CN105566260B - A kind of preparation method of frusemide - Google Patents

A kind of preparation method of frusemide Download PDF

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Publication number
CN105566260B
CN105566260B CN201510888295.5A CN201510888295A CN105566260B CN 105566260 B CN105566260 B CN 105566260B CN 201510888295 A CN201510888295 A CN 201510888295A CN 105566260 B CN105566260 B CN 105566260B
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formula
frusemide
reaction
preparing
representated
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CN105566260A (en
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陶锋
徐树行
夏正君
王剑
张志敏
王德祥
张楠
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Changzhou Yabang Pharmaceutical Co Ltd
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Changzhou Yabang Pharmaceutical Co Ltd
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    • 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

Abstract

The invention belongs to field of medicine and chemical technology, especially a kind of preparation method of frusemide (Furosemide)；Shown in its chemical formula such as formula (1)：The preparation method is as follows：By the tetrahydrofuran-compound representated by formula (2)：Wherein X represents halogen, lower alkyl sulfonyloxy, arylsulfonyloxy or aralkylsulfonyl epoxide, with 2 aminobenzoic acid compounds representated by formula (3) and/or its salt in reaction dissolvent, heat temperature raising, temperature control is 80 150 DEG C, in the presence of acid binding agent and/or catalyst, necleophilic reaction is complete to the formula (3) reaction

Description

A kind of preparation method of frusemide
Technical field
The invention belongs to field of medicine and chemical technology, especially a kind of preparation method of frusemide (Furosemide).
Background technology
Frusemide is a kind of to be used to treat the diuretics of congestive heart failure and oedema, molecular formula C12H11ClN2O5S, Its structure is as follows：
Existing frusemide synthetic route mainly has：Chinese Journal of Pharmaceuticals 1973；1：25 report with 2,4- dichloros Benzoic acid is that initiation material is condensed the frusemide shown in formula (1) after chlorosulfonation, ammonification and with chaff amine.In the route in order to The chloro- 5- sulfamoylbenzoic acids of 2,4- bis- are more converted, improve the molar ratio of chaff amine to 5.5: 1, significantly excessively Although chaff amine can distill rear enclosure use, need to use reduced vacuum system and consume a large amount of heat energy；In frusemide crude product Remaining chaff amine, which still needs to consume more acid, to be neutralized, and causes production cost to improve.
Chinese Journal of Pharmaceuticals 1973；1：The route of 25 reports
Eur.J.Med.Chem.1980,15 (4)：386 report using the chloro- 5- sulfamoylbenzoic acids of 2- amino -4- as rise Beginning raw material, the method through sodium borohydride reduction formula (1) after being condensed with furfural.The route uses sodium borohydride reduction imines, Post processing often want low temperature to be quenched, while produces more inorganic salts, this need to carry out frusemide more to purify to except Inorganic salts are removed, it is cumbersome, it is unfavorable for industrialized production.
Eur.J.Med.Chem.1980,15 (4)：The route of 386 reports.
The content of the invention
The technical problems to be solved by the invention are：There is provided a kind of simple to operate, yield and purity it is high prepare frusemide Method.
In order to solve the above technical problems, the technical solution adopted by the present invention is as follows：
A kind of preparation method of frusemide, shown in its chemical formula such as formula (1)：
The preparation method is as follows：By the tetrahydrofuran-compound representated by formula (2)：
Wherein X represents halogen, lower alkyl sulfonyloxy, arylsulfonyloxy or aralkylsulfonyl epoxide, representative with formula (3) 2- aminobenzoics acid compound and/or its salt in reaction dissolvent, heat temperature raising, temperature control be 82-160 DEG C, tiing up acid In the presence of agent and/or catalyst, necleophilic reaction is complete to the formula (3) reaction,
Reaction time is 24-36h；Reaction solution obtains the frusemide shown in formula (1) through isolating and purifying.
What the reaction of the present invention was generally carried out at a temperature of room temperature to 200 DEG C, preferably from about 80-160 DEG C.Reaction generally exists Completed in about 1-36 hours, preferably from about 5-24 hours interior completion.
Further, the amount ratio of the material of the formula (3) of addition, formula (2) and acid binding agent is：1: 1~4.0: 1~4.0；It is described Acid binding agent be inorganic base, described inorganic base is selected from NaOH, KOH, CsOH, Ba (OH)2、Mg(OH)2、Ca(OH)2、KHCO3、 K2CO3、NaHCO3、Na2CO3、Cs2CO3In any one, or its mixing.
Acid binding agent is inorganic alkaline compound, can be widely used known inorganic alkaline compound, such as NaOH, KOH, CsOH、Ba(OH)2、Mg(OH)2、Ca(OH)2、KHCO3、K2CO3、NaHCO3、Na2CO3、Cs2CO3Deng.These inorganic alkaline chemical combination Thing is either used or with two kinds or more of mixture uses, the wherein material of formula (3), formula (2) and acid binding agent with a kind of Amount ratio be：1: 1~4.0: 1~4.0, preferably 1: 1~2.0: 1~3.0.
Acid binding agent is alternatively organic base, and described organic base is selected from sodium alkoxide, potassium tert-butoxide, triethylamine, DMAP, pyridine, N- Methyl morpholine, any one in tetramethylethylenediamine, tri-n-butylamine, or its mixing.
Further, the amount ratio of the material of the formula (3) of addition, formula (2) and acid binding agent is：1: 1~2.0: 1~3.0.
Further, the amount ratio of the material of the formula (3) of addition, formula (2) and catalyst is：1: 1~4.0: 0~0.5；It is described Catalyst for NaBr, KBr, NaI, KI, cupric iodide, cuprous iodide, TBAB, tri-n-octyl methyl ammonium chloride it is any One kind, or its mixing.
Further, the amount ratio of the material of the formula (3) of addition, formula (2) and catalyst is 1: 1~2.0: 0~0.3.
Further, the reaction dissolvent be selected from water, acetonitrile, acetone, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, One or more in DMF, DMA, dimethyl sulfoxide (DMSO).
Further, in formula (2), the lower alkyl sulfonyloxy representated by X is straight chain or branch with 1-6 carbon atom Alkane sulfonyl oxy.
Further, in formula (2), the arylsulfonyloxy representated by X selects phenylsulfonyloxy or naphthalene sulfonyl epoxide, institute Stating phenylsulfonyloxy, there are 1-3 to be selected from following group as substituent on phenyl ring：Straight chain with 1-6 carbon atom or Branched alkyl, straight or branched alkoxyl, nitro and the halogen atom with 1-6 carbon atom.
Further, in formula (2), the aralkylsulfonyl epoxide representated by X includes the straight or branched being substituted by phenyl C1-6 alkane sulfonyloxies, wherein phenyl ring can have 1-3 to be selected from following group as substituent：With 1-6 carbon atom Straight or branched alkyl, there is straight or branched alkoxyl, nitro and the halogen atom of 1-6 carbon atom.
It is known compound for the 2- aminobenzoic acids representated by the formula (3) of the present invention and its salt.As described salt, The present invention is for example including inorganic salts, such as hydrochloride, sulfate, hydrobromate etc.；And organic salt, such as oxalates, maleic acid Salt, tartrate, benzoate etc..
Reaction can be carried out under agitation makes the reaction of the present invention more advantageously carry out.
Can according to separate mode commonly used in the art and purification mode by the frusemide that the inventive method obtains from reaction It is easily separated and purifies in mixture.As the separation and purification mode, such as：It can be mentioned that organic solvent extraction Method, concentration method, dilution method, fractionating process, recrystallization method, column chromatography etc..
It is using the beneficial effect of technical scheme：Using the present invention method, can by simple step, Without any complicated purification step can high-purity and high yield to prepare frusemide pure, high income is up to 97.0%, purity Up to 99.8%；Therefore, the industrial production process as frusemide, the inventive method have significant economic benefit, are very Favourable.
Embodiment
With reference to specific embodiment, the present invention will be further described.
Embodiment 1
In reaction bulb, addition DMF1000ml, the chloro- 5- sulfamoylbenzoic acids of 2- amino -4- (250.7 grams, 1.0mol), 2- chloromethylfurans (186.4 grams, 1.6mol), KBr (9.5 grams, 0.08mol), 120 degrees Centigrade stirring reactions 24 are small When, after cooling, water 5000ml is added, pH=5 is adjusted with hydrochloric acid, is down to room temperature, separate out crystal, filter, filter cake ethyl acetate Elution, dries to obtain 2- [(2- furfuryls) amino] 320.8 grams of -5- (sulfamoyl) -4- chlorobenzoic acids, yield 97.0% is pure Degree 99.8%.
The purity of frusemide is determined by high performance liquid chromatography (HPLC) under the following conditions：
Chromatographic column：MegresTMC18 (Chinese nation science and technology)
Eluant, eluent：Water/tetrahydrofuran/glacial acetic acid=70/30/1
Flow velocity：1.0mL/min
Detection wavelength：272nm UV
Embodiment 2
In reaction bulb, the chloro- 5- sulfamoylbenzoic acids of addition ethylene glycol 1200ml, 2- amino -4- (250.7 grams, 1.0mol), 2- chloromethylfurans (139.9 grams, 1.2mol), cupric iodide (31.7 grams, 0.1mol), the stirring of 160 degrees Centigrades Reaction 24 hours, after cooling, adds water 5000ml, adjusts pH=5 with hydrochloric acid, is down to room temperature, separate out crystal, filter, filter cake is used Ethyl acetate elutes, and dries to obtain 2- [(2- furfuryls) amino] 269.2 grams of -5- (sulfamoyl) -4- chlorobenzoic acids, yield 81.4%, purity 99.6%.
The purity of frusemide is determined by high performance liquid chromatography (HPLC) under the following conditions：
Chromatographic column：MegresTMC18 (Chinese nation science and technology)
Eluant, eluent：Water/tetrahydrofuran/glacial acetic acid=70/30/1
Flow velocity：1.0mL/min
Detection wavelength：272nm UV
Embodiment 3
In reaction bulb, the chloro- 5- sulfamoylbenzoic acids of DMF 1000ml, 2- amino -4- (250.7 grams, 1.0mol) are added, 2- chloromethylfurans (256.3 grams, 2.2mol), sodium bromide (14.4 grams, 0.14mol), 100 degrees Centigrade stirring reactions 24 are small When, after cooling, water 5000ml is added, pH=5 is adjusted with hydrochloric acid, is down to room temperature, separate out crystal, filter, filter cake ethyl acetate Elution, dries to obtain 2- [(2- furfuryls) amino] 298.7 grams of -5- (sulfamoyl) -4- chlorobenzoic acids, yield 90.3% is pure Degree 99.8%.
The purity of frusemide is determined by high performance liquid chromatography (HPLC) under the following conditions：
Chromatographic column：MegresTMC18 (Chinese nation science and technology)
Eluant, eluent：Water/tetrahydrofuran/glacial acetic acid=70/30/1
Flow velocity：1.0mL/min
Detection wavelength：272nm UV
Embodiment 4
In reaction bulb, the chloro- 5- sulfamoylbenzoic acids of acetonitrile 1000ml, 2- amino -4- (250.7 grams, 1.0mol) are added, 2- chloromethylfurans (233.1 grams, 2.0mol), potassium carbonate (276.4 grams, 2.0mol), 82 degrees Centigrade stirring reactions 36 are small When, after cooling, water 5000ml is added, pH=5 is adjusted with hydrochloric acid, is down to room temperature, separate out crystal, filter, filter cake ethyl acetate Elution, dries to obtain 2- [(2- furfuryls) amino] 305.6 grams of -5- (sulfamoyl) -4- chlorobenzoic acids, yield 92.4% is pure Degree 99.8%.
The purity of frusemide is determined by high performance liquid chromatography (HPLC) under the following conditions：
Chromatographic column：MegresTMC18 (Chinese nation science and technology)
Eluant, eluent：Water/tetrahydrofuran/glacial acetic acid=70/30/1
Flow velocity：1.0mL/min
Detection wavelength：272nm UV
Embodiment 5
In reaction bulb, the chloro- 5- sulfamoylbenzoic acids of 1000ml DMF, 2- amino -4- (250.7 grams, 1.0mol) are added, Furans -2- bases-methyl -4- toluene sulfonic acides ester (353.2 grams, 1.4mol), sodium methoxide (129.6 grams, 2.4mol), 85 degrees Celsius Heating stirring is reacted 36 hours, after cooling, adds water 5000ml, is adjusted pH=5 with hydrochloric acid, is down to room temperature, separates out crystal, take out Filter, filter cake are eluted with ethyl acetate, dry to obtain 2- [(2- furfuryls) amino] -5- (sulfamoyl) -4- chlorobenzoic acids 302.3 Gram, yield 91.4%, purity 99.7%.
The purity of frusemide is determined by high performance liquid chromatography (HPLC) under the following conditions：
Chromatographic column：MegresTMC18 (Chinese nation science and technology)
Eluant, eluent：Water/tetrahydrofuran/glacial acetic acid=70/30/1
Flow velocity：1.0mL/min
Detection wavelength：272nm UV
Embodiment 6
In reaction bulb, the chloro- 5- sulfamoylbenzoic acids of acetonitrile 1000ml, 2- amino -4- (250.7 grams, 1.0mol) are added, 2- chloromethylfurans (233.1 grams, 2.0mol), sodium bromide (13.2 grams, 0.13mol), sodium carbonate (276.4 grams, 2.0mol), 82 Degrees Centigrade stirring reaction 36 hours, after cooling, adds water 5000ml, adjusts pH=5 with hydrochloric acid, is down to room temperature, separates out brilliant Body, filter, filter cake is eluted with ethyl acetate, dries to obtain 2- [(2- furfuryls) amino] -5- (sulfamoyl) -4- chlorobenzoic acids 308.7 grams, yield 93.3%, purity 99.8%.
The purity of frusemide is determined by high performance liquid chromatography (HPLC) under the following conditions：
Chromatographic column：MegresTMC18 (Chinese nation science and technology)
Eluant, eluent：Water/tetrahydrofuran/glacial acetic acid=70/30/1
Flow velocity：1.0mL/min
Detection wavelength：272nm UV.
Embodiment 7
In reaction bulb, the chloro- 5- sulfamoylbenzoic acids of addition triethylamine 1000ml, 2- amino -4- (250.7 grams, 1.0mol), furans -2- bases-methyl -4- methanesulfonate esters (317.2 grams, 1.8mol), KBr (9.5 grams, 0.08mol), room The lower stirring reaction of temperature 10 hours, then 120 degrees Centigrade stirring reaction 24 hours, after cooling, adds water 5000ml, uses hydrochloric acid PH=5 is adjusted, is down to room temperature, separates out crystal, is filtered, filter cake is eluted with ethyl acetate, dries to obtain 2- [(2- furfuryls) ammonia Base] 308.9 grams of -5- (sulfamoyl) -4- chlorobenzoic acids, yield 93.4%, purity 99.8%.
Embodiment 1 is preferred embodiment.
Although above-described embodiment is described in detail to technical scheme, the technical side of the present invention Case is not limited to above example, in the case where not departing from the thought and objective of the present invention, to technical scheme institute Any change done falls within claims of the present invention limited range.

Claims (9)

  1. A kind of 1. preparation method of frusemide, shown in its chemical formula such as formula (1)：
    The preparation method is as follows：By the furan compound representated by formula (2)：
    Wherein X represents halogen, lower alkyl sulfonyloxy, arylsulfonyloxy or aralkylsulfonyl epoxide, with the 2- representated by formula (3) Aminobenzoic acid compound and/or its salt are in reaction dissolvent, heat temperature raising, temperature control be 80-160 DEG C, acid binding agent and/ Or in the presence of catalyst, necleophilic reaction is complete to the formula (3) reaction,
    Reaction time is 24-36h；Reaction solution obtains the frusemide shown in formula (1) through isolating and purifying；
    In formula (2), the lower alkyl sulfonyloxy representated by X is the straight or branched alkane sulfonyloxy with 1-6 carbon atom.
  2. 2. a kind of method for preparing frusemide as claimed in claim 1, it is characterised in that the formula (3) of addition, formula (2) and tie up The amount ratio of the material of sour agent is：1: 1~4.0: 1~4.0；Described acid binding agent is inorganic base, described inorganic base be selected from NaOH, It is any one in KOH, CsOH, Ba (OH) 2, Mg (OH) 2, Ca (OH) 2, KHCO3, K2CO3, NaHCO3, Na2CO3, Cs2CO3 Kind, or its mixing.
  3. 3. a kind of method for preparing frusemide as claimed in claim 2, it is characterised in that the formula (3) of addition, formula (2) and tie up The amount ratio of the material of sour agent is：1: 1~2.0: 1~3.0.
  4. A kind of 4. method for preparing frusemide as claimed in claim 1, it is characterised in that：The formula (3) of addition, formula (2) and tie up The amount ratio of the material of sour agent is：1: 1~4.0: 1~4.0；Described acid binding agent is organic base, described organic base be selected from sodium alkoxide, Potassium tert-butoxide, triethylamine, DMAP, pyridine, N-methylmorpholine, any one in tetramethylethylenediamine, tri-n-butylamine, or it is mixed Close.
  5. 5. a kind of method for preparing frusemide as claimed in claim 1, it is characterised in that the formula (3) of addition, formula (2) and urge The amount ratio of the material of agent is：1: 1~4.0: 0~0.5；Described catalyst is NaBr, KBr, NaI, KI, cupric iodide, iodate Any one of cuprous, TBAB, tri-n-octyl methyl ammonium chloride, or its mixing.
  6. A kind of 6. method for preparing frusemide as claimed in claim 5, it is characterised in that：The formula (3) of addition, formula (2) and urge The amount ratio of the material of agent is 1: 1~2.0: 0~0.3.
  7. A kind of 7. method for preparing frusemide as claimed in claim 1, it is characterised in that：The reaction dissolvent is selected from water, second Nitrile, acetone, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether, DMF, DMA, diformazan One or more in base sulfoxide.
  8. A kind of 8. method for preparing frusemide as claimed in claim 1, it is characterised in that：In formula (2), the virtue representated by X Sulfonyloxy selects phenylsulfonyloxy or naphthalene sulfonyl epoxide, and the phenylsulfonyloxy has 1-3 selected from following on phenyl ring Group as substituent：Straight or branched alkyl with 1-6 carbon atom, the straight or branched with 1-6 carbon atom Alkoxy, nitro and halogen atom.
  9. A kind of 9. method for preparing frusemide as claimed in claim 1, it is characterised in that：In formula (2), the virtue representated by X Alkylsulfonyloxy includes the straight or branched C1-6 alkane sulfonyloxies being substituted by phenyl, and wherein phenyl ring can have 1-3 choosing From following group as substituent：Straight or branched alkyl with 1-6 carbon atom, the straight chain with 1-6 carbon atom Or branched alkoxy, nitro and halogen atom.
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Publication number Priority date Publication date Assignee Title
CN106117168B (en) * 2016-06-30 2018-09-18 东北制药集团股份有限公司 A kind of preparation method of frusemide
CN113004230A (en) * 2019-12-20 2021-06-22 武汉久安药业有限公司 Furosemide and purification method thereof
CN117510444B (en) * 2024-01-06 2024-03-08 成都瑞尔医药科技有限公司 Refining process of furosemide

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037804A1 (en) * 2002-10-22 2004-05-06 Oscotec Inc. Furan derivatives for preventing and curing osteoporosis and pharmaceutical compositions containing the same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004037804A1 (en) * 2002-10-22 2004-05-06 Oscotec Inc. Furan derivatives for preventing and curing osteoporosis and pharmaceutical compositions containing the same

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Facile Access to 2-Arylindolines and 2-Arylindoles by Microwave-Assisted Tandem Radical Cyclization;Inga prediger等;《SYNTHESIS》;20081231(第14期);全文 *
SYNTHESIS AND PROPERTIES OF PHOTOSENSITIVE COMPOUNDS BASED ON BROMINE-CONTAINING 3-ACYL-2-FURYLCHROMONES;K. S. Levchenko等;《Chemistry of Heterocyclic Compounds》;20111231;第47卷(第2期);全文 *
速尿生产工艺成品缩合方法的改进;夏奕等;《中国医药工业杂志》;19911231;第22卷(第11期);全文 *

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