Process for the synthesis of an intermediate of daimorpha-M

Abstract

This invention discloses a method for synthesizing a cyclopentoxate intermediate, comprising the following steps: ① Using 2-methylpropenal and trimethylcyanosilane as starting materials, an addition reaction is first carried out in the presence of a Lewis acid, followed by acid hydrolysis to obtain the intermediate 2-hydroxy-3-methyl-3-butenoic acid; the addition temperature of trimethylcyanosilane is -15℃ to 0℃; the addition reaction temperature is 0℃ to 40℃; ② The intermediate 2-hydroxy-3-methyl-3-butenoic acid obtained in step ① is first reacted with hydrogen chloride and ethanol in a Pinner reaction, followed by hydrolysis to obtain the cyclopentoxate intermediate ethyl 2-hydroxy-3-methyl-3-butenoate; the Pinner reaction temperature is -40℃ to 20℃. The synthetic method of this invention uses inexpensive and readily available starting materials and reagents, resulting in low production costs. Furthermore, the reaction conditions are simple, the operation is convenient, and the reaction yield and product purity are both high, making it suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of herbicide intermediate synthesis technology, specifically relating to a method for synthesizing a cyclooxam intermediate. Background Technology

[0002] Pentoxazone, CAS number 110956-75-7, is an oxazoline dione herbicide and a protoporphyrinogen oxidase (PPO) inhibitor. It is extremely safe for transplanted rice and effectively controls annual barnyard grass and many broadleaf weeds. It can control barnyard grass, duckweed, water chestnut, wild mustard, and awned rice weeds in rice paddies before and after budding. Pentoxazone has advantages such as a broad spectrum of herbicidal activity, excellent efficacy, safety in rice, long-lasting effect, and good resistance to sulfonylurea weeds.

[0003] The structural formula of cyclooxam is as follows: .

[0004] Ethyl 2-hydroxy-3-methyl-3-butenoate is a key intermediate in the synthesis of cyclopentoxane, with CAS number 33537-17-6 and structural formula as follows: .

[0005] The existing technologies disclose two main methods for synthesizing ethyl 2-hydroxy-3-methyl-3-butenoate: I. Using acetone and ethyl chloroacetate as starting materials, ethyl 3,3-dimethylethylene oxide-2-carboxylate was first obtained through the Darzens reaction in the presence of sodium ethoxide, and then ethyl 2-hydroxy-3-methyl-3-butenoate was obtained through a ring-opening reaction in the presence of p-toluenesulfonic acid [see reference WO2012041789A].

[0006] The synthesis route is as follows: .

[0007] The shortcomings of this method are: (1) The first step, Darzens reaction, requires harsh conditions, strong base + anhydrous, and the yield is very unstable; (2) The second step, ring-opening reaction, will produce a large number of isomer products, which will significantly reduce the reaction yield and product purity, making it unsuitable for industrial production.

[0008] II. Using diethyl oxalate and magnesium isopropenyl bromide as starting materials, ethyl 3-methyl-2-oxobut-3-enoate was first obtained by nucleophilic substitution reaction, and then reduced by sodium borohydride to obtain ethyl 2-hydroxy-3-methyl-3-butenoate [see Bioorganic & Medicinal Chemistry Letters 2007, 17(20), 5518-5522].

[0009] The synthesis route is as follows: .

[0010] The shortcomings of this method are: (1) The first step nucleophilic substitution reaction uses magnesium isopropenyl magnesium bromide as an allyl Grignard reagent, which needs to be carried out at extremely low temperatures (e.g. -78℃), and the reaction conditions are harsh; (2) The second step reduction reaction sodium borohydride will not only reduce the ketone carbonyl group, but also the carbon-carbon double bond and ester group, resulting in more by-products, affecting the reaction yield and product purity, and is not suitable for industrial production. Summary of the Invention

[0011] The purpose of this invention is to solve the above-mentioned problems and provide a method for synthesizing cyclopentoxazone intermediates that has simple reaction conditions, is easy to operate, has high reaction yield and product purity, and is suitable for large-scale industrial production.

[0012] The technical solution to achieve the objective of this invention is: a method for synthesizing a cyclopentoxate intermediate, comprising the following steps: ① Starting with 2-methylpropenal and trimethylcyanosilane, an addition reaction was first carried out in the presence of Lewis acid, followed by acid hydrolysis to obtain the intermediate 2-hydroxy-3-methyl-3-butenonitrile.

[0013] ② The intermediate 2-hydroxy-3-methyl-3-butenoic acid obtained in step ① is first reacted with hydrogen chloride and ethanol in a Pinner reaction, and then hydrolyzed to obtain ethyl 2-hydroxy-3-methyl-3-butenoate, an intermediate of cyclopentoxazone.

[0014] The synthesis route is as follows: .

[0015] In step ① above, the molar ratio of 2-methylpropenal to trimethylcyanosilane is 1:1 to 1:2, preferably 1:1.2 to 1:1.5.

[0016] In step ① above, the addition temperature of trimethylcyanosilane is -15℃ to 0℃. If the addition temperature of trimethylcyanosilane exceeds 0℃, it will significantly affect the reaction yield and product purity.

[0017] In step ① above, the molar ratio of 2-methylpropenal to the Lewis acid is 1:0.01 to 1:0.2, preferably 1:0.05 to 1:0.1.

[0018] In step ① above, the Lewis acid is one or more of aluminum trichloride, scandium trifluoromethanesulfonate, boron trifluoride ether, ferric chloride, titanium tetrachloride, tin tetrachloride, antimony pentafluoride, and zinc dichloride; preferably aluminum trichloride, scandium trifluoromethanesulfonate, or boron trifluoride ether, and more preferably aluminum trichloride.

[0019] The addition reaction in step ① above is carried out in an organic solvent; the organic solvent is toluene, dichloromethane, dichloroethane, acetonitrile, or tetrahydrofuran; preferably dichloromethane.

[0020] The addition reaction temperature in step ① above is 0℃~40℃.

[0021] The Pinner reaction temperature in step ② above is -40℃ to 20℃, preferably -5℃ to 5℃.

[0022] In step ② above, the molar ratio of ethanol to 2-methylpropenal in step ① above is 3:1 to 20:1, preferably 5:1 to 10:1.

[0023] The positive effects of this invention are: the starting materials and reaction reagents of this invention are inexpensive and readily available, the production cost is low, the reaction conditions are simple, the operation is easy, and the reaction yield and product purity are both high, making it suitable for large-scale industrial production. Attached Figure Description

[0024] Figure 1 The image shows the GC-MS spectrum of the intermediate obtained in step ① of Example 1.

[0025] Figure 2 The image shows the GC-MS spectrum of the light yellow oily liquid obtained in step ② of Example 1.

[0026] Figure 3 The GC spectrum of the light yellow oily liquid obtained in step ② of Example 1 is shown. Detailed Implementation

[0027] (Example 1) The specific method for synthesizing the cyclopentoxazone intermediate in this embodiment is as follows: ① In a 1000mL four-necked reaction flask, add 70g of 2-methylpropenal (1.0mol), 6.7g of aluminum trichloride (0.05mol, 0.05eq), and 350g of dichloromethane in sequence. Cool the mixture to -10℃ and slowly add 118g of trimethylcyanosilane (1.2mol, 1.2eq). After the addition is complete, allow the mixture to react at room temperature (15~25℃, the same below) for 3h.

[0028] After the reaction was complete, 120 mL of 1N hydrochloric acid was added, and the mixture was stirred for 30 min. After standing and separating into layers, the solvent was removed from the organic phase by evaporation to obtain the intermediate 2-hydroxy-3-methyl-3-butenonitrile. Its GC-MS spectrum is shown in [Figure number missing]. Figure 1 .

[0029] ② Add 276 g of ethanol (6.0 mol, 6 eq) to the four-necked reaction flask from step ①, cool to 0 °C, then purge with dry hydrogen chloride gas. After reacting for 3 h, filter, wash the filter cake with n-hexane, then slowly add it in batches to ice water and stir for 30 min. Then add 150 g of dichloromethane for extraction, evaporate the solvent, and obtain 116 g of a light yellow oily liquid. Its GC-MS spectrum is shown below. Figure 2 The yield was 80.6%, and the GC purity was 96% (see [reference]). Figure 3 ).

[0030] (Example 2) The specific method for synthesizing the cyclopentoxazone intermediate in this embodiment is as follows: ① In a 500mL four-necked reaction flask, add 28g of 2-methylpropenal (0.4mol), 4.9g of aluminum trichloride (0.036mol, 0.09eq), and 120g of dichloromethane in sequence. Cool the mixture to -10℃ and slowly add 40g of trimethylcyanosilane (0.4mol, 1.0eq). After the addition is complete, allow the mixture to react at room temperature for 3 hours.

[0031] After the reaction was completed, 50 mL of 1N hydrochloric acid was added, the mixture was stirred for 30 min, allowed to stand and separate into layers, and the solvent was removed by evaporation of the organic phase to obtain the intermediate 2-hydroxy-3-methyl-3-butenonitrile.

[0032] ② Add 92g of ethanol (2.0mol, 5eq) to the four-necked reaction flask of step ①, cool to 0℃, then pass dry hydrogen chloride gas through, react for 3h, filter, wash the filter cake with n-hexane, then slowly add it in batches to ice water and stir for 30min, then add 90g of dichloromethane for extraction, evaporate the solvent, and obtain 43g of light yellow oily liquid, with a yield of 74.7% and GC purity of 94%.

[0033] (Example 3) The specific method for synthesizing the cyclopentoxazone intermediate in this embodiment is as follows: ① In a 500mL four-necked reaction flask, add 28g of 2-methylpropenal (0.4mol), 2.8g of boron trifluoride ether (0.02mol, 0.05eq), and 120g of dichloromethane in sequence. Cool the mixture to -5℃ and slowly add 40g of trimethylcyanosilane (0.4mol, 1.0eq). After the addition is complete, react at room temperature for 3h.

[0034] After the reaction was completed, 50 mL of 1N hydrochloric acid was added, the mixture was stirred for 30 min, allowed to stand and separate into layers, and the solvent was removed by evaporation of the organic phase to obtain the intermediate 2-hydroxy-3-methyl-3-butenonitrile.

[0035] ② Add 184 g of ethanol (4.0 mol, 10 eq) to the four-necked reaction flask of step ①, cool to 0℃, then pass dry hydrogen chloride gas through, react for 3 h, filter, wash the filter cake with n-hexane, then slowly add it in batches to ice water and stir for 30 min, then add 120 g of dichloromethane for extraction, evaporate the solvent, and obtain 42 g of light yellow oily liquid, with a yield of 72.9% and a GC purity of 93%.

[0036] (Example 4) The specific method for synthesizing the cyclopentoxazone intermediate in this embodiment is as follows: ① In a 500mL four-necked reaction flask, add 21g of 2-methylpropenal (0.3mol), 1.5g of scandium trifluoromethanesulfonate (0.003mol, 0.01eq), and 100g of dichloromethane in sequence. Cool the flask to -10℃ and slowly add 40g of trimethylcyanosilane (0.4mol, 1.33eq). After the addition is complete, react at room temperature for 3h.

[0037] After the reaction was completed, 40 mL of 1N hydrochloric acid was added, the mixture was stirred for 30 min, allowed to stand and separate into layers, and the solvent was removed by evaporation of the organic phase to obtain the intermediate 2-hydroxy-3-methyl-3-butenonitrile.

[0038] ② Add 138 g of ethanol (3.0 mol, 10 eq) to the four-necked reaction flask of step ①, cool to 0℃, then pass dry hydrogen chloride gas through, react for 3 h, filter, wash the filter cake with n-hexane, then slowly add it in batches to ice water and stir for 30 min, then add 80 g of dichloromethane for extraction, evaporate the solvent, and obtain 31 g of light yellow oily liquid, with a yield of 71.8% and a GC purity of 91%.

[0039] (Comparative Example 1) The specific method for synthesizing the cyclopentoxazone intermediate in this comparative example is as follows: ① In a 500mL four-necked reaction flask, add 21g of 2-methylpropenal (0.3mol), 3.9g of aluminum trichloride (0.03mol, 0.1eq), and 100g of dichloromethane in sequence. Cool the mixture to 5℃ and slowly add 40g of trimethylcyanosilane (0.4mol, 1.33eq). After the addition is complete, allow the mixture to react at room temperature for 3 hours.

[0040] After the reaction was completed, 40 mL of 1N hydrochloric acid was added, the mixture was stirred for 30 min, allowed to stand and separate into layers, and the solvent was removed by evaporation of the organic phase to obtain the intermediate 2-hydroxy-3-methyl-3-butenonitrile.

[0041] ② Add 92g of ethanol (2.0mol, 6.6eq) to the four-necked reaction flask of step ①, cool to 0℃, then pass dry hydrogen chloride gas through, react for 2h, filter, wash the filter cake with n-hexane, then slowly add it in batches to ice water and stir for 30min, then add 80g of dichloromethane for extraction, evaporate the solvent, and obtain 27g of light yellow oily liquid, with a yield of 62.5% and a GC purity of 82%.

Claims

1. A method for synthesizing a cyclopentoxate intermediate, comprising the following steps: ① Using 2-methylpropenal and trimethylcyanosilane as starting materials, an addition reaction was first carried out in the presence of Lewis acid, followed by acid hydrolysis to obtain the intermediate 2-hydroxy-3-methyl-3-butenonitrile; ② The intermediate 2-hydroxy-3-methyl-3-butenoic acid obtained in step ① is first reacted with hydrogen chloride and ethanol in a Pinner reaction, and then hydrolyzed to obtain ethyl 2-hydroxy-3-methyl-3-butenoate, an intermediate of cyclopentoxazone.

2. The method for synthesizing the cyclopentoxazone intermediate according to claim 1, characterized in that: In step ① above, the temperature at which the trimethylcyanosilane is added is -15℃ to 0℃.

3. The method for synthesizing the cyclopentoxane intermediate according to claim 1 or 2, characterized in that: In step ① above, the molar ratio of 2-methylpropenal to trimethylcyanosilane is 1:1 to 1:

2.

4. The method for synthesizing the cyclopentoxazone intermediate according to claim 1 or 2, characterized in that: In step ① above, the molar ratio of 2-methylpropenal to the Lewis acid is 1:0.01 to 1:0.

2.

5. The method for synthesizing the cyclopentoxane intermediate according to claim 1 or 2, characterized in that: In step ① above, the Lewis acid is one or more of aluminum trichloride, scandium trifluoromethanesulfonate, boron trifluoride ether, ferric chloride, titanium tetrachloride, tin tetrachloride, antimony pentafluoride, and zinc dichloride.

6. The method for synthesizing the cyclopentoxazone intermediate according to claim 5, characterized in that: The Lewis acid is aluminum trichloride, scandium trifluoromethanesulfonate, or boron trifluoride ether.

7. The method for synthesizing the cyclopentoxazone intermediate according to claim 1 or 2, characterized in that: The addition reaction in step ① above is carried out in an organic solvent; the organic solvent is toluene, dichloromethane, dichloroethane, acetonitrile, or tetrahydrofuran.

8. The method for synthesizing the cyclopentoxane intermediate according to claim 1 or 2, characterized in that: The addition reaction temperature in step ① above is 0℃~40℃.

9. The method for synthesizing the cyclopentoxazone intermediate according to claim 1 or 2, characterized in that: The Pinner reaction temperature in step ② above is -40℃ to 20℃.

10. The method for synthesizing the cyclopentoxane intermediate according to claim 1 or 2, characterized in that: In step ② above, the molar ratio of ethanol to 2-methylpropenal in step ① above is 3:1 to 20:1.

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