CN105566260A - Furosemide preparation method - Google Patents
Furosemide preparation method Download PDFInfo
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- CN105566260A CN105566260A CN201510888295.5A CN201510888295A CN105566260A CN 105566260 A CN105566260 A CN 105566260A CN 201510888295 A CN201510888295 A CN 201510888295A CN 105566260 A CN105566260 A CN 105566260A
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- furosemide
- method preparing
- reaction
- binding agent
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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 38
- 229960003883 furosemide Drugs 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 33
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 17
- -1 tetrahydrofuran compound Chemical class 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 16
- 239000000126 substance Substances 0.000 claims abstract description 15
- 239000011230 binding agent Substances 0.000 claims abstract description 14
- 125000005843 halogen group Chemical group 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims abstract description 5
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims abstract description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 5
- 238000000746 purification Methods 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 238000007344 nucleophilic reaction Methods 0.000 claims abstract description 3
- RWZYAGGXGHYGMB-UHFFFAOYSA-N o-aminobenzenecarboxylic acid Natural products NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims abstract description 3
- 230000035484 reaction time Effects 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 150000001721 carbon Chemical group 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 150000007530 organic bases Chemical group 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Substances [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 4
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- DIYWTQJUKVNACG-UHFFFAOYSA-N S(=O)(=O)=O.C1=CC=CC2=CC=CC=C12 Chemical compound S(=O)(=O)=O.C1=CC=CC2=CC=CC=C12 DIYWTQJUKVNACG-UHFFFAOYSA-N 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 229940086542 triethylamine Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 4
- 239000003054 catalyst Substances 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 238000005516 engineering process Methods 0.000 description 9
- LWDSANAOYPHQAW-UHFFFAOYSA-N 2-chloro-5-sulfamoylbenzoic acid Chemical compound NS(=O)(=O)C1=CC=C(Cl)C(C(O)=O)=C1 LWDSANAOYPHQAW-UHFFFAOYSA-N 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- 239000012065 filter cake Substances 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000012362 glacial acetic acid Substances 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- GANBJDIOIDQSGI-UHFFFAOYSA-N 2-(chloromethyl)furan Chemical compound ClCC1=CC=CO1 GANBJDIOIDQSGI-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 229910017053 inorganic salt Inorganic materials 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 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
- 235000010755 mineral Nutrition 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- FFMXLRXJGJMUDC-UHFFFAOYSA-N C(=O)O.ClC1=CC=CC(=C1)Cl Chemical compound C(=O)O.ClC1=CC=CC(=C1)Cl FFMXLRXJGJMUDC-UHFFFAOYSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 238000004176 ammonification Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000003113 dilution method Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药化工领域，尤其是一种呋塞米(Furosemide)的制备方法；其化学式如式(1)所示：所述制备方法如下：将式(2)所代表的四氢呋喃化合物：其中X代表卤素、低级烷磺酰氧基、芳磺酰氧基或芳烷基磺酰氧基，与式(3)所代表的2-氨基苯甲酸化合物和/或其盐在反应溶剂中，加热升温，温度控制为80-150℃，在缚酸剂和/或催化剂的作用下，亲核反应至所述式(3)反应完全，反应时间为5-36h；反应液经分离纯化得到式(1)所示的呋塞米。采用本发明的方法，可以通过简单的步骤，不用任何复杂的提纯步骤就可以高纯度和高产率的制备呋塞米，收率高达97.0％，纯度高达99.8％；因此，作为呋塞米的工业制备方法，本发明方法具有显著的经济效益，是非常有利的。The present invention belongs to the field of medicine and chemical industry, especially a kind of preparation method of furosemide (Furosemide); Its chemical formula is as shown in formula (1): The preparation method is as follows: the tetrahydrofuran compound represented by formula (2): Wherein X represents a halogen, a lower alkylsulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group, and the 2-aminobenzoic acid compound represented by formula (3) and/or its salt in a reaction solvent, Heating to raise the temperature, the temperature is controlled to be 80-150°C, and under the action of the acid-binding agent and/or catalyst, the nucleophilic reaction is completed until the reaction of the formula (3) is complete, The reaction time is 5-36h; the reaction solution is separated and purified to obtain furosemide represented by formula (1). By adopting the method of the present invention, furosemide can be prepared with high purity and high yield without any complicated purification steps through simple steps, the yield is as high as 97.0%, and the purity is as high as 99.8%; therefore, as an industrial furosemide The preparation method, the method of the present invention has significant economic benefits and is very advantageous.
Description
Technical field
The invention belongs to field of medicine and chemical technology, especially a kind of preparation method of Furosemide (Furosemide).
Background technology
Furosemide is a kind of hydragog(ue) being used for the treatment of congestive heart failure and oedema, and molecular formula is C
12h
11clN
2o
5s, its structure is as follows:
Existing Furosemide synthetic route mainly contains: Chinese Journal of Pharmaceuticals 1973; 1:25 report with 2,4 dichloro benzene formic acid for starting raw material after chlorosulphonation, ammonification and with the Furosemide shown in chaff amine condensation preparation formula (1).In order to be transformed more by chloro-for 2,4-bis-5-sulfamoylbenzoic acid in this route, improve the molar ratio to 5.5 of chaff amine: 1, although greatly excessive chaff amine is applied mechanically after can distilling, need use reduced vacuum system and consume a large amount of heat energy; Chaff amine remaining in Furosemide crude product still needs to consume more acid and neutralizes, and causes production cost to improve.
Chinese Journal of Pharmaceuticals 1973; The route of 1:25 report
Eur.J.Med.Chem.1980,15 (4): 386 report with the chloro-5-sulfamoylbenzoic acid of 2-amino-4-for starting raw material, with after furfural condensation through the method for sodium borohydride reduction preparation formula (1).This route uses sodium borohydride reduction imines, and low temperature cancellation is often wanted in aftertreatment, produces more inorganic salt simultaneously, and this needs to carry out more purifying to removing inorganic salt to Furosemide, and complex operation, is unfavorable for suitability for industrialized production.
Eur.J.Med.Chem.1980, the route of 15 (4): 386 reports.
Summary of the invention
Technical problem to be solved by this invention is: provide a kind of simple to operate, productive rate and the high method preparing Furosemide of purity.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
A preparation method for Furosemide, its chemical formula is such as formula shown in (1):
Described preparation method is as follows: the tetrahydrofuran-compound by representated by formula (2):
Wherein X represents halogen, lower alkyl sulfonyloxy, arylsulfonyloxy or aralkylsulfonyl oxygen base, with the 2-aminobenzoic acid compound representated by formula (3) and/or its salt in reaction solvent, heat temperature raising, temperature controls as 82-160 DEG C, under the effect of acid binding agent and/or catalyzer, nucleophilic reaction to described formula (3) reacts completely
Reaction times is 24-36h; Reaction solution obtains the Furosemide shown in formula (1) through separation and purification.
Reaction of the present invention is carried out usually at the temperature of room temperature to 200 DEG C, preferably about 80-160 DEG C.Reaction completed usually in about 1-36 hour, complete in preferred about 5-24 hour.
Further, the amount of substance ratio of the formula (3) added, formula (2) and acid binding agent is: 1: 1 ~ 4.0: 1 ~ 4.0; Described acid binding agent is mineral alkali, and described mineral alkali is selected from NaOH, KOH, CsOH, Ba (OH)
2, Mg (OH)
2, Ca (OH)
2, KHCO
3, K
2cO
3, NaHCO
3, Na
2cO
3, Cs
2cO
3in any one, or its mixing.
Acid binding agent is inorganic alkaline compound, can use known inorganic alkaline compound widely, such as NaOH, KOH, CsOH, Ba (OH)
2, Mg (OH)
2, Ca (OH)
2, KHCO
3, K
2cO
3, NaHCO
3, Na
2cO
3, Cs
2cO
3deng.These inorganic alkaline compounds or use with one, or use with two kinds or more of mixtures, the amount of substance ratio of its Chinese style (3), formula (2) and acid binding agent is: 1: 1 ~ 4.0: 1 ~ 4.0, preferably 1: 1 ~ 2.0: 1 ~ 3.0.
Acid binding agent also can be organic bases, and described organic bases is selected from sodium alkoxide, potassium tert.-butoxide, triethylamine, DMAP, pyridine, N-methylmorpholine, any one in Tetramethyl Ethylene Diamine, tri-n-butylamine, or its mixing.
Further, the amount of substance ratio of the formula (3) added, formula (2) and acid binding agent is: 1: 1 ~ 2.0: 1 ~ 3.0.
Further, the amount of substance ratio of the formula (3) added, formula (2) and catalyzer is: 1: 1 ~ 4.0: 0 ~ 0.5; Described catalyzer be NaBr, KBr, NaI, KI, cupric iodide, cuprous iodide, Tetrabutyl amonium bromide, tri-n-octyl methyl ammonium chloride any one, or its mixing.
Further, the amount of substance ratio of the formula (3) added, formula (2) and catalyzer is 1: 1 ~ 2.0: 0 ~ 0.3.
Further, described reaction solvent is selected from one or more in water, acetonitrile, acetone, tetrahydrofuran (THF), dioxane, diglyme, DMF, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO).
Further, in formula (2), the lower alkyl sulfonyloxy representated by X is the straight or branched alkane sulfonyloxy with 1-6 carbon atom.
Further, in formula (2), arylsulfonyloxy representated by X selects phenylsulfonyloxy or naphthalene sulfonyl oxygen base, and described phenylsulfonyloxy has 1-3 and is selected from following group alternatively base on phenyl ring: the straight or branched alkyl with 1-6 carbon atom, the straight or branched alkoxyl group with 1-6 carbon atom, nitro and halogen atom.
Further, in formula (2), aralkylsulfonyl oxygen base representated by X comprises the straight or branched C1-6 alkane sulfonyloxy be substituted by phenyl, and wherein phenyl ring can have 1-3 and is selected from following group alternatively base: the straight or branched alkyl with 1-6 carbon atom, the straight or branched alkoxyl group with 1-6 carbon atom, nitro and halogen atom.
Known compound for the 2-benzaminic acid representated by formula of the present invention (3) and salt thereof.As described salt, the present invention such as comprises inorganic salt, such as hydrochloride, vitriol, hydrobromate etc.; And organic salt, such as oxalate, maleate, tartrate, benzoate etc.
Under agitation can carry out reaction makes reaction of the present invention more advantageously carry out.
The Furosemide that the inventive method obtains by the separate mode can commonly used according to this area and purification mode is easily separated and purifies from reaction mixture.As described isolation andpurification mode, such as: the organic solvent extractionprocess that can mention, method of enrichment, dilution method, fractionating process, recrystallization method, column chromatography etc.
Adopt the beneficial effect of technical scheme of the present invention to be: to adopt method of the present invention, can by simple step, need not any complexity purification step just can high purity and high yield to prepare Furosemide pure, yield up to 97.0%, high purity 99.8%; Therefore, as the industrial production process of Furosemide, the inventive method has significant economic benefit, is very favorable.
Embodiment
Below in conjunction with specific embodiment, the present invention will be further described.
Embodiment 1
In reaction flask; add DMF1000ml; the chloro-5-sulfamoylbenzoic acid of 2-amino-4-(250.7 grams, 1.0mol), 2-chloromethylfuran (186.4 grams; 1.6mol); Potassium Bromide (9.5 grams, 0.08mol), 120 degrees Centigrade stirring reactions 24 hours; after cooling; add water 5000ml, regulate pH=5 with hydrochloric acid, be down to room temperature; crystallize out; suction filtration, filter cake ethyl acetate drip washing, dries to obtain 2-[(furfuryl) is amino]-5-(sulfamyl)-4-chloro-benzoic acid 320.8 grams; yield 97.0%, purity 99.8%.
The purity of Furosemide is measured under the following conditions by high performance liquid chromatography (HPLC):
Chromatographic column: Megres
tMc18 (Chinese nation science and technology)
Eluent: water/tetrahydrofuran (THF)/Glacial acetic acid=70/30/1
Flow velocity: 1.0mL/min
Determined wavelength: 272nmUV
Embodiment 2
In reaction flask, add ethylene glycol 1200ml, the chloro-5-sulfamoylbenzoic acid of 2-amino-4-(250.7 grams, 1.0mol), 2-chloromethylfuran (139.9 grams, 1.2mol), cupric iodide (31.7 grams, 0.1mol), 160 degrees Centigrade stirring reactions 24 hours, after cooling, add water 5000ml, pH=5 is regulated with hydrochloric acid, be down to room temperature, crystallize out, suction filtration, filter cake ethyl acetate drip washing, dry to obtain 2-[(furfuryl) is amino]-5-(sulfamyl)-4-chloro-benzoic acid 269.2 grams, yield 81.4%, purity 99.6%.
The purity of Furosemide is measured under the following conditions by high performance liquid chromatography (HPLC):
Chromatographic column: Megres
tMc18 (Chinese nation science and technology)
Eluent: water/tetrahydrofuran (THF)/Glacial acetic acid=70/30/1
Flow velocity: 1.0mL/min
Determined wavelength: 272nmUV
Embodiment 3
In reaction flask; add DMF1000ml; the chloro-5-sulfamoylbenzoic acid of 2-amino-4-(250.7 grams; 1.0mol), 2-chloromethylfuran (256.3 grams, 2.2mol), Sodium Bromide (14.4 grams; 0.14mol); 100 degrees Centigrade stirring reactions 24 hours, after cooling, add water 5000ml; pH=5 is regulated with hydrochloric acid; be down to room temperature, crystallize out, suction filtration; filter cake ethyl acetate drip washing; dry to obtain 2-[(furfuryl) is amino]-5-(sulfamyl)-4-chloro-benzoic acid 298.7 grams, yield 90.3%, purity 99.8%.
The purity of Furosemide is measured under the following conditions by high performance liquid chromatography (HPLC):
Chromatographic column: Megres
tMc18 (Chinese nation science and technology)
Eluent: water/tetrahydrofuran (THF)/Glacial acetic acid=70/30/1
Flow velocity: 1.0mL/min
Determined wavelength: 272nmUV
Embodiment 4
In reaction flask; add acetonitrile 1000ml; the chloro-5-sulfamoylbenzoic acid of 2-amino-4-(250.7 grams; 1.0mol), 2-chloromethylfuran (233.1 grams, 2.0mol), (276.4 grams, salt of wormwood; 2.0mol); 82 degrees Centigrade stirring reactions 36 hours, after cooling, add water 5000ml; pH=5 is regulated with hydrochloric acid; be down to room temperature, crystallize out, suction filtration; filter cake ethyl acetate drip washing; dry to obtain 2-[(furfuryl) is amino]-5-(sulfamyl)-4-chloro-benzoic acid 305.6 grams, yield 92.4%, purity 99.8%.
The purity of Furosemide is measured under the following conditions by high performance liquid chromatography (HPLC):
Chromatographic column: Megres
tMc18 (Chinese nation science and technology)
Eluent: water/tetrahydrofuran (THF)/Glacial acetic acid=70/30/1
Flow velocity: 1.0mL/min
Determined wavelength: 272nmUV
Embodiment 5
In reaction flask, add 1000mlDMF, the chloro-5-sulfamoylbenzoic acid of 2-amino-4-(250.7 grams, 1.0mol), furans-2-base-methyl-4-toluene sulfonic acide ester (353.2 grams, 1.4mol), sodium methylate (129.6 grams, 2.4mol), 85 degrees Centigrade stirring reactions 36 hours, after cooling, add water 5000ml, pH=5 is regulated with hydrochloric acid, be down to room temperature, crystallize out, suction filtration, filter cake ethyl acetate drip washing, dry to obtain 2-[(furfuryl) is amino]-5-(sulfamyl)-4-chloro-benzoic acid 302.3 grams, yield 91.4%, purity 99.7%.
The purity of Furosemide is measured under the following conditions by high performance liquid chromatography (HPLC):
Chromatographic column: Megres
tMc18 (Chinese nation science and technology)
Eluent: water/tetrahydrofuran (THF)/Glacial acetic acid=70/30/1
Flow velocity: 1.0mL/min
Determined wavelength: 272nmUV
Embodiment 6
In reaction flask, add acetonitrile 1000ml, the chloro-5-sulfamoylbenzoic acid of 2-amino-4-(250.7 grams, 1.0mol), 2-chloromethylfuran (233.1 grams, 2.0mol), Sodium Bromide (13.2 grams, 0.13mol), (276.4 grams, sodium carbonate, 2.0mol), 82 degrees Centigrade stirring reactions 36 hours, after cooling, add water 5000ml, pH=5 is regulated with hydrochloric acid, be down to room temperature, crystallize out, suction filtration, filter cake ethyl acetate drip washing, dry to obtain 2-[(furfuryl) is amino]-5-(sulfamyl)-4-chloro-benzoic acid 308.7 grams, yield 93.3%, purity 99.8%.
The purity of Furosemide is measured under the following conditions by high performance liquid chromatography (HPLC):
Chromatographic column: Megres
tMc18 (Chinese nation science and technology)
Eluent: water/tetrahydrofuran (THF)/Glacial acetic acid=70/30/1
Flow velocity: 1.0mL/min
Determined wavelength: 272nmUV.
Embodiment 7
In reaction flask, add triethylamine 1000ml, the chloro-5-sulfamoylbenzoic acid of 2-amino-4-(250.7 grams, 1.0mol), furans-2-base-methyl-4-methanesulfonate ester (317.2 grams, 1.8mol), Potassium Bromide (9.5 grams, 0.08mol), stirred at ambient temperature reacts 10 hours, then 120 degrees Centigrade stirring reaction 24 hours, after cooling, add water 5000ml, pH=5 is regulated with hydrochloric acid, be down to room temperature, crystallize out, suction filtration, filter cake ethyl acetate drip washing, dry to obtain 2-[(furfuryl) is amino]-5-(sulfamyl)-4-chloro-benzoic acid 308.9 grams, yield 93.4%, purity 99.8%.
Embodiment 1 is preferred implementation.
Although above-described embodiment describes in detail technical scheme of the present invention, but technical scheme of the present invention is not limited to above embodiment, when not departing from thought of the present invention and aim, claims limited range of the present invention all will be fallen into any change that technical scheme of the present invention is done.
Claims (10)
1. a preparation method for Furosemide, its chemical formula is such as formula shown in (1):
Described preparation method is as follows: the tetrahydrofuran-compound by representated by formula (2):
Wherein X represents halogen, lower alkyl sulfonyloxy, arylsulfonyloxy or aralkylsulfonyl oxygen base, with the 2-aminobenzoic acid compound representated by formula (3) and/or its salt in reaction solvent, heat temperature raising, temperature controls as 80-160 DEG C, under the effect of acid binding agent and/or catalyzer, nucleophilic reaction to described formula (3) reacts completely
Reaction times is 24-36h; Reaction solution obtains the Furosemide shown in formula (1) through separation and purification.
2. a kind of method preparing Furosemide as claimed in claim 1, it is characterized in that, the amount of substance ratio of the formula (3) added, formula (2) and acid binding agent is: 1: 1 ~ 4.0: 1 ~ 4.0; Described acid binding agent is mineral alkali, and described mineral alkali is selected from NaOH, KOH, CsOH, Ba (OH)
2, Mg (OH)
2, Ca (OH)
2, KHCO
3, K
2cO
3, NaHCO
3, Na
2cO
3, Cs
2cO
3in any one, or its mixing.
3. a kind of method preparing Furosemide as claimed in claim 2, it is characterized in that, the amount of substance ratio of the formula (3) added, formula (2) and acid binding agent is: 1: 1 ~ 2.0: 1 ~ 3.0.
4. a kind of method preparing Furosemide as claimed in claim 1, is characterized in that: the amount of substance ratio of the formula (3) added, formula (2) and acid binding agent is: 1: 1 ~ 4.0: 1 ~ 4.0; Described acid binding agent is organic bases, and described organic bases is selected from sodium alkoxide, potassium tert.-butoxide, triethylamine, DMAP, pyridine, N-methylmorpholine, any one in Tetramethyl Ethylene Diamine, tri-n-butylamine, or its mixing.
5. a kind of method preparing Furosemide as claimed in claim 1, it is characterized in that, the amount of substance ratio of the formula (3) added, formula (2) and catalyzer is: 1: 1 ~ 4.0: 0 ~ 0.5; Described catalyzer be NaBr, KBr, NaI, KI, cupric iodide, cuprous iodide, Tetrabutyl amonium bromide, tri-n-octyl methyl ammonium chloride any one, or its mixing.
6. a kind of method preparing Furosemide as claimed in claim 5, is characterized in that: the amount of substance ratio of the formula (3) added, formula (2) and catalyzer is 1: 1 ~ 2.0: 0 ~ 0.3.
7. a kind of method preparing Furosemide as claimed in claim 1, it is characterized in that: described reaction solvent is selected from water, acetonitrile, acetone, tetrahydrofuran (THF), dioxane, diglyme, N, one or more in dinethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide (DMSO).
8. a kind of method preparing Furosemide as claimed in claim 1, it is characterized in that: in formula (2), the lower alkyl sulfonyloxy representated by X is the straight or branched alkane sulfonyloxy with 1-6 carbon atom.
9. a kind of method preparing Furosemide as claimed in claim 1, it is characterized in that: in formula (2), arylsulfonyloxy representated by X selects phenylsulfonyloxy or naphthalene sulfonyl oxygen base, and described phenylsulfonyloxy has 1-3 and is selected from following group alternatively base on phenyl ring: the straight or branched alkyl with 1-6 carbon atom, the straight or branched alkoxyl group with 1-6 carbon atom, nitro and halogen atom.
10. a kind of method preparing Furosemide as claimed in claim 1, it is characterized in that: in formula (2), aralkylsulfonyl oxygen base representated by X comprises the straight or branched C1-6 alkane sulfonyloxy be substituted by phenyl, and wherein phenyl ring can have 1-3 and is selected from following group alternatively base: the straight or branched alkyl with 1-6 carbon atom, the straight or branched alkoxyl group with 1-6 carbon atom, nitro and halogen atom.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106117168A (en) * | 2016-06-30 | 2016-11-16 | 东北制药集团股份有限公司 | A kind of preparation method of furosemide |
| CN113004230A (en) * | 2019-12-20 | 2021-06-22 | 武汉久安药业有限公司 | Furosemide and purification method thereof |
| CN117510444A (en) * | 2024-01-06 | 2024-02-06 | 成都瑞尔医药科技有限公司 | Refining process of furosemide |
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| WO2004037804A1 (en) * | 2002-10-22 | 2004-05-06 | Oscotec Inc. | Furan derivatives for preventing and curing osteoporosis and pharmaceutical compositions containing the same |
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| WO2004037804A1 (en) * | 2002-10-22 | 2004-05-06 | Oscotec Inc. | Furan derivatives for preventing and curing osteoporosis and pharmaceutical compositions containing the same |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117168A (en) * | 2016-06-30 | 2016-11-16 | 东北制药集团股份有限公司 | A kind of preparation method of furosemide |
| CN113004230A (en) * | 2019-12-20 | 2021-06-22 | 武汉久安药业有限公司 | Furosemide and purification method thereof |
| CN117510444A (en) * | 2024-01-06 | 2024-02-06 | 成都瑞尔医药科技有限公司 | Refining process of furosemide |
| CN117510444B (en) * | 2024-01-06 | 2024-03-08 | 成都瑞尔医药科技有限公司 | Refining process of furosemide |
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