CN101367746B - Novel method for synthesizing -metolachlor - Google Patents

Abstract

The invention relates to a new method for synthesizing (S)-metolachlor, and a full synthesis route using chiral is invented. Specifically, use (D)-methyl lactate or (D)-ethyl lactate as a raw material to react with p-toluenesulfonyl chloride to generate (R)-2-(p-toluenesulfonyloxy)propionate, and then react with 2- Methyl-6-ethylaniline is reacted to give S-(-)-N-(2-methyl-6-ethylphenyl)alanine ester, which is then reacted with reducing agent C to give S-(-)-N -(1'-methyl-2'-hydroxyethyl)-2-methyl-6-ethylaniline, further acylated with chloroacetyl chloride, and finally methylated to obtain (S)-metolachlor. The whole process does not need to be split, the reaction is mild, the yield is high, the optical purity is good, the reaction time is short, the raw materials are cheap and easy to obtain, and the cost is low.

Description

A new method for synthesizing (S)-metolachlor

technical field

The invention belongs to the research field of asymmetric synthesis in organic chemistry, and relates to a new method for synthesizing chiral pesticide (S)-metolachlor.

technical background

In 1952, Monsanto Company of the United States discovered that chloroacetamide compounds had herbicidal activity. During the 1960s and 1970s, amide herbicides developed rapidly, and most varieties were commercialized during this period. Alachlor and metolachlor are typical representatives. With the progress of society and the enhancement of environmental awareness, chiral pesticides have also become a very active research field in pesticide chemistry. (S)-Metolachlor is a typical product among chloroacetamide herbicides. This product is a widely used herbicide. The traditionally used metolachlor is a racemate, only Half of the ingredients have herbicidal effect, and the active ingredient is its S isomer, which accounts for about 50%, while the other 50% of the R isomer is wasted[1]. At present, its main synthesis methods include enzymatic resolution of racemates[2,3], asymmetric catalytic hydrogenation reduction[4], among which asymmetric catalytic hydrogenation reduction is currently the world's largest industrial production of (S)- The method that metolachlor adopts, yet only has the mature production technology of (S)-metolachlor abroad at present.

references

[1] Byung T C, Yu S C. Enantioselective synthesis of optically active metolachlor via asymmetric reduction [J]. Tetrahedron: Asymmetry, 1992, 3(3): 337-340.

[2] Zheng L Y, Zhang S Q, Wang F, et al. Chemoenzymatic synthesis of the chiral herbicide: (S)-metolachlor[J]. Canadian Journal of Chemistry, 2006, 84(8): 1058-1063.

[3] Magden H M, Binningen C V. Preparation of optically active-(1′-methyl-2′-methoxyethyl)-N-chloroacetyl-2-ethyl-6-methylanilineas as herbicide[P].US5002606A, 1991-03 -26.

[4] Blaser H U. The chiral switch of(S)-metolachlor: a personal account of an industrial odyssey in asymmetric catalysis[J]. Advanced Synthesis&Catalysis, 2002, 344(1): 17-31.

Contents of the invention

The purpose of the present invention is to provide a new method for synthesizing (S)-metolachlor in order to overcome the deficiencies in the background technology. The new method for total synthesis of chiral particles adopted by the present invention has the advantages of mild conditions, high yield, high e.e. value, few side reactions, short reaction time, and greatly reduced raw material cost.

The technical scheme of the present invention is: the first step, using (D)-methyl lactate or (D)-ethyl lactate as the starting material, in the presence of alkali, and p-toluenesulfonyl chloride at -10 ° C to 30 ° C The following reaction generates (R)-2-(p-toluenesulfonyloxy)propionate; in the second step, 2-methyl- 6-Ethylaniline, and adding a base, reacting at 110°C to 160°C for 1 to 4 hours to obtain S-(-)-N-(2-methyl-6-ethylphenyl)alanine ester; In the third step, S-(-)-N-(2-methyl-6-ethylphenyl) alanine ester reacts with a reducing agent at -10°C to 30°C for 1 to 24 hours to obtain S-( -)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6-ethylaniline; the fourth step, to S-(-)-N-(1'-methyl -2'-Hydroxyethyl)-2-methyl-6-ethylaniline is added with an acid-binding agent base, and chloroacetyl chloride is added dropwise, the temperature is controlled at -15°C to 30°C, and the reaction is carried out for 1 to 24 hours to obtain S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl)acetamide; the fifth step, the S- (-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl)acetamide and methylating reagent in triethylamine, Under the action of pyridine, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide or potassium carbonate and a phase transfer catalyst, the temperature is controlled at -15°C to 110°C for 1 to 24 hours to obtain (S)-isopropylmethyl Grass Ammonium. The mass ratio of the substances used in the second step reaction is (R)-2-(p-toluenesulfonyloxy) propionate: 2-methyl-6-ethylaniline is 1: 0.8～1.3, (R)- The ratio of 2-(p-toluenesulfonyloxy)propionate:base is 1:0.9~1.5. The base used in the first step, the second step and the fourth step is triethylamine, pyridine, potassium carbonate or sodium carbonate. The reducing agent used in the third step reaction is red aluminum, lithium aluminum hydride, lithium borohydride, sodium borohydride-lithium chloride or potassium borohydride-lithium chloride. The mass ratio of the substances used in the third step reaction S-(-)-N-(2-methyl-6-ethylphenyl) alanine ester: reducing agent is 1: 0.8～3, and the used solvent of reaction is Methanol, ethanol, tetrahydrofuran or ether. The fifth step reaction methylation reagent can be methyl trifluoromethanesulfonate, methyl iodide, dimethyl sulfate or diazomethane, and the phase transfer catalyst used is tetra-n-butyl ammonium iodide, tetra-n-butyl bromide Ammonium, benzyltriethylammonium bromide, benzyltriethylammonium chloride or phenyltriethylammonium bromide, the solvent used for the methylation reaction is dichloromethane, dichloroethane, dimethylmethylene Sulfone, tetrahydrofuran, petroleum ether, toluene or benzene.

Its synthetic route is as follows:

Compared with the existing method, the present invention has the following advantages: the whole process does not need to be split, the reaction is mild, the yield is high, the e.e. value is high, the side reaction is less, the reaction time is short, and various raw materials and catalysts are also cheap and easy to obtain. Moreover, the method can overcome the racemization effect caused by the high-temperature reaction, and also greatly reduce the cost of raw materials.

Detailed ways

Embodiment one:

(c＝0.92，EtOH)(文献

(c＝0.92，EtOH))。In a 250 ml three-necked flask equipped with a stirrer and a thermometer, 125 ml of toluene was added, and then 21 grams (0.11 moles) of p-toluenesulfonyl chloride and 10.4 grams (0.1 moles) of (D)-methyl lactate were dropped into the reaction flask 15.2 g (0.15 mol) of triethylamine was added dropwise, the temperature was controlled in an ice-water bath at -10°C to -5°C, and the reaction was tracked until the reaction of (D)-methyl lactate was complete. Filtrate, wash the filtrate with 45 ml of water, separate layers, extract the aqueous layer with 45 ml of dichloromethane, combine the organic layers, dry with 20 g of anhydrous sodium sulfate, filter, and spin the solvent to obtain a light yellow crude product. Then recrystallized with ether:n-hexane=1:1 to obtain 22 g of colorless crystal (R)-2-(p-toluenesulfonyloxy)methyl propionate, with a yield of 85% and an ee value of 97.1%. 14.1 grams (0.104 moles) of 2-methyl-6-ethylaniline are dropped into 100 milliliters of there-necked flasks equipped with a stirrer and a thermometer, and (R)-2-(p-toluenesulfonyloxy) methyl propionate 21.7 grams (0.08 moles), heat up to 110 ° C, start to slowly drop 9.5 grams of pyridine (0.12 moles), continue to heat up to 150 ° C ~ 160 ° C after the drop, the reaction is completed for 1 hour, cooled, and the reaction solution is poured into 100 ml of ice water, stirred, and washed with water until neutral, the aqueous layer was extracted with 100 ml of ethyl acetate, the organic layers were combined, and dried with 25 g of anhydrous sodium sulfate, filtered, spin-dried to dry the solvent, and distilled under reduced pressure to obtain S- (-)-N-(2-methyl-6-ethylphenyl)alanine methyl ester 15.8 grams, yield 89%, ee value 95%, specific rotation

(c=0.92, EtOH) (ref.

(c=0.92, EtOH)).

(c＝1.941，MeOH))。Add 200 milliliters of absolute ethanol, 7.9 grams (0.21 moles) of sodium borohydride and 8.9 grams (0.21 moles) of lithium chloride successively into a 250 milliliter three-necked flask equipped with a stirrer and a thermometer, stir at room temperature for half an hour, and control the temperature with ice-salt water -10°C～0°C, start to drop 15.5 g (0.07 moles) of S-(-)-N-(2-methyl-6-ethylphenyl)alanine methyl ester, The following reaction was performed for 1 hour, then reacted at room temperature until the reaction was complete, filtered, evaporated to dryness, added 50 ml of water to wash the residue, then extracted the aqueous layer with 50 ml of ethyl acetate, combined the organic layers, and dried with 20 g of anhydrous sodium sulfate , filtered, spin-dried the solvent, and distilled under reduced pressure to obtain 13.1 grams of S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6-ethylaniline, yield 97 %, the measured ee value is 94%, the specific rotation (c=1.94, MeOH) (literature

(c=1.941, MeOH)).

(c＝1.166，MeOH))。Add 30 ml of toluene, S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6- 11.6 grams (0.06 moles) of ethylaniline, 7.3 grams (0.072 moles) of triethylamine, temperature control of ice-salt water -15 ° C ~ 0 ° C, 5.4 grams (0.048 moles) of chloroacetyl chloride dissolved in 50 ml of toluene and began to drop Add, first react at below 0°C for 3 hours, then react at room temperature until the reaction is complete, add 50 ml of water to wash, then extract with 50 ml of ethyl acetate, combine the organic layers, and dry with 20 g of anhydrous sodium sulfate, filter, Spin to dry the solvent, and distill under reduced pressure to obtain S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl)acetamide 9.8g, yield 76%, ee value 92%, specific rotation (c=1.17, MeOH) (literature

(c=1.166, MeOH)).

(c＝2.1，正己烷)(文献

(c＝2.073，正己烷))In a 100 ml four-necked flask equipped with a stirrer and a thermometer, add 30 ml of anhydrous tetrahydrofuran, S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N -(2-Hydroxy-1-methylethyl)acetamide 16.2 g (0.06 mol), content 70% sodium hydride 2.9 g (0.085 mol), iced brine temperature control -15 ℃ ~ 0 ℃, after stirring for 3 hours, Dissolve 17 grams (0.12 moles) of methyl iodide in 50 ml of tetrahydrofuran and start to add it dropwise. After reacting for 3 hours below 0°C, then react at room temperature until the reaction is complete, add 50 ml of water to wash, and then wash with 50 ml of ethyl acetate. Extract, combine the organic layers, and dry with 20 grams of anhydrous sodium sulfate, filter, spin to dry the solvent, and distill under reduced pressure to obtain (S)-metolachlor 14.6 grams, yield 86%, ee value 90%, specific optical rotation Spend

(c=2.1, n-hexane) (literature

(c=2.073, n-hexane))

Embodiment two:

(c＝0.92，EtOH)(文献

(c＝0.92，EtOH))。In a 250 ml three-necked flask equipped with a stirrer and a thermometer, 125 ml of methylene chloride was added, and then 21 grams (0.11 moles) of p-toluenesulfonyl chloride and 10.4 grams (0.1 moles) of (D)-methyl lactate were dropped into 12.1 g (0.12 mol) of triethylamine was added dropwise into the reaction flask, the temperature was controlled in an ice-water bath at -10°C to -5°C, and the reaction was tracked until the reaction of (D)-methyl lactate was complete. Filtrate, wash the filtrate with 45 ml of water, separate layers, extract the aqueous layer with 45 ml of dichloromethane, combine the organic layers, dry with 20 g of anhydrous sodium sulfate, filter, and spin the solvent to obtain a light yellow crude product. Then recrystallized with diethyl ether:n-hexane=1:1 to obtain 21.7 g of colorless crystal (R)-2-(p-toluenesulfonyloxy)methyl propionate, with a yield of 84% and an ee value of 98%. 11.9 grams (0.088 moles) of 2-methyl-6-ethylaniline were dropped into a 100-milliliter three-necked flask equipped with a stirrer and a thermometer, and (R)-2-(p-toluenesulfonyloxy) methyl propionate 21.7 grams (0.08 moles), heat up to 140 ° C, start dropping 12.2 grams (0.12 moles) of triethylamine, continue to heat up to 150 ° C ~ 160 ° C after the drop, the reaction is completed for 2.5 hours, cooled, and the reaction solution is poured into 100 ml of ice water, stirred, and washed with water until neutral, the aqueous layer was extracted with 100 ml of ethyl acetate, the organic layers were combined, and dried with 25 g of anhydrous sodium sulfate, filtered, spin-dried to dry the solvent, and distilled under reduced pressure to obtain S- (-)-N-(2-methyl-6-ethylphenyl)alanine methyl ester 16.1 grams, yield 91%, ee value 95%, specific rotation

(c=0.92, EtOH) (ref.

(c=0.92, EtOH)).

(c＝1.94，MeOH)(文献

(c＝1.941，MeOH))。Add 200 ml of anhydrous methanol, 7.9 g (0.21 mol) of sodium borohydride and 8.9 g (0.21 mol) of lithium chloride in sequence in a 250 ml three-necked flask equipped with a stirrer and a thermometer, stir at room temperature for half an hour, and control the temperature with ice and brine -10°C～0°C, start to drop 15.5 g (0.07 moles) of S-(-)-N-(2-methyl-6-ethylphenyl)alanine methyl ester, The following reaction was performed for 1 hour, then reacted at room temperature until the reaction was complete, filtered, evaporated to dryness, added 50 ml of water to wash the residue, then extracted the aqueous layer with 50 ml of ethyl acetate, combined the organic layers, and dried with 20 g of anhydrous sodium sulfate , filtered, spin-dried the solvent, and distilled under reduced pressure to obtain 13.1 grams of S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6-ethylaniline, yield 97 %, the measured ee value is 94%, the specific rotation

(c=1.94, MeOH) (literature

(c=1.941, MeOH)).

(c＝1.17，MeOH)(文献

(c＝1.166，MeOH))。Add 30 ml of dichloromethane, S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl- 11.6 g (0.06 mol) of 6-ethylaniline, 7.9 g (0.078 mol) of triethylamine, temperature control of ice-salt water -15 ℃ ~ 0 ℃, 7.5 g (0.066 mol) of chloroacetyl chloride dissolved in 50 ml of dichloromethane Add dropwise after neutralization, react at below 0°C for 3 hours, then react at room temperature until the reaction is complete, add 50 ml of water to wash, then extract with 50 ml of ethyl acetate, combine the organic layers, and wash with 20 g of anhydrous sodium sulfate Dry, filter, spin dry the solvent, and distill under reduced pressure to obtain S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl Base) 13 grams of acetamide, yield 80%, ee value 93.8%, specific rotation

(c=1.17, MeOH) (literature

(c=1.166, MeOH)).

(c＝2.1，正己烷)(文献

(c＝2.073，正己烷))。13 grams (0.048 moles) of S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl)acetamide Add 0.6 g (0.0022 mol) of benzyltriethylammonium bromide to 30 ml of benzene, then add 12.1 g (0.096 mol) of dimethyl sulfate, control the temperature of ice-brine at -15°C to 0°C, and start dropping 9.6 grams of 50% sodium hydroxide solution, after the dropwise addition, react at below 0°C for 2 hours, then react at 40°C until the reaction is complete, add 50 ml of water to wash after the reaction, then extract with 50 ml of ethyl acetate, and combine the organic layers , and dried with 20 grams of anhydrous sodium sulfate, filtered, spin-dried the solvent, and distilled under reduced pressure to obtain 11.3 grams of (S)-metolachlor, with a yield of 83%, an ee value of 93%, and a specific optical rotation

(c=2.1, n-hexane) (literature

(c=2.073, n-hexane)).

Embodiment three:

(c＝0.92，EtOH))。In a 250 ml three-necked flask equipped with a stirrer and a thermometer, 125 ml of 1,2-dichloroethane was added, and then 15.3 grams (0.08 moles) of p-toluenesulfonyl chloride and 10.4 grams (D)-methyl lactate ( 0.1 mol) into the reaction flask, drop 12.1 g (0.12 mol) of triethylamine, and control the temperature in an ice-water bath at -10°C to -5°C. Sulfonyl chloride reacts completely. Filtrate, wash the filtrate with 45 ml of water, separate layers, extract the aqueous layer with 45 ml of dichloromethane, combine the organic layers, dry with 20 g of anhydrous sodium sulfate, filter, and spin the solvent to obtain a light yellow crude product. Then recrystallized with ether:n-hexane=1:1 to obtain 17 g of colorless crystal (R)-methyl 2-(p-toluenesulfonyloxy)propionate, with a yield of 82% and an ee value of 94%. Put 7.2 grams (0.053 moles) of 2-methyl-6-ethylaniline in a 100 ml three-necked flask equipped with a stirrer and a thermometer, and (R)-2-(p-toluenesulfonyloxy) methyl propionate 17 grams (0.066 mol), heat up to 110 ° C, start dropping 7.35 g (0.073 mol) of triethylamine, continue to heat up to 140 ° C ~ 150 ° C after the drop, the reaction is completed for 1 hour, cooled, and the reaction solution is poured into 100 ml of ice water, stirred, and washed with water until neutral, the aqueous layer was extracted with 100 ml of ethyl acetate, the organic layers were combined, and dried with 25 g of anhydrous sodium sulfate, filtered, spin-dried to dry the solvent, and distilled under reduced pressure to obtain S- (-)-N-(2-methyl-6-ethylphenyl) alanine methyl ester 9.7 grams, yield 83%, ee value 93%, specific rotation (c=0.92, EtOH) (ref.

(c=0.92, EtOH)).

(c＝1.94，MeOH)(文献

(c＝1.941，MeOH))。In a 100 ml three-necked flask equipped with a stirrer and a thermometer, add 30 ml of anhydrous tetrahydrofuran and 1.68 g (0.044 moles) of lithium aluminum hydride in sequence, and control the temperature of ice brine at -10°C to 0°C, and start adding S-(- )-N-(2-methyl-6-ethylphenyl)alanine methyl ester 9.7 grams (0.044 moles) of anhydrous tetrahydrofuran solution, after the dropwise addition, react at below 0°C for 2 hours, then react at room temperature Until the reaction is complete, add 30 milliliters of water to terminate the reaction, then add 30 milliliters of 15% sodium hydroxide, then add 30 milliliters of water, filter, evaporate the solvent to dryness, then extract the aqueous layer with 30 milliliters of ethyl acetate, combine the organic layers, and Dry with 20 grams of anhydrous sodium sulfate, filter, spin dry the solvent, and distill under reduced pressure to obtain S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6-ethane Aniline 6.9 grams, yield 81.2%, recorded ee value 92%, specific rotation

(c=1.94, MeOH) (literature

(c=1.941, MeOH)).

(c＝1.17，MeOH)(文献

(c＝1.166，MeOH))。Add 30 ml of benzene, S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6- 5.8 grams (0.03 moles) of ethylaniline, 6.2 grams (0.045 moles) of potassium carbonate, temperature control of ice-salt water -15 ° C ~ 0 ° C, 4.1 grams (0.036 moles) of chloroacetyl chloride dissolved in 30 ml of benzene and began to drop , reacted below 0°C for 3 hours, then reacted at room temperature until the reaction was complete, filtered, spin-dried the solvent, and distilled under reduced pressure to obtain S-(-)-2-chloro-N-(2-methyl-6-ethane phenyl)-N-(2-hydroxyl-1-methylethyl)acetamide 5.5 grams, yield 68%, ee value 91.7%, specific rotation

(c=1.17, MeOH) (literature

(c=1.166, MeOH)).

(c＝2.1，正己烷)(文献

(c＝2.073，正己烷))。5.5 grams (0.02 moles) of S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl)acetamide Add 2.4 grams (0.07 moles) of sodium hydride with a content of 70% to 30 milliliters of toluene, heat up to reflux, and after 10 minutes, start to drop 5 grams (0.04 moles) of dimethyl sulfate. After the dropwise addition, continue to reflux Until the reaction is complete, after the reaction is completed, add 15 milliliters of ammonia to wash, and 30 milliliters of water, then extract with 50 milliliters of ethyl acetate, combine the organic layers, and dry with 20 grams of anhydrous sodium sulfate, filter, spin to dry the solvent, and distill under reduced pressure Obtain 5.3 grams of (S)-metolachlor, yield 94%, ee value 91.1%, specific rotation

(c=2.1, n-hexane) (literature

(c=2.073, n-hexane)).

Embodiment four:

In a 250 ml three-necked flask equipped with a stirrer and a thermometer, 125 ml of benzene was added, and then 21 grams (0.11 moles) of p-toluenesulfonyl chloride and 11.8 grams (0.1 moles) of (D)-ethyl lactate were dropped into the reaction flask 15.2 g (0.15 mol) of triethylamine was added dropwise, the temperature was controlled in an ice-water bath at -10°C to -5°C, and the reaction was tracked until the reaction of (D)-ethyl lactate was complete. Filtrate, wash the filtrate with 45 ml of water, separate layers, extract the aqueous layer with 45 ml of dichloromethane, combine the organic layers, dry with 20 g of anhydrous sodium sulfate, filter, and spin the solvent to obtain a light yellow crude product. Then recrystallized with diethyl ether:n-hexane=1:1 to obtain 23.7 g of colorless crystal (R)-2-(p-toluenesulfonyloxy)ethyl propionate, yield 87%. Put 8.7 grams (0.064 moles) of 2-methyl-6-ethylaniline in a 100 ml three-necked flask equipped with a stirrer and a thermometer, and (R)-2-(p-toluenesulfonyloxy) ethyl propionate 21.8 grams (0.08 moles), heated up to 140 ° C, began to drop 7.3 grams of triethylamine (0.072 moles), continued to heat up to 150 ° C after the drop, the reaction was completed for 1.5 hours, cooled, and the reaction solution was poured into 100 ml of ice In water, stirred, and washed with water until neutral, the aqueous layer was extracted with 100 ml of ethyl acetate, the organic layers were combined, and dried with 25 g of anhydrous sodium sulfate, filtered, spin-dried to dry the solvent, and distilled under reduced pressure to obtain S-(-) -11.3 g of ethyl N-(2-methyl-6-ethylphenyl)alanine, yield 75%.

(c＝1.941，MeOH))。In a 100 ml three-neck flask equipped with a stirrer and a thermometer, add 30 ml of anhydrous diethyl ether, 1.63 g (0.043 moles) of lithium aluminum hydride in sequence, and control the temperature of ice brine at -10°C to 0°C, and start adding S-(- )-N-(2-methyl-6-ethylphenyl)alanine ethyl ester 11.3 g (0.048 moles) of anhydrous ether solution, after the dropwise addition, react at below 0°C for 2 hours, then react at room temperature Until the reaction is complete, add 30 milliliters of water to terminate the reaction, then add 30 milliliters of 15% sodium hydroxide, then add 30 milliliters of water, filter, evaporate the solvent to dryness, then extract the aqueous layer with 30 milliliters of ethyl acetate, combine the organic layers, and Dry with 20 grams of anhydrous sodium sulfate, filter, spin dry the solvent, and distill under reduced pressure to obtain S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6-ethane Aniline 6.9 grams, yield 74%, recorded ee value 87%, specific rotation (c=1.94, MeOH) (literature

(c=1.941, MeOH)).

(c＝1.17，MeOH)(文献

(c＝1.166，MeOH))。Add 30 ml of benzene, S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6- 5.8 g (0.03 mol) of ethylaniline, 4.77 g (0.045 mol) of sodium carbonate, temperature control of ice-salt water -15°C to 0°C, dissolve 4.1 g (0.036 mol) of chloroacetyl chloride into 30 ml of benzene and start to add dropwise , reacted below 0°C for 3 hours, then reacted at room temperature until the reaction was complete, filtered, spin-dried the solvent, and distilled under reduced pressure to obtain S-(-)-2-chloro-N-(2-methyl-6-ethane phenyl)-N-(2-hydroxyl-1-methylethyl)acetamide 5.5 grams, yield 68%, ee value 86%, specific rotation

(c=1.17, MeOH) (literature

(c=1.166, MeOH)).

(c＝2.1，正己烷)(文献

(c＝2.073，正己烷))5.5 grams (0.02 moles) of S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl)acetamide In 30 ml of toluene, add 3.2 grams (0.04 moles) of potassium hydride with a content of 50%, and heat up to reflux. After 10 minutes, start to add 5 grams (0.04 moles) of dimethyl sulfate dropwise. After the dropwise addition, continue to reflux Until the reaction is complete, after the reaction is completed, add 15 milliliters of ammonia to wash, and 30 milliliters of water, then extract with 50 milliliters of ethyl acetate, combine the organic layers, and dry with 20 grams of anhydrous sodium sulfate, filter, spin to dry the solvent, and distill under reduced pressure Obtain 5.1 grams of (S)-metolachlor, yield 90%, ee value 84.4%, specific rotation

(c=2.1, n-hexane) (literature

(c=2.073, n-hexane))

Embodiment five:

(c＝0.92，EtOH))。In a 250 ml three-necked flask equipped with a stirrer and a thermometer, 125 ml of methylene chloride was added, and then 21 grams (0.11 moles) of p-toluenesulfonyl chloride and 10.4 grams (0.1 moles) of (D)-methyl lactate were dropped into 12.1 g (0.12 mol) of triethylamine was added dropwise into the reaction flask, the temperature was controlled in an ice-water bath at -10°C to -5°C, and the reaction was tracked until the reaction of (D)-methyl lactate was complete. Filtrate, wash the filtrate with 45 ml of water, separate layers, extract the aqueous layer with 45 ml of dichloromethane, combine the organic layers, dry with 20 g of anhydrous sodium sulfate, filter, and spin the solvent to obtain a light yellow crude product. Then recrystallized with diethyl ether:n-hexane=1:1 to obtain 21.7 g of colorless crystal (R)-2-(p-toluenesulfonyloxy)methyl propionate, with a yield of 84% and an ee value of 98%. Put 10.8 grams (0.08 moles) of 2-methyl-6-ethylaniline into a 100 ml three-necked flask equipped with a stirrer and a thermometer, and (R)-2-(p-toluenesulfonyloxy) methyl propionate 21.7 grams (0.08 moles), heat up to 120 ° C, start dropping 10.5 grams (0.104 moles) of triethylamine, continue to heat up to 150 ° C ~ 160 ° C after the drop, the reaction is completed for 2 hours, cooled, and the reaction solution is poured into 100 ml of ice water, stirred, and washed with water until neutral, the aqueous layer was extracted with 100 ml of ethyl acetate, the organic layers were combined, and dried with 25 g of anhydrous sodium sulfate, filtered, spin-dried to dry the solvent, and distilled under reduced pressure to obtain S- (-)-N-(2-methyl-6-ethylphenyl)alanine methyl ester 16.3 grams, yield 92%, ee value 96.7%, specific rotation (c=0.92, EtOH) (ref.

(c=0.92, EtOH)).

(c＝1.94，MeOH)(文献(c＝1.941，MeOH))。Add 200 milliliters of absolute ethanol alcohol, 11.3 grams (0.21 moles) of potassium borohydride and 8.9 grams (0.21 moles) of lithium chloride successively into a 250 milliliter three-necked flask equipped with a stirrer and a thermometer, and stir at room temperature for half an hour, Temperature -10°C～0°C, start to drop 15.5 grams (0.07 moles) of S-(-)-N-(2-methyl-6-ethylphenyl)alanine methyl ester, ℃ below 1 hour, then react at room temperature until the reaction is complete, filter, evaporate the solvent to dryness, add 50 ml of water to wash the residue, then extract the aqueous layer with 50 ml of ethyl acetate, combine the organic layers, and wash with 20 g of anhydrous sodium sulfate Drying, filtering, spin-drying solvent, vacuum distillation to obtain 13 grams of S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6-ethylaniline, yield 96%, measured ee value 94.2%, specific rotation

(c=1.94, MeOH) (literature (c=1.941, MeOH)).

(c＝1.17，MeOH)(文献

(c＝1.166，MeOH))。Add 30 ml of dichloromethane, S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl- 11.6 g (0.06 mol) of 6-ethylaniline, 7.9 g (0.078 mol) of triethylamine, temperature control of ice-salt water -15 ℃ ~ 0 ℃, 7.5 g (0.066 mol) of chloroacetyl chloride dissolved in 50 ml of dichloromethane Add dropwise after neutralization, react at below 0°C for 3 hours, then react at room temperature until the reaction is complete, add 50 ml of water to wash, then extract with 50 ml of ethyl acetate, combine the organic layers, and wash with 20 g of anhydrous sodium sulfate Dry, filter, spin dry the solvent, and distill under reduced pressure to obtain S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl Base) 13 grams of acetamide, yield 80%, ee value 93.3%, specific rotation

(c=1.17, MeOH) (literature

(c=1.166, MeOH)).

(c＝2.1，正己烷)(文献(c＝2.073，正己烷))13 grams (0.048 moles) of S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl)acetamide Add 0.6 g (0.0026 mol) of benzyltriethylammonium chloride to 30 ml of dichloromethane, then add 7.3 g (0.058 mol) of dimethyl sulfate, control the temperature of ice-brine at -15°C to 0°C, and start Add 9.6 grams of 50% sodium hydroxide solution dropwise, react at 0°C for 2 hours after the dropwise addition, and then react at 40°C until the reaction is complete. After the reaction is completed, add 50 ml of water to wash, then extract with 50 ml of ethyl acetate, and combine The organic layer was dried with 20 grams of anhydrous sodium sulfate, filtered, spin-dried to dry the solvent, and distilled under reduced pressure to obtain 11.3 grams of (S)-metolachlor, with a yield of 83%, an ee value of 92.2%, and a specific rotation

(c=2.1, n-hexane) (literature (c=2.073, n-hexane))

Embodiment six:

(c＝0.92，EtOH))。In a 250 ml three-necked flask equipped with a stirrer and a thermometer, 125 ml of methylene chloride was added, and then 21 grams (0.11 moles) of p-toluenesulfonyl chloride and 10.4 grams (0.1 moles) of (D)-methyl lactate were dropped into 12.1 g (0.12 mol) of triethylamine was added dropwise into the reaction flask, the temperature was controlled in an ice-water bath at -10°C to -5°C, and the reaction was tracked until the reaction of (D)-methyl lactate was complete. Filtrate, wash the filtrate with 45 ml of water, separate layers, extract the aqueous layer with 45 ml of dichloromethane, combine the organic layers, dry with 20 g of anhydrous sodium sulfate, filter, and spin the solvent to obtain a light yellow crude product. Then recrystallized with diethyl ether:n-hexane=1:1 to obtain 21.7 g of colorless crystal (R)-2-(p-toluenesulfonyloxy)methyl propionate, with a yield of 84% and an ee value of 98%. 11.9 grams (0.088 moles) of 2-methyl-6-ethylaniline were dropped into a 100-milliliter three-necked flask equipped with a stirrer and a thermometer, and (R)-2-(p-toluenesulfonyloxy) methyl propionate 21.7 grams (0.08 moles), heated up to 140 ° C, began to drop 10.5 grams of triethylamine (0.104 moles), continued to heat up to 150 ° C after the drop, the reaction was completed for 1.5 hours, cooled, and the reaction solution was poured into 100 ml of ice In water, stirred, and washed with water until neutral, the aqueous layer was extracted with 100 ml of ethyl acetate, the organic layers were combined, and dried with 25 g of anhydrous sodium sulfate, filtered, spin-dried to dry the solvent, and distilled under reduced pressure to obtain S-(-) -N-(2-methyl-6-ethylphenyl) alanine methyl ester 16.6 grams, yield 94%, ee value 99.2%, specific rotation (c=0.92, EtOH) (ref.

(c=0.92, EtOH)).

(c＝1.94，MeOH)(文献(c＝1.941，MeOH))。In a 150 ml three-necked flask equipped with a stirrer and a thermometer, add 60 ml of anhydrous diethyl ether, 28.3 g (0.14 moles) of red aluminum, and control the temperature of ice brine at -10°C to 0°C, and start adding S-(-)- 15.5 grams (0.07 moles) of N-(2-methyl-6-ethylphenyl)alanine methyl ester, after the dropwise addition was completed, reacted below 0°C for 2 hours, then reacted at room temperature until the reaction was complete, filtered, evaporated Dry the solvent, add 50 ml of water to wash the residue, then extract the aqueous layer with 50 ml of ethyl acetate, combine the organic layers, and dry with 20 g of anhydrous sodium sulfate, filter, spin to dry the solvent, and distill under reduced pressure to obtain S-(-) -N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6-ethylaniline 13.1 grams, yield 97%, measured ee value 98%, specific rotation

(c=1.94, MeOH) (literature (c=1.941, MeOH)).

(c＝1.17，MeOH)(文献

(c＝1.166，MeOH))。Add 30 ml of dichloromethane, S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl- 11.6 g (0.06 mol) of 6-ethylaniline, 7.9 g (0.078 mol) of triethylamine, temperature control of ice-salt water -15 ℃ ~ 0 ℃, 7.5 g (0.066 mol) of chloroacetyl chloride dissolved in 50 ml of dichloromethane Add dropwise after neutralization, react at below 0°C for 3 hours, then react at room temperature until the reaction is complete, add 50 ml of water to wash, then extract with 50 ml of ethyl acetate, combine the organic layers, and wash with 20 g of anhydrous sodium sulfate Dry, filter, spin dry the solvent, and distill under reduced pressure to obtain S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl Base) 13 grams of acetamide, yield 80%, ee value 95%, specific rotation

(c=1.17, MeOH) (literature

(c=1.166, MeOH)).

(c＝2.073，正己烷)(文献

(c＝2.073，正己烷))13 grams (0.048 moles) of S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl)acetamide Add 0.6 g (0.0016 mol) of tetra-n-butylammonium iodide to 30 ml of petroleum ether (60 ° C ~ 90 ° C), and then add 50% sodium hydroxide solution 9.6 6.05 grams (0.048 moles) of dimethyl sulfate, start dropwise adding 6.05 grams (0.048 moles) of dimethyl sulfate, react at below 0 ℃ for 2 hours after the completion of the dropwise addition, then react at room temperature until the reaction is complete, add 50 milliliters of water to wash after the completion of the reaction, and then wash with 50 milliliters of ethyl acetate Ester extraction, combined organic layers, and dried with 20 grams of anhydrous sodium sulfate, filtered, spin-dried the solvent, and distilled under reduced pressure to obtain 9 grams of (S)-metolachlor, yield 65%, ee value 92.2%, ratio Optical rotation

(c=2.073, n-hexane) (document

(c=2.073, n-hexane))

Embodiment seven:

(c＝0.92，EtOH)(文献

(c＝0.92，EtOH))。In a 250 ml three-necked flask equipped with a stirrer and a thermometer, 125 ml of methylene chloride was added, and then 21 grams (0.11 moles) of p-toluenesulfonyl chloride and 10.4 grams (0.1 moles) of (D)-methyl lactate were dropped into 12.1 g (0.12 mol) of triethylamine was added dropwise into the reaction flask, the temperature was controlled in an ice-water bath at -10°C to -5°C, and the reaction was tracked until the reaction of (D)-methyl lactate was complete. Filtrate, wash the filtrate with 45 ml of water, separate layers, extract the aqueous layer with 45 ml of dichloromethane, combine the organic layers, dry with 20 g of anhydrous sodium sulfate, filter, and spin the solvent to obtain a light yellow crude product. Then recrystallized with diethyl ether:n-hexane=1:1 to obtain 21.7 g of colorless crystal (R)-2-(p-toluenesulfonyloxy)methyl propionate, with a yield of 84% and an ee value of 98%. 11.9 grams (0.088 moles) of 2-methyl-6-ethylaniline were dropped into a 100-milliliter three-necked flask equipped with a stirrer and a thermometer, and (R)-2-(p-toluenesulfonyloxy) methyl propionate 21.7 grams (0.08 moles), heated up to 140 ° C, began to drop 10.5 grams of triethylamine (0.104 moles), continued to heat up to 150 ° C after the drop, the reaction was completed for 1.5 hours, cooled, and the reaction solution was poured into 100 ml of ice In water, stirred, and washed with water until neutral, the aqueous layer was extracted with 100 ml of ethyl acetate, the organic layers were combined, and dried with 25 g of anhydrous sodium sulfate, filtered, spin-dried to dry the solvent, and distilled under reduced pressure to obtain S-(-) -N-(2-methyl-6-ethylphenyl) alanine methyl ester 16.6 grams, yield 94%, ee value 99.2%, specific rotation

(c=0.92, EtOH) (ref.

(c=0.92, EtOH)).

(c＝1.94，MeOH)(文献

(c＝1.941，MeOH))。Add 30 ml of anhydrous methanol, 3.8 g (0.175 moles) of lithium borohydride, ice-brine temperature control -10°C to 0°C, and start adding S-(-) -N-(2-methyl-6-ethylphenyl)alanine methyl ester 15.5 g (0.07 mol), after the dropwise addition, react at below 0°C for 2 hours, then react at room temperature until the reaction is complete, filter, Evaporate the solvent to dryness, add 50 ml of water to wash the residue, then extract the aqueous layer with 50 ml of ethyl acetate, combine the organic layers, and dry with 20 g of anhydrous sodium sulfate, filter, spin to dry the solvent, and distill under reduced pressure to obtain S-(- )-N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6-ethylaniline 13 grams, yield 96.8%, measured ee value 97%, specific optical rotation

(c=1.94, MeOH) (literature

(c=1.941, MeOH)).

(c＝1.17，MeOH)(文献

(c＝1.166，MeOH))。Add 30 ml of dichloromethane, S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl- 11.6 g (0.06 mol) of 6-ethylaniline, 7.9 g (0.078 mol) of triethylamine, temperature control of ice-salt water -15 ℃ ~ 0 ℃, 7.5 g (0.066 mol) of chloroacetyl chloride dissolved in 50 ml of dichloromethane Add dropwise after neutralization, react at below 0°C for 3 hours, then react at room temperature until the reaction is complete, add 50 ml of water to wash, then extract with 50 ml of ethyl acetate, combine the organic layers, and wash with 20 g of anhydrous sodium sulfate Dry, filter, spin dry the solvent, and distill under reduced pressure to obtain S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl Base) 13 grams of acetamide, yield 80%, ee value 95%, specific rotation

(c=1.17, MeOH) (literature

(c=1.166, MeOH)).

(c＝2.073，正己烷)(文献

(c＝2.073，正己烷))13 grams (0.048 moles) of S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl)acetamide Add 0.6 g (0.0023 mol) of phenyltriethylammonium bromide to 30 ml of 1,2-dichloroethane, and then add 50% sodium hydroxide solution 9.6 6.05 grams (0.048 moles) of dimethyl sulfate, start dropwise adding 6.05 grams (0.048 moles) of dimethyl sulfate, react at below 0 ℃ for 2 hours after the completion of the dropwise addition, then react at room temperature until the reaction is complete, add 50 milliliters of water to wash after the completion of the reaction, and then wash with 50 milliliters of ethyl acetate Ester extraction, combined organic layers, and dried with 20 grams of anhydrous sodium sulfate, filtered, spin-dried the solvent, and distilled under reduced pressure to obtain 8.7 grams of (S)-metolachlor, yield 63%, ee value 91.1%, ratio Optical rotation

(c=2.073, n-hexane) (document

(c=2.073, n-hexane))

Embodiment eight:

(c＝0.92，EtOH))。In a 250 ml three-necked flask equipped with a stirrer and a thermometer, 125 ml of methylene chloride was added, and then 21 grams (0.11 moles) of p-toluenesulfonyl chloride and 10.4 grams (0.1 moles) of (D)-methyl lactate were dropped into 12.1 g (0.12 mol) of triethylamine was added dropwise into the reaction flask, the temperature was controlled in an ice-water bath at -10°C to -5°C, and the reaction was tracked until the reaction of (D)-methyl lactate was complete. Filtrate, wash the filtrate with 45 ml of water, separate layers, extract the aqueous layer with 45 ml of dichloromethane, combine the organic layers, dry with 20 g of anhydrous sodium sulfate, filter, and spin the solvent to obtain a light yellow crude product. Then recrystallized with diethyl ether:n-hexane=1:1 to obtain 21.7 g of colorless crystal (R)-2-(p-toluenesulfonyloxy)methyl propionate, with a yield of 84% and an ee value of 98%. 11.9 grams (0.088 moles) of 2-methyl-6-ethylaniline were dropped into a 100-milliliter three-necked flask equipped with a stirrer and a thermometer, and (R)-2-(p-toluenesulfonyloxy) methyl propionate 21.7 grams (0.08 moles), heated up to 140 ° C, began to drop 10.5 grams of triethylamine (0.104 moles), continued to heat up to 150 ° C after the drop, the reaction was completed for 1.5 hours, cooled, and the reaction solution was poured into 100 ml of ice In water, stirred, and washed with water until neutral, the aqueous layer was extracted with 100 ml of ethyl acetate, the organic layers were combined, and dried with 25 g of anhydrous sodium sulfate, filtered, spin-dried to dry the solvent, and distilled under reduced pressure to obtain S-(-) -N-(2-methyl-6-ethylphenyl) alanine methyl ester 16.6 grams, yield 94%, ee value 99.2%, specific rotation (c=0.92, EtOH) (ref.

(c=0.92, EtOH)).

(c＝1.94，MeOH)(文献

(c＝1.941，MeOH))。Add 30 ml of anhydrous tetrahydrofuran, 3.8 g (0.175 moles) of lithium borohydride, and ice-water brine to control the temperature at -10°C to 0°C, and start adding S-(-) -N-(2-methyl-6-ethylphenyl)alanine methyl ester 15.5 g (0.07 mol), after the dropwise addition, react at below 0°C for 2 hours, then react at room temperature until the reaction is complete, filter, Evaporate the solvent to dryness, add 50 ml of water to wash the residue, then extract the aqueous layer with 50 ml of ethyl acetate, combine the organic layers, and dry with 20 g of anhydrous sodium sulfate, filter, spin to dry the solvent, and distill under reduced pressure to obtain S-(- )-N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6-ethylaniline 12.9 grams, yield 96%, recorded ee value 95%, specific rotation

(c=1.94, MeOH) (literature

(c=1.941, MeOH)).

(c＝1.166，MeOH))。Add 30 ml of dichloromethane, S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl- 11.6 g (0.06 mol) of 6-ethylaniline, 7.9 g (0.078 mol) of triethylamine, temperature control of ice-salt water -15 ℃ ~ 0 ℃, 7.5 g (0.066 mol) of chloroacetyl chloride dissolved in 50 ml of dichloromethane Add dropwise after neutralization, react at below 0°C for 3 hours, then react at room temperature until the reaction is complete, add 50 ml of water to wash, then extract with 50 ml of ethyl acetate, combine the organic layers, and wash with 20 g of anhydrous sodium sulfate Dry, filter, spin dry the solvent, and distill under reduced pressure to obtain S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl Base) 13 grams of acetamide, yield 80%, ee value 95%, specific rotation (c=1.17, MeOH) (literature

(c=1.166, MeOH)).

(c＝2.073，正己烷)(文献

(c＝2.073，正己烷))13 grams (0.048 moles) of S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl)acetamide Add 0.6 g (0.0019 moles) of tetra-n-butylammonium bromide to 30 ml of 1,2-dichloroethane, and then add 9.6 g of 50% sodium hydroxide solution to control the temperature of ice-water brine , began to add 6.05 grams of dimethyl sulfate (0.048 moles) dropwise. After the dropwise addition, it was reacted below 0°C for 2 hours, and then reacted at room temperature until the reaction was complete. Extract, combine the organic layers, and dry with 20 grams of anhydrous sodium sulfate, filter, spin to dry the solvent, and distill under reduced pressure to obtain 8.3 grams of (S)-metolachlor, yield 60%, ee value 90%, specific optical rotation Spend

(c=2.073, n-hexane) (document

(c=2.073, n-hexane))

Embodiment nine:

(c＝0.92，EtOH)(文献

(c＝0.92，EtOH))。In a 250 ml three-necked flask equipped with a stirrer and a thermometer, 125 ml of methylene chloride was added, and then 21 grams (0.11 moles) of p-toluenesulfonyl chloride and 10.4 grams (0.1 moles) of (D)-methyl lactate were dropped into 12.1 g (0.12 mol) of triethylamine was added dropwise into the reaction flask, the temperature was controlled in an ice-water bath at -10°C to -5°C, and the reaction was tracked until the reaction of (D)-methyl lactate was complete. Filtrate, wash the filtrate with 45 ml of water, separate layers, extract the aqueous layer with 45 ml of dichloromethane, combine the organic layers, dry with 20 g of anhydrous sodium sulfate, filter, and spin the solvent to obtain a light yellow crude product. Then recrystallized with diethyl ether:n-hexane=1:1 to obtain 21.7 g of colorless crystal (R)-2-(p-toluenesulfonyloxy)methyl propionate, with a yield of 84% and an ee value of 98%. 11.9 grams (0.088 moles) of 2-methyl-6-ethylaniline were dropped into a 100-milliliter three-necked flask equipped with a stirrer and a thermometer, and (R)-2-(p-toluenesulfonyloxy) methyl propionate 21.7 grams (0.08 moles), heated up to 140 ° C, began to drop 10.5 grams of triethylamine (0.104 moles), continued to heat up to 150 ° C after the drop, the reaction was completed for 1.5 hours, cooled, and the reaction solution was poured into 100 ml of ice In water, stirred, and washed with water until neutral, the aqueous layer was extracted with 100 ml of ethyl acetate, the organic layers were combined, and dried with 25 g of anhydrous sodium sulfate, filtered, spin-dried to dry the solvent, and distilled under reduced pressure to obtain S-(-) -N-(2-methyl-6-ethylphenyl) alanine methyl ester 16.6 grams, yield 94%, ee value 99.2%, specific rotation

(c=0.92, EtOH) (ref.

(c=0.92, EtOH)).

(c＝1.94，MeOH)(文献

(c＝1.941，MeOH))。Add 30 ml of anhydrous tetrahydrofuran, 3.8 g (0.175 moles) of lithium borohydride, and ice-water brine to control the temperature at -10°C to 0°C, and start adding S-(-) -N-(2-methyl-6-ethylphenyl)alanine methyl ester 15.5 g (0.07 mol), after the dropwise addition, react at below 0°C for 2 hours, then react at room temperature until the reaction is complete, filter, Evaporate the solvent to dryness, add 50 ml of water to wash the residue, then extract the aqueous layer with 50 ml of ethyl acetate, combine the organic layers, and dry with 20 g of anhydrous sodium sulfate, filter, spin to dry the solvent, and distill under reduced pressure to obtain S-(- )-N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6-ethylaniline 12.9 grams, yield 96%, recorded ee value 95%, specific rotation

(c=1.94, MeOH) (literature

(c=1.941, MeOH)).

(c＝1.17，MeOH)(文献

(c＝1.166，MeOH))。Add 30 ml of dichloromethane, S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl- 11.6 g (0.06 mol) of 6-ethylaniline, 7.9 g (0.078 mol) of triethylamine, temperature control of ice-salt water -15 ℃ ~ 0 ℃, 7.5 g (0.066 mol) of chloroacetyl chloride dissolved in 50 ml of dichloromethane Add dropwise after neutralization, react at below 0°C for 3 hours, then react at room temperature until the reaction is complete, add 50 ml of water to wash, then extract with 50 ml of ethyl acetate, combine the organic layers, and wash with 20 g of anhydrous sodium sulfate Dry, filter, spin dry the solvent, and distill under reduced pressure to obtain S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl Base) 13 grams of acetamide, yield 80%, ee value 95%, specific rotation

(c=1.17, MeOH) (literature

(c=1.166, MeOH)).

(c＝2.073，正己烷)(文献(c＝2.073，正己烷))13 grams (0.048 moles) of S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl)acetamide To 30 ml of 1,2-dichloroethane, add 9.51 g (0.058 mol) of methyl trifluoromethanesulfonate, pyridine, and ice-water brine to control the temperature -15°C to 0°C, and react at below 0°C for 2 hours. Then gradually heat up to 80°C until the reaction is complete. After the reaction is completed, add 50 ml of water to wash, then extract with 50 ml of ethyl acetate, combine the organic layers, and dry with 20 g of anhydrous sodium sulfate, filter, spin to dry the solvent, and reduce pressure. Distilled (S)- metolachlor 9.7 grams, yield 70%, ee value 91.1%, specific rotation

(c=2.073, n-hexane) (document (c=2.073, n-hexane))

Embodiment ten:

(c＝0.92，EtOH)(文献

(c＝0.92，EtOH))。In a 250 ml three-necked flask equipped with a stirrer and a thermometer, 125 ml of methylene chloride was added, and then 21 grams (0.11 moles) of p-toluenesulfonyl chloride and 10.4 grams (0.1 moles) of (D)-methyl lactate were dropped into 12.1 g (0.12 mol) of triethylamine was added dropwise into the reaction flask, the temperature was controlled in an ice-water bath at -10°C to -5°C, and the reaction was tracked until the reaction of (D)-methyl lactate was complete. Filtrate, wash the filtrate with 45 ml of water, separate layers, extract the aqueous layer with 45 ml of dichloromethane, combine the organic layers, dry with 20 g of anhydrous sodium sulfate, filter, and spin the solvent to obtain a light yellow crude product. Then recrystallized with diethyl ether:n-hexane=1:1 to obtain 21.7 g of colorless crystal (R)-2-(p-toluenesulfonyloxy)methyl propionate, with a yield of 84% and an ee value of 98%. Put 10.8 grams (0.08 moles) of 2-methyl-6-ethylaniline into a 100 ml three-necked flask equipped with a stirrer and a thermometer, and (R)-2-(p-toluenesulfonyloxy) methyl propionate 21.7 grams (0.08 moles), heat up to 120 ° C, start dropping 10.5 grams (0.104 moles) of triethylamine, continue to heat up to 150 ° C ~ 160 ° C after the drop, the reaction is completed for 2 hours, cooled, and the reaction solution is poured into 100 ml of ice water, stirred, and washed with water until neutral, the aqueous layer was extracted with 100 ml of ethyl acetate, the organic layers were combined, and dried with 25 g of anhydrous sodium sulfate, filtered, spin-dried to dry the solvent, and distilled under reduced pressure to obtain S- (-)-N-(2-methyl-6-ethylphenyl)alanine methyl ester 16.3 grams, yield 92%, ee value 96.7%, specific rotation

(c=0.92, EtOH) (ref.

(c=0.92, EtOH)).

(c＝1.94，MeOH)(文献

(c＝1.941，MeOH))。Add 200 milliliters of absolute ethanol alcohol, 11.3 grams (0.21 moles) of potassium borohydride and 8.9 grams (0.21 moles) of lithium chloride successively into a 250 milliliter three-necked flask equipped with a stirrer and a thermometer, and stir at room temperature for half an hour, Temperature -10°C～0°C, start to drop 15.5 grams (0.07 moles) of S-(-)-N-(2-methyl-6-ethylphenyl)alanine methyl ester, ℃ below 1 hour, then react at room temperature until the reaction is complete, filter, evaporate the solvent to dryness, add 50 ml of water to wash the residue, then extract the aqueous layer with 50 ml of ethyl acetate, combine the organic layers, and wash with 20 g of anhydrous sodium sulfate Drying, filtering, spin-drying solvent, vacuum distillation to obtain 13 grams of S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6-ethylaniline, yield 96%, measured ee value 94.2%, specific rotation

(c=1.94, MeOH) (literature

(c=1.941, MeOH)).

(c＝1.17，MeOH)(文献

(c＝1.166，MeOH))。Add 30 ml of dichloromethane, S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl- 11.6 g (0.06 mol) of 6-ethylaniline, 7.9 g (0.078 mol) of triethylamine, temperature control of ice-salt water -15 ℃ ~ 0 ℃, 7.5 g (0.066 mol) of chloroacetyl chloride dissolved in 50 ml of dichloromethane Add dropwise after neutralization, react at below 0°C for 3 hours, then react at room temperature until the reaction is complete, add 50 ml of water to wash, then extract with 50 ml of ethyl acetate, combine the organic layers, and wash with 20 g of anhydrous sodium sulfate Dry, filter, spin dry the solvent, and distill under reduced pressure to obtain S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl Base) 13 grams of acetamide, yield 80%, ee value 93.3%, specific rotation

(c=1.17, MeOH) (literature

(c=1.166, MeOH)).

(c＝2.1，正己烷)(文献

(c＝2.073，正己烷))13 grams (0.048 moles) of S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl)acetamide Add 5.4 grams (0.096 moles) of potassium hydroxide to 30 milliliters of dimethyl sulfoxide, and control the temperature of ice-salt water at -15°C to 0°C. Start to add 8.2 grams (0.058 moles) of methyl iodide dropwise. React below 0°C for 1 hour, then react at 20°C until the reaction is complete, add 50 ml of water to wash after the reaction, then extract with 50 ml of ethyl acetate, combine the organic layers, and dry with 20 g of anhydrous sodium sulfate, filter, and spin Dry solvent, distill under reduced pressure to get (S)- metolachlor 11.7 grams, yield 86%, ee value 90%, specific rotation

(c=2.1, n-hexane) (literature

(c=2.073, n-hexane))

Embodiment eleven:

(c＝0.92，EtOH))。In a 250 ml three-necked flask equipped with a stirrer and a thermometer, 125 ml of methylene chloride was added, and then 21 grams (0.11 moles) of p-toluenesulfonyl chloride and 10.4 grams (0.1 moles) of (D)-methyl lactate were dropped into 12.1 g (0.12 mol) of triethylamine was added dropwise into the reaction flask, the temperature was controlled in an ice-water bath at -10°C to -5°C, and the reaction was tracked until the reaction of (D)-methyl lactate was complete. Filtrate, wash the filtrate with 45 ml of water, separate layers, extract the aqueous layer with 45 ml of dichloromethane, combine the organic layers, dry with 20 g of anhydrous sodium sulfate, filter, and spin the solvent to obtain a light yellow crude product. Then recrystallized with diethyl ether:n-hexane=1:1 to obtain 21.7 g of colorless crystal (R)-2-(p-toluenesulfonyloxy)methyl propionate, with a yield of 84% and an ee value of 98%. Put 10.8 grams (0.08 moles) of 2-methyl-6-ethylaniline into a 100 ml three-necked flask equipped with a stirrer and a thermometer, and (R)-2-(p-toluenesulfonyloxy) methyl propionate 21.7 grams (0.08 moles), heat up to 120 ° C, start dropping 10.5 grams (0.104 moles) of triethylamine, continue to heat up to 150 ° C ~ 160 ° C after the drop, the reaction is completed for 2 hours, cooled, and the reaction solution is poured into 100 ml of ice water, stirred, and washed with water until neutral, the aqueous layer was extracted with 100 ml of ethyl acetate, the organic layers were combined, and dried with 25 g of anhydrous sodium sulfate, filtered, spin-dried to dry the solvent, and distilled under reduced pressure to obtain S- (-)-N-(2-methyl-6-ethylphenyl)alanine methyl ester 16.3 grams, yield 92%, ee value 96.7%, specific rotation (c=0.92, EtOH) (ref.

(c=0.92, EtOH)).

(c＝1.94，MeOH)(文献

(c＝1.941，MeOH))。Add 200 milliliters of absolute ethanol alcohol, 11.3 grams (0.21 moles) of potassium borohydride and 8.9 grams (0.21 moles) of lithium chloride successively into a 250 milliliter three-necked flask equipped with a stirrer and a thermometer, and stir at room temperature for half an hour, Temperature -10°C～0°C, start to drop 15.5 grams (0.07 moles) of S-(-)-N-(2-methyl-6-ethylphenyl)alanine methyl ester, ℃ below 1 hour, then react at room temperature until the reaction is complete, filter, evaporate the solvent to dryness, add 50 ml of water to wash the residue, then extract the aqueous layer with 50 ml of ethyl acetate, combine the organic layers, and wash with 20 g of anhydrous sodium sulfate Drying, filtering, spin-drying solvent, vacuum distillation to obtain 13 grams of S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6-ethylaniline, yield 96%, measured ee value 94.2%, specific rotation

(c=1.94, MeOH) (literature

(c=1.941, MeOH)).

(c＝1.17，MeOH)(文献

(c＝1.166，MeOH))。Add 30 ml of dichloromethane, S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl- 11.6 g (0.06 mol) of 6-ethylaniline, 7.9 g (0.078 mol) of triethylamine, temperature control of ice-salt water -15 ℃ ~ 0 ℃, 7.5 g (0.066 mol) of chloroacetyl chloride dissolved in 50 ml of dichloromethane Add dropwise after neutralization, react at below 0°C for 3 hours, then react at room temperature until the reaction is complete, add 50 ml of water to wash, then extract with 50 ml of ethyl acetate, combine the organic layers, and wash with 20 g of anhydrous sodium sulfate Dry, filter, spin dry the solvent, and distill under reduced pressure to obtain S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl Base) 13 grams of acetamide, yield 80%, ee value 93.3%, specific rotation

(c=1.17, MeOH) (literature

(c=1.166, MeOH)).

(c＝2.1，正己烷)(文献

(c＝2.073，正己烷))13 grams (0.048 moles) of S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl)acetamide Add 4.21 g (0.048 mol) of HBF ₄ into 30 ml of dichloromethane, control the temperature of ice-salt water at -15°C to 0, add 4 g (0.096 mol) of diazomethane, and react at below 0°C for 1 hour, and Add 4.8 grams (0.048 moles) of triethylamine dropwise, then react at room temperature until the reaction is complete, add 50 milliliters of water to wash, then extract with 50 milliliters of ethyl acetate, combine the organic layers, and dry with 20 grams of anhydrous sodium sulfate, filter, The solvent was spin-dried and distilled under reduced pressure to obtain 10.9 grams of (S)-metolachlor, with a yield of 8%, an ee value of 90%, and a specific optical rotation

(c=2.1, n-hexane) (literature

(c=2.073, n-hexane))

Embodiment 12:

(c＝0.92，EtOH)(文献

(c＝0.92，EtOH))。In a 250 ml three-necked flask equipped with a stirrer and a thermometer, 125 ml of methylene chloride was added, and then 21 grams (0.11 moles) of p-toluenesulfonyl chloride and 10.4 grams (0.1 moles) of (D)-methyl lactate were dropped into 12.1 g (0.12 mol) of triethylamine was added dropwise into the reaction flask, the temperature was controlled in an ice-water bath at -10°C to -5°C, and the reaction was tracked until the reaction of (D)-methyl lactate was complete. Filtrate, wash the filtrate with 45 ml of water, separate layers, extract the aqueous layer with 45 ml of dichloromethane, combine the organic layers, dry with 20 g of anhydrous sodium sulfate, filter, and spin the solvent to obtain a light yellow crude product. Then recrystallized with diethyl ether:n-hexane=1:1 to obtain 21.7 g of colorless crystal (R)-2-(p-toluenesulfonyloxy)methyl propionate, with a yield of 84% and an ee value of 98%. 11.9 grams (0.088 moles) of 2-methyl-6-ethylaniline were dropped into a 100-milliliter three-necked flask equipped with a stirrer and a thermometer, and (R)-2-(p-toluenesulfonyloxy) methyl propionate 21.7 grams (0.08 moles), heated up to 140 ° C, began to drop 10.5 grams of triethylamine (0.104 moles), continued to heat up to 150 ° C after the drop, the reaction was completed for 1.5 hours, cooled, and the reaction solution was poured into 100 ml of ice In water, stirred, and washed with water until neutral, the aqueous layer was extracted with 100 ml of ethyl acetate, the organic layers were combined, and dried with 25 g of anhydrous sodium sulfate, filtered, spin-dried to dry the solvent, and distilled under reduced pressure to obtain S-(-) -N-(2-methyl-6-ethylphenyl) alanine methyl ester 16.6 grams, yield 94%, ee value 99.2%, specific rotation

(c=0.92, EtOH) (ref.

(c=0.92, EtOH)).

(c＝1.94，MeOH)(文献

(c＝1.941，MeOH))。Add 30 ml of anhydrous tetrahydrofuran, 3.8 g (0.175 moles) of lithium borohydride, and ice-water brine to control the temperature at -10°C to 0°C, and start adding S-(-) -N-(2-methyl-6-ethylphenyl)alanine methyl ester 15.5 g (0.07 mol), after the dropwise addition, react at below 0°C for 2 hours, then react at room temperature until the reaction is complete, filter, Evaporate the solvent to dryness, add 50 ml of water to wash the residue, then extract the aqueous layer with 50 ml of ethyl acetate, combine the organic layers, and dry with 20 g of anhydrous sodium sulfate, filter, spin to dry the solvent, and distill under reduced pressure to obtain S-(- )-N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6-ethylaniline 12.9 grams, yield 96%, recorded ee value 95%, specific rotation

(c=1.94, MeOH) (literature

(c=1.941, MeOH)).

(c＝1.17，MeOH)(文献

(c＝1.166，MeOH))。Add 30 ml of dichloromethane, S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl- 11.6 g (0.06 mol) of 6-ethylaniline, 7.9 g (0.078 mol) of triethylamine, temperature control of ice-salt water -15 ℃ ~ 0 ℃, 7.5 g (0.066 mol) of chloroacetyl chloride dissolved in 50 ml of dichloromethane Add dropwise after neutralization, react at below 0°C for 3 hours, then react at room temperature until the reaction is complete, add 50 ml of water to wash, then extract with 50 ml of ethyl acetate, combine the organic layers, and wash with 20 g of anhydrous sodium sulfate Dry, filter, spin dry the solvent, and distill under reduced pressure to obtain S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl Base) 13 grams of acetamide, yield 80%, ee value 95%, specific rotation

(c=1.17, MeOH) (literature

(c=1.166, MeOH)).

(c＝2.073，正己烷)(文献

(c＝2.073，正己烷))13 grams (0.048 moles) of S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl)acetamide Add 6.05 g (0.048 mol) of dimethyl sulfate to 30 ml of petroleum ether (60 °C ~ 90 °C), and then reflux until the reaction is complete. After the reaction is completed, add 50 ml of water to wash, and then extract with 50 ml of ethyl acetate. , combined the organic layers, and dried with 20 grams of anhydrous sodium sulfate, filtered, spin-dried the solvent, and distilled under reduced pressure to obtain 12 grams of (S)-metolachlor, with a yield of 88%, an ee value of 90%, and a specific rotation

(c=2.073, n-hexane) (document

(c=2.073, n-hexane))

Although the present invention has been described in detail with preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art should be able to make various modifications and changes without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention should be regarded as the scope defined by the appended claims.

Claims (6)

1. a method for synthesizing (S)-metolachlor is characterized in that: the first step utilizes (D)-methyl lactate or (D)-ethyl lactate as starting raw material, in the presence of alkali , react with p-toluenesulfonyl chloride at -10°C to 30°C to generate (R)-2-(p-toluenesulfonyloxy)propionate; the second step, to (R)-2-(p-toluenesulfonyl Add 2-methyl-6-ethylaniline to acyloxy) propionate, add base, and react at 110°C to 160°C for 1 to 4 hours to obtain S-(-)-N-(2-methyl base-6-ethylphenyl) alanine ester; the third step, S-(-)-N-(2-methyl-6-ethylphenyl) alanine ester and reducing agent at -10°C Reaction at ~30°C for 1 to 24 hours to obtain S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6-ethylaniline; the fourth step, to S-(-)-N-(1'-methyl-2'-hydroxyethyl)-2-methyl-6-ethylaniline is added with an acid-binding agent base, and chloroacetyl chloride is added dropwise, and the temperature is controlled at -15℃～30℃, react for 1～24 hours to get S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methyl base ethyl) acetamide; the fifth step, S-(-)-2-chloro-N-(2-methyl-6-ethylphenyl)-N-(2-hydroxyl-1-methylethyl base) acetamide and methylating reagent under the action of triethylamine, pyridine, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide or potassium carbonate and a phase transfer catalyst, the temperature is controlled at -15°C to 110°C React for 1 to 24 hours to obtain (S)-metolachlor. 2. the method for synthetic (S)-metolachlor according to claim 1, is characterized in that: the used each substance mass ratio of second step reaction is (R)-2-(p-toluenesulfonyloxy ) propionate: 2-methyl-6-ethylaniline 1: 0.8-1.3, (R)-2-(p-toluenesulfonyloxy) propionate: base 1: 0.9-1.5. 3. the method for synthetic (S)-metolachlor according to claim 1 is characterized in that: the alkali used in the first step, the second step and the fourth step is triethylamine, pyridine, salt of wormwood or Sodium carbonate. 4. the method for synthesizing (S)-metolachlor according to claim 1 is characterized in that: the reductant used in the third step reaction is red aluminum, lithium aluminum hydride, lithium borohydride, sodium borohydride - lithium chloride or potassium borohydride - lithium chloride. 5. the method for synthetic (S)-metolachlor according to claim 1, is characterized in that: the used each substance mass ratio of the third step reaction S-(-)-N-(2-methyl- 6-ethylphenyl) alanine ester: reducing agent is 1: 0.8～3, and the used solvent of reaction is methanol, ethanol, tetrahydrofuran or ether. 6. the method for synthetic (S)-metolachlor according to claim 1, is characterized in that: the 5th step reaction methylation reagent can be methyl trifluoromethanesulfonate, methyl iodide, dimethyl sulfate ester or diazomethane, the phase transfer catalyst used is tetra-n-butylammonium iodide, tetra-n-butylammonium bromide, benzyltriethylammonium bromide, benzyltriethylammonium chloride or phenyltriethylammonium Ammonium bromide, the solvent used for the methylation reaction is methylene dichloride, ethylene dichloride, dimethyl sulfoxide, tetrahydrofuran, petroleum ether, toluene or benzene.