CN102531888B - Chemical synthesis method of 3,4,5-trimethoxy benzoyl chloride - Google Patents

Abstract

The invention discloses a chemical synthesis method of 3,4,5-trimethoxybenzoyl chloride. The synthesis method is based on 3,4,5-trimethoxybenzoic acid and bis(trichloromethyl)carbonate The raw material is fully reacted in an organic solvent under the action of an organic amine catalyst at 20-70° C. to prepare the 3,4,5-trimethoxybenzoyl chloride. The invention has the advantages of reasonable process, low production cost, high reaction yield and good product quality, and is suitable for industrialized production.

Description

A kind of chemical synthesis method of 3,4,5-trimethoxybenzoyl chloride

(1) Technical field

The invention relates to a method for synthesizing the key intermediate 3,4,5-trimethoxybenzoyl chloride of the gastrointestinal antispasmodic drug trimebutine maleate. the

(2) Background technology

3,4,5-Trimethoxybenzoyl chloride is a key intermediate in the synthesis of trimebutine maleate, which is an amino ester compound developed by Jouveinal company in France, belonging to the gastric Intestinal motility drugs were first launched in France in 1970 and in my country in 2000; in 2004, they entered the national medical insurance directory. the

Before the present invention provides, the synthetic method of 3,4,5-trimethoxybenzoyl chloride in the prior art is mostly prepared by the chlorination reaction of 3,4,5-trimethoxybenzoic acid and thionyl chloride get. For example, "Heilongjiang Medical Science" 1998, 21 (3): 48-49 proposes the following process: 30 g (0.14 mol) of 3,4,5-trimethoxybenzoic acid is added to 140 g of xylene, and dehydrated at normal pressure. After 50 mL was evaporated, 0.15 g (0.001 mol) of anhydrous aluminum trichloride was added, kept at 80°C, and 16.6 g (0.14 mol) of thionyl chloride was slowly added dropwise within 3 hours. After dropping, the temperature was raised to 85°C, and 3,4,5-trimethoxybenzoyl chloride was obtained after 2 hours of reaction. the

The tail gas of the thionyl chloride process contains a large amount of asphyxiating sulfur dioxide, and the emission of sulfur dioxide is one of the six indicators for national environmental protection to control the atmosphere. The treatment of the three wastes is difficult and expensive. In addition, the transportation and use of thionyl chloride are strictly controlled, which requires high sealing of the reaction equipment, large investment and poor production safety. the

At present, bis(trichloromethyl)carbonate has gradually replaced thionyl chloride as the chlorination reagent in the reaction of preparing acid chlorides from many carboxylic acids. The usual preparation method is to chlorinate carboxylic acid to form acid chloride under the catalysis of organic amine. But we find in experiment, in the reaction of using bis(trichloromethyl)carbonate as 3,4,5-trimethoxybenzoic acid synthetic 3,4,5-trimethoxybenzoyl chloride as chlorination reagent Among them, when conventional organic amines such as triethylamine and DMF are used as catalysts, the reaction yield is low, which is not suitable for industrial production. the

Therefore, for the unfavorable factors of the above industrial production, it is necessary to improve the existing technology. the

(3) Contents of the invention

The technical problem to be solved by the present invention is to provide a chemical synthesis method of 3,4,5-trimethoxybenzoyl chloride with reasonable process, low production cost, high reaction yield and good product quality. the

In order to solve the problems of the technologies described above, the technical scheme adopted in the present invention is as follows:

A kind of chemical synthesis method of 3,4,5-trimethoxybenzoyl chloride, described synthetic method is to be raw material with 3,4,5-trimethoxybenzoic acid and bis(trichloromethyl) carbonate, in Fully react at 20-70°C under the action of an organic amine catalyst in an organic solvent to obtain the 3,4,5-trimethoxybenzoyl chloride; the reaction equation is as follows:

The organic amine catalyst is selected from one of the following: three (2-cyanomethyl) amine, three (2-cyanoethyl) amine, three (2-cyanopropyl) amine, N, N, N ', N'-tetrakis(3-cyanomethyl)ethylenediamine, N,N,N',N'-tetrakis(3-cyanoethyl)ethylenediamine, N,N,N',N' -Tetrakis(3-cyanopropyl)ethylenediamine, N,N-bis(3-cyanomethyl)benzylamine, N,N-bis(3-cyanoethyl)benzylamine, N,N- Di(3-cyanopropyl)benzylamine, N-(3-cyanopropyl)benzylamine;

The reaction solvent is selected from one of the following: toluene, xylene, methylene chloride, carbon tetrachloride, 1,2-dichloroethane, 1,4-dioxane, ethyl acetate, n-hexane, Tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile. the

In the present invention, described 3,4,5-trimethoxybenzoic acid, bis(trichloromethyl)carbonate, the ratio of the amount of feed material of organic amine are 1: 0.33～3.0: 0.03～3.0, preferably 1: 0.33-1.0: 0.05-0.3, more preferably 1: 0.33-0.5: 0.1-0.2. the

In the present invention, the mass usage of the reaction solvent is 1-20 times, preferably 5-20 times, more preferably 10-20 times that of 3,4,5-trimethoxybenzoic acid. the

Further, the organic amine catalyst is preferably N,N,N',N'-tetrakis(3-cyanopropyl)ethylenediamine or tris(2-cyanoethyl)amine, more preferably N,N,N ', N'-tetrakis(3-cyanopropyl)ethylenediamine. the

Further, the reaction solvent is preferably dichloromethane, tetrahydrofuran or 2-methyltetrahydrofuran, more preferably 2-methyltetrahydrofuran. the

For the reaction of the present invention, the reaction time is preferably 4-10 hours; the reaction temperature is preferably 50-70°C. the

The present invention specifically recommends that the chemical synthesis method be carried out according to the following steps: 3,4,5-trimethoxybenzoic acid and organic amine are dissolved in an organic solvent, stirred at 20-70° C. and added dropwise with organic solvent Bis(trichloromethyl)carbonate solution, keep warm for 4-10 hours after the dropwise addition, recover the organic solvent after the reaction, and recrystallize the residual solid to obtain the 3,4,5-trimethoxybenzoyl chloride. The ratio of the amount of the 3,4,5-trimethoxybenzoic acid, bis(trichloromethyl)carbonate, and organic amines is 1:0.33～1.0:0.03～0.1; the organic solvent is 2-methyltetrahydrofuran; the organic amine catalyst is N, N, N', N'-tetrakis (3-cyanopropyl) ethylenediamine; the mass dosage of the 2-methyltetrahydrofuran is 3, 5 to 20 times the mass of 4,5-trimethoxybenzoic acid; the recrystallization solvent is petroleum ether or cyclohexane dried with calcium chloride. the

Compared with the prior art, the present invention uses bis(trichloromethyl)carbonate as a chlorination reagent, and by selecting a suitable organic amine catalyst and matching a suitable reaction solvent, the reaction generates 3,4,5-trimethoxybenzene Formyl chloride has the advantages of low equipment corrosion, low production cost, mild reaction conditions, simple and safe operation, less waste and easy to handle, high product yield and good quality, and avoids the production of aluminum trichloride, which is sensitive to water and air. The use is a new method suitable for industrialized production. the

Therefore, the synthetic method of the present invention has great implementation value and social and economic benefits. the

(4) Specific implementation methods

The technical solutions of the present invention will be further described below in conjunction with the examples, but the protection scope of the present invention is not limited thereto. the

Example 1

The amount ratio of feed material 3,4,5-trimethoxybenzoic acid: bis(trichloromethyl) carbonate: organic amine catalyst is 1: 0.33: 0.1 feed intake, 3,4,5-trimethoxybenzoic acid 21.2 g (0.1mol); bis(trichloromethyl) carbonate 9.8g (0.033mol); the organic amine catalyst is N, N, N', N'-tetrakis(3-cyanopropyl)ethylenediamine, feeding The mass is 3.28g (0.01mol); the organic solvent is tetrahydrofuran 212g, and its total usage is 10 times the mass of 3,4,5-trimethoxybenzoic acid. the

Dissolve 3,4,5-trimethoxybenzoic acid and organic amine in an organic solvent (the amount of organic solvent used is 7 times the mass of 3,4,5-trimethoxybenzoic acid). Dissolve bis(trichloromethyl)carbonate in an organic solvent (the amount of organic solvent is 3 times the mass of 3,4,5-trimethoxybenzoic acid), and slowly add it dropwise to 3,4,5-trimethoxybenzene In the solution of formic acid and organic amine, the reaction temperature is 70°C, and the reaction ends after 5 hours. the

After the reaction was over, the organic solvent was recovered by distillation under reduced pressure, and the solid remaining in the reaction flask was recrystallized from petroleum ether dried with calcium chloride to obtain a white solid, namely 20.2 g of 3,4,5-trimethoxybenzoyl chloride. The yield is 88%, and the purity is 98.7%. the

Nuclear Magnetic Resonance Spectrum (Bruke): ¹ H NMR (CDCl ₃ , 500MHz): δ (ppm) = 3.91 (6H, s), 3.92 (3H, s), 7.36 (2H, s); ¹³ C NMR (CDCl ₃ , 125MHz): δ (ppm) = 56.2, 60.9, 107.4, 124.1, 142.9, 152.9, 171.8.

Example 2

The amount ratio of feed material 3,4,5-trimethoxybenzoic acid: bis(trichloromethyl) carbonate: organic amine catalyst is 1: 0.33: 0.1 feed intake, 3,4,5-trimethoxybenzoic acid 21.2 g (0.1mol); Two (trichloromethyl) carbonate 9.8g (0.033mol); The organic amine catalyst is N, N, N', N'-tetrakis (3-cyanopropyl) ethylenediamine, feed intake The mass is 3.28g (0.01mol); the organic solvent is tetrahydrofuran 212g, and its total usage is 10 times the mass of 3,4,5-trimethoxybenzoic acid. the

The reaction temperature is 70°C, the reaction time is 8 hours, other operations are the same as in Example 1, 18.9 g of 3,4,5-trimethoxybenzoyl chloride, the yield is 82%, and the purity is 99.0%. the

Example 3

The amount ratio of feed material 3,4,5-trimethoxybenzoic acid: bis(trichloromethyl) carbonate: organic amine catalyst is 1: 0.5: 0.1 feeding, 3,4,5-trimethoxybenzoic acid 21.2 g (0.1mol); bis (trichloromethyl) carbonate 14.85g (0.05mol); the organic amine catalyst is three (2-cyanoethyl) amine, and the feeding quality is 1.76g (0.01mol); the organic solvent is 2 -Methyl tetrahydrofuran 212g, its total consumption is 10 times of the mass of 3,4,5-trimethoxybenzoic acid. the

The reaction temperature is 70°C, the reaction time is 8 hours, other operations are the same as in Example 1, 17.9 g of 3,4,5-trimethoxybenzoyl chloride, the yield is 78%, and the purity is 99.2%. the

Example 4

The amount ratio of feed material 3,4,5-trimethoxybenzoic acid: bis(trichloromethyl) carbonate: organic amine catalyst is 1: 0.5: 0.1 feeding, 3,4,5-trimethoxybenzoic acid 21.2 g (0.1mol); bis(trichloromethyl)carbonate 14.85g (0.05mol); the organic amine catalyst is N,N,N',N'-tetrakis(3-cyanopropyl)ethylenediamine, feeding The mass is 3.28g (0.01mol); the organic solvent is 212g of dichloromethane, and its total consumption is 10 times of the mass of 3,4,5-trimethoxybenzoic acid. the

The reaction temperature is 40° C., the reaction time is 10 hours, other operations are the same as in Example 1, 16.3 g of 3,4,5-trimethoxybenzoyl chloride, the yield is 71%, and the purity is 98.6%. the

Example 5

The amount ratio of feed material 3,4,5-trimethoxybenzoic acid: bis(trichloromethyl) carbonate: organic amine catalyst is 1: 0.33: 0.05 feeding, 3,4,5-trimethoxybenzoic acid 21.2 g (0.1mol); bis(trichloromethyl) carbonate 9.8g (0.033mol); the organic amine catalyst is N, N, N', N'-tetrakis(3-cyanopropyl)ethylenediamine, feeding The mass is 1.64g (0.005mol); the organic solvent is 212g of 2-methyltetrahydrofuran, the total amount of which is 8 times the mass of 3,4,5-trimethoxybenzoic acid. the

The reaction temperature is 50° C., and the reaction time is 7 hours. Other operations are the same as in Example 1. 15.9 g of 3,4,5-trimethoxybenzoyl chloride, the yield is 69%, and the purity is 98.8%. the

Example 6

The amount ratio of feed material 3,4,5-trimethoxybenzoic acid: bis(trichloromethyl) carbonate: organic amine catalyst is 1: 0.33: 0.2 feeding, 3,4,5-trimethoxybenzoic acid 21.2 g (0.1mol); bis(trichloromethyl) carbonate 9.8g (0.033mol); the organic amine catalyst is N, N, N', N'-tetrakis(3-cyanopropyl)ethylenediamine, feeding The mass is 6.56g (0.02mol); the organic solvent is 212g of 2-methyltetrahydrofuran, and its total amount is 15 times the mass of 3,4,5-trimethoxybenzoic acid. the

The reaction temperature is 70°C, the reaction time is 9 hours, other operations are the same as in Example 1, 19.8 g of 3,4,5-trimethoxybenzoyl chloride, the yield is 86%, and the purity is 99.0%. the

Example 7

The amount ratio of feed material 3,4,5-trimethoxybenzoic acid: bis(trichloromethyl) carbonate: organic amine catalyst is 1: 0.5: 0.1 feeding, 3,4,5-trimethoxybenzoic acid 21.2 g (0.1mol); bis(trichloromethyl)carbonate 14.85g (0.05mol); the organic amine catalyst is N,N,N',N'-tetrakis(3-cyanopropyl)ethylenediamine, feeding The mass is 3.28g (0.01mol); the organic solvent is 212g of 2-methyltetrahydrofuran, and its total amount is 10 times the mass of 3,4,5-trimethoxybenzoic acid. the

Reaction temperature is 50 DEG C, and reaction time is 4 hours, and other operations are with example 1,3,4,5-trimethoxybenzoyl chloride 18.6g, yield 81%, purity 98.9%. the

Example 8

The amount ratio of feed material 3,4,5-trimethoxybenzoic acid: bis(trichloromethyl) carbonate: organic amine catalyst is 1: 0.5: 0.1 feeding, 3,4,5-trimethoxybenzoic acid 21.2 g (0.1mol); bis(trichloromethyl)carbonate 14.85g (0.05mol); the organic amine catalyst is N,N,N',N'-tetrakis(3-cyanopropyl)ethylenediamine, feeding The mass is 3.28g (0.01mol); the organic solvent is 212g of 2-methyltetrahydrofuran, and its total amount is 10 times the mass of 3,4,5-trimethoxybenzoic acid. the

The reaction temperature is 40° C., the reaction time is 8 hours, other operations are the same as in Example 1, 14.4 g of 3,4,5-trimethoxybenzoyl chloride, the yield is 68%, and the purity is 97.9%. the

Example 9

The amount ratio of feed material 3,4,5-trimethoxybenzoic acid: bis(trichloromethyl) carbonate: organic amine catalyst is 1: 0.5: 0.1 feeding, 3,4,5-trimethoxybenzoic acid 21.2 g (0.1mol); bis(trichloromethyl)carbonate 14.85g (0.05mol); the organic amine catalyst is N,N-di(3-cyanopropyl)benzylamine, and the feeding quality is 2.41g (0.01mol) ; The organic solvent is 212g of 2-methyltetrahydrofuran, and its total consumption is 10 times of the mass of 3,4,5-trimethoxybenzoic acid. the

The reaction temperature is 70° C., the reaction time is 6 hours, other operations are the same as in Example 1, 16.2 g of 3,4,5-trimethoxybenzoyl chloride, the yield is 70%, and the purity is 98.6%. the

Example 10

The amount ratio of feed material 3,4,5-trimethoxybenzoic acid: bis(trichloromethyl) carbonate: organic amine catalyst is 1: 0.5: 0.1 feeding, 3,4,5-trimethoxybenzoic acid 21.2 g (0.1mol); Bis (trichloromethyl) carbonate 14.85g (0.05mol); The organic amine catalyst is N, N-bis (3-cyanopropyl) benzylamine, and the feeding quality is 2.27g (0.01mol ); the organic solvent is 212g of 2-methyltetrahydrofuran, and its total consumption is 10 times of the quality of 3,4,5-trimethoxybenzoic acid. the

The reaction temperature is 70°C, the reaction time is 10 hours, other operations are the same as in Example 1, 14.6 g of 3,4,5-trimethoxybenzoyl chloride, the yield is 63%, and the purity is 99.2%. the

Comparative Example 1

The amount ratio of feed material 3,4,5-trimethoxybenzoic acid: bis(trichloromethyl)carbonate: organic amine catalyst is 1:0.5:0.05 feeding, 3,4,5-trimethoxybenzoic acid 21.2 g (0.1mol); bis(trichloromethyl)carbonate 14.85g (0.05mol); organic amine catalyst is 1,3-dimethyl-2-imidazolidinone, feeding quality 0.57g (0.05mol); organic The solvent is 318g of dichloromethane, and its total consumption is 15 times of the mass of 3,4,5-trimethoxybenzoic acid. the

The reaction temperature is 30°C, the reaction time is 15 hours, other operations are the same as in Example 1, 13.1 g of 3,4,5-trimethoxybenzoyl chloride, the yield is 57%, and the purity is 98.6%. the

Comparative Example 2

The amount ratio of feed material 3,4,5-trimethoxybenzoic acid: bis(trichloromethyl) carbonate: organic amine catalyst is 1: 0.33: 0.1 feed intake, 3,4,5-trimethoxybenzoic acid 21.2 g (0.1mol); Two (trichloromethyl) carbonate 9.8g (0.033mol); The organic amine catalyst is triethylamine, and the feeding quality 1.01g (0.01mol); The organic solvent is tetrahydrofuran 212g, and its total consumption is 3 , 10 times the mass of 4,5-trimethoxybenzoic acid. the

The reaction temperature is 70°C, the reaction time is 5 hours, other operations are the same as in Example 1, 11.7 g of 3,4,5-trimethoxybenzoyl chloride, the yield is 51%, and the purity is 98.4%. the

Comparative Example 3

The molar ratio of feed material 3,4,5-trimethoxybenzoic acid: bis(trichloromethyl) carbonate: organic amine catalyst is 1: 0.33: 0.1 feed intake, 3,4,5-trimethoxybenzene Formic acid 21.2g (0.1mol); bis (trichloromethyl) carbonate 9.8g (0.033mol); organic amine catalyst is N,N-dimethylformamide, feeding quality 0.73g (0.01mol); organic solvent is Tetrahydrofuran 212g, its total consumption is 10 times of the mass of 3,4,5-trimethoxybenzoic acid. the

The reaction temperature is 70° C., the reaction time is 8 hours, other operations are the same as in Example 1, 10.8 g of 3,4,5-trimethoxybenzoyl chloride, the yield is 47%, and the purity is 98.3%. the

Comparative Example 4

The amount ratio of feed material 3,4,5-trimethoxybenzoic acid: bis(trichloromethyl)carbonate: organic amine catalyst is 1:0.5:0.05 feeding, 3,4,5-trimethoxybenzoic acid 21.2 g (0.1mol); bis(trichloromethyl)carbonate 14.85g (0.05mol); the organic amine catalyst is N,N,N',N'-tetrakis(3-cyanopropyl)ethylenediamine, feeding The mass is 3.28g (0.01mol); the organic solvent is 318g of dichloromethane, and its total amount is 10 times the mass of 3,4,5-trimethoxybenzoic acid. the

The reaction temperature is 90° C., the reaction time is 2 hours, other operations are the same as in Example 1, 10.6 g of 3,4,5-trimethoxybenzoyl chloride, the yield is 46%, and the purity is 98.6%. the

Claims (8)

1. one kind 3,4, the chemical synthesis process of 5-trimethoxy-benzoyl chloride, it is characterized in that: described synthetic method is for raw material with 3,4,5-trimethoxybenzoic acid and two (trichloromethyl) carbonic ethers, in reaction solvent, under organic amine catalyst action, fully react in 20-70 ℃, described in making 3,4,5-trimethoxy-benzoyl chloride;

It is one of following that described organic amine catalyzer is selected from: three (2-cyano ethyl) amine, N, N, N ', N '-tetra-(3-cyanopropyl) quadrol, N, N-bis-(3-cyanopropyl) benzylamine;

It is one of following that described reaction solvent is selected from: methylene dichloride, tetrahydrofuran (THF), 2-methyltetrahydrofuran;

Described 3,4, the ratio of the amount of substance that feeds intake of 5-trimethoxybenzoic acid, two (trichloromethyl) carbonic ether, organic amine is 1:0.33-1.0:0.05-0.3; The quality consumption of described reaction solvent is 5-20 times of 3,4,5-trimethoxybenzoic acid.

2. as claimed in claim 13, the chemical synthesis process of 4,5-trimethoxy-benzoyl chloride, is characterized in that: described 3, the ratio of the amount of substance that feeds intake of 4,5-trimethoxybenzoic acid, two (trichloromethyl) carbonic ether, organic amine is 1:0.33-0.5:0.1-0.2; The quality consumption of described reaction solvent is 10-20 times of 3,4,5-trimethoxybenzoic acid.

As described in one of claim 1-2 3,4, the chemical synthesis process of 5-trimethoxy-benzoyl chloride, it is characterized in that: described organic amine catalyzer is N, N, N ', N '-tetra-(3-cyanopropyl) quadrols or three (2-cyano ethyl) amine.

As described in one of claim 1-2 3,4, the chemical synthesis process of 5-trimethoxy-benzoyl chloride, it is characterized in that: described organic amine catalyzer is N, N, N ', N '-tetra-(3-cyanopropyl) quadrol, described reaction solvent is 2-methyltetrahydrofuran.

5. as claimed in claim 13,4, the chemical synthesis process of 5-trimethoxy-benzoyl chloride, is characterized in that: the reaction times is 4-10 hour.

6. as claimed in claim 53,4, the chemical synthesis process of 5-trimethoxy-benzoyl chloride, is characterized in that: temperature of reaction is 50-70 ℃.

7. as claimed in claim 63,4, the chemical synthesis process of 5-trimethoxy-benzoyl chloride, is characterized in that: described organic amine catalyzer is N, N, N ', N '-tetra-(3-cyanopropyl) quadrols or three (2-cyano ethyl) amine.

8. as claimed in claim 63, the chemical synthesis process of 4,5-trimethoxy-benzoyl chloride, is characterized in that: described 3, the ratio of the amount of substance that feeds intake of 4,5-trimethoxybenzoic acid, two (trichloromethyl) carbonic ether, organic amine is 1:0.33-0.5:0.1-0.2; Described organic amine catalyzer is N, N, N ', N '-tetra-(3-cyanopropyl) quadrol; Described reaction solvent is 2-methyltetrahydrofuran.