CN117510444A - Refining process of furosemide - Google Patents
Refining process of furosemide Download PDFInfo
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- CN117510444A CN117510444A CN202410019831.7A CN202410019831A CN117510444A CN 117510444 A CN117510444 A CN 117510444A CN 202410019831 A CN202410019831 A CN 202410019831A CN 117510444 A CN117510444 A CN 117510444A
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- furosemide
- crude product
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- sodium salt
- crystallization
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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 97
- 229960003883 furosemide Drugs 0.000 title claims abstract description 97
- 238000000034 method Methods 0.000 title claims abstract description 30
- 238000007670 refining Methods 0.000 title claims abstract description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 54
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims abstract description 41
- 239000012043 crude product Substances 0.000 claims abstract description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 33
- 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 claims abstract description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 27
- 239000012535 impurity Substances 0.000 claims abstract description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000002425 crystallisation Methods 0.000 claims abstract description 20
- 230000008025 crystallization Effects 0.000 claims abstract description 20
- 229910000029 sodium carbonate Inorganic materials 0.000 claims abstract description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000007864 aqueous solution Substances 0.000 claims abstract description 18
- 239000000243 solution Substances 0.000 claims abstract description 18
- 238000006482 condensation reaction Methods 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 12
- 229940079593 drug Drugs 0.000 claims abstract description 10
- 229960000583 acetic acid Drugs 0.000 claims abstract description 9
- 239000012362 glacial acetic acid Substances 0.000 claims abstract description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 22
- 239000005711 Benzoic acid Substances 0.000 claims description 11
- 235000010233 benzoic acid Nutrition 0.000 claims description 11
- 229940124530 sulfonamide Drugs 0.000 claims description 11
- 238000000746 purification Methods 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 abstract description 7
- 238000000605 extraction Methods 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000004090 dissolution Methods 0.000 abstract description 2
- 239000000049 pigment Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 abstract 1
- 238000005352 clarification Methods 0.000 abstract 1
- 230000002708 enhancing effect Effects 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- DDRPCXLAQZKBJP-UHFFFAOYSA-N furfurylamine Chemical compound NCC1=CC=CO1 DDRPCXLAQZKBJP-UHFFFAOYSA-N 0.000 description 9
- 238000010586 diagram Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000002386 leaching Methods 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- ATCRIUVQKHMXSH-UHFFFAOYSA-N 2,4-dichlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1Cl ATCRIUVQKHMXSH-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000010979 pH adjustment Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000005185 salting out Methods 0.000 description 2
- 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 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-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
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010030124 Oedema peripheral Diseases 0.000 description 1
- 208000009911 Urinary Calculi Diseases 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 229960002798 cetrimide Drugs 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000010959 commercial synthesis reaction Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000002171 loop diuretic Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000012860 organic pigment Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Abstract
The invention discloses a refining process of furosemide, which relates to the technical field of medicine synthesis and comprises the steps of adding sodium hydroxide solution into furosemide condensation reaction liquid for dissolution and clarification, extracting with dichloromethane to remove small polar impurities and tar impurities, taking a water phase, dripping hydrochloric acid to adjust pH for crystallization to obtain a furosemide crude product; salifying the furosemide crude product by using a sodium carbonate aqueous solution, and recrystallizing and refining to obtain furosemide sodium salt; the furosemide sodium salt is dissolved in water, and glacial acetic acid is added dropwise to adjust the pH for crystallization, so as to obtain the furosemide bulk drug. The invention uses an extraction mode to remove small polar impurities and tar impurities in the post-treatment, thereby greatly ensuring the removal of the small polar impurities, the tar impurities and pigments in the condensation reaction and enhancing the robustness of the furosemide refining process; the related substances in the crude product of the furosemide can be removed with high efficiency by salifying and recrystallizing the sodium carbonate aqueous solution, so that the quality of the crude drug of the furosemide is ensured.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a refining process of furosemide.
Background
Furosemide (furosemide), also known as furosemide, is a loop diuretic widely used in the treatment of congestive heart failure and edema, and is clinically used to treat peripheral edema caused by cardiac edema, renal edema, ascites due to cirrhosis, dysfunction or vascular disorder, and to promote the discharge of upper urinary tract stones.
The main commercial synthesis process of the furosemide at present is to take 2, 4-dichlorobenzoic acid as a main raw material, prepare an intermediate 2, 4-dichloro-5-sulfonamide benzoic acid through chlorosulfonation and ammoniation, and then condense the intermediate 2, 4-dichloro-5-sulfonamide benzoic acid with furosemide to prepare the furosemide, wherein the following steps are shown as follows:
because the condensation reaction of the intermediate 2, 4-dichloro-5-sulfonamide benzoic acid and furfuryl amine needs to be carried out at a higher temperature, such as 130-135 ℃ reported by CN201610495908, the impurity content of the crude furosemide product prepared is higher, such as impurity A-F reported by European pharmacopoeia:
the original patent US3780067 reports a preparation method of furosemide, wherein 2, 4-dichloro-5-sulfonamide benzoic acid is condensed with furfuryl amine, a condensation reaction liquid is directly added with water for dissolving and decoloring, sodium chloride saturated salt is added to precipitate furosemide sodium salt, the furosemide sodium salt is refined by sodium bicarbonate aqueous solution, and the refined furosemide sodium salt is dissolved in water and subjected to acid regulation to obtain the furosemide. The process post-treatment carries out salting out by adding sodium chloride, and the repeatability of the salting-out process is poor due to the high solubility of furosemide Mi Nayan in a furfuryl amine/water system, so that large batch-to-batch difference in commercial production is easy to cause.
The preparation method of fast urine (furosemide) is reported in the national pharmaceutical raw materials process assembly, 1980 edition, pages 989-991: in the method, 2, 4-dichloro-5-sulfonamide benzoic acid is condensed with furfuryl amine, the condensation reaction liquid is directly poured into sodium hydroxide aqueous solution to form salt, the salt is decolorized by active carbon and filtered, and the filtrate is directly subjected to pH adjustment by acetic acid to separate out furosemide, and the process does not carry out any refining on the furosemide.
CN201510682715 reports a preparation method of furosemide, in the method, 2, 4-dichloro-5-sulfonamide benzoic acid and furfuryl amine are used for condensation to prepare a furosemide crude product, an organic solvent and water are used as a mixed solvent for the crude product, the pH value is adjusted to be alkaline, the mixture is heated for dissolution, activated carbon is added for decolorization, the furosemide is separated out after thermal filtration and acid adjustment, and I technicians reproduce the process to find that the furosemide crude product contains a large amount of tarry substances brought in at high temperature, so that the furosemide cannot be separated out.
CN201610495908 reports a preparation method of furosemide, in the method, 2, 4-dichloro-5-sulfonamide benzoic acid and furfuryl amine are condensed in ethylene glycol to prepare a furosemide crude product, after the reaction is finished, the solvent and furfuryl amine are distilled off under reduced pressure, and then isopropyl alcohol is used for crystallization to obtain furosemide sodium salt, the furosemide sodium salt is dissolved in water, and after activated carbon is decolorized, glacial acetic acid is used for regulating pH for crystallization of the furosemide. The process post-treatment uses a high-temperature distillation mode to distill out the solvent and the furfuryl amine, and the furosemide is further degraded in the high-temperature distillation process because the boiling point of the solvent glycol is 197 ℃ and the boiling point of the furosemide is 146 ℃, so that the controllability of the production process is poor.
CN201911341518 reports a purification method of furosemide, in the method, 2, 4-dichloro-5-sulfonamide benzoic acid is condensed with furfuryl amine, dilute hydrochloric acid is added into a reaction liquid drop to precipitate a furosemide crude product, the furosemide crude product is added into an inorganic alkali solution to form salt, decoloration and refining are carried out to obtain refined furosemide sodium salt, the refined furosemide sodium salt is dissolved in water, and the furosemide is obtained through acid regulation. When the crude product is crystallized, hydrochloric acid is adopted to directly adjust the pH value to separate out, so that all impurities are separated out in the crude product, and huge refining pressure and process controllability risks are brought for subsequent refining. CN202111634260 improves the solvent of the acid adjusting step on the basis of the process, increases the mixed system of organic solvent and water to precipitate furosemide, and reduces the risk of small polarity unknown single impurity residues, but the use of a large proportion of organic solvent in the final step also leads to the increase of the risk of residual solvents.
Disclosure of Invention
In order to solve the defects in the prior art, the invention provides a refining process of furosemide, which is used for efficiently removing impurities and ensuring the quality of furosemide bulk drug.
The following scheme is adopted:
the invention provides a refining process of furosemide, which comprises the following steps:
s1, adding sodium hydroxide solution into a furosemide condensation reaction solution to dissolve and clarify, extracting with dichloromethane to remove small polar impurities and tar impurities, taking a water phase, and dripping hydrochloric acid to adjust pH for crystallization to obtain a furosemide crude product;
s2, salifying the furosemide crude product by using a sodium carbonate aqueous solution, and recrystallizing and refining to obtain furosemide sodium salt;
s3, dissolving the furosemide sodium salt in water, and dropwise adding glacial acetic acid to adjust pH for crystallization to obtain the furosemide bulk drug.
In the step S1, the dosage of dichloromethane is 0.5-2 times of the dosage of intermediate 2, 4-dichloro-5-sulfonamide benzoic acid, and the pH value is regulated to be less than 1 by hydrochloric acid.
In the step S2, the concentration of the sodium carbonate aqueous solution is 10% -13%, preferably 11% -12%; the reaction temperature is 65-75 ℃ and reflux is carried out.
The invention has the beneficial effects that: (1) The low-polarity impurities and tar impurities are removed in an extraction mode in the post-treatment, so that the removal of the low-polarity impurities, the tar impurities and pigments in the condensation reaction is greatly ensured, and the robustness of the furosemide refining process is enhanced; (2) The related substances in the crude product of the furosemide can be removed with high efficiency by salifying and recrystallizing the sodium carbonate aqueous solution, so that the quality of the crude drug of the furosemide is ensured.
Drawings
FIG. 1 is an HPLC chart of the furosemide condensation reaction solution prepared in example 1.
FIG. 2 is an HPLC chart of crude furosemide prepared in example 1.
Fig. 3 is an HPLC diagram of furosemide sodium salt prepared in example 1.
Fig. 4 is an HPLC diagram of furosemide prepared in example 1.
FIG. 5 is an HPLC chart of the furosemide condensation reaction solution prepared in example 2.
Fig. 6 is an HPLC diagram of the crude furosemide product prepared in example 2.
Fig. 7 is an HPLC diagram of the furosemide sodium salt prepared in example 2.
Fig. 8 is an HPLC diagram of furosemide prepared in example 2.
FIG. 9 is an HPLC chart of the furosemide condensation reaction solution prepared in example 3.
Fig. 10 is an HPLC diagram of the crude furosemide product prepared in example 3.
Fig. 11 is an HPLC diagram of furosemide sodium salt prepared in example 3.
Fig. 12 is an HPLC diagram of furosemide prepared in example 3.
FIG. 13 is a HPLC comparison of crude pH-adjusted in example 5.
FIG. 14 is a HPLC comparison of the salt-forming purification system in example 6.
FIG. 15 is a HPLC comparison of the amount of salt-forming refined solvent in example 7.
Detailed Description
The invention provides a refining process of furosemide, which comprises the following steps:
s1, adding sodium hydroxide solution into a furosemide condensation reaction solution to dissolve and clarify, extracting with dichloromethane to remove small polar impurities and tar impurities, taking a water phase, and dripping hydrochloric acid to adjust pH for crystallization to obtain a furosemide crude product;
s2, salifying the furosemide crude product by using a sodium carbonate aqueous solution, and recrystallizing and refining to obtain furosemide sodium salt;
s3, dissolving the furosemide sodium salt in water, and dropwise adding glacial acetic acid to adjust pH for crystallization to obtain the furosemide bulk drug.
The following disclosure provides many different embodiments, or examples, for implementing different aspects of the invention.
And (3) measuring the furosemide purity and related substances by adopting High Performance Liquid Chromatography (HPLC), wherein the detection conditions are as follows:
instrument model: shimadzu LC-20AD high performance liquid chromatograph;
chromatographic column: waters Symmetry C8 (250 mm. Times.4.6 mm,5 μm);
mobile phase: phosphate buffer (2.0 g of potassium dihydrogen phosphate and 2.5g of cetrimide, dissolved in water and diluted to 700mL, adjusted to pH 7.0 with ammonia water, and added with 300mL of n-propanol);
detection wavelength: 238nm; flow rate: 1.0ml/min; column temperature: 25 ℃; sample injection amount: 20 μl;
2, 4-dichloro-5-sulfonylaminobenzoic acid is prepared by the method of pages 989-991 in 1980 edition of national pharmaceutical Material Process Assembly; the furosemide condensation reaction solution was prepared with reference to CN 201610495908.
Example 1
5.3kg of 2, 4-dichloro-5-sulfonylbenzoic acid to prepare 13.4kg of furosemide condensation reaction liquid (containing 5kg-6kg of furosemide and 77.65 percent of furosemide purity) which is cooled to 90 ℃, 2.5kg of 30 percent aqueous solution of sodium hydroxide and 75kg of water are added, stirred and dissolved and cooled to 20-30 ℃, 2.6kg of dichloromethane is added, the mixture is fully stirred, the mixture is kept stand for separating, and the aqueous layer is extracted with dichloromethane for 2 times, and 2.6kg of dichloromethane is added each time. After the liquid separation is finished, 15kg of hydrochloric acid is added dropwise into the water-taking layer to adjust the pH value to be less than 1, the temperature is reduced to 20-30 ℃ for crystallization, the solution is centrifuged, the filter cake is washed by water until the pH value of the filtrate is more than 5, the furosemide crude product is obtained, the purity of the furosemide crude product is 92.62%, and the furosemide crude product is directly used for the next step without drying.
Adding 31kg of water and 4kg of sodium carbonate into a reaction kettle, stirring and dissolving, adding the furosemide crude product in the previous step, stirring and heating to 50-70 ℃ for dissolving, cooling to 10-20 ℃ for crystallization, filtering, leaching with sodium carbonate aqueous solution to obtain furosemide sodium salt, wherein the purity of the furosemide sodium salt is 99.70%, and directly using the furosemide sodium salt for the next step without drying.
84kg of purified water and the furosemide sodium salt in the previous step are added into a reaction kettle, stirred and dissolved, 2.1kg of glacial acetic acid is added dropwise when the temperature is 50-60 ℃, the mixture is cooled and crystallized, centrifuged, leached by the purified water, the filter cake is dried and crushed to obtain 3.6kg of furosemide bulk drug with the purity of 99.87%, and the results are shown in figures 1-4.
Example 2
1.5kg of 2, 4-dichloro-5-sulfonylbenzoic acid to prepare 4.1kg of furosemide condensation reaction liquid (containing 1.5kg-2kg of furosemide and 76.54 percent of furosemide purity) which is cooled to 90 ℃, 230g of sodium hydroxide and 22.5L of water are added, stirred and dissolved, cooled to 20-30 ℃, 750g of dichloromethane is added, the mixture is fully stirred, the mixture is left to stand for liquid separation, and a water layer is continuously extracted with dichloromethane for 2 times, and 750g of dichloromethane is added each time. After the liquid separation is finished, 1.6kg of hydrochloric acid is added dropwise into the water-taking layer to adjust the pH value to be less than 1, the temperature is reduced to 20-30 ℃ for crystallization, the solution is centrifuged, a filter cake is washed with water until the pH value of the filtrate is more than 5, and the furosemide crude product with the purity of 89.58% is obtained and is directly used for the next step without drying.
Adding 6.7kg of water and 860g of sodium carbonate into a reaction kettle, stirring and dissolving, adding the furosemide crude product in the previous step, stirring and heating to 50-70 ℃ for dissolving, cooling to 10-20 ℃ for crystallization, filtering, leaching with sodium carbonate aqueous solution to obtain furosemide sodium salt, wherein the furosemide sodium salt purity is 99.66%, and directly using the furosemide sodium salt in the next step without drying.
Adding 20kg of purified water and furosemide sodium salt in the previous step into a reaction kettle, stirring and dissolving, filtering to remove mechanical impurities, heating to 50-60 ℃, dropwise adding 1kg of glacial acetic acid, cooling and crystallizing, centrifuging, leaching with purified water, drying and crushing a filter cake to obtain 0.98kg of furosemide bulk drug with the purity of 99.97%, wherein the results are shown in figures 5-8.
Example 3
2.3kg of furosemide condensation reaction liquid (containing about 1kg of furosemide and 81.71 percent of furosemide purity) prepared by 850g of 2, 4-dichloro-5-sulfonamide benzoic acid is cooled to 90 ℃, 130g of sodium hydroxide and 12.5L of water are added, stirring and dissolving are carried out, cooling to 20-30 ℃, 900g of dichloromethane is added, stirring is carried out fully, standing and liquid separation are carried out, and the aqueous layer is extracted with dichloromethane for 2 times continuously, wherein 900g of dichloromethane is added each time. After the liquid separation is finished, 1kg of hydrochloric acid is added dropwise into the water-taking layer to adjust the pH value to be less than 1, the temperature is reduced to 20-30 ℃ for crystallization, the solution is centrifuged, a filter cake is washed by water until the pH value of the filtrate is more than 5, and the furosemide crude product is obtained, the purity of the furosemide crude product is 94.00%, and the furosemide crude product is directly used for the next step without drying.
Adding 1.3kg of water and 170g of sodium carbonate into a reaction kettle, stirring and dissolving, adding the furosemide crude product in the previous step, stirring and heating to 50-70 ℃ for dissolving, cooling to 10-20 ℃ for crystallization, filtering, leaching with a sodium carbonate aqueous solution, and continuously recrystallizing the filter cake once with 1.5L of 10% sodium carbonate aqueous solution to obtain furosemide sodium salt, wherein the furosemide sodium salt purity is 99.82%, and the furosemide sodium salt is directly used in the next step without drying.
Adding 23.5kg of purified water and furosemide sodium salt in the previous step into a reaction kettle, stirring and dissolving, filtering to remove mechanical impurities, heating to 50-60 ℃, dropwise adding 500g of glacial acetic acid, cooling and crystallizing, centrifuging, leaching with purified water, drying and crushing a filter cake to obtain 0.7kg of furosemide bulk drug with the purity of 99.84%, wherein the results are shown in figures 9-12.
Example 4
Comparison of post-treatment dichloromethane extraction
Compared with the prior art (CN 201911341518, CN202111634260, etc.) for preparing the crude product, the method has the advantages that dichloromethane extraction is added, and the purpose is to remove small polar impurities (such as furfural, fat-soluble impurities, etc.) generated in the reaction, tar impurities and organic pigments generated by high-temperature reaction, and the color properties of the crude product are greatly improved after the dichloromethane extraction is added, as shown in Table 1.
Table 1 color-shape comparison of crude furosemide product prepared by different processes
Example 5
Comparison of crude product pH adjustment
The invention compares the influence of the pH value of the crude crystallization callback on the purity and the yield of the crude product, as in the case of application number CN201510682715, example 1 reports that the pH value is regulated to 3-4 by hydrochloric acid, application number CN202111634260, example 3 reports that the pH value is regulated to 2-3 by hydrochloric acid, on the basis of the embodiment 1 of the invention, the single factor parallel investigation is carried out without changing other parameters, the result is shown in FIG. 13 and Table 2, and the screening of the invention finds that the lower the crude crystallization callback, the more complete the product is separated out, and the preferable pH value is less than 1, so that the complete separation of the product is ensured.
TABLE 2 influence of crude crystallization callback pH on crude purity and yield
Example 6
Comparison of salt-forming refining systems
The invention compares crude salt forming refining system, as in the case of application number CN201911341518, example 1 reports that saturated sodium bicarbonate aqueous solution is used for recrystallization, application number CN202111634260 reports that water/organic solvent mixed solution such as sodium hydroxide, potassium hydroxide, sodium chloride and the like is used for recrystallization, on the basis of the invention example 1, single factor parallel investigation is carried out without changing other parameters, the results are shown in fig. 14 and table 3, the invention screens to find that the recrystallization effect of the sodium carbonate aqueous solution is optimal, and the addition of organic solvent for crystallization has no beneficial effect on impurity removal.
TABLE 3 comparison of salt formation refining systems for different crude products
Example 7
Evaluation of the amount of salified refined solvent on Material loss
Based on the embodiment 1 of the invention, the single factor parallel investigation is carried out without changing other parameters, the results are shown in fig. 15 and table 4, the invention uses sodium carbonate aqueous solution for salifying and refining, the system can ensure that furosemide salifies and fully devitrifies after refining, and the specific increase of the solvent quantity can not cause the loss of refining yield. However, the use amount of the sodium carbonate aqueous solution is reduced, so that the sodium carbonate residue is more likely to be caused, and the furosemide sodium salt is subjected to super-yield.
TABLE 4 influence of the amount of aqueous sodium carbonate solution on the purity and yield of Furosemide sodium salt
The above embodiments are merely for illustrating the technical ideas and features of the present invention, and are not meant to be exclusive or limiting. It will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention.
Claims (4)
1. The refining process of the furosemide is characterized by comprising the following steps of:
s1, adding sodium hydroxide solution into a furosemide condensation reaction solution to dissolve and clarify, extracting with dichloromethane to remove small polar impurities and tar impurities, taking a water phase, and dripping hydrochloric acid to adjust pH for crystallization to obtain a furosemide crude product;
s2, salifying the furosemide crude product by using a sodium carbonate aqueous solution, and recrystallizing and refining to obtain furosemide sodium salt;
s3, dissolving the furosemide sodium salt in water, and dropwise adding glacial acetic acid to adjust pH for crystallization to obtain the furosemide bulk drug.
2. The furosemide purification process according to claim 1, characterized in that:
in the step S1, the dosage of dichloromethane is 0.5-2 times of the dosage of intermediate 2, 4-dichloro-5-sulfonamide benzoic acid;
and/or, in the step S1, the pH value is adjusted to be less than 1 by hydrochloric acid.
3. The process for purifying furosemide according to claim 1, wherein in step S2, the concentration of the aqueous sodium carbonate solution used is 10% to 13%.
4. The process for purifying furosemide according to claim 1, wherein in step S2, the concentration of the aqueous sodium carbonate solution used is 11% to 12%.
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