CN101066943A - Synthesis process of 2,4-dichloro-5-sulfonyl benzoic acid - Google Patents
Synthesis process of 2,4-dichloro-5-sulfonyl benzoic acid Download PDFInfo
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- CN101066943A CN101066943A CN 200710023591 CN200710023591A CN101066943A CN 101066943 A CN101066943 A CN 101066943A CN 200710023591 CN200710023591 CN 200710023591 CN 200710023591 A CN200710023591 A CN 200710023591A CN 101066943 A CN101066943 A CN 101066943A
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- compound
- chloro
- synthetic method
- sulfamoylbenzoic
- reaction
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- 238000000034 method Methods 0.000 title abstract description 5
- 230000015572 biosynthetic process Effects 0.000 title abstract description 4
- 238000003786 synthesis reaction Methods 0.000 title abstract description 4
- FKQUJHBLGSIBEE-UHFFFAOYSA-N 4,6-dichloro-3-sulfonylcyclohexa-1,5-diene-1-carboxylic acid Chemical compound ClC=1C(C(=O)O)=CC(C(C1)Cl)=S(=O)=O FKQUJHBLGSIBEE-UHFFFAOYSA-N 0.000 title abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 11
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims abstract description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000001953 recrystallisation Methods 0.000 claims abstract description 4
- LWDSANAOYPHQAW-UHFFFAOYSA-N 2-chloro-5-sulfamoylbenzoic acid Chemical class NS(=O)(=O)C1=CC=C(Cl)C(C(O)=O)=C1 LWDSANAOYPHQAW-UHFFFAOYSA-N 0.000 claims description 22
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 18
- 239000000047 product Substances 0.000 claims description 14
- 238000010189 synthetic method Methods 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 229910021529 ammonia Inorganic materials 0.000 claims description 9
- 239000012043 crude product Substances 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 238000009413 insulation Methods 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- 150000005524 benzylchlorides Chemical class 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 238000002791 soaking Methods 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 3
- 238000005406 washing Methods 0.000 abstract description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract 2
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 abstract 1
- IRHNJWFRBQRCPM-UHFFFAOYSA-N 4,5,6-trichloro-3-sulfonylcyclohexa-1,5-diene-1-carboxylic acid Chemical compound ClC=1C(C(=O)O)=CC(C(C1Cl)Cl)=S(=O)=O IRHNJWFRBQRCPM-UHFFFAOYSA-N 0.000 abstract 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 abstract 1
- 239000005711 Benzoic acid Substances 0.000 abstract 1
- 235000010233 benzoic acid Nutrition 0.000 abstract 1
- 239000003054 catalyst Substances 0.000 abstract 1
- 238000001914 filtration Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- -1 trichloro benzyl Chemical group 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 239000002994 raw material Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229960003883 furosemide Drugs 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- FFMXLRXJGJMUDC-UHFFFAOYSA-N C(=O)O.ClC1=CC=CC(=C1)Cl Chemical compound C(=O)O.ClC1=CC=CC(=C1)Cl FFMXLRXJGJMUDC-UHFFFAOYSA-N 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- HNHHBKDPQPDTMD-UHFFFAOYSA-N furan thiophene Chemical compound O1C=CC=C1.O1C=CC=C1.S1C=CC=C1.S1C=CC=C1 HNHHBKDPQPDTMD-UHFFFAOYSA-N 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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
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) with the 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 I (2,4-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.
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 ℃.
The temperature of the insulation in yet another embodiment of the present invention, steps A) is 0～40 ℃, and soaking time is 4-10h.
In yet another embodiment of the present invention, the ammoniacal liquor 2 that the ammonia step B) is separated is 3-10 with the mol ratio of Compound I: 1.
More of the present invention and among embodiment, step C) alcohol described in is any one in methyl alcohol, ethanol, the Virahol.
In of the present invention and then embodiment, described catalyzer is any one in sulfuric acid, iron trichloride, the zinc dichloride.
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 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 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 (7)
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:
A) prepare Compound I I with Compound I, in the presence of catalyzer, with Compound I (2,4-dichloro three benzyl chlorides) with the 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 I (2,4-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.
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 135-150 ℃.
4, according to claim 12, the synthetic method of 4-two chloro-5-sulfamoylbenzoic acids is characterized in that steps A) described in the temperature of insulation be 0～40 ℃, soaking time is 4-10h.
5, 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.
6, 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.
7, according to claim 1 and 22, the synthetic method of 4-two chloro-5-sulfamoylbenzoic acids is characterized in that described catalyzer is any one in sulfuric acid, iron trichloride, the zinc dichloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100235914A CN100522936C (en) | 2007-06-11 | 2007-06-11 | Synthesis process of 2,4-dichloro-5-sulfonyl benzoic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100235914A CN100522936C (en) | 2007-06-11 | 2007-06-11 | Synthesis process of 2,4-dichloro-5-sulfonyl benzoic acid |
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| Publication Number | Publication Date |
|---|---|
| CN101066943A true CN101066943A (en) | 2007-11-07 |
| CN100522936C CN100522936C (en) | 2009-08-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2007100235914A Expired - Fee Related CN100522936C (en) | 2007-06-11 | 2007-06-11 | Synthesis process of 2,4-dichloro-5-sulfonyl benzoic acid |
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| CN (1) | CN100522936C (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456232A (en) * | 2018-12-17 | 2019-03-12 | 苏州华道生物药业股份有限公司 | A kind of preparation process of pair of ethyl beneznesulfonamide |
| CN112142833A (en) * | 2020-09-24 | 2020-12-29 | 华南农业大学 | A kind of furosemide artificial antigen, antibody and its application in detecting furosemide |
-
2007
- 2007-06-11 CN CNB2007100235914A patent/CN100522936C/en not_active Expired - Fee Related
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109456232A (en) * | 2018-12-17 | 2019-03-12 | 苏州华道生物药业股份有限公司 | A kind of preparation process of pair of ethyl beneznesulfonamide |
| CN112142833A (en) * | 2020-09-24 | 2020-12-29 | 华南农业大学 | A kind of furosemide artificial antigen, antibody and its application in detecting furosemide |
| CN112142833B (en) * | 2020-09-24 | 2021-10-29 | 华南农业大学 | A kind of furosemide artificial antigen, antibody and its application in detecting furosemide |
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| Publication number | Publication date |
|---|---|
| CN100522936C (en) | 2009-08-05 |
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Granted publication date: 20090805 Termination date: 20130611 |