CN117447427A - Preparation method of furosemide - Google Patents
Preparation method of furosemide Download PDFInfo
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- CN117447427A CN117447427A CN202311366339.9A CN202311366339A CN117447427A CN 117447427 A CN117447427 A CN 117447427A CN 202311366339 A CN202311366339 A CN 202311366339A CN 117447427 A CN117447427 A CN 117447427A
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- furosemide
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- dichloro
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- 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 title claims abstract description 64
- 229960003883 furosemide Drugs 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 239000012043 crude product Substances 0.000 claims abstract description 26
- 239000000047 product Substances 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 24
- ATCRIUVQKHMXSH-UHFFFAOYSA-N 2,4-dichlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1Cl ATCRIUVQKHMXSH-UHFFFAOYSA-N 0.000 claims abstract description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 15
- 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 claims abstract description 14
- DDRPCXLAQZKBJP-UHFFFAOYSA-N furfurylamine Chemical compound NCC1=CC=CO1 DDRPCXLAQZKBJP-UHFFFAOYSA-N 0.000 claims abstract description 13
- KOYAQMICBWHMSS-UHFFFAOYSA-N 2,4-dichloro-5-(sulfonylamino)benzoic acid Chemical compound C1=C(C(=CC(=C1N=S(=O)=O)Cl)Cl)C(=O)O KOYAQMICBWHMSS-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000001914 filtration Methods 0.000 claims abstract description 12
- 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 claims abstract description 11
- 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 claims abstract description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 11
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims abstract description 11
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 9
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 9
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 9
- 230000003472 neutralizing effect Effects 0.000 claims abstract description 9
- 229960001669 kinetin Drugs 0.000 claims abstract description 8
- 238000005576 amination reaction Methods 0.000 claims abstract description 6
- 238000009833 condensation Methods 0.000 claims abstract description 6
- 230000005494 condensation Effects 0.000 claims abstract description 6
- 239000012047 saturated solution Substances 0.000 claims abstract description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims abstract description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 229940124530 sulfonamide Drugs 0.000 claims description 15
- 239000005711 Benzoic acid Substances 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 14
- 235000010233 benzoic acid Nutrition 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 10
- 230000007062 hydrolysis Effects 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- 230000007935 neutral effect Effects 0.000 claims description 8
- 238000005406 washing Methods 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 239000000376 reactant Substances 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 239000012065 filter cake Substances 0.000 claims description 5
- 108010009736 Protein Hydrolysates Proteins 0.000 claims description 4
- 239000013078 crystal Substances 0.000 claims description 3
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 27
- 239000002994 raw material Substances 0.000 abstract description 10
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000002920 hazardous waste Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 238000000967 suction filtration Methods 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 238000006386 neutralization reaction Methods 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000005303 weighing Methods 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- DLFCAVBMDSKMEY-UHFFFAOYSA-M sodium;4-chloro-2-(furan-2-ylmethylamino)-5-sulfamoylbenzoate Chemical class [Na+].C1=C(Cl)C(S(=O)(=O)N)=CC(C([O-])=O)=C1NCC1=CC=CO1 DLFCAVBMDSKMEY-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000004042 decolorization Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 239000002934 diuretic Substances 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- GANBJDIOIDQSGI-UHFFFAOYSA-N 2-(chloromethyl)furan Chemical compound ClCC1=CC=CO1 GANBJDIOIDQSGI-UHFFFAOYSA-N 0.000 description 1
- QQLJBZFXGDHSRU-UHFFFAOYSA-N 2-amino-4-chloro-5-sulfamoylbenzoic acid Chemical compound NC1=CC(Cl)=C(S(N)(=O)=O)C=C1C(O)=O QQLJBZFXGDHSRU-UHFFFAOYSA-N 0.000 description 1
- RWZYAGGXGHYGMB-WGGUOBTBSA-N 2-aminobenzoic acid Chemical class NC1=CC=CC=C1[14C](O)=O RWZYAGGXGHYGMB-WGGUOBTBSA-N 0.000 description 1
- 206010059245 Angiopathy Diseases 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 208000009447 Cardiac Edema Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010030124 Oedema peripheral Diseases 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- 208000009911 Urinary Calculi Diseases 0.000 description 1
- ZIDRHHABKNTCAX-UHFFFAOYSA-M [Na+].ClC=1C(C(=O)[O-])=CC(C(C1)Cl)=S(=O)=O Chemical compound [Na+].ClC=1C(C(=O)[O-])=CC(C(C1)Cl)=S(=O)=O ZIDRHHABKNTCAX-UHFFFAOYSA-M 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000007344 nucleophilic reaction Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of furosemide. The preparation method of the furosemide comprises the following steps: chlorosulfonation: the chlorosulfonic acid reacts with 2, 4-dichlorobenzoic acid, then is hydrolyzed and filtered to obtain 2, 4-dichloro-5-sulfonyl chlorobenzoic acid; amination: adding 2, 4-dichloro-5-sulfonylchlorobenzoic acid into ammonia water, reacting, neutralizing, filtering and purifying to obtain 2, 4-dichloro-5-sulfonylaminobenzoic acid; condensation: reacting 2-furanmethanamine with 2, 4-dichloro-5-sulfonylbenzoic acid to obtain a furosemide crude product; decoloring: adding the furosemide crude product into sodium bicarbonate saturated solution, adding active carbon for decoloring, neutralizing and crystallizing to obtain a furosemide product. The method has the advantages of easily available raw materials, low price, short comprehensive reaction period, less hazardous waste, high purity of the prepared furosemide, high total yield and low comprehensive cost in the whole preparation process, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of furosemide.
Background
Furosemide is a powerful diuretic and can inhibit the rising of the marrow part of a marrow loop and the opposite Cl of the cortex part - And Na (Na) + Resorbing to play a diuretic role. Clinically, the composition is mainly used for treating peripheral edema caused by cardiac edema, renal edema, ascites due to cirrhosis, dysfunction or vascular disorder, and can promote the discharge of upper urinary tract stones. The chemical formula is C 12 H 11 ClN 2 O 5 S, the structural formula is as follows:
at present, the common furosemide preparation methods mainly comprise the following steps:
in the method disclosed in patent CN106117168A, 2, 4-dichloro-5-sulfonamide benzoic acid reacts with alkali in the presence of an organic solvent to obtain a reaction solution, and the reaction solution is subjected to post-treatment to obtain 2, 4-dichloro-5-sulfonamide sodium benzoate; reacting the sodium 2, 4-dichloro-5-sulfonylbenzoate with furfuryl amine in the presence of an organic solvent; after the reaction is finished, recovering furfuryl amine and a solvent through reduced pressure distillation to obtain a reaction solution, mixing the reaction solution with isopropanol, stirring, crystallizing and filtering to obtain furosemide sodium salt; and (3) adding water to dissolve the furosemide sodium salt, decoloring by using activated carbon, and acidifying by using glacial acetic acid to obtain a furosemide finished product. The method has low cost, less time consumption, good product quality and high yield. After the reaction is finished, the furfuryl amine and the solvent are required to be recovered by reduced pressure distillation, so that not only is the recovery energy consumption increased, but also mother liquor containing a large amount of organic impurities is produced while furosemide sodium salt is obtained, and the treatment capacity of the mother liquor in the later stage is high, and the treatment difficulty is high.
In the method disclosed in patent CN105566260A, tetrahydrofuran compounds such as 2-chloromethyl furan and 2-aminobenzoic acid compounds such as 2-amino-4-chloro-5-sulfamoyl benzoic acid are heated in a reaction solvent, the temperature is controlled to be 80-150 ℃, nucleophilic reaction is carried out under the action of an acid binding agent and/or a catalyst, and the reaction solution is separated and purified to obtain the furosemide. The method can prepare the furosemide with high purity and high yield by simple steps, the yield is up to 97.0%, and the purity is up to 99.8%. The initial raw materials of the method are not common market raw materials, the price is high, the production cost is high, the reaction time of the method is too long, the waste liquid amount generated by post treatment is also large, excessive materials enter the mother liquor and cannot be recovered, and the method also needs to be processed with high cost.
The method disclosed in the patent CN105906589A comprises the steps of adding 2, 4-dichloro-5-sulfonylaminobenzoic acid and an acid binding agent into a proper solvent, raising the temperature to a certain temperature under the protection of inert gas, dropwise adding furfuryl amine, adjusting the pH value with acid after the reaction is finished, separating out crystals, filtering out to obtain a furosemide crude product, refining the crude product by using an organic solvent and water as a mixed solvent, firstly adjusting the pH value to be alkaline, raising the temperature to dissolve the crude product, adding active carbon for decolorization, carrying out hot filtration, adjusting the pH value of filtrate with acid, separating out solids, filtering, and drying to obtain the furosemide. The method has high conversion rate, less byproducts, high product purity and simple process flow, and the purity is more than or equal to 99.0 percent and the total yield can reach 71.2 percent through HPLC analysis. In the production process of the method, inert gas needs to be introduced for a long time, the market price of the reaction raw material 2, 4-dichloro-5-sulfonylamino benzoic acid is higher, and the production cost is high.
The preparation method of the furosemide has the problems of difficult acquisition and high price of the initial raw materials or high treatment difficulty of mother liquor and waste liquid generated in the reaction process, has the problem of high comprehensive production cost, and is not suitable for large-scale industrial production. Therefore, a new furosemide preparation method needs to be studied to reduce the comprehensive production cost.
Disclosure of Invention
The purpose of the invention is that: the preparation method of the furosemide has the advantages of easily available raw materials, low price, short comprehensive reaction period, less hazardous waste, high purity of the prepared furosemide, high total yield and low comprehensive cost in the whole preparation process, and is suitable for industrial production.
The preparation method of the furosemide comprises the following steps:
(1) Chlorosulfonation: reacting chlorosulfonic acid and 2, 4-dichlorobenzoic acid at 100-155 ℃ for 2-6 hours, then adding reactants into water for hydrolysis, filtering the hydrolysate, and washing a filter cake with water to be neutral to obtain 2, 4-dichloro-5-sulfonyl chlorobenzoic acid;
(2) Amination: adding 2, 4-dichloro-5-sulfonylchlorobenzoic acid into ammonia water, reacting for 2-4 hours at 0-50 ℃, neutralizing, filtering to obtain a 2, 4-dichloro-5-sulfonylaminobenzoic acid crude product, and purifying to obtain 2, 4-dichloro-5-sulfonylaminobenzoic acid;
(3) Condensation: reacting 2-furanmethanamine and 2, 4-dichloro-5-sulfonamide benzoic acid at 80-150 ℃ for 5-12h, adding reactants into a sodium hydroxide aqueous solution, washing with an organic solvent, neutralizing, and separating out crystals to obtain a furosemide crude product;
(4) Decoloring: adding the furosemide crude product into sodium bicarbonate saturated solution, heating to 70-100 ℃, adding active carbon for decoloring, then neutralizing, crystallizing and centrifuging to obtain the furosemide product.
In the step (1), the mole of chlorosulfonic acid and 2, 4-dichlorobenzoic acid is (1-3): 1.
In the step (1), the water consumption is 2-10 times of chlorosulfonic acid mass during hydrolysis; the hydrolysis temperature is not higher than 0 ℃, and the hydrolysis time is 1-3h.
In step (2), the ammonia concentration is 15-25wt.%, preferably 20wt.%; NH contained in ammonia water 3 Calculated as 2, 4-dichloro-5-sulfonylchlorobenzoic acid and NH 3 The molar ratio of (2) is 1 (1) to (3).
In the step (2), hydrochloric acid is added during neutralization, and the pH value of the system is adjusted to be neutral.
In the step (2), the purification process of the crude 2, 4-dichloro-5-sulfonylbenzoic acid product is as follows: adding the 2, 4-dichloro-5-sulfonamide benzoic acid crude product into ethanol water solution, preserving heat for 0.5-2h at 40-80 ℃, cooling, recrystallizing, and drying to obtain the 2, 4-dichloro-5-sulfonamide benzoic acid.
In the step (3), the molar ratio of the 2-furanmethanamine to the 2, 4-dichloro-5-sulfonamide benzoic acid is 1 (1-3).
In step (3), the concentration of the aqueous sodium hydroxide solution is 20-35wt.%; the dosage of the sodium hydroxide aqueous solution is 1-3 times of that of the 2, 4-dichloro-5-sulfonamide benzoic acid.
In the step (3), the organic solvent is dichloromethane; the dosage of the organic solvent is 10-15 times of the mass of the 2, 4-dichloro-5-sulfonamide benzoic acid.
In the step (3), hydrochloric acid is added during neutralization, and the pH value of the system is adjusted to be neutral.
In the step (4), the dosage of the saturated sodium bicarbonate solution (20-35 ℃) is 4-5 times of the mass of the furosemide crude product.
In the step (4), the addition amount of the activated carbon is 0.1 to 0.3 times of the mass of the furosemide crude product; after adding active carbon, decoloring for 0.5-2h at 40-80 ℃.
In the step (4), glacial acetic acid is added during neutralization, and the pH value of the system is adjusted to be neutral.
The synthesis route of the furosemide preparation method is as follows:
compared with the prior art, the invention has the following beneficial effects:
(1) The invention adopts chlorosulfonic acid, 2, 4-dichlorobenzoic acid, ammonia water and 2-furanmethylamine as main raw materials, the raw materials are easy to obtain, and the cost is low;
(2) The preparation method has the advantages of short overall production period, simple production mode, easy control of the production process, detection of the products obtained in each step and stable and controllable product quality;
(3) The hazardous waste amount generated in the reaction process is small, most of the generated waste liquid is aqueous solution, and the waste liquid contains basically inorganic salt, so that the treatment difficulty is low;
(4) The furosemide prepared by the method has the purity of more than 99.95%, the content of single impurities is not more than 0.01%, the total content of impurities is controlled below 0.05%, the yield of each reaction stage is high, and the total yield reaches more than 55%.
Drawings
FIG. 1 is an infrared spectrum of the furosemide product prepared in example 1 of the present invention;
FIG. 2 is an HPLC chart of the furosemide product prepared in example 1 of the present invention.
Detailed Description
The present invention will be further illustrated by the following examples, wherein the raw materials used in the examples are commercially available conventional raw materials unless otherwise specified; the process used in the examples, unless otherwise specified, is conventional in the art.
Example 1
The preparation method for synthesizing the furosemide comprises the following steps:
(1) Chlorosulfonation: adding 60kg (515 mol) of chlorosulfonic acid and 30kg (157 mol) of 2, 4-dichlorobenzoic acid into a reaction kettle, reacting for 6 hours at 100 ℃, then adding the reactants into 500kg of water with the temperature not higher than 0 ℃ while stirring, stirring and hydrolyzing for 2 hours, carrying out suction filtration on the hydrolysate, washing a filter cake with water to be neutral to obtain 2, 4-dichloro-5-sulfonyl-chlorobenzoic acid, weighing 35.6kg, and obtaining the product with the yield of 78.74% and the purity of 88.3%;
(2) Amination: adding 20kg (70 mol) of 2, 4-dichloro-5-sulfonylchlorobenzoic acid into 25kg of ammonia water (294 mol of ammonia) with the concentration of 20wt.% to react for 2 hours at 30 ℃, then adding hydrochloric acid to neutralize, adjusting the pH value of the reaction system to 7-8, carrying out suction filtration to obtain a crude 2, 4-dichloro-5-sulfonylaminobenzoic acid product, adding the crude 2, 4-dichloro-5-sulfonylaminobenzoic acid product into 30kg of 70wt.% ethanol aqueous solution, carrying out heat preservation for 1 hour at 60 ℃, cooling, recrystallizing and drying to obtain the 2, 4-dichloro-5-sulfonylaminobenzoic acid, weighing to 16.8kg, and obtaining 89.92% yield and 99.97% purity;
(3) Condensation: 45kg (463 nol) of 2-furanmethanamine and 15kg (56 mol) of 2, 4-dichloro-5-sulfonamide benzoic acid are reacted for 5 hours at 150 ℃, the reduced pressure is carried out, 40kg of 30wt.% sodium hydroxide aqueous solution is added, then the organic solvent is used for washing for multiple times, hydrochloric acid is used for neutralization, the pH value of the reaction system is adjusted to 7-8, suction filtration is carried out, and a furosemide crude product is obtained, the furosemide crude product is weighed to 16.8kg, the yield is 91.06%, and the yield is 90.18%;
(4) Decoloring: 10kg (30 mol) of furosemide crude product is added into 50kg of saturated sodium bicarbonate aqueous solution, the temperature is raised to 100 ℃, 0.1kg of active carbon is added for decolorization for 0.5h, filtration, glacial acetic acid neutralization, crystallization and suction filtration are carried out, and the furosemide product is obtained, the weight is 9.2kg, the yield is 92%, and the purity is 99.97%.
The infrared spectrum of the furosemide product is shown in figure 1, the HPLC spectrum is shown in figure 2, and from figure 1, the infrared spectrum of the furosemide product is 400-1000 cm -1 The strongest absorption peak in the region appeared at 546cm -1 A place; 1000-1850 cm -1 The strongest absorption peak in the region appears at 1647cm -1 A place; 3000-3800 cm -1 The absorption peaks in the region are few, no strong absorption peak exists, and the characteristic of the furosemide standard infrared spectrum is met; as can be seen from FIG. 2, the furosemide product has a purity of 99.97%, a single impurity content of not more than 0.01%, and a total impurity content of less than 0.05%.
Example 2
The preparation method for synthesizing the furosemide comprises the following steps:
(1) Chlorosulfonation: 90kg (772 mol) of chlorosulfonic acid and 30kg (157 mol) of 2, 4-dichlorobenzoic acid are added into a reaction kettle to react for 2 hours at 155 ℃, then the reactants are added into 400kg of water with the temperature not higher than 0 ℃ while being stirred, the mixture is stirred and hydrolyzed for 1 hour, the hydrolyzed solution is filtered by suction, the filter cake is washed to be neutral by water, and the 2, 4-dichloro-5-sulfonyl-chlorobenzoic acid is obtained, the weight is 36.5kg, the yield is 80.73 percent, and the purity is 89.6 percent;
(2) Amination: adding 22kg (76 mol) of 2, 4-dichloro-5-sulfonylchlorobenzoic acid into 26kg of ammonia water (382 mol of ammonia) with the concentration of 25wt.% for reaction for 4 hours at the temperature of 0 ℃, then adding hydrochloric acid for neutralization, adjusting the pH value of the reaction system to 7-8, carrying out suction filtration to obtain a crude 2, 4-dichloro-5-sulfonylbenzoic acid product, adding the crude 2, 4-dichloro-5-sulfonylbenzoic acid product into 35kg of 70wt.% ethanol aqueous solution, carrying out heat preservation for 1 hour at the temperature of 60 ℃, cooling, recrystallizing and drying to obtain the 2, 4-dichloro-5-sulfonylbenzoic acid, weighing 18.8kg, and obtaining the crude 2, 4-dichloro-5-sulfonylbenzoic acid with the yield of 91.48% and the purity of 99.98%;
(3) Condensation: reacting 30kg (309 mol) of 2-furanmethanamine with 15kg (56 mol) of 2, 4-dichloro-5-sulfonylaminobenzoic acid at 80 ℃ for 12 hours, drying under reduced pressure, adding 30kg of 30wt.% sodium hydroxide aqueous solution, washing for a plurality of times with an organic solvent, neutralizing with hydrochloric acid, adjusting the pH value of the reaction system to 7-8, and carrying out suction filtration to obtain a furosemide crude product, wherein the furosemide crude product is weighed to 17.4kg, and the yield is 94.32%;
(4) Decoloring: 10kg (30 mol) of furosemide crude product is added into 45kg of saturated sodium bicarbonate aqueous solution, the temperature is raised to 70 ℃, 0.1kg of active carbon is added for decoloration for 1h, filtration, glacial acetic acid neutralization, crystallization and suction filtration are carried out, and the furosemide product is obtained, the weight is 8.9kg, the yield is 89%, and the purity is 99.98%.
Example 3
The preparation method for synthesizing the furosemide comprises the following steps:
(1) Chlorosulfonation: adding 60kg (515 mol) of chlorosulfonic acid and 60kg (314 mol) of 2, 4-dichlorobenzoic acid into a reaction kettle, reacting for 4 hours at 130 ℃, then adding 600kg of water with the temperature not higher than 0 ℃ into the reaction kettle while stirring, stirring and hydrolyzing for 2 hours, carrying out suction filtration on the hydrolysate, washing a filter cake with water to be neutral to obtain 2, 4-dichloro-5-sulfonyl-chlorobenzoic acid, weighing 73.6kg, and obtaining the product with the yield of 81.39% and the purity of 90.6%;
(2) Amination: adding 35kg (122 mol) of 2, 4-dichloro-5-sulfonylchlorobenzoic acid into 60kg of ammonia water (706 mol of ammonia) with the concentration of 20wt.% for reaction for 3 hours at the temperature of 20 ℃, then adding hydrochloric acid for neutralization, adjusting the pH value of the reaction system to 7-8, carrying out suction filtration to obtain a crude 2, 4-dichloro-5-sulfonylbenzoic acid product, adding the crude 2, 4-dichloro-5-sulfonylbenzoic acid product into 70kg of 70wt.% ethanol aqueous solution, carrying out heat preservation for 1 hour at the temperature of 60 ℃, cooling, recrystallizing and drying to obtain the 2, 4-dichloro-5-sulfonylbenzoic acid, weighing to 30kg, and obtaining the 2, 4-dichloro-5-sulfonylbenzoic acid with the yield of 91.75% and the purity of 99.96%;
(3) Condensation: 60kg (318 mol) of 2-furanmethanamine and 30kg (112 mol) of 2, 4-dichloro-5-sulfonylaminobenzoic acid are reacted for 9 hours at 120 ℃, dried under reduced pressure, added with 80kg of 30wt.% sodium hydroxide aqueous solution, washed for a plurality of times with organic solvent, neutralized with hydrochloric acid, the temperature and pH value of the reaction system are adjusted to 7-8, and suction filtration is carried out to obtain a furosemide crude product, the furosemide crude product is weighed to 33.8kg, and the yield is 91.61%;
(4) Decoloring: 20kg (60 mol) of furosemide crude product is added into 40kg of saturated sodium bicarbonate aqueous solution, the temperature is raised to 90 ℃, 0.1kg of active carbon is added for decoloration for 2 hours, filtration, glacial acetic acid neutralization, crystallization and suction filtration are carried out, and the furosemide product is obtained, the weight is 18.5kg, the yield is 92.5%, and the purity is 99.97%.
Claims (10)
1. A preparation method of furosemide is characterized in that: the method comprises the following steps:
(1) Chlorosulfonation: reacting chlorosulfonic acid and 2, 4-dichlorobenzoic acid at 100-155 ℃ for 2-6 hours, then adding reactants into water for hydrolysis, filtering the hydrolysate, and washing a filter cake with water to be neutral to obtain 2, 4-dichloro-5-sulfonyl chlorobenzoic acid;
(2) Amination: adding 2, 4-dichloro-5-sulfonylchlorobenzoic acid into ammonia water, reacting for 2-4 hours at 0-50 ℃, neutralizing, filtering to obtain a 2, 4-dichloro-5-sulfonylaminobenzoic acid crude product, and purifying to obtain 2, 4-dichloro-5-sulfonylaminobenzoic acid;
(3) Condensation: reacting 2-furanmethanamine and 2, 4-dichloro-5-sulfonamide benzoic acid at 80-150 ℃ for 5-12h, adding reactants into a sodium hydroxide aqueous solution, washing with an organic solvent, neutralizing, and separating out crystals to obtain a furosemide crude product;
(4) Decoloring: adding the furosemide crude product into sodium bicarbonate saturated solution, heating to 70-100 ℃, adding active carbon for decoloring, then neutralizing, crystallizing and centrifuging to obtain the furosemide product.
2. The method for preparing furosemide according to claim 1, characterized in that: in the step (1), the mole of chlorosulfonic acid and 2, 4-dichlorobenzoic acid is (1-3): 1.
3. The method for preparing furosemide according to claim 1, characterized in that: in the step (1), the water consumption is 2-10 times of chlorosulfonic acid mass during hydrolysis; the hydrolysis temperature is not higher than 0 ℃, and the hydrolysis time is 1-3h.
4. The method for preparing furosemide according to claim 1, characterized in that: in step (2), the ammonia concentration is 15-25wt.%, preferably 20wt.%; NH contained in ammonia water 3 Calculated as 2, 4-dichloro-5-sulfonylchlorobenzoic acid and NH 3 The molar ratio of (2) is 1 (1) to (3).
5. The method for preparing furosemide according to claim 1, characterized in that: in the step (2), the purification process of the crude 2, 4-dichloro-5-sulfonylbenzoic acid product is as follows: adding the 2, 4-dichloro-5-sulfonamide benzoic acid crude product into ethanol water solution, preserving heat for 0.5-2h at 40-80 ℃, cooling, recrystallizing, and drying to obtain the 2, 4-dichloro-5-sulfonamide benzoic acid.
6. The method for preparing furosemide according to claim 1, characterized in that: in the step (3), the molar ratio of the 2-furanmethanamine to the 2, 4-dichloro-5-sulfonamide benzoic acid is 1 (1-3).
7. The method for preparing furosemide according to claim 1, characterized in that: in step (3), the concentration of the aqueous sodium hydroxide solution is 20-35wt.%; the dosage of the sodium hydroxide aqueous solution is 1-3 times of that of the 2, 4-dichloro-5-sulfonamide benzoic acid.
8. The method for preparing furosemide according to claim 1, characterized in that: in the step (3), the organic solvent is dichloromethane; the dosage of the organic solvent is 10-15 times of the mass of the 2, 4-dichloro-5-sulfonamide benzoic acid.
9. The method for preparing furosemide according to claim 1, characterized in that: in the step (4), the dosage of the saturated sodium bicarbonate solution is 4-5 times of the mass of the furosemide crude product.
10. The method for preparing furosemide according to claim 1, characterized in that: in the step (4), the addition amount of the activated carbon is 0.1 to 0.3 times of the mass of the furosemide crude product; after adding active carbon, decoloring for 0.5-2h at 40-80 ℃.
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