Method for catalytically and asymmetrically synthesizing chiral herbicide tetrazolomide

Abstract

The invention relates to a method for catalyzing asymmetric synthesis of a chiral herbicide tetrazolomide, and relates to a herbicide and a synthesis method. The specific method comprises the following steps: catalyzing an asymmetric Michael addition reaction of dithiomalonate and nitroolefin by using a chiral squaramide catalyst based on cinchona alkaloid to obtain a key intermediate, and then carrying out nitro reduction, lactamization, hydrolysis, methylation, amidation and other steps to obtain the dithiomalonate. The chiral tetrazolomide is synthesized with a good total yield and excellent enantioselectivity. The method has the main advantages that the use amount of the chiral catalyst is low, the environmental pollution is reduced by taking water as a solvent, the reaction yield is high, the stereoselectivity is good, the reaction condition is mild, and the post-treatment is simple. The reaction conditions of the method are also suitable for large-scale preparation and industrial production, so that the method has higher application value and social and economic benefits.

Description

Technical Field

[0001] The present invention relates to a method for synthesizing a herbicide, and particularly to a method for catalytic asymmetric synthesis of chiral herbicide flupyrsulfuron-methyl. Background Art

[0002] Flupyrsulfuron-methyl is an aryl pyrrolidone aniline herbicide developed by DuPont (in 2018, DuPont transferred the US and Chinese patents of this compound to FMC Corporation) that inhibits dihydrophosphate dehydrogenase. It is mainly used for wheat, rice, and cash crops (such as sugarcane, citrus, and nuts), and can control important weeds such as barnyard grass, green foxtail, Kochia scoparia, and Heteranthera limosa. The best effect is achieved when used before emergence, and its structure is shown in the following formula (1):

[0003]

[0004] There are two chiral centers in flupyrsulfuron-methyl, and only the S,S isomer among its stereoisomers has herbicidal activity. As shown in the following formula, in the existing reported synthesis methods [T.P. Selby, A.D. Satterfield, A. Puri, T.M. Stevenson, D.A. Travis, M.J. Campbell, A.E. Taggi, K.A. Hughes and J. Bereznak, Bioisosteric Tactics in the Discovery of Tetflupyrolimet: A New Mode-of-Action Herbicide. J. Agric. Food Chem., 2023, 71, 18197.], the asymmetric Michael addition reaction of chiral Ni-catalyzed malonic ester (10) and nitroolefin (8) is used to obtain intermediate (11) with 90% ee. Intermediate (11) is converted into flupyrsulfuron-methyl (1) through multiple steps such as nitro reduction, lactamization, hydrolysis, methylation, and condensation. The existing route has the disadvantages of using environmentally unfriendly metal catalysts, low overall yield, low enantioselectivity (90% ee), high cost, and harsh reaction conditions.

[0005]

[0006] Since the beginning of this century, chiral organic small molecule catalysts have developed rapidly as a type of catalyst with low toxicity, low cost, and stable structure, and have become the third important type of chiral catalyst after asymmetric metal catalysts and enzyme catalysts. Thioesters play important roles in biosynthesis and organic synthesis. Compared with their oxygen ester analogues, thioesters have a smaller overlap between the C(2p) orbital and the S(3p) orbital. Therefore, their α-hydrogen has stronger acidity and is more easily enolized for nucleophilic reactions. In addition, thioesters can be easily converted into functional groups such as aldehydes, ketones, esters, and amides, and also have important value in organic synthesis. In recent years, dithiomalonates, as malonate ester analogues with enhanced nucleophilic activity, have been well applied in asymmetric organic small molecule catalytic reactions. Jin Hui et al. reported an asymmetric Michael addition reaction of nitroolefins with dithiomalonates catalyzed by a novel L-proline-derived tertiary amine bifunctional organic catalyst. The obtained addition product had a yield as high as 99% and a high enantioselectivity as high as 97% [H. Jin, S. T. Kim, G. S. Hwang, D. H. Ryu. L-Proline Derived Bifunctional Organocatalysts: Enantioselective Michael Addition of Dithiomalonates to trans-β-Nitroolefins J. Org. Chem. 2016, 81, 3263]. Summary of the Invention

[0007] The object of the present invention is to provide a method for catalytic asymmetric synthesis of chiral herbicide flupropacil, and the specific method is to use a chiral squaramide catalyst to catalyze the asymmetric Michael addition reaction of dithiomalonate and nitroolefin under "on-water" reaction conditions to obtain a key intermediate, and then through steps such as nitro reduction, lactamization, hydrolysis, methylation, and amidation, chiral flupropacil is synthesized with good overall yield and excellent enantioselectivity.

[0008] The object of the present invention is achieved by the following technical solutions:

[0009] A method for synthesizing chiral herbicide flupropacil, the structure of the flupropacil is shown in formula (1); the structure of the key intermediate is shown in formula (2):

[0010]

[0011] To achieve the above invention object, the chiral squaramide catalyst is a chiral squaramide compound based on cinchona alkaloids; the cinchona alkaloids are quinine, hydroquinine, quinidine, and hydroquinidine.

[0012] To achieve the above-mentioned invention object, the cinchona alkaloid chiral squaramide catalyst is one of the compounds shown in formulas (3) to (6).

[0013]

[0014] To achieve the above-mentioned invention object, the dithioester of malonic acid is the compound shown in chemical structural formula (7):

[0015]

[0016] Wherein R 1 independently selects from halogen, cyano, amino, nitro, hydroxyl, carboxyl, ester group, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 haloalkylthio; n selects from 1, 2, 3, 4 or 5;

[0017] To achieve the above-mentioned invention object, the compound shown in chemical structural formula (8):

[0018] To achieve the above-mentioned invention object, for further optimization, the used dithioester of malonic acid compound, wherein R 1 is 4-methyl.

[0019] To achieve the above-mentioned invention object, for further optimization, the solvent used in the asymmetric Michael addition reaction system of the dithioester of malonic acid and nitroolefin catalyzed by the chiral squaramide catalyst QN-SQA is a co-solvent of toluene and brine. The volume ratio is saturated brine:toluene = 10:1.

[0020] To achieve the above-mentioned invention object, for further optimization, in the asymmetric Michael addition reaction system of the chiral squaramide catalyzing the dithioester of malonic acid and nitroolefin, in terms of molar amount, the dosage of the chiral squaramide is 0.05 mol% of the dithioester of malonic acid compound; the dosage of the nitroolefin compound is 1.5 times that of the dithioester of malonic acid compound; the reaction temperature is room temperature.

[0021] To achieve the above-mentioned invention object, for further optimization, the key intermediate (2) synthesizes flufenacet through the steps shown in the following reaction formula;

[0022]

[0023] The specific steps of step 1 are as follows: zinc powder freshly activated is added to the intermediate (2) dissolved in acetic acid solvent, and after stirring at room temperature for 3 h, a titanium trichloride solution (10 mol%) dissolved in dilute hydrochloric acid is added, and intermediate (9) is obtained after stirring at room temperature for 2 h, wherein the dosage of zinc powder is 10 times that of intermediate (2), and the dosage of titanium trichloride is 0.1 times that of intermediate (2);

[0024] The specific steps of step 2 are as follows: dissolve the intermediate (9) in absolute ethanol, and then slowly add an aqueous sodium hydroxide solution to obtain the crude product A. The volume ratio of absolute ethanol to water is 1:1 (v / v), and the amount of sodium hydroxide used, in terms of molar amount, is 3 times that of the intermediate (9). The reaction temperature is room temperature, and the reaction time is 18 h;

[0025] The specific steps of step 3 are as follows: dissolve the obtained crude product A in an isopropanol solution, add potassium hydroxide thereto, and after the potassium hydroxide is dissolved, add dimethyl sulfate, and stir at room temperature for 12 hours to obtain the crude product B. In terms of molar amount, the amount of potassium hydroxide used is 5 times that of the intermediate (9), and the amount of dimethyl sulfate used is 5 times that of the intermediate (9);

[0026] The specific steps of step 4 are as follows: dissolve the crude product B obtained in the previous step in dichloromethane, add o-fluoroaniline, triethylamine, and TBTU thereto, and stir at room temperature for 12 hours to obtain tefuryltrione. In terms of molar amount, the amount of o-fluoroaniline used is 2 times that of the intermediate (9), the amount of triethylamine used is 3 times that of the intermediate (9), and the amount of TBTU used is 2.2 times that of the intermediate (9).

[0027] The advantages of the present invention are mainly reflected in:

[0028] Two enantiomers of tefuryltrione with high optical purity can be obtained respectively by using different chiral squaramide catalysts;

[0029] The amount of the chiral squaramide catalyst used is low, only 0.5 mol%;

[0030] Using a water-containing reaction solvent in the catalytic reaction reduces environmental pollution, and has excellent stereoselectivity (ee value up to 97%);

[0031] The total reaction yield is high, the conditions are mild, and the post-treatment is simple.

[0032] In summary, the reaction conditions of the present invention can also be applicable to large-scale preparation, are suitable for industrial production, and thus have high application value and social and economic benefits. Specific Embodiments

[0033] The following examples will further illustrate the present invention, but do not limit the present invention thereby. All raw materials used are commercially available, and the nitroolefins and catalysts are synthesized by known methods.

[0034] Example 1

[0035] Synthesis of the compound of formula (7) S,S'-bis(4-methylphenyl) dithiopropionate:

[0036]

[0037] Malonyl chloride (0.19 mL, 2 mmol, 1 equiv) was stirred in dry ethyl acetate (5 mL), and p-toluenethiol (533 mg, 4.4 mmol, 2.2 equiv) was added. The mixture was stirred at room temperature for 16 h. The mixture was quenched with H2O (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (eluent: petroleum ether / ethyl acetate, volume ratio 30:1). 574 mg of white solid was obtained with a yield of 93%. 1 1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.2 Hz, 4H), 7.22 (d, J = 8.0 Hz, 4H), 3.91 (s, 2H), 2.37 (s, 6H) ppm; 13 13C NMR (101 MHz, CDCl3) δ 189.4, 140.3, 134.4, 130.2, 123.4, 56.4, 21.4 ppm; IR (KBr) 2954, 2917, 1712, 1682, 1595, 1492, 1394, 1288, 1178, 984, 799 cm -1 ; MS (ESI-QTOF) m / z: [M+Na] + Calcd for C 17 H 16 O2S2Na 339.0486, found 339.0489; mp: 83 - 84 °C.

[0038] Example 2

[0039] Synthesis of the key intermediate of formula (2):

[0040]

[0041] In a reaction flask, QN-SQA catalyst (0.51 mg, 0.5 mol%), (52 mg, 0.24 mmol) (E) 1-(3-trifluoromethyl)phenyl-2-nitroethylene, (50 mg, 0.16 mmol) S,S'-bis(4-methylphenyl) malonate dithiol, 1.5 mL of saturated brine, (0.17 ml, 1.6 mmol) toluene were added in sequence. The mixture was stirred at room temperature for 50 minutes and monitored by thin layer chromatography. After the reaction was completed, it was washed with saturated brine, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (eluent: petroleum ether / ethyl acetate, volume ratio 20:1) to obtain 80.8 mg of white solid with a yield of 96% and an ee value of 97%. 11H NMR (400 MHz, CDCl3) δ 7.63–7.59 (m, 1H), 7.54–7.46 (m, 3H), 7.31–7.28 (m, 2H), 7.28–7.25 (m, 2H), 7.19–7.16 (m, 2H), 7.05–7.01 (m, 2H), 4.87 (dd, J = 4.0, 2.4 Hz, 2H), 4.49–4.45 (m, 1H), 4.45–4.42 (m, 1H), 2.40 (s, 3H), 2.35 (s, 3H) ppm; 13 13C NMR (101 MHz, CDCl3) δ 190.7, 190.0, 140.9, 140.7, 136.7, 134.2, 134.1, 131.6, 131.3, 130.8 (q, J = 223.3 Hz), 130.4, 130.3 125.5 (q, J = 3.6 Hz), 125.2 (q, J = 3.9 Hz), 122.4 (q, J = 3.9 Hz), 76.6, 68.6, 44.0, 21.4, 21.4, 0.0 ppm; IR (neat) 2924, 1912, 1698, 1617, 1549, 1492, 1453, 1399, 1335, 1317, 1261, 1167, 1075, 980, 810, 706 cm -1 ; HRMS (ESI-QTOF) m / z: [M+Na] + Calcd for C 26 H 22 F3NO4S2Na 556.0845, found 556.0840; HPLC COSMOSIL 5A column, i-PrOH / n-hexane = 30 / 70, 25 °C, 1.0 mL / min, λ = 254 nm, t R = 15.49 min (minor), t R = 19.97 min (major); mp: 137 - 140 °C.

[0042] Example 3

[0043] Synthesis of the key intermediate of formula (2):

[0044]

[0045] In a reaction flask, HQN-SQA catalyst (0.52 mg, 0.5 mol%), (52 mg, 0.24 mmol) (E) 1-(3-trifluoromethyl)phenyl-2-nitroethylene, (50 mg, 0.16 mmol) S,S'-bis(4-methylphenyl) malonate dithiol, 1.5 mL of saturated brine, (0.17 ml, 1.6 mmol) toluene were added successively. The mixture was stirred at room temperature for 50 minutes and monitored by thin-layer chromatography. After the reaction was completed, it was washed with saturated brine, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (the eluent was petroleum ether and ethyl acetate, with a volume ratio of 20:1) to obtain 80.6 mg of a white solid with a yield of 95% and an ee value of 96%.

[0046] Example 4

[0047] Synthesis of the compound of formula ent-(2):

[0048]

[0049] Other steps were the same as in Example 2. The catalyst used was QD-SQA (0.50 mg, 0.5 mol%). The reaction was carried out at room temperature for 30 minutes to obtain 80 mg of ent-(2), a white solid product with a yield of 95% and an ee value of 96%. The analytical data refer to Example 2.

[0050] Example 5

[0051] Synthesis of the compound of formula ent-(2):

[0052]

[0053] Other steps were the same as in Example 2. The catalyst used was HQD-SQA (0.51 mg, 0.5 mol%). The reaction was carried out at room temperature for 30 minutes to obtain 80 mg of a white solid of ent-(2) with a yield of 93% and an ee value of 95%.

[0054] Example 6

[0055] Synthesis of the compound of formula (9):

[0056]

[0057] The intermediate (2) obtained in Example 2 (500 mg, 0.28 mmol, 1.0 equiv) was dissolved in 5.0 mL of glacial acetic acid, and freshly activated zinc powder (618 mg, 2.80 mmol, 10 equiv) was added. The mixture was stirred for 2 hours under nitrogen protection at 25 °C. Then, TiCl3 (30 μL, 0.028 mmol, 0.1 equiv; dissolved in 12% hydrochloric acid solution (5% HCl)) was added to the reaction solution, and the mixture was stirred for another 1 hour. Saturated sodium bicarbonate solution was added, and the reaction solution was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate. The solution was concentrated in vacuo and purified by column chromatography (eluent: petroleum ether / ethyl acetate, volume ratio 1:1) to obtain 332.5 mg of a white solid product with a yield of 93% and an ee value of 97%. 1 1H NMR (400 MHz, CDCl3) δ 7.60 - 7.56 (m, 1H), 7.53 - 7.45 (m, 3H), 7.32 - 7.29 (m, 2H), 7.23 - 7.20 (m, 2H), 6.70 (s, 1H), 4.20 (dd, J = 15.4, 8.0 Hz, 1H), 3.90 - 3.79 (m, 2H), 3.46 (dd, J = 9.8, 7.1 Hz, 1H), 2.37 (s, 3H) ppm; 13 13C NMR (101 MHz, CDCl3) δ 194.0, 171.5, 141.3, 140.3, 134.4, 131.3, 130.2, 128.4 (q, J = 262.8 Hz), 124.7 (q, J = 3.2 Hz), 123.9 (q, J = 3.9 Hz), 123.3, 122.5, 62.1, 47.5, 43.8, 21.4, 0.0 ppm; IR (KBr) 3219, 3112, 2924, 1716, 1686, 1597, 1492, 1449, 1328, 1262, 1197, 1128, 1075, 1008, 800, 701 cm -1 ; HRMS (ESI - QTOF) m / z: [M + Na] + Calcd for C 19 H 16 F3NO2SNa 402.0751, found 402.0752; HPLC Chiracel 5A - H column, i - PrOH / n - hexane = 10 / 90, 25 °C, 1.0 mL / min, λ = 254 nm, t R = 6.11 min (minor), t R = 7.22 min (major); [α] 20 D= +72.8 (c = 1.0, CHCl3); mp: 89 - 94 °C.

[0058] Example 7

[0059] Synthesis of the ent-(9) compound of the formula:

[0060]

[0061] The ent-(2) intermediate obtained in Example 5 (500 mg, 0.28 mmol, 1.0 equiv) was dissolved in 5.0 mL of AcOH. Freshly activated zinc powder (618 mg, 2.80 mmol, 10 equiv) was added, and the mixture was stirred under argon at 25 °C for 2 hours. After some time, a solution of TiCl3 (30 μL, 0.028 mmol, 0.1 equiv dissolved in 12% hydrochloric acid solution (5% HCl)) was added to the reaction solution, and the mixture was stirred for another 1 hour. The mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The resulting solution was concentrated in vacuo. Purification by column chromatography (eluent: petroleum ether and ethyl acetate, volume ratio 1:1) gave 336 mg of a white solid product with a yield of 95% and an ee value of 96%.

[0062] Example 8

[0063] Synthesis of the flufenacet tetrafluoride compound of the formula (1):

[0064]

[0065] The compound (9) obtained in Example 6 (200 mg, 0.53 mmol), aqueous sodium hydroxide solution (50%, 63.3 mg, 1.59 mmol) and ethanol (5 mL) were mixed and stirred at 26 °C for 18 h. Then the reaction mixture was diluted with water (5 mL) and extracted with diethyl ether (2 × 5 mL). The aqueous phase was acidified to pH 2 with concentrated hydrochloric acid and then extracted with dichloromethane (3 × 5 mL). The combined dichloromethane extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a white solid compound A. Dimethyl sulfate (150 μL, 2.65 mmol) was added dropwise to a mixture of the obtained crude product A (theoretical amount 144 mg, 0.53 mmol) and potassium hydroxide (148 mg, 2.65 mmol) in isopropanol (5 mL). The reaction mixture was stirred at 20 °C for 16 h and then quenched with water (2 mL). The resulting solution was concentrated under reduced pressure to remove the excess isopropanol, acidified with concentrated hydrochloric acid, extracted with dichloromethane (2 × 20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a white solid compound B. At room temperature, 2-fluoroaniline (100 μL, 1.06 mmol) and triethylamine (219 μL, 1.59 mmol) were added dropwise to the dichloromethane solution of the crude product B. Then TBTU (371 mg, 1.17 mmol) dissolved in dichloromethane was added dropwise to the above mixture and stirred at room temperature overnight. The reaction solution was extracted with dichloromethane, the extract was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and purified by column chromatography (eluent: petroleum ether and ethyl acetate, volume ratio 3:1) to give a light brown solid compound (1) (130 mg, 65% yield, 97% ee). 1 H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 8.25 - 8.19 (m, 1H), 7.55 (ddd, J = 26.2, 14.1, 6.4 Hz, 4H), 7.12 - 6.99 (m, 3H), 4.19 (dd, J = 17.3, 9.0 Hz, 1H), 3.86 - 3.62 (m, 2H), 3.47 (dd, J = 10.1, 8.0 Hz, 1H), 3.01 (s, 3H); 1313C NMR (101 MHz, CDCl3) δ 170.4, 165.0, 152.9 (d, J = 245.0 Hz), 142.6, 131.4 (q, J = 32.4 Hz), 129.6, 128.0, 126.2, 126.1, 124.5 (d, J = 7.6 Hz), 124.3 (q, 3.7 Hz), 124.1 (q, J = 3.8 Hz), 124.0 (q, J = 272.4 Hz), 121.8, 115.0 (d, J = 19.1 Hz), 54.7, 54.7, 39.0, 30.2, 29.7 ppm; IR (neat) 3065, 2924, 1703, 1617, 1597, 1548, 1492, 1456, 1395, 1325, 1259, 1175, 1116, 1072, 902, 802, 757, 701 cm -1 ; HRMS (ESI-QTOF) m / z: [M+Na] + Calcd for C 19 H 16 F4N2O2Na 403.1050, found 403.1046; HPLC Chiracel 5A-H column, i-PrOH / n-hexane = 30 / 70, 25 °C, 1.0 mL / min, λ = 254 nm, t R = 6.82 min (minor), t R = 9.95 min (major); [α] 20 D = +22.5 (c = 0.9, CHCl3); mp: 116 - 120 °C.

[0066] Example 9

[0067] Synthesis of the enantiomeric compound of formula (ent-1) flufenacet:

[0068]

[0069] Using the compound ent-(9) obtained in Example 7, and the remaining steps referring to Example 8, a light brown solid compound ent-(1) (126 mg, 63% yield, 96% ee) was obtained.

[0070] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements on some of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A method for catalytic asymmetric synthesis of chiral herbicide flupropacil, characterized in that, The method includes: asymmetric Michael addition reaction of dithio malonate and nitroolefin catalyzed by chiral squaramide to obtain a key intermediate, and then chiral flufenacet is synthesized through steps such as nitro reduction, lactamization, hydrolysis, methylation, amidation, etc.; The structure of the chiral flufenacet is shown in formula (1); the structure of the key intermediate is shown in formula (2):

2. The method for catalytic asymmetric synthesis of chiral herbicide flupropacil according to claim 1, wherein, The chiral squaramide catalyst is a chiral squaramide compound based on cinchona alkaloid; the cinchona alkaloid is quinine, hydroquinine, quinidine, hydroquinidine.

3. A method for catalytic asymmetric synthesis of chiral herbicide flupropacil according to claim 1 or 2, characterized in that, The chiral squaramide catalyst is one of the compounds shown in formulas (3) to (6); 4. A method for catalytic asymmetric synthesis of chiral herbicide flupropacil according to claim 1, characterized in that, The dithio malonate is the compound shown in chemical structural formula (7): wherein R 1 is independently selected from halogen, cyano, amino, nitro, hydroxy, carboxy, ester, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 haloalkoxy, C1-C6 haloalkylthio; n is selected from 1, 2, 3, 4 or 5; The nitroalkene is a compound represented by the chemical structural formula (8):

5. A method for catalytic asymmetric synthesis of chiral herbicide flupropacil according to claim 4, characterized in that, Wherein R1 is 4-methyl.

6. The method for catalytic asymmetric synthesis of chiral herbicide flupropacil according to claim 1, characterized in that, The solvent used in the asymmetric Michael addition reaction system of dithio malonate and nitroolefin catalyzed by chiral squaramide is one or more of toluene, xylene, mesitylene, chlorobenzene, dichloromethane, ether, tetrahydrofuran, water, saturated brine.

7. The method for catalytic asymmetric synthesis of chiral herbicide flupropacil according to claim 6, wherein Wherein the solvent used is a mixture of saturated brine and toluene, and the volume ratio is saturated brine: toluene = 10:

1.

8. A method for catalytic asymmetric synthesis of chiral herbicide flupropacil according to claim 1, characterized in that, In the asymmetric Michael addition reaction system of dithio malonate and nitroolefin catalyzed by chiral squaramide, in terms of molar amount, the dosage of the chiral squaramide is 0.05 mol% of the dithio malonate compound; the dosage of the nitroolefin compound is 1.5 times that of the dithio malonate compound; the reaction temperature is room temperature.

9. A method for catalytic asymmetric synthesis of chiral herbicide flupropacil according to claim 1, characterized in that, The key intermediate (2) synthesizes chiral flufenacet through the steps shown in the following reaction formula; The specific steps of step 1 are as follows: add newly activated zinc powder to the intermediate (2) dissolved in acetic acid solvent, stir at room temperature for 3 h, then add titanium trichloride solution (10 mol%) dissolved in dilute hydrochloric acid, and stir at room temperature for 2 h to obtain intermediate (9), wherein the dosage of zinc powder is 10 times that of intermediate (2), and the dosage of titanium trichloride is 0.1 times that of intermediate (2); The specific steps of step 2 are as follows: dissolve intermediate (9) in absolute ethanol, and then slowly add sodium hydroxide aqueous solution to obtain crude product A. The volume ratio of absolute ethanol to water is 1:1 (v / v), and the dosage of sodium hydroxide, in terms of molar amount, is 3 times that of intermediate (9). The reaction temperature is room temperature, and the reaction time is 18 h; The specific steps of step 3 are as follows: dissolve the crude product A in isopropanol solution, add potassium hydroxide to it, after potassium hydroxide dissolves, add dimethyl sulfate, and stir at room temperature for 12 hours to obtain crude product B. In terms of molar amount, the dosage of potassium hydroxide is 5 times that of intermediate (9), and the dosage of dimethyl sulfate is 5 times that of intermediate (9); The specific steps of step 4 are as follows: dissolve the crude product B obtained in the previous step in dichloromethane, add o-fluoroaniline, triethylamine, TBTU to it, and stir at room temperature for 12 hours to obtain chiral flufenacet. In terms of molar amount, the dosage of o-fluoroaniline is 2 times that of intermediate (9), the dosage of triethylamine is 3 times that of intermediate (9), and the dosage of TBTU is 2.2 times that of intermediate (9).

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