CN100522936C

CN100522936C - Synthesis process of 2,4-dichloro-5-sulfonyl benzoic acid

Info

Publication number: CN100522936C
Application number: CNB2007100235914A
Authority: CN
Inventors: 谭建平
Original assignee: JIANGSU TIANZE CHEMICAL CO Ltd
Current assignee: JIANGSU TIANZE CHEMICAL CO Ltd
Priority date: 2007-06-11
Filing date: 2007-06-11
Publication date: 2009-08-05
Anticipated expiration: 2027-06-11
Also published as: CN101066943A

Abstract

The synthesis process of 2, 4-dichloro-5-sulfonyl benzoic acid belongs to the field of medicine intermediate synthesizing technology. The synthesis process includes the following steps: preparing compound II (2, 4-dichloro-5-sulfurylchloro benzoic acid) through reaction between compound I (2, 4-dichrloro trichloro benzyl) and chloro sulfonic acid in the presence of catalyst, ice dissociating the resultant, filtering and washing; obtaining coarse compound III (2, 4- dichrloro-5-sulfonyl benzoic acid) product with the compound II, and through aminolsys and acidifying; and preparing 2, 4-dichloro-5-sulfonyl benzoic acid product with the coarse compound III product, and through dissolving in water, decolorizing and recrystallization. The present invention has the advantages of low material cost, high product yield, high product purity, and is suitable for industrial production.

Description

2, the synthetic method of 4-two chloro-5-sulfamoylbenzoic acids

Technical field:

The present invention relates to 2, the synthetic method of 4-two chloro-5-sulfamoylbenzoic acids belongs to the synthesis technical field of medicine intermediate.

Background technology:

2,4-two chloro-5-sulfamoylbenzoic acids are a kind of important medicine intermediates, are the important source material that is used for medicines such as synthetic furan thiophene miaow, furosemide.Its structural formula is as follows:

At present, Synthetic 2, the traditional technology of 4-two chloro-5-sulfamoylbenzoic acids is with 2, the 4-dichlorobenzoic acid is a raw material, and periodical report (Shanghai No.6 Pharmaceutical Factory, the trial-production method of new diuresis-furosemide are arranged, Chinese Journal of Pharmaceuticals, 1973 (01), 25-26), ice in frozen water after this raw material and the chlorsulfonic acid reaction and separate, ammonia is separated in ammoniacal liquor again, gets crude product through acidifying, to crude product refining, specifically be then with a large amount of hydro-thermal dissolvings, decolouring, recrystallization gets 2,4-two chloro-5-sulfamoylbenzoic acids.This technology is because reaction raw materials is a 2,4 dichloro benzene formic acid, so cost is higher; Owing to 2,4-two chloro-5-sulfamoylbenzoic acids solubleness in water is less in treating process, and the consumption of water is very big, and therefore big to the consumption of the energy, the device space is utilized rate variance; Yield is low, only is 49.5%.Synthetic route is as follows:

Summary of the invention:

The object of the present invention is to provide a kind of 2, the synthetic method of 4-two chloro-5-sulfamoylbenzoic acids, this method material choice is reasonable, the product yield height, consumes energy is few and be beneficial to and reduce preparation cost and be suitable for suitability for industrialized production.

The objective of the invention is to reach like this, a kind of 2, the synthetic method of 4-two chloro-5-sulfamoylbenzoic acids, it may further comprise the steps:

A) prepare Compound I I with Compound I, in the presence of catalyzer, with Compound I 2,4-dichloro three benzyl chlorides and chlorsulfonic acid reaction, after reaction finishes reactant joined in the frozen water ice and separate, ice is separated and is finished laggard row insulation, filters then, washes, obtain Compound I I2,4-two chloro-5-SULPHURYL CHLORIDE phenylformic acid;

B) prepare compound III by Compound I I, Compound I I is carried out ammonia separate, acidifying obtains crude product compound III 2,4-two chloro-5-sulfamoylbenzoic acids;

C) dissolving in alcohol solution of crude product compound III, decolouring, recrystallization are obtained 2,4-two chloro-5-sulfamoylbenzoic acid finished products, wherein: the catalyzer steps A) is any one in sulfuric acid, iron trichloride, the zinc dichloride, the temperature of the insulation steps A) is 0～40 ℃, and soaking time is 4-10h.

The mol ratio of Compound I steps A in one embodiment of the invention) and chlorsulfonic acid, catalyzer is 1:4-10:0.7-1.0.

The reaction times of the reaction in another embodiment of the present invention, steps A) is 1-6h, and temperature of reaction is 130-150 ℃.

In yet another embodiment of the present invention, the ammonia that the ammonia step B) is separated and the mol ratio of Compound I are 3-10:1.

In another embodiment of the present invention, step C) alcohol described in is any one in methyl alcohol, ethanol, the Virahol.

Preparation method disclosed in this invention is owing to selected 2 for use, 4-dichloro three benzyl chlorides are raw material and preferred processing step, therefore compared with the prior art, not only reduced raw materials cost, and improved 2, the yield of 4-two chloro-5-sulfamoylbenzoic acids, yield 70%, fusing point 232-234 ℃, content are more than 99%, for industrial mass manufacture provides guarantee.

Embodiment

The reaction formula of the synthetic method that the present invention recommended is as follows:

Embodiment 1:

A) produce Compound I I by Compound I, specifically: in three mouthfuls of reaction flasks of 250ml, input is as 2 of Compound I, 4-dichloro three benzyl chloride 30g (0.11mol), chlorsulfonic acid 100g (0.86mol), catalyzer vitriol oil 8g (0.08mol), slowly be heated to 135 ℃, reaction 4h, reduce to room temperature, reactant is added drop-wise to ice in the frozen water of 400g and separates, ice is separated temperature control below 2 ℃, drips off the back and stirs 5h 20 ℃ (holding temperature), and suction filtration gets white solid then, extremely neutral with clear water washing filter cake, Compound I I, promptly 2,4-two chloro-5-SULPHURYL CHLORIDE phenylformic acid;

B) produce compound III by Compound I I, will be by steps A) the Compound I I of gained joins in the ammoniacal liquor of 70g20% (0.4mol) in batches, temperature of reaction is controlled at below 10 ℃, add back room temperature reaction 1h, drop to pH1-2 with 30% hydrochloric acid again, the dropping temperature of hydrochloric acid is below 10 ℃, stir 15min, suction filtration obtains the crude product compound III of white solid, and promptly 2,4-two chloro-5-sulfamoylbenzoic acid crude products;

C) the crude product compound III is joined 250g and contain in the 10% alcoholic acid aqueous solution, be heated to backflow, decolorizing with activated carbon, hot suction filtration, filtrate are reduced to 0 ℃, and cold analysis gets pure product, through suction filtration, dry finished product 2,4-two chloro-5-sulfamoylbenzoic acid 20.8g (HPLC〉99%).

Embodiment 2:

Only with steps A) in chlorsulfonic acid change 64g (0.55mol) into by 100g, finished product 15.6g (HPLC〉99%).All the other are with the description to embodiment 1.

Embodiment 3:

Only with steps A) in chlorsulfonic acid change 116.5g (1.0mol) into by 100g, frozen water changes 600g into by 400g, finished product 20g (HPLC〉99%).All the other are all with the description to embodiment 1.

Embodiment 4:

Only with steps A) in temperature of reaction change 145 ℃ into by 135 ℃, the reaction times changes 2h into, finished product 19.6g (HPLC〉99%).All the other are with the description to embodiment 1.

Embodiment 5:

Only with steps A) in catalyzer change iron trichloride into by the vitriol oil, finished product 20.1g (HPLC〉99%).All the other are with the description to embodiment 1.

Embodiment 6:

Only with steps A) in ice separate the back holding temperature and change 35 ℃ into by 20 ℃, finished product 16.4g (HPLC〉99%).All the other are all with the description to embodiment 1.

Embodiment 7:

Only with steps A) in ice separate the back holding temperature and change 5 ℃ into by 20 ℃, soaking time 8h, finished product 18.4g (HPLC〉99%).All the other are with the description to embodiment 1.

Embodiment 8:

Only with step B) in ammonia when separating ammonia change 60g 20% (0.34mol) into by 70g 20% (0.4mol), finished product 16.4g (HPLC〉99%).All the other are with the description to embodiment 1.

Embodiment 9:

Only with step B) in ammonia when separating ammoniacal liquor change 140g 20% (0.8mol) into by 70g 20% (0.4mol), finished product 20.7g (HPLC〉99%).All the other are with the description to embodiment 1.

Embodiment 10:

Only with step C) in ethanol change methyl alcohol into, finished product 20.5g (HPLC〉99%).All the other are all with the description to embodiment 1.

Claims

1, a kind of 2, the synthetic method of 4-two chloro-5-sulfamoylbenzoic acids is characterized in that it may further comprise the steps:

2, according to claim 12, the synthetic method of 4-two chloro-5-sulfamoylbenzoic acids is characterized in that steps A) described in Compound I and the mol ratio of chlorsulfonic acid, catalyzer be 1:4-10:0.7-1.0.

3, according to claim 12, the synthetic method of 4-two chloro-5-sulfamoylbenzoic acids is characterized in that steps A) described in reaction times of reaction be 1-6h, temperature of reaction is 130-150 ℃.

4, according to claim 12, the synthetic method of 4-two chloro-5-sulfamoylbenzoic acids is characterized in that step B) described in the ammonia separated of ammonia and the mol ratio of Compound I be 3-10:1.

5, according to claim 12, the synthetic method of 4-two chloro-5-sulfamoylbenzoic acids is characterized in that step C) described in alcohol be in methyl alcohol, ethanol, the Virahol any one.