Process for the preparation of propachlor

Abstract

The present invention relates to an improved process for the preparation of propaquizafop, characterized in that, after obtaining the crude propaquizafop, the following impurity 1 is removed from the system in order to eliminate emulsification:

Description

TECHNICAL FIELD

[0001] The present application relates to an improved preparation method of propaquizafop. BACKGROUND

[0002] Propaquizafop belongs to 2-chloroacetanilide, is a high selective rice field specific pre-emergence herbicide, can prevent and treat rice field barnyard grass, haircap and other weeds, is widely used.

[0003] The current production process of propaquizafop widely adopts: 2,6-diethyl aniline and ethylene glycol monopropyl ether are reacted under the action of a catalyst to obtain the intermediate N-propoxyethyl-2,6-diethyl aniline shown in formula (1), and then acylated with chloroacetyl chloride to prepare propaquizafop shown in formula (2).

[0004]

[0005] It is reported that the intermediate N-propoxyethyl-2,6-diethyl aniline shown in formula (1) can be synthesized by one-step method through the following route (see, for example, US4183868 and US4921980):

[0006] SUMMARY

[0007] When the present inventors produce propaquizafop by the above method, it is found that emulsification occurs in the reaction system in the propaquizafop synthesis step, especially when the step is a solvent-free reaction, the emulsification is more serious, which affects the product post-treatment.

[0008] The present inventors have tried various demulsification measures, for example, the emulsification is eliminated by standing for 1-2 days, but such long standing leads to low production efficiency; the emulsification can also be eliminated by adding a large amount of solvent, but such treatment method will cause solvent residue, and the use of a large amount of solvent will also increase the production cost and environmental burden.

[0009] In order to better solve the above emulsification problem, the present inventors have conducted in-depth research on the emulsification causes, and found that the emulsification may be related to the impurities generated in the synthesis step of N-propoxyethyl-2,6-diethyl aniline. Based on this idea, the present inventors have researched the impurities in the reaction system and their elimination method, and found that the emulsification can be eliminated by adding an acid to the reaction system after the propaquizafop synthesis step to adjust the pH of the system to be acidic.

[0010] Specifically, the present application provides:

[0011] (1) An improved preparation method of propaquizafop, characterized in that after obtaining the crude propaquizafop, the following impurity 1 in the system is removed to eliminate emulsification:

[0012]

[0013] (2) The process according to (1), wherein the pH of the system is adjusted to below 6, preferably to pH 1-3, by adding an acid to the system, thereby removing impurity 1 and eliminating emulsification.

[0014] (3) The process according to (1) or (2), wherein the crude propaquizafop is prepared by the following reaction steps:

[0015] Step 1:

[0016]

[0017] Step 2:

[0018]

[0019] (4) The process according to (2), wherein the reaction of Step 2 is carried out in the absence of solvent.

[0020] (5) The process according to any one of (1) to (4), wherein any one or both of the following impurities 2 and 3 are also removed by adding an acid:

[0021]

[0022] (6) The process according to any one of (1) to (5), wherein any one or both of the following impurities 4 and 5 are also removed by adding an acid:

[0023]

[0024] (7) The process according to any one of (1) to (6), wherein the acid is an inorganic acid, preferably hydrochloric acid, sulfuric acid or phosphoric acid, preferably hydrochloric acid.

[0025] (8) The process according to any one of (1) to (7), wherein the amount of chloroacetyl chloride in Step 2 is 0.98 to 1.05 mole equivalents of the intermediate N-propoxyethyl-2,6-diethyl aniline of formula (1).

[0026] (9) The process according to any one of (1) to (8), wherein the catalyst in Step 1 is a catalyst containing 0.05 to 10% palladium (Pd) or 0.2 to 10% platinum (Pt). DETAILED DESCRIPTION

[0027] One aspect of the present application relates to an improved process for preparing propaquizafop, characterized in that after obtaining the crude propaquizafop, an acid is added to the system to adjust the pH of the system to below 6, preferably to pH 1-3.

[0028] The present inventors have found that the crude propaquizafop prepared by known methods (for example, US patents US4183868 and US4921980) contains the following impurities:

[0029]

[0030] Among these impurities, impurity 1 and impurity 2 are new impurities that have not been reported and were first discovered by the present inventors. In particular, impurity 1 is a hydrophilic-lipophilic amphiphilic substance that is highly related to emulsification.

[0031] Therefore, the present application eliminates emulsification by adding an acid to the reaction system after obtaining the crude propaquizafop, so that the amines are converted into salts and enter the aqueous phase, and the target product propaquizafop remains in the organic phase, thereby allowing the aqueous phase and the organic phase in the reaction system to be successfully separated, and facilitating the separation and post-treatment of the propaquizafop product.

[0032] Although the above impurities are mainly generated in the preparation step of the intermediate N-propoxyethyl-2,6-diethyl aniline shown in formula (1), the present inventors did not choose to remove these impurities by adding an acid after this step, because the intermediate N-propoxyethyl-2,6-diethyl aniline shown in formula (1) itself is an amine, and if an acid is added at this stage, it will cause a large loss of the intermediate.

[0033] In some specific embodiments, the pH of the system is adjusted to 1-6, preferably 1-3, by using an acid, so that the impurities are fully salified with the acid and dissolved in the aqueous phase, thereby achieving the effect of breaking the emulsion. When the pH is greater than 6, the impurities cannot be fully salified, and the emulsion cannot be broken.

[0034] In some specific embodiments, the acid is an inorganic acid such as hydrochloric acid, sulfuric acid or phosphoric acid, and preferably is hydrochloric acid.

[0035] In the present application, the crude propaquizafop can be prepared by, for example, the following reaction steps:

[0036] Step one:

[0037]

[0038] Step two:

[0039]

[0040] In some specific embodiments, the catalyst in step one is a catalyst containing 0.05-10% palladium (Pd) or 0.2-10% platinum (Pt), the reaction temperature is 190-270°C, the reaction pressure is 1-2 atm, and the reaction is carried out under solvent-free conditions.

[0041] In some embodiments, the reaction of step ii is carried out under solvent-free conditions. In a solvent-free reaction system, emulsification is more serious. Therefore, the demulsification method of the present application can be preferably applied to such solvent-free reaction system.

[0042] In other embodiments, the amount of chloroacetyl chloride in step ii is 0.98 to 1.05 mole equivalents of the intermediate N-propoxyethyl-2,6-diethyl aniline of formula (1), so as to ensure that the N-propoxyethyl-2,6-diethyl aniline can be fully reacted.

[0043] Examples

[0044] The method of the present application is described in detail below with reference to specific examples.

[0045] In the examples and comparative examples of the present application, the detection is carried out by gas chromatography under the following conditions:

[0046] Gas chromatography conditions: instrument: SP-2100A gas chromatograph, hydrogen flame ionization detector; column: 30 m long, 0.32 mm in diameter; stationary liquid: SE-54 weakly polar column; microsyringe: 1 μl; column temperature: 90°C for 3.5 min, then increased to 280°C at a rate of 20°C / min and maintained for 25 min; vaporization chamber temperature: 290°C; detector temperature: 290°C; carrier gas: nitrogen; nitrogen pressure: 0.08 MPa; hydrogen pressure: 0.2 MPa; air pressure: 0.2 MPa.

[0047] Preparation of intermediate N-propoxyethyl-2,6-diethyl aniline in Example 1

[0048] A 1 L reactor was charged with 40 g of a catalyst containing 5% palladium (Pd), and activated by reduction with hydrogen at 200°C for 1 hour. Then, 104.2 g of ethylene glycol monopropyl ether (1.0 mol) and 298.5 g of 2,6-diethyl aniline (2.0 mol) were added, and the reaction was carried out at a temperature of 190 to 200°C, a pressure of 1 to 2 atm, and for a period of 4 hours. The crude product was detected by the above gas chromatography normalization method, and was found to contain 15.3% of ethylene glycol monopropyl ether (peak relative retention time: 4.0 min), 30.0% of residual 2,6-diethyl aniline (peak relative retention time: 10.5 min), 50.7% of N-propoxyethyl-2,6-diethyl aniline (peak relative retention time: 12.6 min), and 4.0% of other impurities.

[0049] The crude product was separated in a separatory funnel, the water layer was discarded, and the organic layer was placed in a 500 mL three-necked flask and subjected to vacuum distillation at a pressure of -0.095 to -0.098 MPa, with a reflux ratio of 4:1, and a temperature of 190 to 200°C, to distill off the ethylene glycol monopropyl ether and 2,6-diethyl aniline and the like, and then a temperature of 200 to 240°C, to continue distillation, to obtain the intermediate N-propoxyethyl-2,6-diethyl aniline. The intermediate N-propoxyethyl-2,6-diethyl aniline was subjected to the above gas chromatography normalization method, and the area normalization content of N-propoxyethyl-2,6-diethyl aniline was 96.7%.

[0050] The intermediate N-propoxyethyl-2,6-diethyl aniline was subjected to the above gas chromatography normalization method, and the molecular weight was determined by a gas chromatograph-mass spectrometer, and the peak relative retention times of the main impurities were:

[0051] 10.7 minutes (MS-ESI (m / z): 151.13 [M+H] + , impurity 5);

[0052] 11.5 minutes (MS-ESI (m / z): 192.17 [M+H] + , impurity 4);

[0053] 13.6 minutes (MS-ESI (m / z): 264.28 [M+H] + , impurity 3);

[0054] 14.1 minutes (MS-ESI (m / z): 278.31 [M+H] + , impurity 2);

[0055] 15.2 minutes (MS-ESI (m / z): 280.26 [M+H] + , impurity 1).

[0056] The intermediate was subjected to distillation again, at a pressure of -0.095 to -0.098 MPa, a reflux ratio of 10:1, and a temperature of 200°C, to collect fractions in which the area normalization contents of the last three impurities were greater than 5%, and then the fractions were separated by the following preparative chromatography conditions.

[0057] The detection conditions for the preparative chromatography were as follows: the chromatographic column was a C18 column, with a diameter of 30 mm, a length of 250 mm, and a packing particle size of 10 um; the mobile phase was acetonitrile: water (containing 0.1% by weight of ammonium acetate) = 80:20; the flow rate was 40 mL / min; and the detection wavelength was 280 nm.

[0058] In the preparative chromatography, impurities 1 to 3 were obtained, each with a content of greater than 95%, and were subjected to hydrogen spectrum detection:

[0059] 15.2 minute impurity 1 H NMR: 1 HNMR (400 MHz, DMSO) δ 6.96 (br d, J = 7.5 Hz, 2H), δ 6.84 (dd, J = 7.1, 8.0 Hz, 1H), δ 3.73 (br m, 2H), δ 3.51 (m, 6H), δ 3.35 (t, J = 6.6 Hz, 2H), δ 3.01 (m, 2H), δ 2.61 (q, J = 7.6 Hz, 4H), δ 1.50 (m, 2H), δ 1.15 (t, J = 7.6 Hz, 6H), δ 0.86 (t, J = 7.4 Hz, 3H).

[0060] 14.2 minute impurity 2 H NMR: 1 HNMR (400 MHz, DMSO) δ 7.05 (m, 3H), δ 3.34 (t, J = 6.2 Hz, 2H), δ 3.27 (t, J = 6.5 Hz, 2H), δ 3.11 (t, J = 6.2 Hz, 2H), δ 2.94 (m, 2H), δ 2.66 (q, J = 7.6 Hz, 4H), δ 1.47 (m, 2H), δ 1.38 (m, 2H) δ 1.15 (t, J = 7.6 Hz, 6H), δ 0.84 (t, J = 7.4 Hz, 3H), δ 0.79 (t, J = 7.3 Hz, 3H).

[0061] 13.6 minute impurity 3 H NMR: 1 HNMR (400 MHz, DMSO) δ 7.05 (m, 3H), δ 3.34 (t, J = 6.2 Hz, 2H), δ 3.27 (t, J = 6.5 Hz, 2H), δ 3.11 (t, J = 6.2 Hz, 2H), δ 3.05 (q, J = 7.1 Hz, 2H), δ 2.66 (q, J = 7.5 Hz, 4H), δ 1.47 (m, 2H), δ 1.15 (t, J = 7.5 Hz, 6H), δ 0.95 (t, J = 7.1 Hz, 3H), δ 0.84 (t, J = 7.4 Hz, 3H).

[0062] The N-propyloxyethyl-2,6-diethyl aniline used in the following examples and comparative examples had a content of 96.7% with a content of 0.94% of impurity 1, 0.65% of impurity 2, 0.88% of impurity 3, 0.3% of impurity 4, and 0.23% of impurity 5.

[0063] Example 2

[0064] Into a reaction flask were added 106.4 g of N-propoxyethyl-2,6-diethyl aniline (0.437 mol) and 130 g of 23% aqueous Na2CO3 solution (0.283 mol). At 30-40°C, 50.3 g of chloroacetyl chloride (0.446 mol) was added dropwise over a period of 1 h. After the addition was completed, the reaction was continued for 1 h. The reaction was followed until the remaining amount of the starting material was within 1.0%. The reaction system was emulsified. The pH was adjusted to 6 with hydrochloric acid. Slow separation began. After standing for about 2 h, the liquid was separated. The aqueous phase was discarded. The organic phase was analyzed. The content of impurity 1 was 0.34%, the content of impurity 2 was 0.32%, the content of impurity 3 was 0.37%, the content of impurity 4 was 0.02%, and the content of impurity 5 was 0.02%. The organic phase was washed with 50 g of water. The remaining water was removed with a rotary evaporator at a temperature of ≤ 80°C until the water content was < 0.3%. The product, propachlor, was obtained. The content was 97.5%.

[0065] Example 3

[0066] Into a reaction flask were added 106.4 g of N-propoxyethyl-2,6-diethyl aniline (0.437 mol) and 130 g of 23% aqueous Na2CO3 solution (0.283 mol). At 30-40°C, 50.3 g of chloroacetyl chloride (0.446 mol) was added dropwise over a period of 1 h. After the addition was completed, the reaction was continued for 1 h. The reaction was followed until the remaining amount of the starting material was within 1.0%. The reaction system was emulsified. The pH was adjusted to 3 with hydrochloric acid. Immediate separation began. After standing for about 10 min, the liquid was separated. The aqueous phase was discarded. The organic phase was analyzed. The content of impurity 1 was 0.04%, the content of impurity 2 was 0.03%, the content of impurity 3 was 0.04%, the content of impurity 4 was 0.01%, and the content of impurity 5 was 0.01%. The organic phase was washed with 50 g of water. The remaining water was removed with a rotary evaporator at a temperature of ≤ 80°C until the water content was < 0.3%. The product, propachlor, was obtained. The content was 98.3%.

[0067] Example 4

[0068] Into a reaction flask were added 106.4 g of N-propoxyethyl-2,6-diethyl aniline (0.437 mol) and 130 g of 23% aqueous Na2CO3 solution (0.283 mol), and 50.3 g of chloroacetyl chloride (0.446 mol) was added dropwise at 30-40°C over a period of 1 h. After the dropwise addition was completed, the reaction was continued for 1 h, and the reaction was followed until the remaining amount of the starting material was within 1.0%. The reaction system was emulsified, and the pH was adjusted to 1 with hydrochloric acid. The separation into layers started immediately, and after standing for about 10 min, the layers were separated, and the aqueous phase was discarded. The organic phase was detected, and the content of impurity 1 was 0.03%, the content of impurity 2 was 0.02%, the content of impurity 3 was 0.03%, the content of impurity 4 was 0.01%, and the content of impurity 5 was 0.01%. The organic phase was washed with 50 g of water, and then the remaining water was distilled off with a rotary evaporator at ≤80°C until the water content was <0.3%. The product, propachlor, was obtained in a content of 98.4%.

[0069] Comparative Example 1

[0070] Into a reaction flask were added 106.4 g of N-propoxyethyl-2,6-diethyl aniline (0.437 mol) and 130 g of 23% aqueous Na2CO3 solution (0.283 mol), and 50.3 g of chloroacetyl chloride (0.446 mol) was added dropwise at 30-40°C over a period of 1 h. After the dropwise addition was completed, the reaction was continued for 1 h, and the reaction was followed until the remaining amount of the starting material was within 1.0%. The reaction system was emulsified, and after standing for about 24 h, the layers were separated, and the aqueous phase was discarded. The organic phase was detected, and the content of impurity 1 was 0.79%, the content of impurity 2 was 0.64%, the content of impurity 3 was 0.84%, the content of impurity 4 was 0.1%, and the content of impurity 5 was 0.1%. The organic phase was washed with 50 g of water, and then the remaining water was distilled off with a rotary evaporator at ≤80°C until the water content was <0.3%. The product, propachlor, was obtained in a content of 96.0%.

[0071] Comparative Example 2

[0072] Into a reaction flask were added 106.4 g of N-propoxyethyl-2,6-diethyl aniline (0.437 mol) and 130 g of 23% aqueous Na2CO3 solution (0.283 mol), and 50.3 g of chloroacetyl chloride (0.446 mol) was added dropwise at 30-40°C over a period of 1 h. After the dropwise addition was completed, the reaction was continued for 1 h, and the reaction was followed until the remaining amount of the starting material was within 1.0%. The reaction system was emulsified, and the pH was adjusted to 7 with hydrochloric acid. No improvement in emulsification was observed, and after standing for about 20 h, the layers were separated, and the aqueous phase was discarded. The organic phase was detected, and the content of impurity 1 was 0.75%, the content of impurity 2 was 0.62%, the content of impurity 3 was 0.81%, the content of impurity 4 was 0.1%, and the content of impurity 5 was 0.1%. The organic phase was washed with 50 g of water, and then the remaining water was distilled off with a rotary evaporator at ≤80°C until the water content was <0.3%. The product, propachlor, was obtained in a content of 96.1%.

Claims

1. A method for preparing pretilachlor, characterized in that, After obtaining the crude pretilachlor product, the pH of the system was adjusted to below 6 by adding acid to remove the following impurity 1 from the system and eliminate emulsification:

2. The method according to claim 1, wherein the pH of the system is adjusted to 1-3 by adding acid to the system, thereby removing impurity 1 and eliminating emulsification.

3. The method according to claim 1 or 2, wherein, Crude propachlor is prepared via the following reaction steps: Step 1: Step Two:

4. The method according to claim 3, wherein the reaction in step two is carried out under solvent-free conditions.

5. The method according to claim 1 or 2, wherein adding acid further removes any one or both of the following impurities 2 and 3:

6. The method according to claim 1 or 2, wherein adding acid further removes any one or both of the following impurities 4 and 5:

7. The method according to claim 1 or 2, wherein the acid is an inorganic acid.

8. The method according to claim 7, wherein the acid is hydrochloric acid, sulfuric acid, or phosphoric acid.

9. The method according to claim 3, wherein the chloroacetyl chloride in step two is 0.98 to 1.05 molar equivalents of the intermediate N-propoxyethyl-2,6-diethylaniline shown in formula (1).

10. The method according to claim 3, wherein the catalyst in step one is a catalyst containing 0.05-10% palladium or 0.2-10% platinum.

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