CN115677544A - Preparation method of bumetanide - Google Patents
Preparation method of bumetanide Download PDFInfo
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- CN115677544A CN115677544A CN202110885951.1A CN202110885951A CN115677544A CN 115677544 A CN115677544 A CN 115677544A CN 202110885951 A CN202110885951 A CN 202110885951A CN 115677544 A CN115677544 A CN 115677544A
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- Prior art keywords
- acid
- tert
- butyl
- sulfamoyl
- reaction
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- 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 30
- 229960004064 bumetanide Drugs 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 59
- -1 3- (N- (tert-butyl) sulfamoyl) -4-chloro-5-nitrobenzoic acid Chemical compound 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 27
- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006396 nitration reaction Methods 0.000 claims abstract description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 39
- 239000007787 solid Substances 0.000 claims description 32
- 239000012065 filter cake Substances 0.000 claims description 25
- 239000000243 solution Substances 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 239000003960 organic solvent Substances 0.000 claims description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- AFRAGFLBINOHDV-UHFFFAOYSA-N 4-chloro-3-chlorosulfonyl-5-nitrobenzoic acid Chemical compound OC(=O)C1=CC([N+]([O-])=O)=C(Cl)C(S(Cl)(=O)=O)=C1 AFRAGFLBINOHDV-UHFFFAOYSA-N 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 14
- 238000005406 washing Methods 0.000 claims description 14
- LYBQQYNSZYSUMT-UHFFFAOYSA-N 4-chloro-3-chlorosulfonylbenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C(S(Cl)(=O)=O)=C1 LYBQQYNSZYSUMT-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- 238000001816 cooling Methods 0.000 claims description 11
- 238000010438 heat treatment Methods 0.000 claims description 11
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 239000005457 ice water Substances 0.000 claims description 7
- 239000003208 petroleum Substances 0.000 claims description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 238000006268 reductive amination reaction Methods 0.000 claims description 6
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 6
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 6
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims description 5
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 5
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000011790 ferrous sulphate Substances 0.000 claims description 5
- 235000003891 ferrous sulphate Nutrition 0.000 claims description 5
- 229910000359 iron(II) sulfate Inorganic materials 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 230000000802 nitrating effect Effects 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000004317 sodium nitrate Substances 0.000 claims description 3
- 235000010344 sodium nitrate Nutrition 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 238000004537 pulping Methods 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 2
- BAUYGSIQEAFULO-UHFFFAOYSA-L iron(2+) sulfate (anhydrous) Chemical compound [Fe+2].[O-]S([O-])(=O)=O BAUYGSIQEAFULO-UHFFFAOYSA-L 0.000 claims 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 1
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 230000008569 process Effects 0.000 abstract description 10
- 238000009776 industrial production Methods 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract description 2
- 238000007086 side reaction Methods 0.000 abstract description 2
- 238000007098 aminolysis reaction Methods 0.000 abstract 1
- 238000004809 thin layer chromatography Methods 0.000 description 22
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 8
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- SURQXAFEQWPFPV-UHFFFAOYSA-L iron(2+) sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Fe+2].[O-]S([O-])(=O)=O SURQXAFEQWPFPV-UHFFFAOYSA-L 0.000 description 5
- 238000007171 acid catalysis Methods 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 206010030113 Oedema Diseases 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical class CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- 208000004880 Polyuria Diseases 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000006208 butylation Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000035619 diuresis Effects 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 241001081179 Litsea Species 0.000 description 1
- 235000012854 Litsea cubeba Nutrition 0.000 description 1
- 244000061176 Nicotiana tabacum Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 231100000643 Substance intoxication Toxicity 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 208000012998 acute renal failure Diseases 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000012822 chemical development Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000005245 nitryl group Chemical group [N+](=O)([O-])* 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 210000003516 pericardium Anatomy 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 210000004888 thoracic abdominal cavity Anatomy 0.000 description 1
- 210000000115 thoracic cavity Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of bumetanide, which comprises the steps of using p-chlorobenzoic acid as a starting material, performing chlorosulfonation, nitration and aminolysis to obtain a key intermediate of 3- (N- (tert-butyl) sulfamoyl) -4-chloro-5-nitrobenzoic acid, and performing phenoxyation, nitro reduction, N-butylation and tert-butyl removal reaction to finally obtain bumetanide. Compared with the synthesis process in the prior art, the operation of the invention has the advantages of less side reaction, low cost, high yield and high safety, and is beneficial to industrial production.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of bumetanide.
Background
Bumetanide (Bumetanide) is a powerful marrow mixing diuretic with 40-60 times of the effect of barking anilinic acid (quick urination). It is mainly used for treating various cardiac, hepatic, renal and nutritional edemas in clinic. It is also used for patients with drug intoxication requiring forced diuresis, edema (including venous obstructive edema) and body fluid accumulation such as thoracic cavity, abdominal cavity, and pericardium. It is especially suitable for patients with acute and chronic renal failure to induce diuresis and lower blood pressure. The chemical name of bumetanide is 5-n-butylamino-4-phenoxy-3-aminosulfonylbenzoic acid, and the name of English is 3- (aminosulfonyl) -5- (butyllamino) -4-phenoxybenzoic acid.
The reported synthetic routes of bumetanide all use a key intermediate 4-chloro-5-chlorosulfonyl-3-nitrobenzoic acid (p-chlorobenzoic acid is subjected to chlorosulfonation and nitration synthesis) as an initial raw material, and the difference lies in whether a carboxyl protection and deprotection process is adopted or not (1); (2) the carboxyl protecting groups are different; (3) the butylation is reduced by reductive amination of n-butyl aldehyde or n-butyl alcohol condensation or substitution of butyryl chloride and amino.
The route reported by the invention patent US3991097A adopts a carboxyl protection and deprotection process, and the fourth step is to substitute butyryl chloride and amino, and then to reduce carbonyl by boron trifluoride or sodium borohydride to obtain n-butyl. In the first step, sulfonic ester which is a toxic impurity is easily generated by acid catalysis, in the fourth step, toxic acyl chloride is used, in the fifth step, boron trifluoride is used, and safety risks exist in production. The reaction process is complex, the steps are complicated, the controllability is poor, the industrial production is not facilitated, and the reaction route is as follows:
the route reported by the U.S. patent application US2008262086A1 still adopts a carboxyl protection and deprotection process, methyl is replaced by n-butyl protection carboxyl, and the butyryl chloride substitution in the fourth step is also changed into n-butyraldehyde reductive amination. The second step is to reduce the nitryl by using a hydrogenation process, the reaction is a dangerous reaction, the palladium-carbon catalyst is expensive, the requirements on reaction environment and equipment are high, and the third step is to use acid catalysis to easily generate base toxic impurity sulfonate. The reaction route is as follows:
the invention patent CN106748906B in China reports that the route does not adopt carboxyl protection and deprotection process, the fourth step uses Lewis acid catalysis, n-butyl alcohol and 3-amino are directly substituted and reacted, and the carboxyl is esterified into n-butyl ester and then hydrolyzed to obtain bumetanide. The method uses acid catalysis, is easy to generate sulfonate and has genotoxicity. The reaction route is as follows:
disclosure of Invention
In order to solve the above problems of the prior art, the present invention aims to provide a method for preparing bumetanide. The method does not adopt carboxyl protection and deprotection processes, but adopts tertiary butyl protection and deprotection processes for sulfamide, uses boron trifluoride diethyl etherate as a catalyst for butylation, uses triethylsilane as a reducing agent, has mild reaction conditions and simple operation, successfully avoids the traditional reductive amination dangerous reaction of sodium borohydride and triacetyl sodium borohydride, has less side reactions, low cost, high yield and high safety compared with the synthesis process in the prior art, and is beneficial to industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of bumetanide is characterized by comprising the following steps: the method takes p-chlorobenzoic acid as a raw material and 3- (N- (tert-butyl) sulfamoyl) -4-chloro-5-nitrobenzoic acid as a key intermediate, and comprises the following steps:
step 1, reacting p-chlorobenzoic acid with chlorosulfonic acid to prepare an intermediate 4-chloro-3- (chlorosulfonyl) benzoic acid;
step 2, carrying out nitration reaction on 4-chloro-3- (chlorosulfonyl) benzoic acid under a nitration reagent to prepare an intermediate 4-chloro-3- (chlorosulfonyl) -5-nitrobenzoic acid;
step 3, reacting 4-chloro-3- (chlorosulfonyl) -5-nitrobenzoic acid with tert-butylamine to obtain an intermediate N- (tert-butyl) sulfamoyl) -4-chloro-5-nitrobenzoic acid;
step 4, performing substitution reaction on the N- (tert-butyl) sulfamoyl) -4-chloro-5-nitrobenzoic acid and phenol to prepare an intermediate 3- (N- (tert-butyl) sulfamoyl) -5-nitro-4-phenoxybenzoic acid;
step 5, carrying out reduction reaction on 3- (N- (tert-butyl) sulfamoyl) -5-nitro-4-phenoxybenzoic acid to prepare an intermediate 3-amino-5- (N- (tert-butyl) sulfamoyl) -4-phenoxybenzoic acid;
step 6, subjecting 3-amino-5- (N- (tert-butyl) sulfamoyl) -4-phenoxybenzoic acid and N-butyraldehyde to reductive amination reaction to prepare an intermediate 3- (N- (tert-butyl) sulfamoyl) -5- (butylamino) -4-phenoxybenzoic acid;
step 7,3- (N- (tert-butyl) sulfamoyl) -5- (butylamino) -4-phenoxybenzoic acid is subjected to tert-butyl removal to obtain bumetanide.
The reaction equation is as follows:
further, the step 1 comprises the following steps:
step 11, adding p-chlorobenzoic acid serving as a raw material into chlorosulfonic acid in batches, heating to 120-140 ℃, and reacting for 2-5 hours, preferably for 4 hours;
and step 12, cooling to room temperature after the reaction is finished, dripping into ice water, filtering, washing and drying a filter cake to obtain the 4-chloro-3- (chlorosulfonyl) benzoic acid.
Further, the step 2 comprises the following steps:
step 21, dissolving 4-chloro-3- (chlorosulfonyl) benzoic acid in concentrated sulfuric acid, heating to 60-90 ℃, preferably to 80 ℃, adding a nitrating reagent, heating to 80-100 ℃, preferably to 90 ℃, and reacting for 4-6 hours;
and step 22, cooling to room temperature after the reaction is finished, pouring into ice water, separating out solids, filtering, washing and drying filter cakes to obtain the 4-chloro-3- (chlorosulfonyl) -5-nitrobenzoic acid.
Further, the step 3 comprises the following steps:
step 31, 4-chloro-3- (chlorosulfonyl) -5-nitrobenzoic acid is dissolved in an organic solvent, slowly dropped into the organic solvent of tert-butylamine at a low temperature (below 0 ℃), and reacted for 0.5 to 5 hours, preferably 1 hour at a low temperature (below 0 ℃); more preferably, the organic solvent is selected from one or more of tetrahydrofuran, ethyl acetate, dichloromethane, isopropyl acetate, dioxane, dimethyl sulfoxide, N '-dimethylformamide, N' -dimethylacetamide, N-methylpyrrolidone and the like;
step 32, concentrating after the reaction is finished, mixing with an organic solvent, and pulping to obtain N- (tert-butyl) sulfamoyl) -4-chloro-5-nitrobenzoic acid; preferably, the mixed organic solvent is ethyl acetate and petroleum ether.
Further, the step 4 comprises the following steps:
step 41, dissolving N- (tert-butyl) sulfamoyl) -4-chloro-5-nitrobenzoic acid in an organic solvent, adding phenol and alkali, heating to 60-90 ℃, and reacting for 10-40 hours; preferably, the temperature is increased to 80 ℃ and the reaction is carried out for 24 hours; more preferably, the organic solvent is one or more of N, N' -dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran, acetonitrile and the like, and the base is one or more of sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide and the like;
and step 42, cooling to room temperature after the reaction is finished, adjusting acid with dilute hydrochloric acid, adding water, precipitating solids, adding water, stirring, filtering, washing filter cakes with water, and drying to obtain the 3- (N- (tert-butyl) sulfamoyl) -5-nitro-4-phenoxybenzoic acid.
Further, the step 5 comprises the following steps:
step 51, dissolving 3- (N- (tert-butyl) sulfamoyl) -5-nitro-4-phenoxybenzoic acid in 20-28% of ammonia water and water, preferably 25% of ammonia water and water, stirring to dissolve the mixture, dropwise adding the mixture into a ferrous sulfate aqueous solution heated to 60-90 ℃, preferably into a ferrous sulfate aqueous solution heated to 80 ℃, and after dropwise adding, carrying out heat preservation reaction for 0.2-2 hours, preferably, carrying out heat preservation reaction for 0.5 hour;
and step 52, filtering while hot after the reaction is finished, washing filter cakes with water, combining filter liquor, adjusting acid with dilute hydrochloric acid, separating out solids, cooling, filtering, washing filter cakes with water and drying to obtain the 3-amino-5- (N- (tert-butyl) sulfamoyl) -4-phenoxybenzoic acid.
Further, the step 6 comprises the following steps:
step 61, dissolving 3- (N- (tert-butyl) sulfamoyl) -5-amino-4-phenoxybenzoic acid, boron trifluoride diethyl etherate and triethylsilane in an organic solvent, cooling, dropwise adding an organic solvent solution of N-butyraldehyde, and reacting at a low temperature (below 0 ℃) for 0.5-2 hours, preferably for 1 hour; more preferably, the organic solvent is one or more of acetonitrile, tetrahydrofuran, ethyl acetate, dioxane, dimethyl sulfoxide and the like.
And step 62, adding water after the reaction is finished, stirring, filtering, washing a filter cake with water, adding ethanol, and recrystallizing to obtain the 3- (N- (tert-butyl) sulfamoyl) -5- (butylamino) -4-phenoxybenzoic acid.
Further, the step 7 includes the steps of:
step 71, dissolving 3- (N- (tert-butyl) sulfamoyl) -5- (butylamino) -4-phenoxybenzoic acid in acid, heating and stirring for 0.2-2 hours, preferably, heating and stirring for 0.5 hour;
and step 72, concentrating to remove acid after the reaction is finished, and adding ethyl acetate to recrystallize to obtain a pure bumetanide product.
Preferably, the nitrating agent is a combination of one or more selected from sodium nitrate, nitric acid, fuming nitric acid, and the like.
Preferably, the acid is one or a combination selected from hydrochloric acid, trifluoroacetic acid, and the like.
Compared with the prior art, the invention has the following advantages:
in the method, phenoxy is coupled on 4-site chlorine, nitro is reduced, reducing agent is used for reductive amination, and tert-butyl is removed to obtain bumetanide, and the total molar yield is about 50%. The method has the advantages of short steps, mild reaction conditions, no dangerous reactions such as hydrogenation and the like, low cost, no special toxicity, low requirement on equipment, no generation of base toxic impurity sulfonate and suitability for industrial production, and all reagents are conventional and easily purchased.
Detailed Description
The method of the present invention is illustrated below by means of specific examples, which are to be understood as being illustrative of the basic principles, essential features and advantages of the invention, without limiting the scope of the invention by the following examples; the implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments.
In the following examples 1 The H NMR spectrum was obtained using a Bruker instrument (400 MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 Method for H NMR expression: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broadened, dd = doublet of doublets, dt = doublet of triplets. If a coupling constant is provided, it is in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode is ESI.
The high performance liquid chromatograph model: agilent 1260 and Silmer fly U3000; the type of the chromatographic column: waters xbrige C18 (4.6 × 150 mm,3.5 μm); mobile phase: a: ACN, B: water (0.1%) 3 PO 4 ) (ii) a Flow rate: 1.0mL/min; gradient: 5% A for 1min, increase to 20% A within 4min, increase to 80% A within 8min,80% A for 2min, back to 5% A within 0.1min; wavelength: 220nm; column oven: 35 ℃ is carried out.
TLC: thin layer chromatography. The thin layer chromatography silica gel plate is HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of silica gel plate used by Thin Layer Chromatography (TLC) is 0.2mm-0.3mm, and the specification of thin layer chromatography separation and purification product is 0.4mm-0.5mm.
The column chromatography is carried out by using 200-300 mesh silica gel of Litsea crassirhizomes as carrier.
In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and unless otherwise indicated, the various starting materials and reagents are commercially available or synthesized according to known methods, and none of the commercially available materials and reagents are used without further purification and unless otherwise indicated, commercially available manufacturers include, but are not limited to, the national drug group, the welfare technology limited, the schehia (shanghai) chemical development limited, the shanghai bibi medical technology limited, the shanghai meihel chemical technology limited, and the like.
In the examples, the solution in the reaction is an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, without specific indication, from 20 ℃ to 30 ℃ at room temperature.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing agent used for the reaction, a system of eluents for column chromatography employed for purifying compounds or a developing agent system for thin layer chromatography including: a: petroleum ether and ethyl acetate systems; b: dichloromethane and methanol systems; c: n-hexane: ethyl acetate; the volume ratio of the solvent is different according to the polarity of the compound, and a small amount of acidic or basic reagent such as acetic acid or triethylamine can be added for adjustment.
Step 1 Synthesis of 4-chloro-3- (chlorosulfonyl) benzoic acid
Example 1: chlorosulfonic acid (1.49Kg, 12.77mol) was added to a 2L three-necked flask and stirred, p-chlorobenzoic acid (400.00g, 2.55mol) was added in portions at room temperature, after the addition, the temperature was raised to 120 ℃ and stirred for 2 hours, the temperature was raised to 140 ℃ and stirred for 4 hours, and the reaction was monitored by TLC for completion. The reaction solution is cooled to room temperature, slowly dropped into ice water, the temperature is controlled between 0 ℃ and 5 ℃, the mixture is stirred for 10 minutes below 0 ℃ to 5 ℃ after the addition, the mixture is filtered, and filter cakes are washed and dried to obtain a white solid compound, namely 4-chloro-3- (chlorosulfonyl) benzoic acid (484.88 g, the yield is 74.4%).
Step 2 Synthesis of 4-chloro-3- (chlorosulfonyl) -5-nitrobenzoic acid
Example 2: 4-chloro-3- (chlorosulfonyl) benzoic acid (100.00g, 0.392mol) is dissolved in concentrated sulfuric acid (500 mL) and stirred, the temperature is raised to 80 ℃, sodium nitrate (83.31g, 0.980mmol) is added in batches, the temperature is slightly raised in the process, then the temperature is raised to 90 ℃, the stirring is carried out for 4 hours, and the TLC monitors that the reaction is complete. The reaction mixture was slowly poured into ice water to precipitate a solid, which was then filtered and the filter cake was washed with water to give 4-chloro-3- (chlorosulfonyl) -5-nitrobenzoic acid as a white solid (62.00 g, 52.7% yield).
Example 3: 4-chloro-3- (chlorosulfonyl) benzoic acid (140.00g, 0.548mol) is dissolved in concentrated sulfuric acid (270 mL) and stirred, the temperature is increased to 80 ℃, a mixed solution of fuming nitric acid (85 mL) and concentrated sulfuric acid (80 mL) is dripped, the temperature is slightly increased in the dripping process, then the temperature is increased to 90 ℃, the stirring is carried out for 6 hours, and the TLC monitors the completion of the reaction. The reaction mixture was cooled to room temperature, slowly poured into ice water to precipitate a solid, filtered, the filter cake was dissolved in ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 4-chloro-3- (chlorosulfonyl) -5-nitrobenzoic acid (120.0 g, yield 72.8%) as a white solid.
Step 3 Synthesis of N- (tert-butyl) sulfamoyl) -4-chloro-5-nitrobenzoic acid
Example 4: 4-chloro-3- (chlorosulfonyl) -5-nitrobenzoic acid (120.00g, 0.400mol) was dissolved in tetrahydrofuran (250 mL), added slowly dropwise to a solution of tert-butylamine (117.00g, 1.600mol) in tetrahydrofuran (360 mL) maintaining the temperature below 0 deg.C, stirred at 0 deg.C for 1 hour after addition was complete, and the reaction was monitored by TLC for completion. The reaction solution was concentrated to give a yellow solid, water was added and the pH was adjusted to 3 with dilute hydrochloric acid to precipitate a yellow solid, which was filtered, the filter cake was washed with water and dried to give a crude yellow solid, which was slurried with ethyl acetate/petroleum ether =3/1 to give N- (tert-butyl) sulfamoyl) -4-chloro-5-nitrobenzoic acid (98.8 g, yield 74.0%, purity 96.1%) as a pale yellow solid.
LC-MS:m/z＝335.0[M-H] -
1 H NMR(400MHz,DMSO-d 6 )δ14.13(s,1H),8.68(dd,J＝4.0,2.0Hz,1H),8.27(s,1H), 1.16(s,9H).
Example 5: 4-chloro-3- (chlorosulfonyl) -5-nitrobenzoic acid (23.55g, 0.078mol) was dissolved in ethyl acetate (40 mL), slowly added dropwise to a solution of tert-butylamine (22.96g, 0.314mol) in ethyl acetate (85 mL), the temperature was maintained below 0 ℃ and the reaction was stirred for 1 hour at 0 ℃ after the completion of the addition, and the completion of the reaction was monitored by TLC. The reaction solution was concentrated to give a yellow solid, water was added and the pH was adjusted to 3 with dilute hydrochloric acid to precipitate a yellow solid, which was filtered, the filter cake was washed with water and dried to give a crude yellow solid, which was slurried with ethyl acetate/petroleum ether =3/1 to give N- (tert-butyl) sulfamoyl) -4-chloro-5-nitrobenzoic acid (19.8 g, yield 75.0%, purity 96.0%) as a pale yellow solid.
LC-MS:m/z＝335.0[M-H] -
1 H NMR(400MHz,DMSO-d 6 )δ14.13(s,1H),8.68(dd,J＝4.0,2.0Hz,1H),8.27(s,1H), 1.16(s,9H).
Step 4 Synthesis of 3- (N- (tert-butyl) sulfamoyl) -5-nitro-4-phenoxybenzoic acid
Example 6: n- (tert-butyl) sulfamoyl) -4-chloro-5-nitrobenzoic acid (30.52g, 90.63mmol), phenol (17.06 g, 180.27 mmol) and lithium hydroxide monohydrate (9.51g, 226.58mmol) were dispersed in N, N-dimethyl sulfoxide (150 mL), warmed to 60 ℃ and stirred for 6 hours, and TLC monitored for reaction completion. The reaction solution is cooled to room temperature, the pH value is adjusted to 3 by dilute hydrochloric acid, petroleum ether (150 mL) and ethyl acetate (30 mL) are added and stirred overnight, a large amount of solid is separated out, water (300 mL) is added and stirring is continued for half an hour, the mixture is filtered, the filter cake is washed by water and dried to obtain a light yellow solid 3- (N- (tert-butyl) sulfamoyl) -5-nitro-4-phenoxybenzoic acid (33.8 g, the yield is 94.6 percent and the purity is 97.7 percent).
1 H NMR(400MHz,DMSO-d 6 )δ14.02(s,1H),8.71(d,J＝2.0Hz,1H),8.63(d,J＝2.0Hz, 1H),7.86(s,1H),7.34-7.30(m,2H),7.10(t,J＝7.6Hz,1H)
Example 7: n- (tert-butyl) sulfamoyl) -4-chloro-5-nitrobenzoic acid (50.00g, 148.5 mmol), phenol (20.96 g, 222.3 mmol) and sodium carbonate (31.48g, 279.0 mmol) were dispersed in N, N-dimethyl sulfoxide (200 mL), warmed to 80 ℃ and stirred for 24 hours, and the reaction was monitored by TLC for completion. The reaction solution is cooled to room temperature, the pH value is adjusted to 3 by dilute hydrochloric acid, petroleum ether (250 mL) and ethyl acetate (50 mL) are added and stirred overnight, a large amount of solid is separated out, water (500 mL) is added and stirring is continued for half an hour, the mixture is filtered, a filter cake is washed by water and dried to obtain a light yellow solid 3- (N- (tert-butyl) sulfamoyl) -5-nitro-4-phenoxybenzoic acid (55.30 g, the yield is 94.4 percent and the purity is 97.5 percent).
LC-MS:m/z＝393.0[M-H] -
1 H NMR(400MHz,DMSO-d 6 )δ14.02(s,1H),8.71(d,J＝2.0Hz,1H),8.63(d,J＝2.0Hz, 1H),7.86(s,1H),7.34-7.30(m,2H),7.10(t,J＝7.6Hz,1H),6.92(d,J＝8.0Hz,2H),1.13(s,9H).
Example 8: n- (tert-butyl) sulfamoyl) -4-chloro-5-nitrobenzoic acid (60.00g, 178.2 mmol), phenol (25.17 g, 267.5 mmol) and potassium carbonate (61.61g, 443.2 mmol) were dispersed in N, N-dimethyl sulfoxide (300 mL), warmed to 85 ℃ and stirred for 24 h, and the reaction was monitored by TLC for completion. Cooling the reaction solution to room temperature, adjusting the pH value to 1-2 with dilute hydrochloric acid, adding water (800 mL), stirring for 2 hours at room temperature to precipitate a large amount of solid, supplementing water (300 mL), continuing stirring for half an hour, filtering, washing filter cakes with water, and drying to obtain a light yellow solid compound, namely 3- (N- (tert-butyl) sulfamoyl) -5-nitro-4-phenoxybenzoic acid (64.30 g, the yield is 91.5%, and the purity is 98.8%).
LC-MS:m/z＝393.0[M-H] -
1 H NMR(400MHz,DMSO-d 6 )δ14.02(s,1H),8.71(d,J＝2.0Hz,1H),8.63(d,J＝2.0Hz, 1H),7.86(s,1H),7.34-7.30(m,2H),7.10(t,J＝7.6Hz,1H),6.92(d,J＝8.0Hz,2H),1.13(s,9H).
Step 5 Synthesis of 3-amino-5- (N- (tert-butyl) sulfamoyl) -4-phenoxybenzoic acid
Example 9: 3- (N- (tert-butyl) sulfamoyl) -5-nitro-4-phenoxybenzoic acid (40.00g, 101.4mmol) was dissolved in ammonia (25%, 200 mL) and the solution was stirred to obtain an ammonium salt solution. Ferrous sulfate heptahydrate (137.87g, 495.9mmol) is dissolved in water (500 mL) and heated to 80 ℃ to obtain ferrous sulfate solution. And (3) dropwise adding the ammonium salt solution into the ferrous sulfate solution, keeping the temperature for reaction for 30 minutes after dropwise adding, and monitoring the reaction completion by TLC. The reaction solution was filtered while hot, the filter cake was washed with water, the filtrates were combined, pH =4-5 was adjusted with dilute hydrochloric acid, a large amount of solid was precipitated, cooled to 0-10 ℃, stirred for 1 hour, filtered, and the filter cake was washed with water and dried to obtain 3-amino-5- (N- (tert-butyl) sulfamoyl) -4-phenoxybenzoic acid (32.08 g, yield 86.7%, purity 98.3%) as a white solid.
LC-MS:m/z＝363.1[M-H] -
1 H NMR(400MHz,DMSO-d 6 )δ13.04(s,1H),7.67(d,J＝2.0Hz,1H),7.61(d,J＝2.0Hz, 1H),7.28(t,J＝8.0Hz,2H),7.02-6.98(m,2H),6.83(d,J＝8.0Hz,2H),5.75(s,1H),5.29(s,2H), 1.06(s,9H).
Step 6 Synthesis of 3- (N- (tert-butyl) sulfamoyl) -5- (butylamino) -4-phenoxybenzoic acid
Example 10: 3-amino-5- (N- (tert-butyl) sulfamoyl) -4-phenoxybenzoic acid (27.08g, 74.3mmol), boron trifluoride etherate (7.91g, 55.7mmol) and triethylsilane (17.27g, 148.52mmol) were dissolved in acetonitrile (100 mL), a solution of N-butyraldehyde (8.43g, 116.9mmol) in acetonitrile (40 mL) was added dropwise at 0 deg.C, and the mixture was stirred for 1 hour at 0 deg.C, and the reaction was monitored by TLC for completion. The reaction mixture was stirred for 2 hours with water, filtered, the filter cake was washed with water, and recrystallized from ethanol to give 3- (N- (tert-butyl) sulfamoyl) -5- (butylamino) -4-phenoxybenzoic acid as a white solid (25.30 g, yield 80.9%, purity 98.9%).
LC-MS:m/z＝421.2[M+H] +
1 H NMR(400MHz,DMSO-d 6 )δ13.18(s,1H),7.70(d,J＝2.0Hz,1H),7.42(d,J＝2.0Hz, 1H),7.28(t,J＝7.2Hz,2H),7.04-7.00(m,2H),6.83(d,J＝8.0Hz,1H),5.06(t,J＝5.6Hz,1H), 3.05(dd,J＝12.8,6.8Hz,2H),1.40-1.33(m,2H),1.15-1.06(m,11H),0.77(t,J＝7.6Hz,3H).
Example 11: 3- (N- (tert-butyl) sulfamoyl) -5-amino-4-phenoxybenzoic acid (10.00g, 27.4 mmol), boron trifluoride diethyl etherate (2.92g, 25.1 mmol) and triethylsilane (6.38g, 54.9 mmol) were dissolved in tetrahydrofuran (100 mL), a solution of N-butyraldehyde (3.00g, 41.6 mmol) in tetrahydrofuran (10 mL) was added dropwise at 0 ℃ and the mixture was stirred for 1 hour with incubation at 0 ℃ and monitored by TLC for completion of the reaction. The reaction mixture was stirred for 2 hours with water, filtered, the filter cake was washed with water, and recrystallized from ethanol to give 3- (N- (tert-butyl) sulfamoyl) -5- (butylamino) -4-phenoxybenzoic acid as a white solid (9.30 g, yield 80.7%, purity 98.7%).
LC-MS:m/z＝421.2[M+H] +
1 H NMR(400MHz,DMSO-d 6 )δ13.18(s,1H),7.70(d,J＝2.0Hz,1H),7.42(d,J＝2.0Hz, 1H),7.28(t,J＝7.2Hz,2H),7.04-7.00(m,2H),6.83(d,J＝8.0Hz,1H),5.06(t,J＝5.6Hz,1H), 3.05(dd,J＝12.8,6.8Hz,2H),1.40-1.33(m,2H),1.15-1.06(m,11H),0.77(t,J＝7.6Hz,3H).
Step 7 Synthesis of bumetanide
Example 12: 3- (N- (tert-butyl) sulfamoyl) -5- (butylamino) -4-phenoxybenzoic acid (15.57g, 37.0 mmol) was dissolved in trifluoroacetic acid (70 mL), heated to 70 ℃ and stirred for half an hour, and the completion of the reaction of the starting material was monitored by TLC. The reaction solution was concentrated to remove trifluoroacetic acid, and ethyl acetate was added thereto for recrystallization to obtain pure bumetanide (10.20 g, yield 75.5%, purity 99.9%) as a white solid.
LC-MS:m/z＝365.2[M+H] +
1 H NMR(400MHz,DMSO-d 6 )δ13.17(s,1H),7.69(d,J＝1.6Hz,1H),7.42(d,J＝2.0Hz, 1H),7.34(s,2H),7.27(dd,J＝8.4,7.6Hz,2H),7.01(t,J＝7.2Hz,1H),6.84(d,J＝12Hz,2H), 5.06(t,J＝5.6Hz,1H),3.06(dd,J＝8.8,6.4Hz,2H),1.40-1.33(m,2H),1.16-1.07(m,2H),0.77 (t,J＝7.2Hz,3H).
Example 13: 3- (N- (tert-butyl) sulfamoyl) -5- (butylamino) -4-phenoxybenzoic acid (3.00g, 7.1mmol) was dissolved in concentrated hydrochloric acid (15 mL), heated to 45-50 deg.C, and after clearing, stirring was continued for 0.5 h, and the reaction was monitored by TLC for completion. Filtering the reaction solution, washing a filter cake with water to obtain a white solid crude product, adding ethyl acetate for recrystallization to obtain a white solid bumetanide pure product (1.95 g, the yield is 75.4 percent, and the purity is 99.8 percent).
LC-MS:m/z＝365.2[M+H] +
1 H NMR(400MHz,DMSO-d 6 )δ13.17(s,1H),7.69(d,J＝1.6Hz,1H),7.42(d,J＝2.0Hz, 1H),7.34(s,2H),7.27(dd,J＝8.4,7.6Hz,2H),7.01(t,J＝7.2Hz,1H),6.84(d,J＝12Hz,2H), 5.06(t,J＝5.6Hz,1H),3.06(dd,J＝8.8,6.4Hz,2H),1.40-1.33(m,2H),1.16-1.07(m,2H),0.77 (t,J＝7.2Hz,3H).
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.
Claims (10)
1. A preparation method of bumetanide is characterized in that the preparation method takes p-chlorobenzoic acid as a raw material and comprises the following steps:
step 1, reacting p-chlorobenzoic acid with chlorosulfonic acid to prepare an intermediate 4-chloro-3- (chlorosulfonyl) benzoic acid;
step 2, carrying out nitration reaction on 4-chloro-3- (chlorosulfonyl) benzoic acid under a nitration reagent to prepare an intermediate 4-chloro-3- (chlorosulfonyl) -5-nitrobenzoic acid;
step 3, reacting 4-chloro-3- (chlorosulfonyl) -5-nitrobenzoic acid with tert-butylamine to obtain an intermediate N- (tert-butyl) sulfamoyl) -4-chloro-5-nitrobenzoic acid;
step 4, carrying out substitution reaction on N- (tert-butyl) sulfamoyl) -4-chloro-5-nitrobenzoic acid and phenol to prepare an intermediate 3- (N- (tert-butyl) sulfamoyl) -5-nitro-4-phenoxybenzoic acid;
step 5, carrying out reduction reaction on 3- (N- (tert-butyl) sulfamoyl) -5-nitro-4-phenoxybenzoic acid to prepare an intermediate 3-amino-5- (N- (tert-butyl) sulfamoyl) -4-phenoxybenzoic acid;
step 6, carrying out reductive amination reaction on 3-amino-5- (N- (tert-butyl) sulfamoyl) -4-phenoxybenzoic acid and N-butyraldehyde to obtain an intermediate 3- (N- (tert-butyl) sulfamoyl) -5- (butylamino) -4-phenoxybenzoic acid;
step 7,3- (N- (tert-butyl) sulfamoyl) -5- (butylamino) -4-phenoxybenzoic acid is subjected to tert-butyl removal to obtain bumetanide.
2. The method of preparing bumetanide according to claim 1, wherein the step 1 comprises the steps of:
step 11, adding p-chlorobenzoic acid serving as a raw material into chlorosulfonic acid in batches, heating to 120-140 ℃, and reacting for 2-5 hours;
and step 12, cooling to room temperature after the reaction is finished, dripping into ice water, filtering, washing and drying a filter cake to obtain the 4-chloro-3- (chlorosulfonyl) benzoic acid.
3. The method of preparing bumetanide according to claim 1, wherein the step 2 comprises the steps of:
step 21, dissolving 4-chloro-3- (chlorosulfonyl) benzoic acid in concentrated sulfuric acid, heating to 60-90 ℃, adding a nitrating reagent, heating to 80-100 ℃, and reacting for 4-6 hours;
and step 22, cooling to room temperature after the reaction is finished, pouring into ice water, separating out solids, filtering, washing and drying a filter cake to obtain the 4-chloro-3- (chlorosulfonyl) -5-nitrobenzoic acid.
4. The method of preparing bumetanide according to claim 1, wherein the step 3 comprises the steps of:
step 31, dissolving 4-chloro-3- (chlorosulfonyl) -5-nitrobenzoic acid in an organic solvent, slowly dripping the solution into an organic solvent solution of tert-butylamine at a low temperature, and reacting for 0.5 to 5 hours at the low temperature after the dripping is finished; preferably, the organic solvent is selected from one or more of tetrahydrofuran, ethyl acetate, dichloromethane, isopropyl acetate, dioxane, dimethyl sulfoxide, N '-dimethylformamide, N' -dimethylacetamide and N-methylpyrrolidone;
and step 32, concentrating after the reaction is finished, and pulping the mixed organic solvent to obtain the N- (tert-butyl) sulfamoyl) -4-chloro-5-nitrobenzoic acid, wherein the preferable mixed organic solvent is ethyl acetate and petroleum ether.
5. The method of preparing bumetanide according to claim 1, wherein the step 4 comprises the steps of:
41, dissolving N- (tert-butyl) sulfamoyl) -4-chloro-5-nitrobenzoic acid in an organic solvent, adding phenol and alkali, heating to 60-90 ℃, and reacting for 10-40 hours; preferably, the organic solvent is one or more of N, N' -dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, tetrahydrofuran and acetonitrile, and the base is one or more of sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and lithium hydroxide.
And step 42, cooling to room temperature after the reaction is finished, adjusting acid with dilute hydrochloric acid, adding water, precipitating solids, adding water, stirring, filtering, washing filter cakes with water, and drying to obtain the 3- (N- (tert-butyl) sulfamoyl) -5-nitro-4-phenoxybenzoic acid.
6. The method of preparing bumetanide according to claim 1, wherein the step 5 comprises the steps of:
step 51, dissolving 3- (N- (tert-butyl) sulfamoyl) -5-nitro-4-phenoxybenzoic acid in 20-28% ammonia water and water, stirring to dissolve the mixture clearly, dropwise adding the mixture into a ferrous sulfate aqueous solution heated to 60-90 ℃, and after the dropwise adding, keeping the temperature and reacting for 0.2-2 hours;
and step 52, filtering while the reaction is hot after the reaction is finished, washing filter cakes with water, combining filter liquor, adjusting acid with dilute hydrochloric acid, separating out solids, cooling, filtering, washing filter cakes with water and drying to obtain the 3-amino-5- (N- (tert-butyl) sulfamoyl) -4-phenoxybenzoic acid.
7. The method of preparing bumetanide according to claim 1, wherein the step 6 comprises the steps of:
step 61, dissolving 3- (N- (tert-butyl) sulfamoyl) -5-amino-4-phenoxybenzoic acid, boron trifluoride diethyl etherate and triethylsilane in an organic solvent, cooling, dropwise adding an organic solvent solution of N-butyl aldehyde, and reacting at low temperature for 0.5-2 hours; preferably, the organic solvent is one or more of acetonitrile, tetrahydrofuran, ethyl acetate, dioxane and dimethylsulfoxide.
And step 62, adding water after the reaction is finished, stirring, filtering, washing a filter cake with water, adding ethanol, and recrystallizing to obtain the 3- (N- (tert-butyl) sulfamoyl) -5- (butylamino) -4-phenoxybenzoic acid.
8. The method of preparing bumetanide according to claim 1, wherein the step 7 comprises the steps of:
step 71, dissolving 3- (N- (tert-butyl) sulfamoyl) -5- (butylamino) -4-phenoxybenzoic acid in acid, and heating and stirring for 0.2-2 hours;
and step 72, concentrating and removing acid after the reaction is finished, and adding ethyl acetate for recrystallization to obtain a pure bumetanide product.
9. The method of claim 1 or 3, wherein the nitrating agent is one or more selected from the group consisting of sodium nitrate, nitric acid, and fuming nitric acid.
10. The process for preparing bumetanide according to claim 8, wherein the acid is one or a combination selected from hydrochloric acid and trifluoroacetic acid.
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| CN116283673B (en) * | 2023-03-29 | 2024-05-17 | 成都瑞尔医药科技有限公司 | Preparation method of high-purity bumetanide |
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