CN109456295B - Micro-channel method synthesis process of 3-isochromanone - Google Patents
Micro-channel method synthesis process of 3-isochromanone Download PDFInfo
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- CN109456295B CN109456295B CN201811511061.9A CN201811511061A CN109456295B CN 109456295 B CN109456295 B CN 109456295B CN 201811511061 A CN201811511061 A CN 201811511061A CN 109456295 B CN109456295 B CN 109456295B
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- isochromanone
- phenylacetic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
Abstract
The invention discloses a micro-channel synthesis process of 3-isochromanone, which comprises the following reaction steps: 1) preparing o-chloromethyl phenylacetic acid by taking sulfonyl chloride as a chlorination reagent at a proper temperature in a proper solvent by using a microchannel reaction technology and taking o-methyl phenylacetic acid as a raw material; 2) the synthesized o-chloromethyl phenylacetic acid is cyclized under proper alkali and temperature without purification to obtain the 3-isochromanone. Through the mode, the method can produce the o-chloromethyl phenylacetic acid with high yield, high purity and controllability, and the o-chloromethyl phenylacetic acid can successfully produce the target product, namely the 3-isochromanone under the alkaline condition.
Description
Technical Field
The invention relates to the field of production processes of medicine and pesticide intermediates, in particular to a micro-channel synthesis process of 3-isochromanone.
Background
The strobilurin fungicide is a new fungicide in recent years, has the advantages of broad spectrum, high efficiency, systemic property, low toxicity, environmental friendliness and the like, has ever-increasing market demand, and has new products; 3-isochromanone is mostly needed to be used as an upstream compound for synthesizing an active group of the product, and is an essential important intermediate, so the market demand of 3-isochromanone is continuously increased.
Various methods are available for synthesizing 3-isochromanone, but factors such as raw material cost, product yield and the like can influence the production of the 3-isochromanone, so that the selection of proper raw materials and production process is very important for realizing the industrial production of the 3-isochromanone. At present, the process used in large-scale production mostly uses o-methylphenylacetic acid as a raw material, performs methyl chlorination reaction through chlorine gas to generate o-chloromethylphenylacetic acid, and then closes a ring to form 3-isochromanone under an alkaline condition; however, the chlorination reaction of o-tolylacetic acid belongs to a free radical reaction, which comprises three stages of chain initiation, chain growth and chain termination, wherein the methyl can still undergo chlorination reaction after being chlorinated once, so that polychlorinated side reactions are generated, byproducts are increased, and the yield of the product 3-isochromanone is not high and the purity is low.
In view of the good market prospect of the 3-isochromanone, the development of a new process can limit the polychlorinated side reaction of o-tolylacetic acid, can improve the yield and purity of the product 3-isochromanone, and can generate good social benefit and economic benefit, which is very significant.
Disclosure of Invention
The invention mainly solves the technical problem of providing a micro-channel synthesis process of 3-isochromanone, which can produce o-chloromethyl phenylacetic acid with high yield, high purity and controllability, and can produce a target product of 3-isochromanone smoothly under an alkaline condition.
In order to solve the technical problems, the invention adopts a technical scheme that:
provides a micro-channel method synthesis process of 3-isochromanone, and the production process route is as follows:
1) preparing o-chloromethyl phenylacetic acid by taking sulfonyl chloride as a chlorination reagent at a proper temperature in a proper solvent by using a microchannel reaction technology and taking o-methyl phenylacetic acid as a raw material;
2) the synthesized o-chloromethyl phenylacetic acid is cyclized under proper alkali and temperature without purification to obtain the 3-isochromanone.
In a preferred embodiment of the present invention, the temperature in step 1) is 80-120 ℃.
In a preferred embodiment of the present invention, the solvent used in step 1) is one or more of dichloromethane, chloroform, benzene, toluene, chlorobenzene, o-dichlorobenzene, 1, 2-dichloroethane, and tetrachloroethylene.
In a preferred embodiment of the present invention, the molar mass ratio of o-tolylacetic acid to sulfonyl chloride in step 1) is 1: 1 to 2.
In a preferred embodiment of the present invention, the temperature in step 2) is in the range of 40 to 100 ℃.
In a preferred embodiment of the present invention, the temperature in step 2) is in the range of 50 to 80 ℃.
In a preferred embodiment of the present invention, the base used in step 2) is a mixture of one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
In a preferred embodiment of the present invention, in the cyclization reaction system of step 2), the pH value is maintained in the range of 7.5-8.5.
The invention has the beneficial effects that: the micro-channel method synthesis process of the 3-isochromanone can limit the polychlorinated side reaction of the o-tolylacetic acid, improve the yield and the purity of the product 3-isochromanone, and can controllably produce the o-tolylacetic acid with high yield and high purity, and the o-tolylacetic acid can smoothly produce the target product 3-isochromanone under the alkaline condition.
Drawings
FIG. 1 is a nuclear magnetic spectrum of a 3-isochromanone product produced by the synthetic method of the present invention.
Detailed Description
The following detailed description of the preferred embodiments of the present invention is provided to enable those skilled in the art to more readily understand the advantages and features of the present invention, and to clearly and unequivocally define the scope of the present invention.
A micro-channel synthesis process of 3-isochromanone comprises the following production process route:
1) preparing o-chloromethylphenylacetic acid by taking sulfonyl chloride as a chlorination reagent at a temperature of 80-120 ℃ in a proper solvent by using a microchannel reaction technology by taking o-methylphenylacetic acid as a raw material; wherein the solvent is one or more of dichloromethane, trichloromethane, benzene, toluene, chlorobenzene, o-dichlorobenzene, 1, 2-dichloroethane and tetrachloroethylene; the molar mass ratio of the o-tolylacetic acid to the sulfonyl chloride is 1: 1-2; in the step, the temperature is preferably in the range of 100-120 ℃.
2) The synthesized o-chloromethyl phenylacetic acid is subjected to cyclization reaction in proper alkali at the temperature of 40-100 ℃ without purification to obtain 3-isochromanone; the base used is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate, wherein lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate are preferably adopted; in the step, the reaction temperature is preferably 50-80 ℃, and the pH value in the cyclization reaction system is kept in the range of 7.5-8.5.
Example 1:
50 g of o-tolylacetic acid and 50 g of sulfonyl chloride are respectively prepared into 250 mL of chlorobenzene solution, the temperature of the microchannel reactor is set to be 80 ℃, and the chlorobenzene solution of the two raw materials is input into the microchannel reactor at the flow rate of 5mL/min for reaction; collecting reaction liquid, washing the reaction liquid once by cold water, adjusting the pH value to 8 by 20 percent liquid alkali, preserving the temperature for reaction at 60 ℃, detecting that a reaction system is unchanged by HPLC, washing the reaction liquid by 100 ml of water, drying the organic phase, concentrating the organic phase to remove the solvent, recrystallizing the remainder by using methanol, filtering and drying the residue to obtain 18 g of 3-isochromanone with the yield of 36 percent and the purity of 99.1 percent, wherein 1HNMR (CDCl3,400MHz) delta is 3.72(s,2H, CH2),5.32(s,2H, CH2),7.22 to 7.35(m,4H, ArH).
Example 2:
50 g of o-tolylacetic acid and 50 g of sulfonyl chloride are respectively prepared into 250 mL of chlorobenzene solution, the temperature of the microchannel reactor is set to be 90 ℃, and the chlorobenzene solution of the two raw materials is input into the microchannel reactor at the flow rate of 5mL/min for reaction; collecting reaction liquid, washing the reaction liquid once by cold water, adjusting the pH value to 8 by using 10% potassium carbonate aqueous solution, preserving the temperature for reaction at 60 ℃, detecting that a reaction system is unchanged by HPLC, washing the reaction system by using 100 ml of water, drying the organic phase, concentrating the organic phase to remove a solvent, recrystallizing the remainder by using methanol, filtering and drying the residue to obtain 24 g of 3-isochromanone, wherein the yield is 49%, and the purity is 99.2%.
Example 3:
50 g of o-tolylacetic acid and 50 g of sulfonyl chloride are respectively prepared into 250 mL of chlorobenzene solution, the temperature of the microchannel reactor is set to be 120 ℃, and the chlorobenzene solution of the two raw materials is input into the microchannel reactor at the flow rate of 5mL/min for reaction; collecting reaction liquid, washing once with cold water, adjusting the pH value to 7.5 with saturated sodium bicarbonate water solution, keeping the temperature at 50 ℃ for reaction, detecting that a reaction system is unchanged by HPLC, washing with 100 ml of water, drying with organic phase, concentrating to remove a solvent, recrystallizing residues with methanol, filtering, and drying to obtain 36 g of 3-isochromanone with the yield of 73% and the purity of 99.5%.
Example 4:
respectively preparing 50 g of o-tolylacetic acid and 50 g of sulfonyl chloride into 250 mL of o-dichlorobenzene solutions, setting the temperature of a microchannel reactor to be 120 ℃, and inputting the o-dichlorobenzene solutions of the two raw materials into the microchannel reactor at the flow rate of 5mL/min for reaction; collecting reaction liquid, washing once with cold water, adjusting the pH value to 7.5 with saturated potassium bicarbonate water solution, keeping the temperature at 80 ℃ for reaction, detecting that a reaction system is unchanged by HPLC, washing with 100 ml of water, drying with an organic phase, concentrating to remove a solvent, recrystallizing residues with methanol, filtering by suction, and drying to obtain 30 g of 3-isochromanone with the yield of 61% and the purity of 99.4%.
Example 5:
50 g of o-tolylacetic acid and 50 g of sulfonyl chloride are respectively prepared into 250 mL of tetrachloroethylene solution, the temperature of the microchannel reactor is set to be 120 ℃, and the tetrachloroethylene solutions of the two raw materials are input into the microchannel reactor at the flow rate of 5mL/min for reaction; collecting reaction liquid, washing once with cold water, adjusting the pH value to 7.2 with saturated potassium bicarbonate water solution, keeping the temperature at 50 ℃ for reaction, detecting that a reaction system is unchanged by HPLC, washing with 100 ml of water, drying with an organic phase, concentrating to remove a solvent, recrystallizing residues with methanol, filtering by suction, and drying to obtain 39 g of 3-isochromanone with the yield of 79 percent and the purity of 99.5 percent.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all modifications of equivalent structures and equivalent processes performed by the present specification and drawings, or directly or indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (1)
1. A micro-channel method synthesis process of 3-isochromanone is characterized in that the production process route is as follows:
1) 50 g of o-tolylacetic acid is taken as a raw material, 50 g of sulfonyl chloride is taken as a chlorination reagent to prepare o-chloromethylphenylacetic acid by using a microchannel reaction technology at 120 ℃ in a tetrachloroethylene solution;
2) the synthesized o-chloromethyl phenylacetic acid is subjected to cyclization reaction without purification by adjusting the pH to 7.2 and 50 ℃ with a saturated potassium bicarbonate aqueous solution to obtain the 3-isochromanone.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1222150A (en) * | 1996-06-17 | 1999-07-07 | 曾尼卡有限公司 | Process for preparing 3-isochromanone |
| CN102796039A (en) * | 2012-08-16 | 2012-11-28 | 浙江工业大学 | Method for continuous preparation of 2-chloro-5-chloromethylpyridine in microchannel |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1222150A (en) * | 1996-06-17 | 1999-07-07 | 曾尼卡有限公司 | Process for preparing 3-isochromanone |
| CN102796039A (en) * | 2012-08-16 | 2012-11-28 | 浙江工业大学 | Method for continuous preparation of 2-chloro-5-chloromethylpyridine in microchannel |
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