 90.2%.

[0027] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A highly efficient method for synthesizing (R)-(2-(4-((6-chlorobenzoxazol-2-yl)oxy)phenoxy)propionyl)glycine ethyl ester, characterized in that, The method described above uses (R)-2-(4-(((6-chlorobenzoxazol-2-yl)oxy)phenoxy)propionic acid, methanesulfonyl chloride, and glycine ethyl ester hydrochloride as raw materials, and synthesizes (R)-2-(4-((6-chlorobenzoxazol-2-yl)oxy)phenoxy)propionyl)glycine ethyl ester through an amidation reaction in the presence of a solvent and an acid-binding agent in a one-pot process. The reaction equation for the synthesis method is as follows:

2. The method as described in claim 1, characterized in that, The solvent is an organic solvent.

3. The method as described in claim 2, characterized in that, The organic solvent is one or a mixture of dichloromethane, dichloroethane, tetrahydrofuran, toluene, acetonitrile, DMF, NMP, and chloroform.

4. The method as described in claim 1, characterized in that, The acid-binding agent is one or a mixture of triethylamine, DIPEA, pyridine, 2,6-dimethylpyridine, 3,5-dimethylpyridine, 3-methylpyridine, potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate.

5. The method as described in claim 1, characterized in that, The molar ratio of (R)-2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionic acid to the acid-binding agent is 1:2-10.

6. The method as described in claim 5, characterized in that, The molar ratio of (R)-2-(4-((6-chlorobenzoxazole-2-yl)oxy)phenoxy)propionic acid to the acid-binding agent is 1:3-6.

7. The method as described in claim 1, characterized in that, The molar ratio of (R)-2-(4-((6-chlorobenzoxazol-2-yl)oxy)phenoxy)propionic acid to methanesulfonyl chloride is 1:1.1-3.

8. The method as described in claim 1, characterized in that, The molar ratio of (R)-2-(4-((6-chlorobenzoxazol-2-yl)oxy)phenoxy)propionic acid and glycine ethyl ester hydrochloride is 1:1.1-2.

9. The method as described in claim 1, characterized in that, The reaction temperature is 0-45℃.

10. The method as described in claim 1, characterized in that, The feeding sequence is as follows: glycine ethyl ester hydrochloride is released under the action of an acid-binding agent, (R)-2-(4-((6-chlorobenzoxazol-2-yl)oxy)phenoxy)propionic acid raw material is added to the system, and then methanesulfonyl chloride is added dropwise to the system.

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