CN117466783A - Preparation method of bumetanide - Google Patents
Preparation method of bumetanide Download PDFInfo
- Publication number
- CN117466783A CN117466783A CN202311428149.5A CN202311428149A CN117466783A CN 117466783 A CN117466783 A CN 117466783A CN 202311428149 A CN202311428149 A CN 202311428149A CN 117466783 A CN117466783 A CN 117466783A
- Authority
- CN
- China
- Prior art keywords
- bumetanide
- reaction
- preparation
- phenoxy
- nitro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- MAEIEVLCKWDQJH-UHFFFAOYSA-N bumetanide Chemical compound CCCCNC1=CC(C(O)=O)=CC(S(N)(=O)=O)=C1OC1=CC=CC=C1 MAEIEVLCKWDQJH-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 229960004064 bumetanide Drugs 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 238000006722 reduction reaction Methods 0.000 claims abstract description 19
- 238000006268 reductive amination reaction Methods 0.000 claims abstract description 18
- 230000035484 reaction time Effects 0.000 claims abstract description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 44
- 239000005711 Benzoic acid Substances 0.000 claims description 22
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 claims description 22
- 235000010233 benzoic acid Nutrition 0.000 claims description 22
- 229940124530 sulfonamide Drugs 0.000 claims description 22
- 230000002829 reductive effect Effects 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 239000003054 catalyst Substances 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 10
- 238000004537 pulping Methods 0.000 claims description 10
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 claims description 10
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 8
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 7
- -1 3-nitro-4-phenoxy-5-sulfonylaminobenzoic acid Chemical compound 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 239000004280 Sodium formate Substances 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 claims description 4
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 4
- 235000019254 sodium formate Nutrition 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 2
- 238000006243 chemical reaction Methods 0.000 abstract description 29
- 239000003814 drug Substances 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 6
- 238000005580 one pot reaction Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 230000007547 defect Effects 0.000 abstract description 2
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 239000008213 purified water Substances 0.000 description 14
- 239000012065 filter cake Substances 0.000 description 12
- 238000001816 cooling Methods 0.000 description 9
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 238000007664 blowing Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 238000001228 spectrum Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000007605 air drying Methods 0.000 description 2
- 238000010009 beating Methods 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 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 2
- 229960003883 furosemide Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 239000002171 loop diuretic Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000009103 reabsorption Effects 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- 210000002565 arteriole Anatomy 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 230000006208 butylation Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 239000011790 ferrous sulphate Substances 0.000 description 1
- 235000003891 ferrous sulphate Nutrition 0.000 description 1
- 150000004675 formic acid derivatives Chemical class 0.000 description 1
- 230000024924 glomerular filtration Effects 0.000 description 1
- 239000000852 hydrogen donor Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 description 1
- 229910000359 iron(II) sulfate Inorganic materials 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000008327 renal blood flow Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000006226 wash reagent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of raw material medicine synthesis, and particularly relates to a preparation method of bumetanide. The preparation method provided by the invention has the advantages of one-step reaction, few steps, simple reaction route, higher efficiency, and high purity of the prepared bumetanide, and stably meets the requirements of bumetanide bulk drug pharmacopoeia. The invention overcomes the defects of the prior art, synthesizes the bumetanide through one-step reaction, and provides reference for the industrialization of the bumetanide bulk drug as a high-quality bumetanide synthesis strategy. Further, the temperature of the reduction reaction and the reductive amination reaction is 50-55 ℃, and the reaction time is 1-2 h. The preparation method has short reaction time and higher efficiency, and has potential of industrial production. The preparation method provided by the invention has the advantages of mild reaction conditions, no dangerous reactions such as hydrogenation and the like, low equipment requirements and safe operation.
Description
Technical Field
The invention belongs to the technical field of raw material medicine synthesis, and particularly relates to a preparation method of bumetanide.
Background
The bumetanide serving as a loop diuretic is mainly used for inhibiting active reabsorption of thick-wall segment sodium chloride of a loop, and inhibiting reabsorption of sodium, and can dilate systemic arterioles, reduce peripheral vascular resistance, increase renal blood flow without reducing glomerular filtration rate while promoting urination, so that the bumetanide is the strongest diuretic at present. The bumetanide is a furosemide (tachyuria) derivative, has the characteristics of quick response and good diuretic effect as a loop diuretic, and has the characteristics of high efficiency, quick response, short duration and low toxicity compared with the furosemide, and the structure of the bumetanide is shown as a formula I:
the key technical point of the preparation of bumetanide is the butylation reaction of 3-amino-4-phenoxy-5-sulfonamide benzoic acid, and the preparation method mainly comprises the following steps:
tang Weigao and Peng Chongying publication "synthesis of bumetanide", report a method for synthesizing bumetanide: reducing 3-nitro-4-phenoxy-5-sulfonamide benzoic acid under the catalysis of ferrous sulfate to obtain 3-amino-4-phenoxy-5-sulfonamide benzoic acid, refluxing with n-butanol, and catalyzing and dehydrating with concentrated sulfuric acid; finally, sodium hydroxide is used for hydrolysis to obtain the bumetanide, and the process route is shown as a formula II. The method provided by the article has complicated steps, and can synthesize the bumetanide through three steps of reactions.
Chinese patent CN10591276a reports a method for synthesizing bumetanide: and (3) dehydrating 3-amino-4-phenoxy-5-sulfonamide benzoic acid and n-butyraldehyde to form imine by using boron trihalide diethyl ether as a catalyst, and carrying out palladium-carbon catalytic hydrogenation to obtain the bumetanide, wherein the process route is shown in a formula III. The method synthesizes the bumetanide through two steps of reactions, and the reactions are complex and complicated.
Disclosure of Invention
The invention aims to provide a preparation method of bumetanide, which is used for synthesizing bumetanide in one step.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of bumetanide, which comprises the following steps:
3-nitro-4-phenoxy-5-sulfonamide benzoic acid, butyraldehyde, formate, catalyst and good solvent are mixed in a pot to carry out reduction reaction and reductive amination reaction, thus obtaining the bumetanide.
Preferably, the temperature of the reduction reaction and the reductive amination reaction is 50-55 ℃, and the reaction time is 1-2 h.
Preferably, the mass ratio of the 3-nitro-4-phenoxy-5-sulfonamide benzoic acid to the catalyst is 100:1.0-2.0.
Preferably, the catalyst comprises one or both of palladium on carbon and Raney nickel.
Preferably, the formate comprises one or more of ammonium formate, potassium formate and sodium formate.
Preferably, the mass ratio of the 3-nitro-4-phenoxy-5-sulfonamide benzoic acid to the butyraldehyde is 1:1.5-2.
Preferably, the molar ratio of the 3-nitro-4-phenoxy-5-sulfonamide benzoic acid to formate is 1:4-6.
Preferably, the mass volume ratio of the 3-nitro-4-phenoxy-5-sulfoaminobenzoic acid to the good solvent is 1 g:5-10 mL.
Preferably, the good solvent comprises one or more of tetrahydrofuran, dioxane and N, N-dimethylformamide.
Preferably, the reduction reaction and the reductive amination reaction further comprise post-treatment; the post-treatment is as follows: the reaction product is cooled and then is subjected to reduced pressure concentration, pulping, filtering, washing and drying in sequence.
The invention provides a preparation method of bumetanide. The preparation method provided by the invention has the advantages of one-step reaction, few steps, simple reaction route, higher efficiency, high purity of the prepared bumetanide, purity of more than 99.4 percent, and yield of more than 82 percent, and stably meets the requirements of bumetanide bulk drug pharmacopoeia. The invention overcomes the defects of the prior art, synthesizes the bumetanide through one-step reaction, and provides reference for the industrialization of the bumetanide bulk drug as a high-quality bumetanide synthesis strategy.
Further, the temperature of the reduction reaction and the reductive amination reaction is 50-55 ℃, and the reaction time is 1-2 h. The preparation method has short reaction time and higher efficiency, and has potential of industrial production. The preparation method provided by the invention has the advantages of mild reaction conditions, no dangerous reactions such as hydrogenation and the like, low equipment requirements and safe operation.
Further, the good solvent comprises one or more of tetrahydrofuran, dioxane and N, N-dimethylformamide. The preparation method provided by the invention has the advantages that raw materials are easy to purchase, the reacted solvent can be recycled and used, the solvent unit consumption is low, the cost is low, the operation is simple, and the method is suitable for industrial production.
Further, the reduction reaction and the reductive amination reaction further comprise post-treatment; the post-treatment is as follows: the reaction product is cooled and then is subjected to reduced pressure concentration, pulping, filtering, washing and drying in sequence. The preparation method provided by the invention is used for post-treatment, and impurities such as byproducts, inorganic salts and the like can be well removed through simple steps such as reduced pressure concentration, pulping, drying and the like, so that the obtained bumetanide has high content and purity, and can stably meet the requirements of bumetanide bulk drug pharmacopoeia.
Detailed Description
The invention provides a preparation method of bumetanide, which comprises the following steps:
3-nitro-4-phenoxy-5-sulfonamide benzoic acid, butyraldehyde, formate, catalyst and good solvent are mixed in a pot to carry out reduction reaction and reductive amination reaction, thus obtaining the bumetanide.
In the present invention, the mass ratio of 3-nitro-4-phenoxy-5-sulfonylaminobenzoic acid to butyraldehyde is preferably 1:1.5 to 2, more preferably 1:1.6 to 1.9, and even more preferably 1:1.7 to 1.8.
In the present invention, the molar ratio of 3-nitro-4-phenoxy-5-sulfonylaminobenzoic acid to formate is preferably 1:4 to 6, more preferably 1:4 to 5, still more preferably 1:4; the formate preferably comprises one or more of ammonium formate, potassium formate and sodium formate. In the present invention, formate salt is used as hydrogen donor to participate in reduction reaction and reductive amination reaction.
In the present invention, the mass ratio of the 3-nitro-4-phenoxy-5-sulfonamide benzoic acid to the catalyst is preferably 100:1.0 to 2.0, more preferably 100:1.2 to 1.8, and even more preferably 100:1.4 to 1.6.
In the present invention, the catalyst preferably includes one or both of palladium carbon and raney nickel, and more preferably palladium carbon. The invention catalyzes the reduction reaction by adding the catalyst, thereby improving the reaction rate.
In the present invention, the mass/volume ratio of the 3-nitro-4-phenoxy-5-sulfoaminobenzoic acid to the good solvent is preferably 1g:5 to 10mL, more preferably 1g:6 to 9mL, and even more preferably 1g:7 to 8mL.
In the present invention, the good solvent preferably includes one or more of tetrahydrofuran, dioxane and N, N-dimethylformamide.
In the present invention, the temperature of the reduction reaction and the reductive amination reaction is preferably 50 to 55 ℃, more preferably 51 to 54 ℃, still more preferably 52 to 53 ℃, and the reaction time is preferably 1 to 2 hours, more preferably 1.3 to 1.7 hours, still more preferably 1.5 hours. In the invention, the chemical reaction equation of the reduction reaction and the reductive amination reaction is shown as a formula IV:
the intermediate product 3-amino-4-phenoxy-5-sulfonamide benzoic acid is obtained through reduction reaction, and the intermediate product 3-amino-4-phenoxy-5-sulfonamide benzoic acid is used as a reactant of reductive amination reaction, and is subjected to reductive amination reaction to obtain the bumetanide. In the actual reaction process, the intermediate product obtained by the reduction reaction rapidly undergoes the reductive amination reaction, so that the reduction reaction and the reductive amination reaction are performed simultaneously, and the reaction efficiency is high.
In the present invention, the reduction reaction and reductive amination reaction preferably further comprises a post-treatment; the post-treatment is preferably: the reaction product is cooled and then is subjected to reduced pressure concentration, pulping, filtering, washing and drying in sequence.
In the present invention, the cooling is preferably natural cooling; the final temperature of the cooling is preferably room temperature.
In the present invention, the pressure of the reduced pressure concentration is preferably not more than-0.085 MPa, more preferably not more than-0.080 MPa; the reduced pressure concentration is preferably continued until no fraction is distilled off. According to the invention, the good solvent in the reaction system is distilled out through reduced pressure concentration, so that most of the bumetanide product is separated out.
In the present invention, the beating is preferably: heating and mixing the concentrate obtained by concentrating under reduced pressure with water; the water is preferably purified water; the mass ratio of the 3-nitro-4-phenoxy-5-sulfonamide benzoic acid to the water is 1:30; the temperature of the heating and mixing is preferably 50 to 55 ℃, more preferably 51 to 54 ℃, still more preferably 52 to 53 ℃, and the heat preservation time is preferably 1 to 3 hours, more preferably 1 to 2 hours, still more preferably 1 hour.
In the present invention, the filtration is preferably suction filtration.
In the present invention, the washing is preferably rinsing; the wash reagent is preferably water; the water is preferably purified water.
In the present invention, the drying is preferably forced air drying; the temperature of the air-drying is preferably 55 to 60 ℃, more preferably 57 to 59 ℃.
The following describes the invention in detail with reference to examples for further illustration of the invention, but they should not be construed as limiting the scope of the invention.
Example 1
Preparation of bumetanide:
3-nitro-4-phenoxy-5-sulfonamide benzoic acid (50.00 g,0.148 mol), ammonium formate (37.33 g,0.148 mol), tetrahydrofuran (500 mL) and palladium carbon (1.0 g, 16.01g,0.222 mol) are added into a reaction bottle, the temperature is raised to 50-55 ℃ for reaction for 2 hours, the temperature is reduced to room temperature, the reduced pressure concentration is carried out until no fraction is distilled out, the distillation is stopped, 1500mL of purified water is added, and the temperature is controlled to be 50-55 ℃ for stirring and pulping for 1 hour; cooling to room temperature, suction filtering, leaching the obtained filter cake with 250mL of purified water, and then drying the filter cake to constant weight at 55-60 ℃ by blowing to obtain 45.98g of bumetanide with 86% yield and 99.5% HPLC purity. The bumetanide prepared in this example was subjected to a hydrogen spectrum test, and the results are shown below:
1 HNMR(600MHz,DMSO):13.16(s,1H,COOH),7.70(s,1H,Ar),7.42(s,1H,Ar),7.34(s,2H,Ar),7.27(t,2H,Ar),7.01(t,1H,Ar),6.84(s,2H,NH 2 ),5.05(t,1H,NH),3.06(q,2H,CH 2 ),1.34-1.39(m,2H,CH 2 ),1.08-1.14(m,2H,CH 2 ),0.78(d，3H,CH 3 ). Therefore, the invention successfully prepares the bumetanide.
Example 2
Preparation of bumetanide:
3-nitro-4-phenoxy-5-sulfonamide benzoic acid (50.00 g,0.148 mol), ammonium formate (37.33 g,0.148 mol), tetrahydrofuran (500 mL) and palladium carbon (1.0 g, 16.01g,0.222 mol) are added into a reaction bottle, the temperature is raised to 50-55 ℃ for reaction for 2 hours, the temperature is reduced to room temperature, the reduced pressure concentration is carried out until no fraction is distilled out, the distillation is stopped, 1500mL of purified water is added, and the temperature is controlled to be 50-55 ℃ for stirring and pulping for 1 hour; cooling to room temperature, suction filtering, rinsing the obtained filter cake with 250mL of purified water, and then drying the filter cake to constant weight by blowing at 55-60 ℃ to obtain 48.12g of bumetanide, wherein the yield is 90%, the HPLC purity is 99.8%, and the hydrogen spectrum test result is the same as that of the example 1.
Example 3
Preparation of bumetanide:
3-nitro-4-phenoxy-5-sulfonamide benzoic acid (50.00 g,0.148 mol), ammonium formate (37.33 g,0.148 mol), dioxane 500mL and palladium carbon 1.0g, butyraldehyde (16.01 g,0.222 mol) are added into a reaction bottle, the temperature is raised to 50-55 ℃ for reaction for 2 hours, the temperature is reduced to room temperature, reduced pressure concentration is carried out until no fraction is distilled out, distillation is stopped, 1500mL of purified water is added, and stirring and beating are carried out for 1 hour at the temperature of 50-55 ℃; cooling to room temperature, suction filtering, rinsing the obtained filter cake with 250mL of purified water, and then drying the filter cake to constant weight by blowing at 55-60 ℃ to obtain 47.58g of bumetanide, wherein the yield is 89%, the HPLC purity is 99.7%, and the hydrogen spectrum test result is the same as that of the example 1.
Example 4
Preparation of bumetanide:
3-nitro-4-phenoxy-5-sulfonamide benzoic acid (50.00 g,0.148 mol), ammonium formate (37.33 g,0.222 mol), N-dimethylformamide (500 mL) and palladium on carbon (1.0 g) are added into a reaction bottle, butyraldehyde (16.01 g,0.222 mol) are heated to 50-55 ℃ for reaction for 2 hours, cooled to room temperature, concentrated under reduced pressure until no fraction is distilled off, distilled is stopped, 1500mL of purified water is added, and the temperature is controlled to be 50-55 ℃ for stirring and pulping for 1 hour; cooling to room temperature, suction filtering, rinsing the obtained filter cake with 250mL of purified water, and then drying the filter cake to constant weight by blowing at 55-60 ℃ to obtain 45.44g of bumetanide with the yield of 85%, the HPLC purity of 99.5%, and the hydrogen spectrum test result being the same as in example 1.
Example 5
Preparation of bumetanide:
3-nitro-4-phenoxy-5-sulfonamide benzoic acid (50.00 g,0.148 mol), potassium formate (74.60 g,0.88 mol), N-dimethylformamide (500 mL) and palladium-carbon (1.0 g) are added into a reaction bottle, butyraldehyde (16.01 g,0.222 mol) are heated to 50-55 ℃ for reaction for 2 hours, cooled to room temperature, decompressed and concentrated until no fraction is distilled out, distilled is stopped, and 1500mL of purified water is added, and the temperature is controlled to be 50-55 ℃ for stirring and pulping for 1 hour; cooling to room temperature, suction filtering, rinsing the obtained filter cake with 250mL of purified water, and then drying the filter cake to constant weight by blowing at 55-60 ℃ to obtain 44.37g of bumetanide with the yield of 83%, the HPLC purity of 99.4%, and the hydrogen spectrum test result is the same as that of the example 1.
Example 6
Preparation of bumetanide:
3-nitro-4-phenoxy-5-sulfonamide benzoic acid (50.00 g,0.148 mol), sodium formate (50.32, 0.740 mol), N-dimethylformamide (500 mL) and palladium on carbon (1.0 g) are added into a reaction bottle, butyraldehyde (16.01 g,0.222 mol) are heated to 50-55 ℃ for reaction for 2 hours, cooled to room temperature, decompressed and concentrated until no fraction is distilled out, distilled is stopped, and 1500mL of purified water is added, and the temperature is controlled to be 50-55 ℃ for stirring and pulping for 1 hour; cooling to room temperature, suction filtering, rinsing the obtained filter cake with 250mL of purified water, and then drying the filter cake to constant weight by blowing at 55-60 ℃ to obtain 43.83g of bumetanide with a yield of 82%, an HPLC purity of 99.4%, and a hydrogen spectrum test result identical to that of example 1.
According to the embodiment, the preparation method provided by the invention has the advantages of one-step synthesis of the bumetanide, few steps, simple reaction route, high purity of the prepared bumetanide, purity of over 99.4 percent, stable compliance with the requirement of bumetanide bulk drug pharmacopoeia, mild reaction conditions, high synthesis efficiency, over 82 percent of yield, simple post-treatment and cost reduction.
Although the foregoing embodiments have been described in some, but not all embodiments of the invention, other embodiments may be obtained according to the present embodiments without departing from the scope of the invention.
Claims (10)
1. The preparation method of the bumetanide is characterized by comprising the following steps of:
3-nitro-4-phenoxy-5-sulfonamide benzoic acid, butyraldehyde, formate, catalyst and good solvent are mixed in a pot to carry out reduction reaction and reductive amination reaction, thus obtaining the bumetanide.
2. The preparation method according to claim 1, wherein the temperature of the reduction reaction and the reductive amination reaction is 50-55 ℃ and the reaction time is 1-2 h.
3. The preparation method according to claim 1, wherein the mass ratio of the 3-nitro-4-phenoxy-5-sulfonamide benzoic acid to the catalyst is 100:1.0-2.0.
4. A method of preparation according to claim 1 or 3, wherein the catalyst comprises one or both of palladium on carbon and raney nickel.
5. The method according to claim 1, wherein the formate comprises one or more of ammonium formate, potassium formate and sodium formate.
6. The preparation method according to claim 1, wherein the mass ratio of 3-nitro-4-phenoxy-5-sulfonamide benzoic acid to butyraldehyde is 1:1.5-2.
7. The process according to claim 1 or 5, wherein the molar ratio of 3-nitro-4-phenoxy-5-sulfonylaminobenzoic acid to formate is 1:4-6.
8. The preparation method according to claim 1, wherein the mass-volume ratio of the 3-nitro-4-phenoxy-5-sulfoaminobenzoic acid to the good solvent is 1 g:5-10 mL.
9. The production method according to claim 1 or 8, wherein the good solvent comprises one or more of tetrahydrofuran, dioxane and N, N-dimethylformamide.
10. The production method according to claim 1 or 2, characterized in that the reduction reaction and the reductive amination reaction further comprise a post-treatment; the post-treatment is as follows: the reaction product is cooled and then is subjected to reduced pressure concentration, pulping, filtering, washing and drying in sequence.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311428149.5A CN117466783A (en) | 2023-10-31 | 2023-10-31 | Preparation method of bumetanide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311428149.5A CN117466783A (en) | 2023-10-31 | 2023-10-31 | Preparation method of bumetanide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117466783A true CN117466783A (en) | 2024-01-30 |
Family
ID=89634241
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311428149.5A Pending CN117466783A (en) | 2023-10-31 | 2023-10-31 | Preparation method of bumetanide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117466783A (en) |
-
2023
- 2023-10-31 CN CN202311428149.5A patent/CN117466783A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114031551B (en) | Fluopicolide and synthesis method thereof | |
| CN105801436A (en) | Synthesizing method for N,N,N'-trimethyl-N'-ethoxyl-ethidene diamine | |
| EP2524909B1 (en) | Preparation method of 4-aminomethylbenzoic acid | |
| CN117466783A (en) | Preparation method of bumetanide | |
| CN111440171A (en) | Method for synthesizing guanine by hydrolysis of guanosine | |
| CN111138351A (en) | Synthetic method of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine acetate | |
| CN110963946B (en) | Preparation method of sodium methyl taurate | |
| CN113336761B (en) | Preparation method of JAK inhibitor key intermediate | |
| CN115557928A (en) | Synthetic method of 2-chlorothiophene-5-formic acid | |
| CN107935892A (en) | A kind of method for preparing ethylenediamine base ethyl sulfonic acid sodium | |
| JPH08319277A (en) | Production of 2,4-diamino-5-formylamino-6-hydroxypyrimidine | |
| CN102344378B (en) | Amino alcohol preparation method using aqueous amino acid | |
| CN110590683A (en) | Preparation method of intermediate of targeting drug AZD3759 | |
| CN114262340B (en) | Preparation method of aminophenylboric acid | |
| CN110590580A (en) | Method for increasing production of monoethanolamine and diethanolamine | |
| CN115784925B (en) | Continuous preparation method of 2-methyl-6-nitrobenzaldehyde oxime | |
| CN112300059B (en) | Preparation method of PF-06651600 intermediate | |
| CN114890950B (en) | Preparation method of 2-imidazolidone | |
| CN115819221B (en) | Preparation method of (R) -2-hydroxymethyl propionic acid and (S) -2-hydroxymethyl propionic acid | |
| CN117567326A (en) | Preparation method of bumetanide | |
| CN116444783A (en) | Polyether amine ethyl sodium sulfonate, preparation method and application thereof | |
| CN101270039A (en) | Method for synthesizing anisyl methyl ketone | |
| CN115784925A (en) | Continuous preparation method of 2-methyl-6-nitrobenzaldehyde oxime | |
| CN110590579B (en) | Method for synthesizing monoethanolamine and diethanolamine | |
| CN116396194A (en) | Preparation method of bumetanide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |