CN103232344B - A kind of method of synthesizing S-2-methyl chloropropionate - Google Patents

Abstract

The invention discloses a method for synthesizing methyl S-2-chloropropionate. The method comprises the following steps: (1) preparing Vilmerier reagent: adding a chlorinating agent to a reaction kettle, and adding a short-chain aliphatic substituted amide dropwise As a solvent, stir and react to obtain a Vilmierer reagent solution; (2) Synthesis of methyl S-2-chloropropionate: add a small amount of solvent to the Vilmierer reagent solution obtained in the first step to obtain a mixed solution, and add R dropwise to the mixed solution - Methyl lactate, and stirring to carry out chlorination reaction to obtain the product solution that is S-2-methyl chloropropionate solution; (3) washing the S-2-methyl chloropropionate solution obtained in step 2 with water, eluting, Distillation gave the product S-methyl 2-chloropropionate. The synthesis method has mild reaction conditions, is easy to operate, has little environmental pollution, and is suitable for large-scale industrial production.

Description

A kind of method of synthesizing S-2-methyl chloropropionate

technical field

The invention relates to the technical field of synthesis of pesticide intermediates, in particular to a method for synthesizing S-2-methyl chloropropionate.

Background technique

Aryloxyphenoxypropionate herbicides are typical representatives of single isomers with high efficacy, and their proportion in chiral pesticides is increasing. In recent years, it has been continuously developed and applied due to its characteristics of long growth and safety to subsequent crops. And S-2-methyl chloropropionate is the synthetic aryloxyphenoxypropionic acid herbicides such as fenoxaprop-methyl (trade name), Jingai grass energy, high-efficiency flurifop-p-methyl, cyhalofop-ethyl, etc. Important intermediate, so the synthesis of S-2-methyl chloropropionate is of great significance.

There are three methods for the synthesis of methyl S-2-chloropropionate at home and abroad: directional synthesis of chiral raw materials, resolution of racemates and asymmetric synthesis. Among them, the directional synthesis method of chiral raw materials has the advantages of low cost, simple synthesis steps, mature process, and high optical purity of the obtained substances, and is currently the most commonly used method. The directional synthesis of chiral raw materials can be divided into two types: one type uses chiral methyl lactate as raw material, and directly uses chlorinating reagents for chlorination reaction to generate the target product. The traditional process uses cheap L-methyl lactate directly through The direct chlorination of thionyl chloride can obtain the S-2-chloropropionate methyl ester that configuration keeps, or take R-methyl lactate as raw material, add catalyst and solvent (such as pyridine, dioxane etc.), obtain the structure The high optical purity of S-2-chloropropionate methyl ester that flips type; The other is to first synthesize optically pure methyl p-methylsulfonylpropionate (or methyl p-toluenesulfonylpropionate), and then combine with trichloro Aluminum reaction gives very high e.e% value of methyl S-2-chloropropionate.

Vilsmeier reagent, as a kind of novel chlorination reagent, is commonly used in the chlorination of alcohol hydroxyl group, document 1 (Vilsmeir-Hack reagent synthesizes optically pure methyl 2-chloropropionate. Wen Hui, Wang Min. Chemical Reagents, 2005, 27 (8 ): 491-492) disclose a kind of method that reacts the Vilsmeier reagent that forms with PCl5 and DMF and generates R- _{2 -} methyl chloropropionate, but because the PCl5 that uses in this technique corrodes equipment seriously, and synthetic steps Complex, post-processing trouble, serious environmental pollution, not suitable for industrial production.

Contents of the invention

The purpose of the present invention is to provide a kind of mild reaction condition, easy to operate, little to environmental pollution, and the method for the synthetic S-2-chloropropionate methyl ester that is suitable for large-scale industrialized production.

The technical solution that realizes the object of the present invention is: a kind of method for synthesizing S-2-methyl chloropropionate, comprises the following steps:

The first step is to prepare Vilmierer reagent: add chlorinating agent to the reaction kettle, and dropwise add short-chain aliphatic substituted amides as solvent, stir and react to obtain Vilmierer reagent solution;

The 2nd step, synthesizing methyl S-2-chloropropionate: add a small amount of solvent to the Vilmierier reagent solution obtained in the 1st step to obtain a mixed solution, add R-methyl lactate dropwise to the mixed solution, and stir for chlorine Substitution reaction obtains product solution namely S-2-methyl chloropropionate solution;

In the third step, the S-2-chloropropionic acid methyl ester solution obtained in the second step is washed with water, desolvated, and distilled to obtain the product S-2-chloropropionic acid methyl ester.

In the method for synthesizing methyl S-2-chloropropionate of the present invention, the chlorination agent described in the first step is thionyl chloride or bis(trichloromethyl)carbonate; the short-chain aliphatic substitution of the solvent The amide is N,N-dimethylformamide or N,N-dimethylacetamide; the molar ratio of the chlorinating agent to the solvent is 1:1~1:2; the stirring reaction temperature is 0°C ~10°C, the time is 1~2h. The solvent described in the second step is a short-chain aliphatic substituted amide, pyridine or dioxane; the molar ratio of R-methyl lactate to Vilmerier reagent is 1:1.1~1.4; the temperature of the chlorination reaction is 50°C~ 60°C, the time is 5~8h.

Compared with the prior art, the present invention has significant advantages: (1) the novel Vilmeier reagent prepared is simple to prepare and does not require aftertreatment, which improves the existing preparation method; (2) replaces traditional chlorinated reagents with Vilmeier reagent, solving The problem of high toxicity and high corrosiveness of phosphorus oxychloride or phosphorus pentachloride; (3) the consumption of solvent DMF has been greatly reduced, and the problem of using a large amount of pyridine as solvent consumption and serious pollution in the traditional process has been overcome; (4) using The one-pot method for synthesizing the target product greatly simplifies the process flow and is simple to operate; (5) the reaction conditions are mild, the reaction time is short, the yield and purity are greatly improved, and it is suitable for large-scale industrial production.

Description of drawings

Fig. 1 is the synthesis flowchart of the method for the synthesis of S-2-methyl chloropropionate of the present invention.

detailed description

The present invention will be described in further detail below in conjunction with the accompanying drawings.

In conjunction with Fig. 1, the method for the synthesis of methyl S-2-chloropropionate of the present invention may further comprise the steps:

The first step is to prepare Vilmierer reagent: add chlorinating agent to the reaction kettle, and drop short-chain aliphatic substituted amides as solvent, stir and react to obtain Vilmierer reagent solution; the chlorinating agent is thionyl chloride or bis (trichloromethyl) carbonate; the short-chain aliphatic substituted amide is N,N-dimethylformamide or N,N-dimethylacetamide; the molar ratio of the chlorinating agent to the solvent 1:1~1:2; the stirring reaction described

The temperature is 0°C~10°C, and the time is 1~2h.

The 2nd step, synthesizing methyl S-2-chloropropionate: add a small amount of solvent to the Vilmierier reagent solution obtained in the 1st step to obtain a mixed solution, add R-methyl lactate dropwise to the mixed solution, and stir for chlorine Generation reaction obtains product solution and is S-2-methyl chloropropionate solution; Described solvent is short-chain aliphatic substituted amide, pyridine or dioxane; The mol ratio of R-methyl lactate and Vilmerier reagent is 1: 1.1~1.4; the temperature of chlorination reaction is 50℃~60℃, and the time is 5~8h.

In the 3rd step, the S-2-methyl chloropropionate solution obtained in the 2nd step is washed with water, desolvated, and distilled to obtain the product S-2-methyl chloropropionate;

The present invention will be described in further detail below in conjunction with specific embodiments.

Example 1

Step 1, prepare Vilmerier reagent: Add 71.4g (0.6mol) of thionyl chloride to a 250ml four-neck flask, cool to 5~10°C with ice water, and dropwise add 50.43g (0.69mol) of anhydrous N, N-dimethylformamide was used as a solvent, and the temperature was significantly increased, and mechanically stirred at a temperature of 5-10°C for 1-2 hours to react to obtain a colorless Vilmierer reagent solution;

Step 2, Synthesis of methyl S-2-chloropropionate: Add a small amount of N,N-dimethylformaldehyde to the Vilmerie reagent solution obtained in step 1 using a constant pressure dropping funnel at a temperature of 20~30°C Add 54.2g (0.52mol) R-lactate methyl ester dropwise to the mixed solution, the temperature of the reaction rises significantly, and gas is generated; after the dropwise addition, the temperature is raised to 60°C and stirred for 5 hours, and the chlorination reaction is carried out to obtain the product The solution is S-2-methyl chloropropionate solution, the gas phase tracks the reaction process, and cools after the reaction;

In the 3rd step, the S-2-methyl chloropropionate solution obtained in the 2nd step is washed with water, and the solvent is removed, and the product S-2-methyl chloropropionate is distilled to obtain 56.4g, and the productive rate is 89%, and the optical purity is 98%. .

Example 2

Step 1, prepare Vilmierer reagent: Add 178.0g (0.6mol) of bis(trichloromethyl)carbonate to a 500ml four-necked bottle, cool to 0~5°C with ice water, and add 43.8g (0.6mol) dropwise Anhydrous N,N-dimethylformamide was used as a solvent, the temperature was significantly increased, and the reaction was mechanically stirred for 1 to 2 hours to obtain a colorless Vilmierer reagent solution;

Step 2, Synthesis of methyl S-2-chloropropionate: Add a small amount of N,N-dimethylformaldehyde to the Vilmerie reagent solution obtained in step 1 using a constant pressure dropping funnel at a temperature of 20~30°C Add 62.4g (0.6mol) R-methyl lactate dropwise to the mixed solution, the temperature of the reaction rises significantly, and gas is generated; after the dropwise addition, the temperature is raised to 55°C and stirred for 5 hours, and the chlorination reaction is carried out to obtain the product The solution is S-2-methyl chloropropionate solution, the gas phase tracks the reaction process, and cools after the reaction;

In the third step, the S-2-methyl chloropropionate solution obtained in the second step was washed with water, desolvated, and distilled to obtain the product S-2-methyl chloropropionate; 50.7g, the yield was 80%, and the optical purity was 96.0 %.

Example 3

Step 1, prepare Vilmierer reagent: Add 178.0g (0.6mol) of bis(trichloromethyl)carbonate to a 250ml four-necked bottle, cool to 0~5°C with ice water, and add 62.7g (0.72mol) dropwise Anhydrous N, N-dimethylacetamide was used as a solvent, the temperature was significantly increased, and the reaction was mechanically stirred for 1 to 2 hours to obtain a colorless Vilmierer reagent solution;

Step 2, Synthesis of methyl S-2-chloropropionate: Add a small amount of N,N-dimethylethyl ether to the Vilmerie reagent solution obtained in Step 1 using a constant pressure dropping funnel at a temperature of 20~30°C Add 44.6g (0..43mol) R-methyl lactate dropwise to the mixed solution, the temperature of the reaction rises significantly, and gas is generated; after the dropwise addition, the temperature is raised to 60°C and stirred for 5 hours to carry out the chlorination reaction Obtain product solution and be S-2-methyl chloropropionate solution, follow the reaction process in gas phase, cool after reaction finishes;

In the third step, the S-2-methyl chloropropionate solution obtained in the second step was washed with water, desolvated, and distilled to obtain the product S-2-methyl chloropropionate; 57.0g, the yield was 90%, and the optical purity was 97 %.

Example 4

Step 1, prepare Vilmerie reagent: Add 178.0g (0.6mol) of bis(trichloromethyl)carbonate to a 500ml four-neck bottle, cool to 0~5°C with ice water, and add 52.2g (0.6mol) dropwise Anhydrous N, N-dimethylacetamide was used as a solvent, the temperature was significantly increased, and the reaction was mechanically stirred for 1 to 2 hours to obtain a colorless Vilmierer reagent solution;

Step 2, synthesis of methyl S-2-chloropropionate: at a temperature of 20~30°C, use a constant pressure dropping funnel to add a small amount of pyridine to the Vilmierier reagent solution obtained in step 1 to obtain a mixed solution, and add to the mixed solution 48.0g (0.46mol) R-methyl lactate was added dropwise to the solution, the reaction temperature rose significantly, and gas was generated; after the dropwise addition, the temperature was raised to 50°C and stirred for 6 hours, and the chlorination reaction was carried out to obtain the product solution, namely S-2-chloropropane Acid methyl ester solution, gas phase tracking reaction process, cooling after the end of the reaction;

In the 3rd step, the S-2-methyl chloropropionate solution obtained in the 2nd step is washed with water, solvent removal, and distillation obtains 52.6 g of the product S-2-methyl chloropropionate, with a yield of 84% and an optical purity of 90%. .

Example 5

Step 1, prepare Vilmierer reagent: Add 71.4g (0.6mol) of thionyl chloride to a 250ml four-neck flask, cool to 5~10°C with ice water, and drop 50.4g (0.69mol) of anhydrous N, N-dimethylformamide is used as a solvent, the temperature is significantly increased, and the reaction is mechanically stirred for 1 to 2 hours to obtain a colorless Vilmierer reagent solution;

The 2nd step, synthesizing S-2-methyl chloropropionate: at 20 ~ 30 ℃ temperature, add a small amount of dioxane to the Vilmierier reagent solution obtained in the 1st step with a constant pressure dropping funnel to obtain a mixed solution, Add 62.4g (0.6mol) R-methyl lactate dropwise to the mixed solution, the temperature of the reaction rises significantly, and gas is generated; after the dropwise addition, the temperature is raised to 55°C and stirred for 6 hours, and the chlorination reaction is carried out to obtain the product solution, namely S-2 - Methyl chloropropionate solution, gas phase tracking reaction process, cooling after the reaction finishes;

In the 3rd step, the S-2-methyl chloropropionate solution obtained in the 2nd step is washed with water, solvent removal, and distillation obtains 54.4 g of the product S-2-methyl chloropropionate, with a yield of 86% and an optical purity of 87%. .

Example 6

Step 1, prepare Vilmerier reagent: add 71.4g (0.6mol) of thionyl chloride to a 250ml four-neck flask, cool to 5~10°C with ice water, and dropwise add 52.6g (0.72mol) of anhydrous N, N-dimethylformamide is used as a solvent, the temperature is significantly increased, and the reaction is mechanically stirred for 1 to 2 hours to obtain a colorless Vilmierer reagent solution;

Step 2, synthesis of methyl S-2-chloropropionate: at a temperature of 20~30°C, use a constant pressure dropping funnel to add a small amount of pyridine to the Vilmierier reagent solution obtained in step 1 to obtain a mixed solution, and add to the mixed solution 52g (0.5mol) R-methyl lactate was added dropwise to the solution, the reaction temperature rose significantly, and gas was generated; after the dropwise addition, the temperature was raised to 55°C and stirred for 5 hours, and the chlorination reaction was carried out to obtain the product solution, namely S-2-chloropropionic acid Methyl ester solution, follow the reaction process in gas phase, and cool after the reaction;

In the 3rd step, the S-2-methyl chloropropionate solution obtained in the 2nd step was washed with water, desolvated, and distilled to obtain 56.9 g of the product S-2-methyl chloropropionate, with a yield of 90% and an optical purity of 99% .

Example 7

Step 1, prepare Vilmerier reagent: add 71.4g (0.6mol) of thionyl chloride to a 250ml four-necked bottle, cool to 5~10°C with ice water, and dropwise add 61.7g (0.7mol) of anhydrous anhydrous N, N-dimethylacetamide was used as a solvent, the temperature was significantly increased, and the reaction was mechanically stirred for 1-2 hours to obtain a colorless Vilmierer reagent solution;

Step 2, Synthesis of methyl S-2-chloropropionate: Add a small amount of N,N-dimethylethyl ether to the Vilmerie reagent solution obtained in Step 1 using a constant pressure dropping funnel at a temperature of 20~30°C Add 44.6g (0.43mol) R-lactate methyl ester dropwise to the mixed solution, the temperature of the reaction rises significantly, and gas is generated; after the dropwise addition, the temperature is raised to 60°C and stirred for 6 hours, and the chlorination reaction is carried out to obtain the product The solution is S-2-methyl chloropropionate solution, the gas phase tracks the reaction process, and cools after the reaction;

In the 3rd step, the S-2-methyl chloropropionate solution obtained in the 2nd step was washed with water, desolvated, and distilled to obtain 47.4 g of the product S-2-methyl chloropropionate, with a yield of 75% and an optical purity of 98%. .

Example 8

Step 1, prepare Vilmerier reagent: Add 71.4g (0.6mol) of thionyl chloride to a 250ml four-neck flask, cool to 5~10°C with ice water, and drop 60.1g (0.69mol) of anhydrous N, N-dimethylacetamide is used as a solvent, the temperature is significantly increased, and the reaction is mechanically stirred for 1 to 2 hours to obtain a colorless Vilmierer reagent solution;

The 2nd step, synthesizing S-2-methyl chloropropionate: at 20 ~ 30 ℃ temperature, add a small amount of dioxane to the Vilmierier reagent solution obtained in the 1st step with a constant pressure dropping funnel to obtain a mixed solution, Add 62.4g (0.6mol) R-methyl lactate dropwise to the mixed solution, the temperature of the reaction rises significantly, and gas is generated; after the dropwise addition, the temperature is raised to 55°C and stirred for 8 hours, and the chlorination reaction is carried out to obtain the product solution, namely S-2 - Methyl chloropropionate solution, gas phase tracking reaction process, cooling after the reaction finishes;

In the 3rd step, the S-2-methyl chloropropionate solution obtained in the 2nd step was washed with water, desolvated, and distilled to obtain 44.3 g of the product S-2-methyl chloropropionate, with a yield of 70% and an optical purity of 98%. .

Product structure determination:

¹ HNMR (500 MHz, CDCl ₃ ): 4.41 (dd, 1H, CH), 3.79 (s, 3H, CH ₃ ), 1.69 (d, 1H, CH ₃ ).

MS, m/z: 122 (M ⁺ ), 87, 63, 59, 43, 31.

IR (KBr), v, cm ^-1 : 3010, 2950, 1740, 1390, 1260, 1200, 860, 692.

Claims (5)

1. a method for synthesizing S-2-methyl chloropropionate, is characterized in that, comprises the following steps: The 1st step, preparation Vilmierier reagent: add chlorinating agent in reactor, described chlorinating agent is sulfur oxychloride or bis (trichloromethyl) carbonate, and drop short chain aliphatic substituted amide as Solvent, stirred and reacted to obtain a Vilmierer reagent solution, the stirred reaction temperature is 0°C to 10°C, and the time is 1 to 2h; Step 2, synthesis of methyl S-2-chloropropionate: add solvent to the Vilmierer reagent solution obtained in step 1 to obtain a mixed solution, add R-methyl lactate dropwise to the mixed solution, and stir for chlorination reaction The obtained product solution is methyl S-2-chloropropionate solution, the temperature of the chlorination reaction is 50°C-60°C, and the time is 5-8h; In the third step, water and an extractant are added to the methyl S-2-chloropropionate solution obtained in the second step for extraction, after separation, the organic phase is taken and distilled to obtain the product methyl S-2-chloropropionate. 2. the method for the synthetic S-2-chloropropionic acid methyl ester according to claim 1 is characterized in that, the short-chain aliphatic substituted amide described in the 1st step is N, N-dimethylformamide or N,N-Dimethylacetamide. 3. the method for the synthetic S-2-methyl chloropropionate according to claim 1, is characterized in that, the mol ratio 1:1～1:2 of the chlorination agent described in the 1st step and solvent. 4. the method for synthesizing S-2-methyl chloropropionate according to claim 1 is characterized in that, the solvent described in the 2nd step is short-chain aliphatic substituted amides, pyridine or dioxane. 5. the method for the synthetic S-2-methyl chloropropionate according to claim 1, is characterized in that, the mol ratio of R-methyl lactate described in the 2nd step and Vilmerier reagent is 1:1.1～1.4 .