Preparation method of (R) 2-(4-chloro-2-methylphenoxy) isooctyl propionate root inhibitor

Abstract

The invention discloses a preparation method of an (R) 2-(4-chloro-2-methylphenoxy) isooctyl propionate root inhibitor. The method comprises the following steps: carrying out condensation reaction on L-2-chloropropionic acid and o-cresol under the promotion of alkali to obtain (R) 2-methylphenoxypropionic acid; carrying out esterification reaction on the (R) 2-methyl phenoxy propionic acid and isooctyl alcohol (2-ethyl hexanol) under the action of a catalyst to obtain (R) 2-methyl phenoxy isooctyl propionate; the (R) 2-methyl phenoxy isooctyl propionate is chlorinated by a chlorination reagent to obtain (R) 2-(4-chloro-2-methyl phenoxy) isooctyl propionate; the (R) 2-(4-chloro-2-methylphenoxy) isooctyl propionate obtained by the method disclosed by the invention is high in yield, good in optical activity and excellent in quality; the method has the advantages of novel synthesis route, easily available raw materials, low cost, simple and feasible process operation, short time consumption, less waste, small pollution and suitability for industrial production, and can fill the domestic blank and relieve the current situation of dependence on import.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and in particular relates to a method for preparing a (R) 2-(4-chloro-2-methylphenoxy) propionate root inhibitor. Background Art

[0002] With global warming and the improvement of greenhouse effect, the country is vigorously advocating the construction of "sponge cities" and green buildings. Green roofs represent an important element in building design and lead the trend of green and environmentally friendly buildings in the future. Root-penetration-resistant waterproofing membranes play an indispensable role in this architectural trend. Chemical root inhibitors play a pivotal role in the production and use of root-penetration-resistant materials, and the demand for them in industrial production is also increasing day by day. (R) 2-(4-chloro-2-methylphenoxy) propionate has a certain inhibitory effect on the main root growth of evergreen shrubs and small trees with relatively developed root systems at an appropriate dosage, and plays a role in cultivating the growth of lateral roots. This can be applied to roof planting technology and root-penetration-resistant waterproofing membranes. At present, there is no report on synthesis in China. There are literatures showing that chiral L-ethyl lactate is used as a raw material, and a similar compound (R)-2-(4-chloro-2-methylphenoxy) propionate that can be used as a root inhibitor is finally synthesized through sulfonation, etherification and ester exchange. However, the post-treatment of the sulfonation reaction of the preparation method is time-consuming and has a great influence on the chirality of the sulfonyl ester intermediate product; when the raw materials remain after the etherification reaction for a certain period of time, other unknown impurities will appear in the system, affecting the yield and purity of the aromatic ether ester compound; after the transesterification reaction is carried out to a certain extent, the conversion rate of the raw material aromatic ether ester compound slows down, so that the entire transesterification process is prolonged, affecting the yield and purity of the final product. Therefore, it is very important to explore a process scheme that is more conducive to industrial production to meet the market demand and promotion of (R)-2-(4-chloro-2-methylphenoxy) propionate. L-2-chloropropionic acid of the present invention is the starting material, and after condensation with o-cresol, it is esterified with isooctyl alcohol, and finally chlorinated by NCS to synthesize the root inhibitor (R) 2-(4-chloro-2-methylphenoxy) propionate with a higher yield, better chirality and quality. Summary of the invention

[0003] The purpose of the present invention is to solve the above problems and provide a method for preparing a (R) 2-(4-chloro-2-methylphenoxy) propionate root inhibitor. The raw materials of the preparation method are cheap and easily available, the process flow is short, the operation is simple and convenient, there is no waste acid and no environmental pollution, the yield is higher and the quality is better, thereby filling the gap in the domestic synthesis technology of the compound and solving the problem of having to rely on imports and having few sources.

[0004] In order to solve the above problems, the present invention adopts the following technical solutions:

[0005] The synthetic route is as follows:

[0006]

[0007] The present invention specifically comprises the following steps:

[0008] Step 1. Synthesis of (R) 2-methylphenoxypropionic acid:

[0009] L-2-chloropropionic acid and o-cresol undergo condensation reaction under the promotion of base to obtain (R) 2-methylphenoxypropionic acid.

[0010] The base in the condensation reaction of step 1 is one or more of the inorganic base sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate. Sodium hydroxide and potassium hydroxide are preferred, and sodium hydroxide is most preferred;

[0011] In step 1, the molar ratio of L-2-chloropropionic acid, o-cresol and sodium hydroxide in the condensation reaction is 1:1.0:1.0 to 1:1.5:3.0, preferably, the molar ratio of L-2-chloropropionic acid, o-cresol and sodium hydroxide is 1:1.0:2.0 to 1:1.5:2.5, and most preferably, the molar ratio of L-2-chloropropionic acid, o-cresol and sodium hydroxide is 1:1.0:2.2.

[0012] Step 1: Condensation reaction: The reaction temperature is 0°C to 100°C, preferably 30°C to 70°C, and most preferably 55°C.

[0013] Step 1: Condensation reaction The condensation reaction time is 1 d to 4 d, preferably 2 d to 3 d, and most preferably 2 d.

[0014] Step 2. Synthesis of (R) 2-methylphenoxypropionate:

[0015] The (R) 2-methylphenoxypropionic acid obtained in step 1 is subjected to an esterification reaction with isooctyl alcohol (2-ethylhexanol) in the presence of a catalyst to obtain (R) 2-methylphenoxypropionic acid isooctyl ester.

[0016] Step 2: The catalyst for the esterification reaction is concentrated sulfuric acid, phosphoric acid, p-toluenesulfonic acid, benzenesulfonic acid, solid acid or ionic liquid, preferably concentrated sulfuric acid, p-toluenesulfonic acid, benzenesulfonic acid; most preferably p-toluenesulfonic acid.

[0017] In step 2, the molar ratio of the (R) 2-methylphenoxypropionic acid, isooctyl alcohol (2-ethylhexanol) and catalyst in the esterification reaction is 1:0.8:0.005 to 1:2.0:0.015, preferably 1:1.0:0.008 to 1:1.5:0.012; most preferably 1:1.0:0.010.

[0018] Step 2: The solvent for the esterification reaction is: n-hexane, cyclohexane or toluene, preferably cyclohexane, toluene, and most preferably toluene.

[0019] Step 2: Esterification reaction: The reaction temperature is 60°C to 113°C, preferably 80°C to 113°C, and most preferably 112°C.

[0020] Step 2: The reaction time of the esterification reaction is 2 h to 8 h, preferably 4 h to 8 h, and most preferably 6 h.

[0021] Step 3. Synthesis of (R) 2-(4-chloro-2-methylphenoxy)propanoic acid isooctyl ester:

[0022] The (R) isooctyl 2-methylphenoxypropionate obtained in step 2 is chlorinated with a chlorinating agent to obtain (R) isooctyl 2-(4-chloro-2-methylphenoxy)propionate.

[0023] Step 3: The chlorination reagent in the chlorination reaction is NCS (N-chlorosuccinimide), chlorine gas or phosphorus pentachloride, preferably NCS (N-chlorosuccinimide), phosphorus pentachloride, and most preferably NCS (N-chlorosuccinimide).

[0024] Step 3 Chlorination Reaction: The molar ratio of (R) 2-methylphenoxypropionate to the chlorinating agent is 1:1.0 to 1:2.0, preferably 1:1.0 to 1:1.5, and most preferably 1:1.1.

[0025] Step 3: The solvent for the chlorination reaction is one or more of dichloromethane, chloroform, carbon tetrachloride or tetrahydrofuran, preferably dichloromethane or carbon tetrachloride; and most preferably dichloromethane.

[0026] Step 3 Chlorination reaction The reaction temperature is 20°C to 80°C, preferably 30°C to 62°C, and most preferably 40°C.

[0027] Step 3: Chlorination reaction: The reaction time is 24 h to 72 h, preferably 24 h to 48 h, and most preferably 26 h.

[0028] The beneficial effects of the present invention are as follows:

[0029] The invention adopts cheap and readily available raw materials and a novel route to synthesize (R) 2-(4-chloro-2-methylphenoxy) propionic acid isooctyl ester with good optical activity, high yield and high quality. The method has low cost, short route, simple and easy operation, mild reaction conditions, less time consumption, less waste, less pollution and is easy to industrialize. DETAILED DESCRIPTION

[0030] The present invention is further described below in conjunction with specific embodiments.

[0031] The invention discloses a method for preparing a root inhibitor (R) 2-(4-chloro-2-methylphenoxy) propionate isooctyl ester. The invention uses L-2-chloropropionic acid as a starting material, condenses with o-cresol, and then esterifies with isooctyl alcohol, and finally chlorinates with NCS (N-chlorosuccinimide) to obtain the root inhibitor (R) 2-(4-chloro-2-methylphenoxy) propionate isooctyl ester. The (R) 2-(4-chloro-2-methylphenoxy) propionate isooctyl ester obtained by the method provided by the invention has a high yield, good optical activity and excellent quality. The advantages of the invention are that the synthetic route is novel, the raw materials are easy to obtain and the cost is low, the process operation is simple and easy, the time consumption is short, the waste is small, the pollution is small, it is suitable for industrial production, it can fill the domestic gap, and alleviate the current situation of dependence on imports.

[0032] Example 1 (R) The synthesis of 2-methylphenoxy propionic acid is as follows: (1:1.0:2.0)

[0033] 28 kg (MW = 108.52, 258 mol) of 2-chloropropionic acid was added to a 100L reactor, 34.4 kg (MW = 40, 258 mol) of 30% aqueous sodium hydroxide solution was added dropwise below 10°C, pH was adjusted to 7-8, stirred for 0.5 hours, 27.9 kg (MW = 108.14, 258 mol) of o-cresol was added, the temperature was controlled at 10-15°C and solid sodium hydroxide (4+4+2.32) 10.32 kg (MW = 40, 258 mol) was added three times with an interval of 0.5 hours each time. l), keep warm at 10-15℃ for 2 hours, slowly heat to 55℃ and keep warm for 48 hours (PH becomes 7-8), cool to 20-25℃, add 50kg water, adjust the reaction solution PH=6.5 with 30% hydrochloric acid (measured by pH meter), extract with dichloromethane twice, 16kg each time, control the temperature of the water layer at 20-25℃, adjust the reaction solution PH=1 with 30% hydrochloric acid, stir for 0.5 hour, re-measure PH=1, cool to 5-10℃, stir and crystallize for 4-8 hours, centrifuge and dry to obtain 41.8kg of crude (R) 2-methylphenoxypropionic acid.

[0034] Purification: After heating 5 times the amount of water to dissolve, cool to 5-10°C and stir for crystallization for 4-8 hours. After centrifugal drying, 37.6 kg of (R) 2-methylphenoxypropionic acid was obtained, with a crystallization yield of 90%, a total molar yield of 81%, a liquid chromatography content of 99.2%, and a specific rotation of +18° (anhydrous ethanol).

[0035] Example 2 (R) The synthesis of 2-methylphenoxy propionic acid is as follows: (1:1.0:2.2)

[0036] 28 kg (MW = 108.52, 258 mol) of 2-chloropropionic acid was added to a 100L reactor, 34.4 kg (MW = 40, 258 mol) of 30% aqueous sodium hydroxide solution was added dropwise below 10°C, pH was adjusted to 7-8, stirred for 0.5 hours, 27.9 kg (MW = 108.14, 258 mol) of o-cresol was added, the temperature was controlled at 10-15°C and solid sodium hydroxide (4+4+4.38) was added 3 times with an interval of 0.5 hours each time. l), keep warm at 10-15℃ for 2 hours, slowly heat to 55℃ and keep warm for 48 hours (PH becomes 7-8), cool to 20-25℃, add 50kg water, adjust the reaction solution PH=6.5 with 30% hydrochloric acid (measured by pH meter), extract with dichloromethane twice, 16kg each time, control the temperature of the water layer at 20-25℃, adjust the reaction solution PH=1 with 30% hydrochloric acid, stir for 0.5 hour, re-measure PH=1, cool to 5-10℃, stir and crystallize for 4-8 hours, centrifuge and dry to obtain 43.9kg of crude (R)2-methylphenoxypropionic acid.

[0037] Purification: After the solution is dissolved by heating 5 times the amount of water, the temperature is lowered to 5-10°C and stirred for crystallization for 4-8 hours. After centrifugal drying, 39.5 kg of (R) 2-methylphenoxypropionic acid is obtained, with a crystallization yield of 90%, a total molar yield of 85%, a liquid chromatography content of 99.3%, and a specific rotation of +19° (anhydrous ethanol).

[0038] Example 3 (R) The synthesis of 2-methylphenoxy propionic acid is as follows: (1:1.5:3.0)

[0039] 28 kg (MW = 108.52, 258 mol) of 2-chloropropionic acid was added to a 100L reactor, 34.4 kg (MW = 40, 258 mol) of 30% aqueous sodium hydroxide solution was added dropwise below 10°C, pH was adjusted to 7-8, stirred for 0.5 hours, 41.8 kg (MW = 108.14, 387 mol) of o-cresol was added, the temperature was controlled at 10-15°C and divided into 3 times, each time with an interval of 0.5 hours, 20.64 kg (MW = 40, 516 mol) of solid sodium hydroxide (7+7+6.64) was added. l), keep warm at 10-15℃ for 2 hours, slowly heat to 55℃ and keep warm for 48 hours (PH becomes 7-8), cool to 20-25℃, add 50kg water, adjust the reaction solution PH=6.5 with 30% hydrochloric acid (measured by pH meter), extract with dichloromethane twice, 16kg each time, control the temperature of the water layer at 20-25℃, adjust the reaction solution PH=1 with 30% hydrochloric acid, stir for 0.5 hour, re-measure PH=1, cool to 5-10℃, stir and crystallize for 4-8 hours, centrifuge and dry to obtain 43.8kg of crude (R)2-methylphenoxypropionic acid.

[0040] Purification: After heating 5 times the amount of water to dissolve, cool to 5-10°C and stir for crystallization for 4-8 hours. After centrifugal drying, 37.2 kg of (R) 2-methylphenoxypropionic acid was obtained, with a crystallization yield of 85%, a total molar yield of 83%, a liquid chromatography content of 98.0%, and a specific rotation of +16° (anhydrous ethanol).

[0041] Example 4 (R) The synthesis of 2-methylphenoxy propionic acid is as follows: (1:1.0:2.5)

[0042] 28 kg (MW = 108.52, 258 mol) of 2-chloropropionic acid was added to a 100L reactor, 34.4 kg (MW = 40, 258 mol) of 30% aqueous sodium hydroxide solution was added dropwise below 10°C, pH was adjusted to 7-8, stirred for 0.5 hours, 27.9 kg (MW = 108.14, 258 mol) of o-cresol was added, the temperature was controlled at 10-15°C and divided into 3 times, each time with an interval of 0.5 hours, 15.5 kg (MW = 40, 387 mol) of solid sodium hydroxide (5 + 5 + 5.2) was added. ), after keeping warm at 10-15℃ for 2 hours, slowly heat to 55℃ and keep warm for 48 hours (PH becomes 7-8), cool to 20-25℃, add 50kg of water, adjust the PH of the reaction solution to 6.5 with 30% hydrochloric acid (measured by PH meter), extract with dichloromethane twice, 16kg each time, control the temperature of the water layer at 20-25℃, adjust the PH of the reaction solution to 1 with 30% hydrochloric acid, stir for 0.5 hour, re-measure PH=1, cool to 5-10℃, stir and crystallize for 4-8 hours, and centrifuge and dry to obtain 42.8kg of crude (R) 2-methylphenoxypropionic acid.

[0043] Purification: After the solution is dissolved by heating 5 times the amount of water, the temperature is lowered to 5-10°C and stirred for crystallization for 4-8 hours. After centrifugal drying, 38.6 kg of (R) 2-methylphenoxypropionic acid is obtained, with a crystallization yield of 90%, a total molar yield of 83%, a liquid chromatography content of 99.0%, and a specific rotation of +18.2° (anhydrous ethanol).

[0044] Example 5 (R) The synthesis of 2-methylphenoxy propionic acid is as follows: (1:1:2.0)

[0045] 28 kg (MW = 108.52, 258 mol) of L-2-chloropropionic acid was added to a 100L reactor, 34.4 kg (MW = 40, 258 mol) of 30% potassium hydroxide aqueous solution was added dropwise below 10°C, pH was adjusted to 7-8, stirred for 0.5 hours, 27.9 kg (MW = 108.14, 258 mol) of o-cresol was added, the temperature was controlled at 10-15°C and divided into 3 times, each time with an interval of 0.5 hours, 10.32 kg (MW = 56, 258 mol) of solid potassium hydroxide (5+5+4.45) was added. mol), 10-15℃ for 2 hours, slowly heat to 50℃ for 48 hours (PH becomes 7-8), cool to 20-25℃, add 50kg water, adjust the PH of the reaction solution to 6.5 (measured by PH meter) with 30% hydrochloric acid, extract with toluene twice, 16kg each time, control the temperature of the water layer at 20-25℃, adjust the PH of the reaction solution to 1 with 30% hydrochloric acid, stir for 0.5 hour, re-measure PH to 1, cool to 5-10℃, stir for 4-8 hours, and centrifuge to dry to obtain 41.8kg of crude (R) 2-methylphenoxypropionic acid.

[0046] Purification: After the solution is dissolved by heating 5 times the amount of water, the temperature is lowered to 5-10°C and stirred for crystallization for 4-8 hours. After centrifugal drying, 37.6 kg of (R) 2-methylphenoxypropionic acid is obtained, with a crystallization yield of 90%, a total molar yield of 81%, a liquid chromatography content of 99.1%, and a specific rotation of +17° (anhydrous ethanol).

[0047] Example 6 (R) The synthesis of 2-methylphenoxy propionic acid is as follows: (1:1:1.5)

[0048] 28 kg of L-2-chloropropionic acid (MW = 108.52, 258 mol) was added to a 100L reactor, 79.5 kg of saturated sodium carbonate aqueous solution (MW = 106, 179 mol) was added dropwise below 10°C, the pH was adjusted to 7-8, stirred for 0.5 hours, 27.9 kg of o-cresol (MW = 108.14, 258 mol) was added, the temperature was controlled at 10-15°C, and solid sodium hydroxide (4+4+2.32) was added 3 times with an interval of 0.5 hours each time. g (MW = 40, 258 mol), keep warm at 10-15°C for 2 hours, slowly heat to 60°C and keep warm for 72 hours (PH becomes 7-8), cool to 20-25°C, add 50 kg of water, adjust the pH of the reaction solution to 6.5 (measured by pH meter) with 30% hydrochloric acid, extract with toluene twice, 16 kg each time, control the temperature of the water layer at 20-25°C, adjust the pH of the reaction solution to 1 with 30% hydrochloric acid, stir for 0.5 hours, re-measure the pH to 1, cool to 5-10°C, stir and crystallize for 4-8 hours, and centrifuge. 42.2 kg of crude (R) 2-methylphenoxypropionic acid is obtained.

[0049] Purification: After heating 5 times the amount of water to dissolve, cool to 5-10°C and stir for crystallization for 4-8 hours. After centrifugal drying, 38 kg of (R) 2-methylphenoxypropionic acid was obtained, with a crystallization yield of 90%, a total molar yield of 82%, a liquid chromatography content of 99.0%, and a specific rotation of +17.2° (anhydrous ethanol).

[0050] Example 7 (R) The synthesis of 2-methylphenoxy propionic acid is as follows: (1:1:1)

[0051] 28 kg of L-2-chloropropionic acid (MW = 108.52, 258 mol) was added to a 100L reactor, 49.4 kg of 30% potassium carbonate aqueous solution (MW = 138, 179 mol) was added dropwise below 10°C, the pH was adjusted to 7-8, stirred for 0.5 hours, 27.9 kg of o-cresol (MW = 108.14, 258 mol) was added, the temperature was controlled at 10-15°C, and 24.7 kg of solid potassium carbonate (4+4+2.32) was added three times with an interval of 0.5 hours each time. (MW=138, 179mol), keep warm at 10-15℃ for 2 hours, slowly heat to 70℃ and keep warm for 72 hours (PH becomes 7-8), cool to 20-25℃, add 50kg water, adjust the reaction solution PH=6.5 (measured by pH meter) with 30% hydrochloric acid, extract with toluene twice, 16kg each time, control the temperature of the water layer at 20-25℃, adjust the reaction solution PH=1 with 30% hydrochloric acid, stir for 0.5 hours, re-measure PH=1, cool to 5-10℃, stir and crystallize for 4-8 hours, centrifuge. Obtain 42.3kg crude (R) 2-methylphenoxypropionic acid.

[0052] Purification: After the solution is dissolved by heating 5 times the amount of water, the temperature is lowered to 5-10°C and stirred for crystallization for 4-8 hours. After centrifugal drying, 38 kg of (R) 2-methylphenoxypropionic acid is obtained, with a crystallization yield of 90%, a total molar yield of 81.9%, a liquid chromatography content of 98.1%, and a specific rotation of +16.8° (anhydrous ethanol).

[0053] Example 8 (R) The synthesis of 2-methylphenoxy propionic acid is as follows: (1:1.0:2.2)

[0054] 28 kg (MW = 108.52, 258 mol) of 2-chloropropionic acid was added to a 100L reactor, 20.64 kg (MW = 24, 258 mol) of 30% lithium hydroxide aqueous solution was added dropwise below 10°C, pH was adjusted to 7-8, stirred for 0.5 hours, 27.9 kg (MW = 108.14, 258 mol) of o-cresol was added, the temperature was controlled at 10-15°C and divided into 3 times, each time with an interval of 0.5 hours, 7.43 kg (MW = 40, 309 mol) of solid lithium hydroxide (2+2+2.43) was added. l), keep warm at 10-15℃ for 2 hours, slowly heat to 55℃ and keep warm for 48 hours (PH becomes 7-8), cool to 20-25℃, add 50kg water, adjust the reaction solution PH=6.5 with 30% hydrochloric acid (measured by pH meter), extract with dichloromethane twice, 16kg each time, control the temperature of the water layer at 20-25℃, adjust the reaction solution PH=1 with 30% hydrochloric acid, stir for 0.5 hour, re-measure PH=1, cool to 5-10℃, stir and crystallize for 4-8 hours, centrifuge and dry to obtain 43.9kg of crude (R)2-methylphenoxypropionic acid.

[0055] Purification: After the solution is dissolved by heating 5 times the amount of water, the temperature is lowered to 5-10°C and stirred for crystallization for 4-8 hours. After centrifugal drying, 39.5 kg of (R) 2-methylphenoxypropionic acid is obtained, with a crystallization yield of 90%, a total molar yield of 85%, a liquid chromatography content of 97.4%, and a specific rotation of +16.2° (anhydrous ethanol).

[0056] Example 9 (R) The synthesis of 2-methylphenoxy propionate isooctyl ester is as follows: (1:1:0.01)

[0057] Put 36kg (WM=180,200mol) of (R)2-methylphenoxypropionic acid, 26kg (WM=130,200mol) of isooctyl alcohol (2-ethylhexanol), 0.344kg (WM=172,2mol) of p-toluenesulfonic acid as catalyst, and 180kg of n-hexane into a 500L reactor, turn on stirring, heat up to reflux for dehydration, react for about 8 hours, and detect by GC when the isooctyl alcohol reacts completely.

[0058] Post-treatment: Cool to room temperature, centrifuge, solid is catalyst p-toluenesulfonic acid, the liquid is washed with 180 kg of 3% sodium bicarbonate aqueous solution for 30 minutes and then allowed to stand for stratification. The organic layer is washed with 180 kg of water for 30 minutes and then allowed to stand for stratification. The organic layer is dried with anhydrous magnesium sulfate, filtered, and the filtrate is distilled at atmospheric pressure to recover n-hexane. The base material is (R) 2-methylphenoxy propionate, light yellow liquid, about 55.48 kg, molar yield 95%, liquid chromatography content 99.5%, specific rotation +19° (anhydrous ethanol).

[0059] Example 10 The synthesis of (R) 2-methylphenoxy propionate isooctyl ester is as follows: (1:1:0.01)

[0060] Put 36kg (WM=180,200mol) of (R)2-methylphenoxypropionic acid, 26kg (WM=130,200mol) of isooctyl alcohol (2-ethylhexanol), 0.344kg (WM=172,2mol) of catalyst p-toluenesulfonic acid, and 180kg of toluene into a 500L reactor, turn on stirring, heat up to reflux for dehydration, react for about 5 hours, and detect by GC when the isooctyl alcohol reacts completely.

[0061] Post-treatment: Cool to room temperature, centrifuge, solid is catalyst p-toluenesulfonic acid, the liquid is washed with 180 kg of 3% sodium bicarbonate aqueous solution for 30 minutes and then allowed to stand for stratification. The organic layer is washed with 180 kg of water for 30 minutes and then allowed to stand for stratification. The organic layer is dried with anhydrous magnesium sulfate, filtered, and the filtrate is distilled at atmospheric pressure to recover toluene. The base material is (R) 2-methylphenoxy propionic acid isooctyl ester, light yellow liquid, about 56.6 kg, molar yield 96%, liquid chromatography content 99.8%, specific rotation +19.5° (anhydrous ethanol).

[0062] Example 11 (R) The synthesis of 2-methylphenoxy propionate isooctyl ester is as follows: (1:0.8:0.005)

[0063] Put 36kg (WM=180, 200mol) of (R)2-methylphenoxypropionic acid, 20.8kg (WM=130, 160mol) of isooctyl alcohol (2-ethylhexanol), 0.172kg (WM=172, 1mol) of p-toluenesulfonic acid as catalyst, and 180kg of cyclohexane into a 500L reactor, turn on stirring, raise the temperature to reflux for dehydration, react for about 8 hours, and detect by GC when the isooctyl alcohol reacts completely.

[0064] Post-treatment: Cool to room temperature, centrifuge, solid is catalyst p-toluenesulfonic acid, liquid is washed with 180kg of 5% sodium bicarbonate aqueous solution for 30 minutes and then allowed to stand for stratification. The organic layer is washed with 180kg of water for 30 minutes and then allowed to stand for stratification. The organic layer is dried with anhydrous magnesium sulfate, filtered, and the filtrate is distilled at atmospheric pressure to recover cyclohexane. The base material is (R) 2-methylphenoxy propionate, light yellow liquid, about 45.2KG, molar yield 80%, liquid chromatography content 99.3%, specific rotation +18.3° (anhydrous ethanol).

[0065] Example 12 (R) The synthesis of 2-methylphenoxy propionate isooctyl ester is as follows: (1:2:0.015)

[0066] A 500L reactor was charged with 36kg (WM=180,200mol) of (R)2-methylphenoxypropionic acid, 52kg (WM=130,400mol) of isooctyl alcohol (2-ethylhexanol), 0.516kg (WM=172,3mol) of p-toluenesulfonic acid as catalyst, and 180kg of toluene. The stirring was turned on, the temperature was raised to reflux for dehydration, and the reaction was carried out for about 8 hours. The reaction of (R)2-methylphenoxypropionic acid was completed by liquid chromatography.

[0067] Post-treatment: Cool to room temperature, centrifuge, solid is catalyst p-toluenesulfonic acid, the liquid is washed with 180kg of 3% sodium bicarbonate aqueous solution for 30 minutes and then allowed to stand for stratification. The organic layer is washed with 180kg of water for 30 minutes and then allowed to stand for stratification. The organic layer is dried with anhydrous magnesium sulfate, filtered, and the filtrate is distilled at normal pressure to recover toluene. The base material is (R) 2-methylphenoxy propionic acid isooctyl ester, a light yellow liquid, about 80.2KG, a molar yield of 137%, a liquid chromatography content of 99.6%, and a specific rotation of +14.7° (anhydrous ethanol). The isooctyl alcohol liquid phase does not produce a peak and is excessive, so the yield exceeds the standard and the specific rotation is low.

[0068] Example 13 (R) The synthesis of 2-methylphenoxy propionate isooctyl ester is as follows: (1:1.15:0.012)

[0069] Put 36 kg (WM = 180, 200 mol) of (R) 2-methylphenoxypropionic acid, 30 kg (WM = 130, 230 mol) of isooctyl alcohol (2-ethylhexanol), 0.413 kg (WM = 172, 2.4 mol) of p-toluenesulfonic acid as catalyst, and 180 kg of cyclohexane into a 500 L reactor, turn on stirring, raise the temperature to reflux for dehydration, react for about 8 hours, and detect by liquid chromatography. The reaction of (R) 2-methylphenoxypropionic acid is complete.

[0070] Post-treatment: Cool to room temperature, centrifuge, solid is catalyst p-toluenesulfonic acid, the liquid is washed with 180 kg of 3% sodium bicarbonate aqueous solution for 30 minutes and then allowed to stand for stratification. The organic layer is washed with 180 kg of water for 30 minutes and then allowed to stand for stratification. The organic layer is dried with anhydrous magnesium sulfate, filtered, and the filtrate is distilled at atmospheric pressure to recover cyclohexane. The base material is (R) 2-methylphenoxy propionate, light yellow liquid, about 52.6 kg, molar yield 90%, liquid chromatography content 99.3%, specific rotation +17.3° (anhydrous ethanol).

[0071] Example 14 (R) The synthesis of 2-methylphenoxy propionate isooctyl ester is as follows: (1:0.96:0.01)

[0072] Put 36kg (WM=180,200mol) of (R)2-methylphenoxypropionic acid, 25kg (WM=130,192.3mol) of isooctyl alcohol (2-ethylhexanol), 0.316kg (WM=158,2mol) of catalyst benzenesulfonic acid, and 180kg of cyclohexane into a 500L reactor, turn on stirring, heat and reflux for dehydration, react for about 8 hours, and detect the complete reaction of isooctyl alcohol by GC.

[0073] Post-treatment: Cool to room temperature, wash with 180 kg of 3% sodium bicarbonate aqueous solution for 30 minutes and then stand for stratification. The organic layer is on the top and the water layer is on the bottom (pH of the water layer is 7-8). The organic layer is washed with 180 kg of water for 30 minutes and then stood for stratification. The organic layer is dried with anhydrous magnesium sulfate for 30 minutes, filtered, and the filtrate is distilled at normal pressure to recover cyclohexane. The bottom material is the product (R) 2-methylphenoxy propionate, yellow liquid, about 54.3 KG, molar yield 93%, liquid chromatography content 99%, specific rotation +18.2° (anhydrous ethanol).

[0074] Example 15 (R) The synthesis of 2-methylphenoxy propionate isooctyl ester is as follows: (1:1:0.01)

[0075] Put 36kg (WM=180) of (R)2-methylphenoxypropionic acid, 26kg (WM=130) of isooctyl alcohol (2-ethylhexanol), 0.2kg (WM=98,2mol) of concentrated sulfuric acid as a catalyst, and 180kg of n-hexane into a 500L reactor, turn on stirring, heat up to reflux for dehydration, react for about 6 hours, and detect the complete reaction of isooctyl alcohol by GC.

[0076] Post-treatment: Cool to room temperature, wash with 180 kg of 3% sodium bicarbonate aqueous solution for 30 minutes and then stand for stratification. The organic layer is on the top and the water layer is on the bottom (pH of the water layer is 7-8). The organic layer is washed with 180 kg of water for 30 minutes and then stand for stratification. The organic layer is dried with anhydrous magnesium sulfate for 30 minutes, filtered, and the filtrate is distilled at normal pressure to recover n-hexane. The bottom material is the product (R) 2-methylphenoxy propionic acid isooctyl ester, a yellow liquid, about 53.7 KG, a molar yield of 92%, a liquid chromatography content of 99.2%, and a specific rotation of +18° (anhydrous ethanol).

[0077] Example 16 The synthesis of (R) 2-(4-chloro-2-methylphenoxy) propionate is as follows: (1:1.1)

[0078] A 500L reactor was charged with 29.2kg (WM=292, 100mol) of (R) 2-methylphenoxypropionate, 14.7kg (WM=133.5, 110mol) of chlorination reagent NCS (N-chlorosuccinimide), and 240kg of dichloromethane, and stirred at 40°C for 26 hours. The raw materials were subjected to post-processing after the reaction was complete by liquid chromatography.

[0079] Post-treatment: After the reaction is completed, the temperature is lowered to 0-5°C for 4 hours. The solid is centrifuged to recover NHS (succinimide), which can be re-chlorinated to NCS (N-chlorosuccinimide) and then used.

[0080] The filtrate was washed once with 200 kg of 5% sodium bicarbonate aqueous solution and once with 200 kg of water. The organic layer was dried with anhydrous magnesium sulfate and then filtered. The filtrate was added with activated carbon and refluxed for 30 minutes for decolorization, then filtered and the solvent dichloromethane was removed by atmospheric distillation to obtain 30.7 kg of light yellow liquid. The molar yield was 94%, the liquid content was 99.4%, and the specific rotation was +20° (anhydrous ethanol).

[0081] Example 17 The synthesis of (R) 2-(4-chloro-2-methylphenoxy) propionate is as follows: (1:2.0)

[0082] A 500L reactor was charged with 29.2kg (WM=292, 100mol) of (R) 2-methylphenoxypropionate, 26.7kg (WM=133.5, 200mol) of chlorination reagent NCS (N-chlorosuccinimide), and 240kg of dichloromethane, and stirred at 40°C for 26 hours. The raw materials were subjected to post-processing after the reaction was complete by liquid chromatography.

[0083] Post-treatment: After the reaction is completed, the temperature is lowered to 0-5°C for 4 hours. The solid is centrifuged to recover NHS (succinimide), which can be re-chlorinated to NCS (N-chlorosuccinimide) and then used.

[0084] The filtrate was washed once with 200 kg of 5% sodium bicarbonate aqueous solution and once with 200 kg of water. The organic layer was dried with anhydrous magnesium sulfate and then filtered. The filtrate was added with activated carbon and refluxed for 30 minutes for decolorization. Then, it was filtered and the solvent dichloromethane was removed by atmospheric distillation to obtain 29.4 kg of light yellow liquid. The molar yield was 90%, the liquid content was 96.4%, and the specific rotation was +16.9° (anhydrous ethanol). (There were more dichlorinated and polychlorinated by-products.)

[0085] Example 18 The synthesis of (R) 2-(4-chloro-2-methylphenoxy) propionate is as follows: (1:1.5)

[0086] A 500L reactor was charged with 29.2kg (WM=292, 100mol) of (R) 2-methylphenoxypropionate, 14.7kg (WM=133.5, 110mol) of chlorination reagent NCS (N-chlorosuccinimide), and 240kg of dichloromethane, and stirred at 40°C for 26 hours. The raw materials were subjected to post-processing after the reaction was complete by liquid chromatography.

[0087] Post-treatment: After the reaction is completed, the temperature is lowered to 0-5°C for 4 hours. The solid is centrifuged to recover NHS (succinimide), which can be re-chlorinated to NCS (N-chlorosuccinimide) and then used.

[0088] The filtrate was washed once with 200 kg of 5% sodium bicarbonate aqueous solution and once with 200 kg of water. The organic layer was dried with anhydrous magnesium sulfate and then filtered. The filtrate was added with activated carbon and refluxed for 30 minutes for decolorization, then filtered and the solvent dichloromethane was removed by atmospheric distillation to obtain 29.7 kg of light yellow liquid. The molar yield was 91%, the liquid content was 98.2%, and the specific rotation was +17.3° (anhydrous ethanol).

[0089] Example 19 The synthesis of (R) 2-(4-chloro-2-methylphenoxy) propionate is as follows: (1:1.0)

[0090] A 500L reactor was charged with 29.2 kg (WM = 292, 100 mol) of (R) 2-methylphenoxypropionate, 13.4 kg (WM = 133.5, 110 mol) of chlorination reagent NCS (N-chlorosuccinimide), and 240 kg of dichloromethane, and stirred at 40°C for 26 hours. The raw materials were subjected to post-processing after the reaction was complete by liquid chromatography.

[0091] Post-treatment: After the reaction is completed, the temperature is lowered to 0-5°C for 4 hours. The solid is centrifuged to recover NHS (succinimide), which can be re-chlorinated to NCS (N-chlorosuccinimide) and then used.

[0092] The filtrate was washed once with 200 kg of 5% sodium bicarbonate aqueous solution and once with 200 kg of water. The organic layer was dried with anhydrous magnesium sulfate and then filtered. The filtrate was added with activated carbon and refluxed for 30 minutes for decolorization, then filtered and the solvent dichloromethane was removed by atmospheric distillation to obtain 30.4 kg of light yellow liquid. The molar yield was 93%, the liquid content was 98.4%, and the specific rotation was +18.6° (anhydrous ethanol).

[0093] Example 20 The synthesis of (R) 2-(4-chloro-2-methylphenoxy) propionate is as follows: (1:1.1)

[0094] A 500L reactor was charged with 29.2kg (WM=292, 100mol) of (R) 2-methylphenoxypropionate, 14.7kg (WM=133.5, 110mol) of chlorination reagent NCS (N-chlorosuccinimide), and 240kg of carbon tetrachloride, and stirred at 50°C for 24 hours. The raw materials were subjected to post-processing after the reaction was complete by liquid chromatography.

[0095] Post-treatment: After the reaction is completed, the temperature is lowered to 0-5°C for 4 hours. The solid is centrifuged to recover NHS (succinimide), which can be re-chlorinated to NCS (N-chlorosuccinimide) and then used.

[0096] The filtrate was washed once with 200 kg of 5% sodium bicarbonate aqueous solution and once with 200 kg of water. The organic layer was dried with anhydrous magnesium sulfate and then filtered. The filtrate was added with activated carbon and refluxed for 30 minutes for decolorization, then filtered and the solvent dichloromethane was removed by atmospheric distillation to obtain 30.7 kg of light yellow liquid. The molar yield was 92.2%, the liquid content was 99.2%, and the specific rotation was +19.8° (anhydrous ethanol).

[0097] Example 21 The synthesis of (R) 2-(4-chloro-2-methylphenoxy) propionate is as follows: (1:1.2)

[0098] A 500L reactor was charged with 29.2 kg (WM = 292, 100 mol) of (R) 2-methylphenoxypropionate, 240 kg of carbon tetrachloride, and 14.7 kg (WM = 133.5, 110 mol) of chlorination reagent NCS (N-chlorosuccinimide) in sequence, and the mixture was heated to 55°C and stirred for 20 hours. The raw materials were subjected to post-processing after the reaction was complete by liquid chromatography.

[0099] Post-treatment: After the reaction is completed, the temperature is lowered to 0-5°C for 4 hours. The solid is centrifuged to recover NHS (succinimide), which can be re-chlorinated to NCS (N-chlorosuccinimide) and then used.

[0100] The filtrate was washed once with 200 kg of 5% sodium bicarbonate aqueous solution and once with 200 kg of water. The organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was added with activated carbon and refluxed for decolorization for 30 minutes, then filtered and the solvent carbon tetrachloride was removed by atmospheric distillation to obtain 29.4 kg of yellow liquid with a molar yield of 90%, a liquid content of 99%, and a specific rotation of +19.2° (anhydrous ethanol).

[0101] Example 22 The synthesis of (R) 2-(4-chloro-2-methylphenoxy) propionate is as follows: (1:1.1)

[0102] A 500L reactor was charged with 29.2 kg (WM=292, 100 mol) of (R) 2-methylphenoxypropionate, 240 kg of dichloromethane, and 23 kg (WM=208, 110 mol) of chlorination reagent phosphorus pentachloride in sequence, and the temperature was raised to 40°C and stirred for 20 hours. The raw materials were subjected to post-processing after the reaction was complete by liquid chromatography.

[0103] Post-treatment: After the reaction is completed, the temperature is lowered to 0-5°C and then slowly transferred into another 500L reactor filled with 200kg ice water, and kept at 0-15°C. After stirring for 1 hour, the mixture is allowed to stand for stratification. The organic layer is at the bottom, washed twice with water, 200kg each time, and then washed once with 200kg of 5% sodium bicarbonate aqueous solution, and washed once with 200kg of water. The organic layer is dried with anhydrous magnesium sulfate and then filtered. After adding activated carbon to the filtrate for 30 minutes of reflux decolorization, the filtrate is filtered, and the solvent carbon tetrachloride is removed by atmospheric distillation to obtain 29.4kg of yellow liquid, with a molar yield of 90%, a liquid content of 98%, and a specific rotation of +17.5° (anhydrous ethanol).

[0104] Comparative Example 1 The synthesis of (R) 2-(4-chloro-2-methylphenoxy) propionate is as follows:

[0105] A 500L reactor was charged with 29.2kg (WM=292,100mol) of (R)2-methylphenoxypropionic acid isooctyl ester, 8.52kg (WM=71,120mol) of chlorination reagent chlorine, and 240kg of carbon tetrachloride, and stirred at 10°C for 24 hours. Liquid chromatography showed that the reaction of the raw materials was not complete. The product content was 69%, and the raw material content was 20%.

[0106] Comparative Example 2 (R) The synthesis of 2-(4-chloro-2-methylphenoxy)propionate is as follows:

[0107] A 500L reactor was charged with 29.2kg (WM=292, 100mol) of (R) 2-methylphenoxypropionic acid isooctyl ester, 200kg of water, and 4.4kg (WM=36.5, 120mol) of 30% hydrochloric acid, and the temperature was controlled below 15°C. Hydrogen peroxide was added dropwise and stirred for 24 hours. Liquid chromatography showed that the reaction of the raw materials was not complete. The product content was 73%, and the raw material content was 15%.

[0108] Example 23 Recovery of NHS (succinimide) to synthesize NCS (N-chlorosuccinimide)

[0109] A 100L reactor was added with 10kg NHS (succinimide), 3kg sodium acetate and 50kg water in sequence. After stirring to dissolve, chlorine gas was introduced at 25°C until the reaction was complete. The mixture was cooled to 10°C and stirred for 2 hours, then centrifuged and dried to obtain 10.4kg of the mixture, with a liquid content of 99.4% and a molar yield of 80%.

[0110] Example 24 Recovery of NHS (succinimide) to synthesize NCS (N-chlorosuccinimide)

[0111] 300L reactor NHS (succinimide) 20kg, hydrochloric acid 10kgkg, acetic acid 20kg, water 80kg, heated and stirred, dissolved at about 35℃, then cooled to -5℃, added 10% sodium hypochlorite aqueous solution 195kg at 0℃, and completed in about 1 hour. After the addition, heat and stir for 2 hours, centrifuge, dry to obtain 23kg, liquid content 99.6%, molar yield 86%.

[0112] Table 1: Step 1 condensation reaction condition parameter table

[0113]

[0114]

[0115] Table 2: Step 2 Esterification Reaction Conditions Parameters

[0116]

[0117]

[0118] Table 3: Step 3 Chlorination Reaction Conditions Parameters

[0119]

Claims

1. A method for preparing a (R) 2-(4-chloro-2-methylphenoxy) propionate root inhibitor, characterized in that: The steps include: Step 1. Synthesis of (R)2-methylphenoxypropionic acid: L-2-chloropropionic acid and o-cresol undergo condensation reaction under the promotion of a base to obtain (R)2-methylphenoxypropionic acid; Step 2. Synthesis of (R)2-methylphenoxypropionic acid isooctyl ester: (R)2-methylphenoxypropionic acid and isooctyl alcohol (2-ethylhexanol) are subjected to an esterification reaction in the presence of a catalyst to obtain (R)2-methylphenoxypropionic acid isooctyl ester; Step 3. Synthesis of (R)2-(4-chloro-2-methylphenoxy)propionate isooctyl ester: (R)2-methylphenoxypropionate is chlorinated with a chlorinating agent to obtain (R)2-(4-chloro-2-methylphenoxy)propionate isooctyl ester; The synthetic route is as follows:

2. The method for preparing the (R) 2-(4-chloro-2-methylphenoxy) propionate root inhibitor as claimed in claim 1, characterized in that: The alkali described in step 1 is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide potassium carbonate, and sodium carbonate.

3. The method for preparing the (R) 2-(4-chloro-2-methylphenoxy) propionate root inhibitor as claimed in claim 2, characterized in that: In step 1, the molar ratio of L-2-chloropropionic acid, o-cresol and alkali is 1:1.0:1.0 to 1:1.5:3.

0.

4. The method for preparing the (R) 2-(4-chloro-2-methylphenoxy) propionate root inhibitor as claimed in claim 2 or 3, characterized in that: The temperature of the condensation reaction in step 1 is 0° C. to 100° C., and the time of the condensation reaction is 1 d to 4 d.

5. The method for preparing the (R) 2-(4-chloro-2-methylphenoxy) propionate root inhibitor as claimed in claim 1, characterized in that: The catalyst described in step 2 is one or more of concentrated sulfuric acid, phosphoric acid, p-toluenesulfonic acid, benzenesulfonic acid, solid acid or ionic liquid.

6. The method for preparing the (R) 2-(4-chloro-2-methylphenoxy) propionate root inhibitor as claimed in claim 5, characterized in that: In step 2, the molar ratio of (R)2-methylphenoxypropionic acid, isooctyl alcohol (2-ethylhexanol) and catalyst is 1:0.8:0.005 to 1:2.0:0.

015.

7. The method for preparing the (R) 2-(4-chloro-2-methylphenoxy) propionate root inhibitor as claimed in claim 5, characterized in that: In step 2, the esterification reaction is carried out in a solvent, and the solvent is one or more of n-hexane, cyclohexane or toluene.

8. The method for preparing the (R) 2-(4-chloro-2-methylphenoxy) propionate root inhibitor as claimed in claim 5, characterized in that: The temperature of the esterification reaction in step 2 is 60° C. to 113° C., and the time of the esterification reaction is 2 h to 8 h.

9. The method for preparing the (R) 2-(4-chloro-2-methylphenoxy) propionate root inhibitor as claimed in claim 1, characterized in that: The chlorination reagent described in step 3 is one or more of NCS (N-chlorosuccinimide), chlorine gas or phosphorus pentachloride.

10. The method for preparing the (R) 2-(4-chloro-2-methylphenoxy) propionate root inhibitor as claimed in claim 9, characterized in that: The molar ratio of (R)2-methylphenoxypropionate to the chlorinating agent is 1:1.0 to 1.0:2.

0.

11. The method for preparing the (R) 2-(4-chloro-2-methylphenoxy) propionate root inhibitor as claimed in claim 9, characterized in that: The chlorination reaction is carried out in a solvent, which is one or more of dichloromethane, chloroform, carbon tetrachloride or tetrahydrofuran.

12. The method for preparing the (R) 2-(4-chloro-2-methylphenoxy) propionate root inhibitor as claimed in claim 9, characterized in that: The temperature of the chlorination reaction is 20°C to 80°C, and the time of the chlorination reaction is 24h to 72h.

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