Preparation method of benzovindiflupyr intermediate 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methanonaphthalene

Abstract

The present invention discloses a preparation method of a benzovindiflupyr intermediate 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methanoaphthalene, which comprises the following steps: The tetrachloride shown in formula (II) reacts with the diaryliodonium salt shown in formula (III) in the presence of a solvent and a base to obtain 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methanoaphthalene shown in formula (I), and the reaction process is as follows: wherein the substituent R in formula (III) is substituted or unsubstituted, and when substituted, the substituent R is an alkyl group or an alkoxy group. The present invention solves the problems of instability of dichlorofulvene and difficulty in post-treatment of preparation, and at the same time avoids the use of expensive triphenylphosphine when introducing dichloromethylene.

Description

Technical Field

[0001] The present invention belongs to the technical field of the preparation method of pesticide intermediates, and particularly relates to a preparation method of the benzovindiflupyr intermediate 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methanonaphthalene. Background Art

[0002] Benzovindiflupyr is a pyrazole amide fungicide developed by Syngenta. Its mechanism of action is to inhibit the activity of succinate dehydrogenase of pathogenic bacteria, thereby interfering with their respiration. It has broad-spectrum bactericidal activity and has good control effects on wheat leaf blight, peanut black spot, wheat take-all, and wheat basal rot, etc. In particular, it has a special effect on Asian soybean rust and leaf spot, is significantly different from other existing succinate dehydrogenase inhibitors, and can be compounded with a variety of fungicides without cross-resistance.

[0003] 9-Dichloromethylene-1,4-dihydro-5-nitro-1,4-methanonaphthalene is a key intermediate for synthesizing benzovindiflupyr. The currently reported synthetic routes are mainly the following several:

[0004] 1) 6-Nitro-anthranilic acid reacts with dichlorofulvene through a nitrobenzyne intermediate in the presence of an alkyl nitrite to obtain the benzovindiflupyr intermediate 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methanonaphthalene of formula I. The reaction formula is as follows:

[0005]

[0006] For the detailed preparation method, see the patent with the publication number CN102197016A. The disadvantage of this method is that dichlorofulvene is unstable and difficult to post-treat. The scale-up reaction of unstable dichlorofulvene with nitrobenzyne is challenging, and the yield of a relatively large-scale reaction is relatively low.

[0007] 2) The product obtained by reacting 6-nitro-anthranilic acid with 2,4-cyclopentadien-1-one reacts with carbon tetrachloride in the presence of triphenylphosphine to obtain the target product. The reaction formula is as follows:

[0008]

[0009] For the detailed preparation method, see the literature: Yin Kai, Synthesis Research of the New Fungicide Benzovindiflupyr [J]. World Pesticides, 2021, 43(9), 27 - 31. The disadvantage of this method is the use of expensive triphenylphosphine in the Appel-Wittig reaction.

[0010] 3) 9-Isopropylidene-1,4-dihydro-5-nitro-1,4-methano-naphthalene, an intermediate of isopyrazam, is subjected to ozonation, Appel-Wittig, and reduction reactions to obtain 9-dichloromethylene-1,2,3,4-tetrahydro-5-amino-1,4-methano-naphthalene. The reaction formula is as follows:

[0011]

[0012] For the detailed preparation method, see Patent CN 101296913B. The disadvantages of this method are that ozonation is difficult to control and the introduction of dichloromethylene requires the use of triphenylphosphine. Summary of the Invention

[0013] In view of the above technical problems existing in the prior art, the object of the present invention is to provide a preparation method of 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methano-naphthalene, an intermediate of benzovindiflupyr.

[0014] Considering the problems of instability of dichlorofulvene and difficulty in post-treatment after preparation, as well as the disadvantages such as the use of expensive triphenylphosphine for the introduction of dichloromethylene, the present invention selects the use of tetrachloride (the addition product of carbon tetrachloride and cyclopentadiene, Formula II) and diaryliodonium salt (R represents H, alkyl, alkoxy, Formula III), the raw materials for the preparation of dichlorofulvene, to react under the action of a base and obtain the benzovindiflupyr intermediate 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methano-naphthalene of Formula I after post-treatment.

[0015] The specific technical solution is as follows:

[0016] A preparation method of 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methano-naphthalene, an intermediate of benzovindiflupyr, includes the following steps: The tetrachloride shown in Formula (II) and the diaryliodonium salt shown in Formula (III) react in the presence of a solvent and a base to obtain 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methano-naphthalene shown in Formula (I). The reaction process is as follows:

[0017]

[0018] Among them, the substituent R in Formula (III) is substituted or unsubstituted. When substituted, the substituent R is alkyl or alkoxy. Preferably, the substituent R is methoxy or methyl.

[0019] Furthermore, the solvent is tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, diethylene glycol dimethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone, dimethyl carbonate, propyl ester, dichloroethane, chloroform, chlorobenzene, dichloromethane, acetonitrile or toluene. Preferably, it is tetrahydrofuran or methyl tert-butyl ether.

[0020] Further, the base is sodium tert-butoxide, potassium tert-butoxide, lithium bis(trimethylsilyl)amide, sodium amide, sodium methoxide, sodium ethoxide, triethylamine, pyridine or DBU. Preferably, the base is sodium tert-butoxide.

[0021] Further, the molar ratio of the tetrachloride shown in formula (II) to the diaryliodonium salt shown in formula (III) in the feeding is 1-10:1, and the molar ratio of the base to the diaryliodonium salt shown in formula (III) in the feeding is 3-30:1.

[0022] Preferably, the molar ratio of the tetrachloride shown in formula (II) to the diaryliodonium salt shown in formula (III) in the feeding is 3-5:1, and the molar ratio of the base to the diaryliodonium salt shown in formula (III) in the feeding is 6-10:1.

[0023] Further, the reaction temperature is 10-45 °C.

[0024] The post-treatment method of the present invention is: washing with an aqueous hydrochloric acid solution, extracting with an organic solvent to obtain an organic layer for concentration, and subjecting to column chromatography to obtain the benzovindiflupyr intermediate 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methanonaphthalene of formula I.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0026] The problems of instability of dichlorofulvene and difficulty in post-treatment of preparation are solved, and at the same time, the use of expensive triphenylphosphine when introducing dichloromethylene is avoided. Specific Embodiments

[0027] The present invention will be further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0028] Example 1: Synthesis of diaryl(TMP)iodonium salt

[0029]

[0030] Into a 250 mL three-necked flask equipped with a thermometer, 3-nitroiodobenzene (0.1 mol, 24.89 g), 100 mL of acetonitrile, and p-toluenesulfonic acid monohydrate (0.1 mol, 19.02 g) were added, and the mixture was stirred and dissolved at room temperature. After adding meta-chloroperbenzoic acid (0.105 mol, 21.32 g), the mixture was refluxed and stirred at 70 °C. When the conversion rate of 3-nitroiodobenzene monitored by GC was greater than 95%, 1,3,5-trimethoxybenzene (0.105 mol, 17.65 g) was immediately added. After 10 minutes, TLC analysis showed that 1,3,5-trimethoxybenzene had completely disappeared, and the heating was stopped. The reaction solution was cooled to room temperature and methyl tert-butyl ether was added to precipitate 54.56 g of a white powder with a yield of 93%. 1H NMR (δ ppm): 8.70 (t, J J = 2.0 Hz, 1H), 8.43 – 8.37 (m, 1H), 8.25 (ddd, J J = 8.0, 1.7, 1.0 Hz, 1H), 7.75 (t, J J = 8.2 Hz, 1H), 7.49 – 7.41 (m, 2H), 7.11 (d, J J = 7.8 Hz, 2H), 6.51 (s, 2H), 3.96 (s, 6H), 3.89 (s, 3H), 2.29 (s, 3H).

[0031] Example 2: Synthesis of diaryl(Mes)iodonium salt

[0032]

[0033] Into a 250 mL three-necked flask equipped with a thermometer, add 3-nitroiodobenzene (0.1 mol, 24.89 g), 100 mL of acetonitrile, and p-toluenesulfonic acid monohydrate (0.1 mol, 19.02 g). Stir and dissolve at room temperature. After adding m-chloroperbenzoic acid (0.105 mol, 21.32 g), reflux and stir at 70 °C. Monitor the conversion of 3-nitroiodobenzene by GC. When the conversion is greater than 95%, immediately add 1,3,5-trimethylbenzene (0.105 mol, 12.62 g). After 10 minutes, analyze by TLC. When 1,3,5-trimethylbenzene has completely disappeared, stop heating. Cool the reaction solution to room temperature and add methyl tert-butyl ether to precipitate 43.66 g of white powder, with a yield of 81%.

[0034] Example 3: Synthesis of diaryl iodonium salt

[0035]

[0036] Into a 250 mL three-necked flask equipped with a thermometer, add 3-nitroiodobenzene (0.1 mol, 24.89 g), 100 mL of acetonitrile, and p-toluenesulfonic acid monohydrate (0.1 mol, 19.02 g). Stir and dissolve at room temperature. After adding m-chloroperbenzoic acid (0.105 mol, 21.32 g), reflux and stir at 70 °C. Monitor the conversion of 3-nitroiodobenzene by GC. When the conversion is greater than 95%, immediately add benzene (0.105 mol, 8.20 g). After 10 minutes, analyze by TLC. When benzene has completely disappeared, stop heating. Cool the reaction solution to room temperature and add methyl tert-butyl ether to precipitate 33.32 g of solid, with a yield of 67%.

[0037] Example 4: Synthesis of tetrachloride

[0038] Preparation of raw material solution: The depolymerized cyclopentadiene (0.50 mol, 33.05 g) and carbon tetrachloride (1.00 mol, 153.82 g) were mixed to obtain the raw material solution; Preparation of catalyst solution: Copper chloride (0.006 mol, 0.594 g), tetramethyldiethylamine (0.012 mol, 1.394 g) and acetonitrile (75 mL) were added to a flask at room temperature, heated to 75 °C and stirred for 0.5 h, and then cooled to room temperature for standby; 25 mL of the catalyst solution and 20 mL of acetonitrile were added to a 150 mL four-necked flask under nitrogen, and the temperature was raised to 70 °C. A part of the raw material mixed solution was added, and then the raw material solution and the catalyst solution were added simultaneously. The reaction temperature was controlled at 70 °C. After the addition, the reaction was stopped after reacting at 70 °C for 4 h. It was cooled to room temperature, and the crude product was transferred out and distilled under reduced pressure to obtain 93.47 g of the tetrachloride, with a purity of 96% and a yield of 85%.

[0039] Example 5: Synthesis of 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methanonaphthalene

[0040] To a 100 mL three-necked flask equipped with a thermometer, the diaryl (TMP) iodonium salt (10 mmol, 5.87 g) prepared in Example 1, 50 ml of tetrahydrofuran, and the tetrachloride (20 mmol, 4.40 g) prepared in Example 4 were added, and stirred and dissolved at room temperature. Sodium tert-butoxide (60 mmol, 5.77 g) was added, and mechanically stirred at room temperature. The reaction process was monitored by GC until the reaction ended. The reaction solution was washed with hydrochloric acid aqueous solution, extracted with ethyl acetate, concentrated, and column chromatographed (petroleum ether: ethyl acetate = 15:1) to obtain 1.90 g of a yellow solid. The purity analyzed by gas chromatography was 100%, and the yield was 71%. MS (m / e): 267 (60%), 269 (30%), 271 (10%); 1 H NRM (δ ppm): 7.83 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 7.1 Hz, 1H), 7.22 (d, J = 1.3 Hz, 1H), 7.02 (t, J = 2.0 Hz, 2H), 5.44 (d, J = 2.2 Hz, 1H), 4.61 (d, J = 2.1 Hz, 1H).

[0041] Example 6: Synthesis of 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methanonaphthalene

[0042] Into a 100 mL three-necked flask equipped with a thermometer, add the diaryl (Mes) iodonium salt (10 mmol, 5.39 g) prepared in Example 2, 50 ml of tetrahydrofuran, and the tetrachloride (20 mmol, 4.40 g) prepared in Example 4. Stir and dissolve at room temperature, add sodium tert-butoxide (60 mmol, 5.77 g), stir mechanically at room temperature, and monitor the reaction progress by GC until the reaction is completed. The reaction solution is washed with aqueous hydrochloric acid, extracted with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain 1.71 g of a yellow solid. The purity is 96% by gas chromatography analysis, and the yield is 64%.

[0043] Example 7: Synthesis of 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methano-naphthalene

[0044] Into a 100 mL three-necked flask equipped with a thermometer, add the diaryl iodonium salt (10 mmol, 4.97 g) prepared in Example 3, 50 ml of tetrahydrofuran, and the tetrachloride (20 mmol, 4.40 g) prepared in Example 4. Stir and dissolve at room temperature, add sodium tert-butoxide (60 mmol, 5.77 g), stir mechanically at room temperature, and monitor the reaction progress by GC until the reaction is completed. The reaction solution is washed with aqueous hydrochloric acid, extracted with ethyl acetate, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 15:1) to obtain 1.20 g of a yellow solid. The purity is 96% by gas chromatography analysis, and the yield is 45%.

[0045] Example 8: Synthesis of 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methano-naphthalene

[0046] Into a 150 mL three-necked flask equipped with a thermometer, add the diaryl (TMP) iodonium salt (10 mmol, 5.87 g), 50 ml of tetrahydrofuran, and the tetrachloride (30 mmol, 6.60 g). Stir and dissolve at room temperature, add sodium tert-butoxide (80 mmol, 7.69 g), stir mechanically at room temperature, and monitor the reaction progress by GC until the reaction is completed. The reaction solution is washed with aqueous hydrochloric acid, extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain 1.92 g of a yellow solid. The purity is 97% by gas chromatography analysis, and the yield is 72%.

[0047] Example 9: Synthesis of 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methano-naphthalene

[0048] Into a 150 mL three-necked flask equipped with a thermometer, add diaryl (TMP) iodonium salt (10 mmol, 5.87 g), 50 mL of tetrahydrofuran, and tetrachloride (40 mmol, 8.80 g). Stir and dissolve at room temperature. Add sodium tert-butoxide (100 mmol, 9.61 g), and stir mechanically at room temperature. Monitor the reaction progress by GC until the reaction is complete. Wash the reaction solution with aqueous hydrochloric acid, extract with ethyl acetate, concentrate, and perform column chromatography to obtain 2.08 g of a yellow solid. The purity analyzed by gas chromatography is 98%, and the yield is 78%.

[0049] Example 10: Synthesis of 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methano-naphthalene

[0050] Into a 150 mL three-necked flask equipped with a thermometer, add diaryl (TMP) iodonium salt (10 mmol, 5.87 g), 50 mL of tetrahydrofuran, and tetrachloride (50 mmol, 11.00 g). Stir and dissolve at room temperature. Add sodium tert-butoxide (120 mmol, 11.53 g), and stir mechanically at room temperature. Monitor the reaction progress by GC until the reaction is complete. Wash the reaction solution with aqueous hydrochloric acid, extract with ethyl acetate, concentrate, and perform column chromatography to obtain 1.97 g of a yellow solid. The purity analyzed by gas chromatography is 97%, and the yield is 74%.

[0051] Example 11: Synthesis of 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methano-naphthalene

[0052] Into a 150 mL three-necked flask equipped with a thermometer, add diaryl (TMP) iodonium salt (10 mmol, 5.87 g), 60 mL of tetrahydrofuran, and tetrachloride (60 mmol, 13.20 g). Stir and dissolve at room temperature. Add sodium tert-butoxide (150 mmol, 14.42 g), and stir mechanically at room temperature. Monitor the reaction progress by GC until the reaction is complete. Wash the reaction solution with aqueous hydrochloric acid, extract with ethyl acetate, concentrate, and perform column chromatography to obtain 1.84 g of a yellow solid. The purity analyzed by gas chromatography is 98%, and the yield is 69%.

[0053] Example 12: Synthesis of 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methano-naphthalene

[0054] Into a 250 mL three-necked flask equipped with a thermometer, diaryl (TMP) iodonium salt (10 mmol, 5.87 g), 80 mL of tetrahydrofuran, and tetrachloride (100 mmol, 22.00 g) were added and dissolved by stirring at room temperature. Sodium tert-butoxide (250 mmol, 24.03 g) was added, and the mixture was mechanically stirred at room temperature. The reaction progress was monitored by GC until the reaction was completed. The reaction solution was washed with aqueous hydrochloric acid, extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain 1.60 g of a yellow solid. The purity was 97% by gas chromatography analysis, and the yield was 60%.

[0055] Example 13: Synthesis of 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methano-naphthalene

[0056] Into a 150 mL three-necked flask equipped with a thermometer, diaryl (TMP) iodonium salt (10 mmol, 5.87 g), 50 mL of tetrahydrofuran, and tetrachloride (40 mmol, 8.80 g) were added and dissolved by stirring at room temperature. Potassium tert-butoxide (100 mmol, 11.22 g) was added, and the mixture was mechanically stirred at room temperature. The reaction progress was monitored by GC until the reaction was completed. The reaction solution was washed with aqueous hydrochloric acid, extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain 1.66 g of a yellow solid. The purity was 97% by gas chromatography analysis, and the yield was 62%.

[0057] Example 14: Synthesis of 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methano-naphthalene

[0058] Into a 150 mL three-necked flask equipped with a thermometer, diaryl (TMP) iodonium salt (10 mmol, 5.87 g), 50 mL of tetrahydrofuran, and tetrachloride (40 mmol, 8.80 g) were added and dissolved by stirring at 10 °C. Sodium tert-butoxide (100 mmol, 9.61 g) was added, and the mixture was mechanically stirred at 10 °C. The reaction progress was monitored by GC until the reaction was completed. The reaction solution was washed with aqueous hydrochloric acid, extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain 1.23 g of a yellow solid. The purity was 95% by gas chromatography analysis, and the yield was 46%.

[0059] Example 15: Synthesis of 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methano-naphthalene

[0060] Into a 150 mL three-necked flask equipped with a thermometer, diaryl (TMP) iodonium salt (10 mmol, 5.87 g), 50 mL of tetrahydrofuran, and tetrachloride (40 mmol, 8.80 g) were added and dissolved by stirring at 45 °C. Sodium tert-butoxide (100 mmol, 9.61 g) was added, and mechanical stirring was carried out at 45 °C. The reaction process was monitored by GC until the reaction was completed. The reaction solution was washed with aqueous hydrochloric acid solution, extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain 1.34 g of a yellow solid. The purity was analyzed by gas chromatography to be 94%, and the yield was 50%.

[0061] Example 16: Synthesis of 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methano-naphthalene

[0062] Into a 150 mL three-necked flask equipped with a thermometer, diaryl (TMP) iodonium salt (10 mmol, 5.87 g), 50 mL of toluene, and tetrachloride (40 mmol, 8.80 g) were added and dissolved by stirring at room temperature. Sodium tert-butoxide (100 mmol, 9.61 g) was added, and mechanical stirring was carried out at room temperature. The reaction process was monitored by GC until the reaction was completed. The reaction solution was washed with aqueous hydrochloric acid solution, extracted with ethyl acetate, concentrated, and purified by column chromatography to obtain 1.09 g of a yellow solid. The purity was analyzed by gas chromatography to be 93%, and the yield was 41%.

[0063] Example 17: Synthesis of 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methano-naphthalene

[0064] Into a 150 mL three-necked flask equipped with a thermometer, diaryl (TMP) iodonium salt (10 mmol, 5.87 g), 50 mL of dichloromethane, and tetrachloride (40 mmol, 8.80 g) were added and dissolved by stirring at room temperature. Sodium tert-butoxide (100 mmol, 9.61 g) was added, and mechanical stirring was carried out at room temperature. The reaction process was monitored by GC until the reaction was completed. The reaction solution was washed with aqueous hydrochloric acid solution, extracted with dichloromethane, concentrated, and purified by column chromatography to obtain 0.93 g of a yellow solid. The purity was analyzed by gas chromatography to be 94%, and the yield was 35%.

Claims

1. A preparation method of the benzovindiflupyr intermediate 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methanonaphthalene, characterized in that It includes the following steps: The tetrachloride shown in formula (II) reacts with the diaryliodonium salt shown in formula (III) in the presence of a solvent and a base to obtain 9-dichloromethylene-1,4-dihydro-5-nitro-1,4-methano naphthalene shown in formula (I). The reaction process is as follows: ， Among them, the substituent R in formula (III) is hydrogen, methoxy, or methyl, the base is sodium tert-butoxide or potassium tert-butoxide, and the reaction temperature is 10 - 45 °C.

2. The preparation method according to claim 1, characterized in that, The solvent is tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, diethylene glycol dimethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, acetone, dimethyl carbonate, propyl ester, dichloroethane, chloroform, chlorobenzene, dichloromethane, acetonitrile, or toluene.

3. The preparation method according to claim 2, characterized in that, The solvent is tetrahydrofuran or methyl tert-butyl ether.

4. The preparation method according to claim 1, characterized in that The feeding molar ratio of the tetrachloride shown in formula (II) to the diaryliodonium salt shown in formula (III) is 1 - 10:1, and the feeding molar ratio of the base to the diaryliodonium salt shown in formula (III) is 3 - 30:

1.

5. The preparation method according to claim 4, characterized in that, The feeding molar ratio of the tetrachloride shown in formula (II) to the diaryliodonium salt shown in formula (III) is 3 - 5:1, and the feeding molar ratio of the base to the diaryliodonium salt shown in formula (III) is 6 - 10:1.

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