CN1011779B - Synthetic method of diuretic bumetanide - Google Patents
Synthetic method of diuretic bumetanideInfo
- Publication number
- CN1011779B CN1011779B CN 86108913 CN86108913A CN1011779B CN 1011779 B CN1011779 B CN 1011779B CN 86108913 CN86108913 CN 86108913 CN 86108913 A CN86108913 A CN 86108913A CN 1011779 B CN1011779 B CN 1011779B
- Authority
- CN
- China
- Prior art keywords
- benzoic acid
- bumetanide
- acid
- nitro
- sulfonyl
- 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.)
- Expired
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to bumetanide, namely 3-n-butyl-4-phenoxyl-5-sulphonyl aminobenzoic acid which is a very efficient diuretic. From 3, 5-dinitro-4-chlorobenzoic acid, operation of phenoxyation, dinitro partial reduction, chlorosulfonation and ammonolysis is carried out to the 3, 5-dinitro-4-chlorobenzoic acid to obtain a key intermediate 3-nitryl-5-aminosulfonylthiophene-4-phenodecem ybenzoic acid, and after nitroreduction, the latter completes butylation by a single step through sodium borohydride (or kalium boron hydrogen)-butyric acid agent to obtain bumetanide. The total yield of the method is as high as 12% to 14% measured by para-chlorobenzoic acid. The present invention has the advantages of available raw material with low price, convenient and safe process, and better production quality, and is suitable for industrial production.
Description
The invention belongs to the production technique of diuretic.
Bumetanide (Bumetanide) chemistry 3-n-butyl amine base by name-4-phenoxy group-5-sulfonyl-benzoic acid (I), the derivative of position White streptocide between system, be invention such as the seventies Denmark Leo pharmaceutical factory Feit.P.W a kind of onset rapidly, the of short duration potent loop hydragog(ue) of effect.The diuretic properties intensity of bumetanide is 40-60 times of loop hydragog(ue) furosemide (Furosemide) commonly used by weight, and some is effective to the invalid nephrotic's bumetanide of furosemide.
Existing bumetanide synthetic route according to reported in literature, roughly has three, and there are five kinds of methods in its one step of crucial butylation.The route I is raw material with the Chlorodracylic acid, through chlorosulphonation, nitrated, ammonia is separated, phenoxy groupization, 3-nitro-4-phenoxy group-5-sulfonyl-benzoic acid, and then carry out butylation and form.The butylation method has three kinds: (1) is through the Pd-C catalytic hydrogenation, with butanols reaction, go 1 butyl to get bumetanide with basic hydrolysis again; (2) through the Pd-C catalytic hydrogenation, with butyraldehyde addition (US3933906), sodium borohydride reduce bumetanide; (3) in the presence of acetic acid, p-methyl benzenesulfonic acid and butyraldehyde, get bumetanide (ES45044) through the Pd-C catalytic one-stage.It is dangerous, seriously polluted that this route total recovery is low, high-temperature chlorine sulfonation and excessive greatly chlorsulfonic acid ice are separated operation; Nitration reaction must be used high-concentration sulfuric acid; Butylation (1) and (2) all need through two-step reaction, and method (1) also must be used nuclear magnetic resonance analyser detection reaction terminal point, method (3) will be used expensive Pd-C(palladium-carbon though can obtain bumetanide from one step of intermediate) catalytic hydrogenation, hydrogenation equipment requires also higher.The route II is from Chlorodracylic acid; separate and N through chlorosulphonation, ammonia; dinethylformamide addition, nitrated, chlorine displacement, alcoholysis, phenoxy groupization and eight steps of hydrogenation react 3-amino-4-phenoxy group-5-sulfonyl-benzoic acid methyl esters; again with butyryl chloride acidylate (DF2345229), sodium borohydride reduction; remove 1 methyl esters with alkaline hydrolysis at last, get bumetanide.This route and route I are approaching, but more loaded down with trivial details, and butylation also needed for three steps.Route III and I, II are different; after Chlorodracylic acid two is nitrated, carry out the phenoxy group reaction; improved yield; but be thereafter to carry out 3 reduction and butylation earlier; and then carry out 5 sulfonylations and form, the front and back reaction had more than 9 steps, especially butylation; must divide for two steps, react and just can finish (GB1317941) in 60 hours.Therefore, to be used for industrial production all dissatisfied for existing bumetanide synthetic route and butylation method.
The invention provides a new bumetanide synthetic route and a kind of new butylation method.
The present invention is 3, and 5-dinitrobenzene-4-chloro-benzoic acid is a raw material, obtains bumetanide through six-step process, and concrete route is shown below:
(1) 3,5-dinitrobenzene-4-chloro-benzoic acid (II) reacts in weak alkaline medium with phenol, obtains 3,5-dinitrobenzene-4-phenoxy benzoate (III).Weak alkaline medium can be alkali-metal carbonate or acid carbonate, is good with sodium bicarbonate wherein.
(2) III and reductive agent react in weak alkaline medium, obtain 5-amino-3-nitro-4-phenoxy benzoic acid (IV).Weak alkaline medium can be alkali-metal carbonate or acid carbonate, also can be ammoniacal liquor or organic bases, is good with sodium bicarbonate and ammoniacal liquor wherein; Reductive agent is a vat powder.
(3) IV and Sodium Nitrite in reaction below 4 ℃, obtain diazonium salt in hydrochloric acid soln, and the latter and sulfurous gas-acetum obtain 3-nitro-4-phenoxy group-5-chlorine sulfonyl benzoate (V) under cupric chloride catalysis.
(4) V ammonia in ammoniacal liquor is separated and is obtained 3-nitro-4-phenoxy group-5-sulfonyl-benzoic acid (VI).
(5) VI and reductive agent react in weak alkaline medium, obtain 3-amino-4-phenoxy group-5-sulfonyl-benzoic acid (VII).Alkaline medium can be alkali-metal carbonate or acid carbonate, also can be ammoniacal liquor or organic bases, is good with ammoniacal liquor and yellow soda ash wherein; Reductive agent is a vat powder.
(6) in exsiccant organic solvent such as benzene or toluene, VII and butyric acid are in the presence of alkali metal borohydride such as sodium borohydride or potassium boron hydrogen, and reacting by heating obtains bumetanide, and its temperature of reaction is good with 80～85 ℃.
The present invention compares with existing synthetic method, and circuit is short, yield is high, calculates with Chlorodracylic acid, and total recovery reaches 12-14%, and the total recovery of circuit I only has 3.8%.The present invention replaces rare, valuable and dangerous raw material with the raw material of common, inexpensive and safety, has cut off the strong chlorsulfonic acid of corrodibility and has at high temperature reacted, and reacted at low temperatures with sulfurous gas-acetic acid, has avoided severe contamination; Replace the high purity vitriol oil with the industrial vitriol oil; Avoid using the precious metal chemical complex Palladous chloride to carry out catalytic hydrogenation, reduce with vat powder and replace in weakly alkaline solution as catalyzer.Especially the butylation method among the present invention, technology is simple, and a step finishes, and reaction time is short, the yield height.Therefore the present invention is applicable to suitability for industrialized production.
Most preferred embodiment:
Example 1.3, the preparation of 5-dinitrobenzene-4-phenoxy benzoic acid (III):
In 1000 milliliters of there-necked flasks, add 200 milliliters in water and phenol 50 grams (0.532 mole), start stirring, add 3,5-dinitrobenzene-4-chloro-benzoic acid (fusing point 160-163 ℃) 123 gram (0.5 mole), then, gradation slowly adds sodium bicarbonate 90 grams (1.07 moles), has the carbonic acid gas bubble to emit.After sodium bicarbonate added, stirring heating refluxed 1 hour, put be chilled to room temperature after, with hcl acidifying to pH～1.Cooling, suction filtration, fully washing, oven dry, approximately III 145 grams, fusing point is more than 210 ℃, yield 95.40%.The crude product washing with alcohol, fusing point can significantly improve; Use ethyl alcohol recrystallization, fusing point 222-224 ℃.
The preparation of example 2.5-amino-3-nitro-4-phenoxy benzoic acid (IV):
Add 2000 milliliters of entry, sodium bicarbonate 45 grams (or 20% ammoniacal liquor 40 milliliters), III 121.6 grams (0.4 mole) in 5000 milliliters of there-necked flasks, heated and stirred makes its dissolving, is chilled to then below 20 ℃.In stirring powder 182.4 grams that take a policy down, at room temperature stirring reaction is 30 minutes, adds 30% sulfuric acid acidation to pH2, continue then to stir 5 hours, crystallization, suction filtration, with washing on a small quantity, dry IV.Crude product is dried with the ethyl alcohol recrystallization of 10 times of amounts, gets elaboration 82 grams, and fusing point 228-230 ℃, yield 75%.
The preparation of example 3.3-nitro-4-phenoxy group-5-chlorine sulfonyl benzoate (V):
In 1000 milliliters of there-necked flasks, drop into 600 milliliters of 30% hydrochloric acid, under agitation add IV 82.2 grams (0.3 mole), make dissolving, be cooled to below 4 ℃.In addition Sodium Nitrite 22 grams (about 0.32 mole) are dissolved in 60 ml waters, under agitation, sodium nitrite solution are slowly splashed in the reactant of there-necked flask (noticing that the mouth of pipe gos deep under the liquid level), temperature is controlled at below 4 ℃.Before will adding, often tests Sodium Nitrite, till reaction solution makes test paper become basket immediately with potassiumiodide-starch test paper.Restir 2 minutes, as splash into a sodium nitrite solution reaction solution and still can make test paper become blue immediately, the expression reaction has reached terminal point, yellow-green colour diazonium salt suspension.
In 2000 milliliters of there-necked flasks, add cupric chloride (Cucl in addition
22H
2O) 20.5 grams add water 25 milliliters of dissolvings.Add 400 milliliters of 30% sulfurous gas-acetum again, under agitation impouring diazonium salt suspension.Temperature rises gradually and begins to emit nitrogen, and about 10 minutes put the nitrogen end, and temperature no longer rises, again in 40 ℃ of heating 30 minutes.Suction filtration is fully washed then, and filter is done, and gets the wet product 170 of V approximately and restrains.
Get a small amount of oven dry of the wet product of V, molten some 175-180 ℃, in chlorinity, its content 82.36%.Chloroform recrystallization three times of oven dry back get white crystals, and fusing point 202-203 ℃, content 97.29%.
The preparation of example 4.3 nitros-4-phenoxy group-5-sulfonyl-benzoic acid (VI):
Add 100 milliliters of 20-25% ammoniacal liquor in 300 ml beakers, gradation adds the wet product of V of example 3 under cooling and stirring, treats to add volatile salt crystallization 15 grams after all dissolvings, continues to be stirred to and separates out crystal, places in refrigerator and spends the night.Suction filtration with a small amount of volatile salt saturated solution washing, adds an amount of furnishing pasty state of water with yellow crystal,, fully stirs evenly to pH1 with hcl acidifying, and suction filtration, oven dry gets about 28 grams of VI, fusing point 245-250 ℃.
Mother liquor and washing lotion merge, and to pH1, separate out yellow crystal and jelly, suction filtration with hcl acidifying, with the dissolving of an amount of strong aqua, and add volatile salt (ammonia vol 1/5), room temperature is placed and is spent the night, the same processing of the ammonium salt of the sulphonamide of separating out, the about 6-7 of sulphonamide restrains, fusing point＞245 ℃.Both merge common VI 34-35 gram.Two step yields about 34%.
Sulphonamide is with 50% ethyl alcohol recrystallization, fusing point 255-256 ℃
The preparation of example 5.3 amino-4-phenoxy group-5-sulfonyl benzoic acid (VII):
VI 34 gram (0.1 mole) is dissolved in 200 milliliters of 15% ammoniacal liquor, filters this yellow solution is under agitation splashed in the solution of vat powder 80 grams (0.36 mole) and 400 ml waters, fade the temperature rising immediately.Again with boiling water bath heating 30 minutes, be chilled to suction filtration after the room temperature after dripping off, washing, oven dry, about 29 grams of product VII, fusing point 250-253 ℃, receive filter 94%.
The preparation of example 6. bumetanide (I):
In 1000 milliliters of exsiccant there-necked flasks, drop into 220 milliliters of dry toluene (or benzene) and content butyric acid 80 grams more than 98%.Under agitation, sodium borohydride 10.7 gram gradation are added, temperature is controlled at below 30 ℃.After adding, continued stirring reaction 20 minutes in 30 ℃.Then, drop into, be heated to 80 ℃ with water-bath with being ground into fine powder and drying to VII 27.7 gram (0.09 mole) of constant weight, and in 80-85 ℃ of stirring reaction 5 hours.Reaction is finished, and reclaim under reduced pressure toluene (or benzene) is to doing.Add water 200 milliliters of dissolvings then, change beaker over to.Be adjusted to pH7.5-8 with 40% sodium hydroxide solution, separate out flake-like crystal, room temperature is placed and is spent the night.
Next day suction filtration, filtrate is waited until the recovery butyric acid.Filter cake is with the distilled water thorough washing, and filter is done, 400 milliliters of adding distil waters, and heating for dissolving, with decolorizing with activated carbon, filtered while hot, and be acidified to pH1 with pure hydrochloric acid.The white crystals of separating out is chilled to suction filtration after the room temperature, washing, 100 ℃ of oven dry, bumetanide 21 grams, fusing point 232-234 ℃, yield 46%.
Claims (5)
1, from 3, the method for the synthetic diuretics ding bumetanide (I) of 5-dinitrobenzene-4-chloro-benzoic acid comprising:
(1) 3,5-dinitrobenzene-4-chloro-benzoic acid (II) reacts in weak alkaline medium with phenol and obtains 3,5-dinitrobenzene-4-phenoxy benzoic acid (III).
(2) 3,5-dinitrobenzene-4-phenoxy benzoic acid reacts with a kind of reductive agent in weak alkaline medium, and partial reduction obtains 3-amino-5-nitro-4-phenoxy benzoic acid (IV).
(3) 3-amino-5-nitro-4-phenoxy benzoic acid and Sodium Nitrite react in hydrochloric acid soln and generate diazonium salt, and the latter obtains 3-nitro-4-phenoxy group-5-chlorine sulfonyl benzoate (V) with the sulfurous gas reaction under the catalysis of cupric chloride.
(4) 3-nitro-4-phenoxy group-5-chlorine sulfonyl benzoate ammonia is separated and is obtained 3-nitro-4-phenoxy group-5-sulfonyl-benzoic acid (VI).
(5) 3-nitro-4-phenoxy group-5-sulfonyl-benzoic acid reacts with a kind of reductive agent in weak alkaline medium, obtains 3-amino-4-phenoxy group-5-sulfonyl-benzoic acid (VII).
(6) in organic solvent, alkali metal borohydride reacts with butyric acid at 20～30 ℃, then 3-amino-4-phenoxy group-5-sulfonyl-benzoic acid is added, and turns to bumetanide at 80～85 ℃ of following butyl.
2, the method for said synthetic bumetanide in the claim 1 is characterized in that said weak alkaline medium is alkali-metal carbonate in (1) item, as salt of wormwood, yellow soda ash or acid carbonate such as sodium bicarbonate.
3, the method for the said synthetic bumetanide of claim 1 is characterized in that said weak alkaline medium is alkali-metal acid carbonate such as sodium bicarbonate or ammoniacal liquor or organic bases in the item of (2) (5).
4, the method for the said synthetic bumetanide of claim 1 is characterized in that said reductive agent is a vat powder in the item of (2) (5).
5, the method for the said synthetic bumetanide of claim 1 is characterized in that said organic solvent is benzene or toluene in (6) item, and said alkali metal borohydride is sodium borohydride or potassium boron hydrogen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 86108913 CN1011779B (en) | 1986-12-31 | 1986-12-31 | Synthetic method of diuretic bumetanide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 86108913 CN1011779B (en) | 1986-12-31 | 1986-12-31 | Synthetic method of diuretic bumetanide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN86108913A CN86108913A (en) | 1988-02-03 |
| CN1011779B true CN1011779B (en) | 1991-02-27 |
Family
ID=4804104
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 86108913 Expired CN1011779B (en) | 1986-12-31 | 1986-12-31 | Synthetic method of diuretic bumetanide |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1011779B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101591276B (en) * | 2009-05-21 | 2012-07-04 | 苏州立新制药有限公司 | Method for preparing bumetanide |
| CN106748906B (en) * | 2016-12-04 | 2018-08-17 | 枣庄市润安制药新材料有限公司 | A kind of synthetic method of bumetanide |
| CN116041228B (en) * | 2022-05-16 | 2024-03-12 | 沈阳希贝康医药科技有限公司 | Synthesis method of bumetanide |
-
1986
- 1986-12-31 CN CN 86108913 patent/CN1011779B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CN86108913A (en) | 1988-02-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4579683A (en) | 5-Cyano-10-isonitroso-10,11-dihydro-5H-dibenz[b,f]azepine | |
| CN115286514B (en) | Preparation method of 4' -chloro-2-aminobiphenyl sulfate | |
| JPH10195030A (en) | Production of aromatic halogen-amino compound | |
| US5763650A (en) | Process for the preparation of a halosubstituted aromatic acid | |
| CN112110804B (en) | Preparation method of 3, 5-dihalo trifluoro acetophenone and its derivative | |
| CN1011779B (en) | Synthetic method of diuretic bumetanide | |
| CN1214002C (en) | Process for synthesizing hydrate of calcium phenolsulfonate | |
| CN115611803B (en) | Synthesis method of 2, 3-dichloropyridine | |
| US5162584A (en) | Fluorobenzene derivatives | |
| KR100199335B1 (en) | Process for the synthesis of nabumetone | |
| CN114057588B (en) | Synthesis method of 8-amino-2-naphthol | |
| CN1050374C (en) | Temporary soluble blue dispersed dye and synthesis method thereof | |
| US4129740A (en) | Process for the preparation of para-nitroso-diphenylhydroxylamines | |
| JPH04360879A (en) | Purification of aromatic triazoles | |
| EP0089805A2 (en) | Process for preparing phenylalkanoic acids | |
| US4288620A (en) | Process for the production of 4-acylamido-2-nitro-1-alkoxybenzenes | |
| US4540817A (en) | Process for the preparation of 5-amino-2,4-dimethylacetanilide | |
| CN114507156B (en) | Preparation method of benzonitrile compound | |
| CN114621109B (en) | Synthesis method of apatamide and intermediate thereof | |
| CN1136037A (en) | 2,6-dibromo-4-carboxysulfonateacyl aminobenzene and its synthesis | |
| EP0161499B1 (en) | Process for preparation of aminophthalideisoquinolines | |
| KR950006799B1 (en) | Preparation of phenylhydroquinone | |
| FR2489317A1 (en) | ||
| EP0745594A1 (en) | Process for producing 6-substituted 2(1h)-quinoxalinone | |
| JP4072651B2 (en) | Process for producing 4-aminoresorcinol or a salt thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C13 | Decision | ||
| GR02 | Examined patent application | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| C15 | Extension of patent right duration from 15 to 20 years for appl. with date before 31.12.1992 and still valid on 11.12.2001 (patent law change 1993) | ||
| OR01 | Other related matters | ||
| C17 | Cessation of patent right | ||
| CX01 | Expiry of patent term |