CN116283673B - Preparation method of high-purity bumetanide - Google Patents
Preparation method of high-purity bumetanide Download PDFInfo
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- CN116283673B CN116283673B CN202310320865.5A CN202310320865A CN116283673B CN 116283673 B CN116283673 B CN 116283673B CN 202310320865 A CN202310320865 A CN 202310320865A CN 116283673 B CN116283673 B CN 116283673B
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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 44
- 229960004064 bumetanide Drugs 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract description 47
- 229940124530 sulfonamide Drugs 0.000 claims abstract description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000005711 Benzoic acid Substances 0.000 claims abstract description 23
- 235000010233 benzoic acid Nutrition 0.000 claims abstract description 23
- 238000006266 etherification reaction Methods 0.000 claims abstract description 21
- 238000005576 amination reaction Methods 0.000 claims abstract description 14
- 239000000047 product Substances 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 12
- 238000006722 reduction reaction Methods 0.000 claims abstract description 12
- 150000007524 organic acids Chemical class 0.000 claims abstract description 9
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000003054 catalyst Substances 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- 238000002425 crystallisation Methods 0.000 claims description 14
- 230000008025 crystallization Effects 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-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
- 239000003377 acid catalyst Substances 0.000 claims description 6
- 159000000011 group IA salts Chemical class 0.000 claims description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 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
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 230000009467 reduction Effects 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000002994 raw material Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- MGAXYKDBRBNWKT-UHFFFAOYSA-N (5-oxooxolan-2-yl)methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1OC(=O)CC1 MGAXYKDBRBNWKT-UHFFFAOYSA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- ZGJADVGJIVEEGF-UHFFFAOYSA-M potassium;phenoxide Chemical compound [K+].[O-]C1=CC=CC=C1 ZGJADVGJIVEEGF-UHFFFAOYSA-M 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 230000002829 reductive effect Effects 0.000 abstract description 17
- 238000007670 refining Methods 0.000 abstract description 9
- 239000012535 impurity Substances 0.000 abstract description 6
- 238000003916 acid precipitation Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000007086 side reaction Methods 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000002699 waste material Substances 0.000 abstract description 2
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 26
- 238000001914 filtration Methods 0.000 description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 19
- 239000012065 filter cake Substances 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 229910052739 hydrogen Chemical group 0.000 description 14
- 239000001257 hydrogen Chemical group 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- UKTAXRCQHASRNV-UHFFFAOYSA-N 3-amino-4-phenoxy-5-(sulfonylamino)benzoic acid Chemical compound NC=1C=C(C(=O)O)C=C(C1OC1=CC=CC=C1)N=S(=O)=O UKTAXRCQHASRNV-UHFFFAOYSA-N 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 235000017557 sodium bicarbonate Nutrition 0.000 description 8
- -1 4-chloro-3-nitro-5-sulfonylaminobenzoic acid Chemical compound 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 230000001376 precipitating effect Effects 0.000 description 6
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 150000002431 hydrogen Chemical group 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- 238000006268 reductive amination reaction Methods 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000004299 sodium benzoate Substances 0.000 description 5
- 235000010234 sodium benzoate Nutrition 0.000 description 5
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 206010030113 Oedema Diseases 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 208000004880 Polyuria Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 3
- 238000005086 pumping Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000035619 diuresis Effects 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 238000010521 absorption reaction Methods 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
- 239000003513 alkali Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 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
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000002156 mixing 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
- 239000012071 phase Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/42—Separation; Purification; Stabilisation; Use of additives
- C07C303/44—Separation; Purification
-
- 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
- Y02P20/584—Recycling of catalysts
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of high-purity bumetanide, which comprises the following specific steps: 4-chloro-3-nitro-5-sulfonamide benzoic acid is taken as a starting material, 3-nitro-4-phenoxy-5-sulfonamide benzoate is obtained through etherification reaction, then reduction reaction and amination reaction are respectively carried out, and finally, the final hydrogenation is carried out to obtain the final product of the bumetanide. The method optimizes the feeding ratio of the etherification reaction, and the etherification reaction is carried out under the lower temperature condition to control side reaction, the purity of the obtained etherification reaction product is more than 99.8 percent, the yield is more than 60 percent, acid precipitation refining is not needed, the operation steps are simplified, and the waste acid water production amount is reduced; the amination reaction is catalyzed by organic acid, the impurity yield is obviously reduced, the purity of the obtained crude bumetanide product is more than 99.5%, and the product meeting pharmacopoeia standards can be obtained by only one-step refining, so that the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of high-purity bumetanide.
Background
Bumetanide is a potent diuretic with a diuretic effect 40-60 times that of furbenidic acid (tachyuria). Clinically, it is mainly used for various cardiac, hepatic, renal and nutritional oedema. It is also used for patients with drug poisoning and edema (including venous obstructive edema) requiring forced diuresis, and body cavity dropsy such as chest, abdomen, pericardium, etc. It is especially suitable for patients with acute and chronic renal failure, which need to induce diuresis and reduce blood pressure. The existing preparation forms of bumetanide on the market mainly comprise tablets and injections. Has wide market prospect in clinical application.
The synthesis of bumetanide mainly comprises the following two routes:
route one: patent document US20080262086A1 discloses a method for synthesizing bumetanide, which has the following synthetic route:
The method takes 4-chloro-3-nitro-5-sulfonamide benzoic acid as a starting material, and obtains bumetanide through etherification, reduction, esterification, reductive amination, ester group hydrolysis and refining. The route carries out ester formation protection and deprotection process on carboxyl, and is longer. Etherification reaction mol feed ratio 4-chloro-3-nitro-5-sulfonamide benzoic acid: phenol: sodium bicarbonate (eq) =1:2.1:4, the reaction temperature is 85 ℃, the reaction solution is crystallized to obtain an intermediate crude product, and the intermediate is obtained by hydrochloric acid precipitation; the etherification yield is 34%, side reactions are increased due to higher temperature in the reaction process, and impurities are not easy to be effectively controlled. Because the intermediate crude product obtained by etherification reaction has low purity, acid precipitation and refining are needed, and the post-treatment is complicated. The reductive amination reaction produces more impurities, and the impurities are removed by adopting a chromatography method, which is not beneficial to industrial production.
Route two: patent document CN101591276a discloses a method for synthesizing bumetanide, which uses 3-amino-4-phenoxy-5-sulfonamide benzoic acid as a starting material, and obtains bumetanide through reductive amination and post-treatment. The reductive amination reaction uses boron trihalide diethyl ether as a catalyst, and the reaction generates more EP impurity D. The impurity content is high, the crystallization is not easy to remove, the crude product needs repeated refining for many times, the quality is difficult to control, and the refining process is complicated. The reaction conditions are unfavorable for industrial production.
Disclosure of Invention
The invention aims to overcome at least one defect of the prior art and provides a preparation method of high-purity bumetanide.
The technical scheme adopted by the invention is as follows:
the invention provides a preparation method of high-purity bumetanide, which takes 4-chloro-3-nitro-5-sulfonamide benzoic acid as a raw material and comprises the following steps:
1) Etherification reaction: the 4-chloro-3-nitro-5-sulfonamide benzoic acid and the phenoxyation reagent carry out etherification reaction under the condition of an alkaline salt catalyst, the molar feed ratio of the 4-chloro-3-nitro-5-sulfonamide benzoic acid to the phenoxyation reagent is 1 (2.0-5.0), and the molar feed ratio of the alkaline salt catalyst to the phenoxyation reagent is 1 (1.0-1.6); after the etherification reaction is completed, the intermediate product is dissolved in an extractant and crystallized to obtain 3-nitro-4-phenoxy-5-sulfonamide benzoate;
2) Reduction reaction: the 3-nitro-4-phenoxy-5-sulfonamide benzoate obtained in the step 1) undergoes a reduction reaction under the condition of an inorganic base catalyst, and is hydrolyzed to obtain 3-amino-4-phenoxy-5-sulfonamide benzoic acid;
3) Amination reaction: the 3-amino-4-phenoxy-5-sulfonamide benzoic acid obtained in the step 2) is subjected to amination reaction with n-butyraldehyde under the condition of an organic acid catalyst, and then hydrogenation reduction is carried out to obtain a bumetanide crude product;
4) And (3) crystallization: and 3) dissolving the crude product of the bumetanide obtained in the step 3) in an organic solvent, and then washing and crystallizing to obtain a bumetanide finished product.
In some examples, the etherification reaction conditions in step 1) satisfy at least one of the following:
The reaction temperature is 70-80 ℃;
The alkaline salt catalyst is at least one of sodium bicarbonate, sodium carbonate and potassium carbonate;
The phenoxy reagent is at least one of phenol, potassium phenoxide and sodium phenoxide;
the extractant is at least one selected from n-heptane, toluene, ethyl acetate and dichloromethane.
In some examples, the inorganic base catalyst in step 2) is selected from at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide.
In some examples, the feed molar ratio of the organic acid catalyst to 3-amino-4-phenoxy-5-sulfonylaminobenzoic acid in step 3) is from 0.4 to 1.2.
In some examples, the organic acid catalyst in step 3) is selected from at least one of formic acid, acetic acid, butyric acid, propionic acid, and maleic acid.
In some examples, the feed molar ratio of 3-amino-4-phenoxy-5-sulfonylaminobenzoic acid to n-butyraldehyde in step 3) is 1: (1.1-1.3).
In some examples, the amination reaction temperature in step 3) is 20 to 30 ℃.
In some examples, the organic solvent in step 4) is selected from at least one of methanol, ethanol, acetonitrile, ethyl acetate, water, and dichloromethane.
The beneficial effects of the invention are as follows:
1) The invention optimizes the feeding ratio of etherification reaction, and reacts at a lower temperature to control side reaction, the purity of the 3-nitro-4-phenoxy-5-sulfonamide benzoate obtained by primary crystallization of the reaction solution is more than 99.8%, the yield is more than 60%, acid precipitation refining is not needed, the operation steps are simplified, the waste acid water production is reduced, the intermediate does not need to be protected by ester formation, and the carboxylate can be directly reduced in the next step, so that the process route is shortened;
2) The amination reaction is catalyzed by organic acid, the impurity yield is obviously reduced, the purity of the obtained bumetanide crude product is more than 99.5%, the content of the EP impurity D is less than 0.2%, and the product meeting the pharmacopoeia standard can be obtained by only one-step refining;
3) The invention has low equipment requirement, simple operation, no concentration, hydrolysis and other steps, and is energy-saving and environment-friendly.
Drawings
FIG. 1 is an HPLC chart of crude bumetanide prepared in example 1.
FIG. 2 is an infrared spectrum of the preparation of bumetanide of example 1.
Fig. 3 is an XRD pattern of bumetanide prepared in example 1.
FIG. 4 is an HPLC chromatogram of bumetanide prepared in example 1.
FIG. 5 is an HPLC chart of crude bumetanide prepared in comparative example 3.
Detailed Description
In order to overcome the defects of the existing preparation technology, the invention provides a preparation method of bumetanide, which has the advantages of simple operation, short period, environmental protection and high yield, is suitable for industrial production, and the specific technical scheme and flow are as follows:
(1) 4-chloro-3-nitro-5-sulfonamide benzoic acid and n-butyraldehyde are used as raw materials, and the 4-chloro-3-nitro-5-sulfonamide benzoic acid is etherified with a phenoxyation reagent in the presence of alkali, and then the 3-nitro-4-phenoxy-5-sulfonamide benzoate is obtained through crystallization. The method improves the molar feed ratio of each material, and adopts the molar feed ratio of 4-chloro-3-nitro-5-sulfonamide benzoic acid: phenoxy reagent: catalyst=1:2.0 to 5.0: 5-8, and reacting at a lower temperature to control side reactions. The purity of the 3-nitro-4-phenoxy-5-sulfonamide benzoate obtained by the primary crystallization of the reaction solution is 100 percent, and the yield is more than 60 percent.
(2) The 3-nitro-4-phenoxy-5-sulfonamide benzoate obtained in the step (1) does not need acid precipitation for refining; the carboxylate is directly subjected to the next reduction. The catalyst is one or more of sodium carbonate, potassium carbonate and sodium bicarbonate.
(3) The reductive amination reaction adopts 3-amino-4-phenoxy-5-sulfonamide benzoic acid to carry out condensation dehydration reaction with n-butyraldehyde in the presence of organic acid, so as to generate 3-n-butylimino-4-phenoxy-5-sulfonamide benzoic acid.
(4) The 3-n-butylamino-4-phenoxy-5-sulfonamide benzoic acid obtained in the step (3) is hydrogenated to generate 3-n-butylamino-4-phenoxy-5-sulfonamide benzoic acid in the presence of palladium-carbon, namely bumetanide.
(5) The refined crystallization solvent of bumetanide is selected from one or more of methanol, ethanol, acetonitrile, ethyl acetate, water and dichloromethane, so that the product EP has low impurity D content, and the infrared spectrum is consistent with a standard spectrum.
The following disclosure provides many different embodiments, or examples, for implementing different aspects of the invention.
Example 1
1) Etherification reaction: 3kg of 4-chloro-3-nitro-5-sulfonylaminobenzoic acid, 5.03kg of phenol, 7.18kg of sodium bicarbonate and 60kg of water are stirred; the mixture is replaced by nitrogen for 5 times, and the reaction process is protected from light by positive pressure of nitrogen; the internal temperature is controlled to 78 ℃ for reaction for 20 hours. 15L of toluene is added into the reaction solution to extract twice, the aqueous phase is cooled and crystallized, and the internal temperature is maintained at 0-5 ℃ for crystallization for 2 hours. Filtering and leaching the filter cake by 3L of frozen saturated saline (-10-0 ℃). Drying under reduced pressure gives 2.4 kg of sodium 3-nitro-4-phenoxy-5-sulfonamide benzoate with an HPLC purity of 99.95% and a yield of 62.3%.
2) Reduction reaction: 2.4kg of sodium 3-nitro-4-phenoxy-5-sulfonamide, 2.4g of lithium hydroxide, 240g of 5% palladium on charcoal and 36kg of water were mixed and stirred, and the reaction system was replaced with nitrogen and hydrogen, respectively. Controlling the hydrogen pressure to be 0.3-0.5 MPa and reacting for 4h at 20 ℃. And (5) filtering. Cooling the filtrate to 0-5 ℃, slowly dripping 4mol/L hydrochloric acid solution until the pH value is 3-4, and precipitating out. Filtering, and leaching a filter cake by using 2.4kg of water; filtering, and drying the filter cake under reduced pressure to obtain 1.6kg of 3-amino-4-phenoxy-5-sulfonylaminobenzoic acid with HPLC purity not less than 99.5%.
3) Amination and hydrogenation: 1.6kg of 3-amino-4-phenoxy-5-sulfonylaminobenzoic acid, 250g of acetic acid, 490g of n-butyraldehyde, 160g of 10% palladium on charcoal and 32L of methanol are mixed and stirred; the reaction system was replaced with nitrogen and hydrogen, respectively. Controlling the hydrogen pressure to be 0.1-0.2 MPa and reacting for 6h at 25 ℃. Filtering; adding 240ml of water into the filtrate for crystallization, filtering, and drying the filter cake under reduced pressure to obtain 1.42kg of bumetanide crude product, wherein the HPLC chart is shown in figure 1, the HPLC purity is more than or equal to 99.5%, and the EP impurity D is less than or equal to 0.15%.
4) Preparation of a bumetanide finished product: 1.42kg of crude bumetanide, 71g of active carbon and 21.3L of methanol are stirred and decolorized for 30min and then filtered; heating the filtrate to 60-65 ℃, dropwise adding 10.6kg of water, slowly cooling and crystallizing, and cooling to 25-30 ℃ for crystallizing for 2h. Filtering, and drying the filter cake under reduced pressure to obtain 1.28kg of bumetanide finished product; the HPLC purity is above 99.9%, the infrared spectrum is shown in figure 2, the XRD pattern is shown in figure 3, and the HPLC pattern is shown in figure 4.
Example 2
1) Etherification reaction: 80g of 4-chloro-3-nitro-5-sulfonylaminobenzoic acid, 134g of phenol, 191g of sodium bicarbonate and 1.6L of water are stirred; the mixture is replaced by nitrogen for 5 times, and the reaction process is protected from light by positive pressure of nitrogen; the internal temperature is controlled to 83 ℃ for reaction for 18h. 400ml of toluene with the concentration of 2 is added into the reaction solution for extraction twice, the aqueous phase is cooled and crystallized, and the internal temperature is maintained at 0-5 ℃ for crystallization for 2 hours. The mixture is filtered and the filter cake is rinsed with 80mL of frozen saturated saline (-10-0 ℃). Drying under reduced pressure gave 45g of sodium 3-nitro-4-phenoxy-5-sulfonylamide benzoate, 99.8% purity by HPLC, 43.8% yield.
2) Reduction reaction: 45g of sodium 3-nitro-4-phenoxy-5-sulfonamide, 4.5g of 5% palladium on charcoal and 675ml of water were mixed and stirred, and the reaction system was replaced with nitrogen and hydrogen, respectively. Controlling the hydrogen pressure to be 0.3-0.5 MPa and reacting for 12h at 25 ℃. And (5) filtering. Cooling the filtrate to 0-5 ℃, slowly dripping 4mol/L hydrochloric acid solution until the pH value is 3-4, and precipitating out. Filtering, and leaching a filter cake with 45ml of water; the mixture was filtered and the filter cake was dried under reduced pressure to give 25.3g of 3-amino-4-phenoxy-5-sulfonylaminobenzoic acid with a purity of 98.6% by HPLC.
3) Amination and hydrogenation: 25.3g of 3-amino-4-phenoxy-5-sulfonylaminobenzoic acid, 3.9g of acetic acid, 7.1g of n-butyraldehyde, 2.5g of 10% palladium on charcoal and 500mL of methanol are mixed and stirred; the reaction system was replaced with nitrogen and hydrogen, respectively. Controlling the hydrogen pressure to be 0.1-0.2 MPa and reacting for 8h at 25 ℃. Filtering; 330ml of water is added into the filtrate for crystallization, the filtrate is filtered, and a filter cake is dried under reduced pressure to obtain 18.0g of crude bumetanide product, the HPLC purity is 98.5%, and the yield is 60.0%.
4) Preparation of a bumetanide finished product: mixing 18g of bumetanide crude product, 0.9g of active carbon and 580mL of ethanol, decoloring for 30min under stirring, and filtering; heating the filtrate to 60-65 ℃, dropwise adding 145ml of water, slowly cooling and crystallizing, and cooling to 25-30 ℃ for crystallizing for 2h. Filtering, and drying the filter cake under reduced pressure to obtain 14.4g of bumetanide finished product; HPLC purity 99.6%.
Example 3
1) Etherification reaction: 80g of 4-chloro-3-nitro-5-sulfonylaminobenzoic acid, 107g of phenol, 167g of sodium bicarbonate and 1.6L of water are stirred; the mixture is replaced by nitrogen for 5 times, and the reaction process is protected from light by positive pressure of nitrogen; the internal temperature is controlled to 78 ℃ for reaction for 20 hours. And adding 400 x 2 toluene into the reaction solution, extracting twice, cooling the water phase, crystallizing, and maintaining the internal temperature at 0-5 ℃ for 2h. The mixture is filtered and the filter cake is rinsed with 80ml of frozen saturated saline (-10-0 ℃). Drying under reduced pressure gave 50g of sodium 3-nitro-4-phenoxy-5-sulfonylamide benzoate having an HPLC purity of 99.8% and a yield of 48.7%.
2) Reduction reaction: 50g of 3-nitro-4-phenoxy-5-sulfonamide sodium benzoate, 0.05g of lithium hydroxide, 5.0g of 5% palladium on charcoal and 750ml of water are mixed and stirred, and the reaction system is replaced by nitrogen and hydrogen respectively. Controlling the hydrogen pressure to be 0.3-0.5 MPa and reacting for 4h at 30 ℃. And (5) filtering. Cooling the filtrate to 0-5 ℃, slowly dripping 4mol/L hydrochloric acid solution until the pH value is 3-4, and precipitating out. Filtering, and leaching a filter cake by using 50ml of water; the mixture was filtered and the filter cake was dried under reduced pressure to give 30.1g of 3-amino-4-phenoxy-5-sulfonylaminobenzoic acid with an HPLC purity of 98.8%.
3) Amination and hydrogenation: 30.1g of 3-amino-4-phenoxy-5-sulfonylaminobenzoic acid, 3.9g of acetic acid, 7.7g of n-butyraldehyde, 3.0g of 10% palladium on charcoal and 600mL of methanol are mixed and stirred; the reaction system was replaced with nitrogen and hydrogen, respectively. Controlling the hydrogen pressure to be 0.1-0.2 MPa and reacting for 10h at 25 ℃. Filtering; 400ml of water is added into the filtrate for crystallization, the filtrate is filtered, and a filter cake is dried under reduced pressure to obtain 20.0g of crude bumetanide product, the HPLC purity is 98.2%, and the yield is 56.2%.
4) Preparation of a bumetanide finished product: 20g of bumetanide crude product, 1g of active carbon and 300mL of methanol are stirred and decolorized for 30min and then filtered; heating the filtrate to 60-65 ℃, dropwise adding 145ml of water, slowly cooling and crystallizing, and cooling to 25-30 ℃ for crystallizing for 2h. Filtering, and drying the filter cake under reduced pressure to obtain 18g of bumetanide finished product; the HPLC purity is more than 99.9%.
Comparative example 1
This comparative example differs from example 1 in that the molar ratio of 4-chloro-3-nitro-5-sulfonylaminobenzoic acid, phenol, sodium bicarbonate fed in this comparative example is 1:2.1:4. the specific operation flow is as follows:
500mg of 4-chloro-3-nitro-5-sulfonylaminobenzoic acid was added to 4ml of water, 600mg of sodium hydrogencarbonate and 360mg of phenol were added, and the mixture was stirred well. The reaction mixture was heated to 78℃with stirring and reacted for 16h. Cooling the reaction solution to room temperature for crystallization, filtering and pumping to obtain 3-nitro-4-phenoxy-5-sulfonamide sodium benzoate. Adding 3-nitro-4-phenoxy-5-sulfonamide sodium benzoate solution into 10ml of water, heating to dissolve, dripping 4mol/L hydrochloric acid, and precipitating. Filtration and collection of the filter cake gave 205mg of brown solid in 34% yield.
Comparative example 2
This comparative example differs from example 1 in that the etherification reaction temperature was 85 ℃. The specific operation flow is as follows:
500mg of 4-chloro-3-nitro-5-sulfonylaminobenzoic acid was added to 4ml of water, 1197mg of sodium hydrogencarbonate and 838mg of phenol were added, and the mixture was stirred well. The reaction mixture was heated to 85℃with stirring and reacted for 16h. Cooling the reaction solution to room temperature for crystallization, filtering and pumping to obtain 3-nitro-4-phenoxy-5-sulfonamide sodium benzoate. Adding 3-nitro-4-phenoxy-5-sulfonamide sodium benzoate solution into 10ml of water, heating to dissolve, dripping 4mol/L hydrochloric acid, and precipitating. Filtration and collection of the filter cake gave 309mg of brown solid in 48.2% yield.
Comparative example 3
The difference between this comparative example and example 1 is that acetic acid was used as the catalyst for the amination reaction in example 1, boron trifluoride diethyl etherate was used as the catalyst for the amination reaction, and the specific operation procedure is as follows:
60g of 3-amino-4-phenoxy-5-sulfonamide benzoic acid, 22ml of n-butyraldehyde, 42ml of boron trifluoride diethyl etherate (containing about 47% of boron trifluoride), 600ml of methanol and 10g of 5% palladium carbon are added into a 1000ml high-pressure reaction kettle, and are respectively replaced by nitrogen and hydrogen for 3 times, so that the temperature of materials in the kettle is 20-25 ℃ and the hydrogenation pressure is 1-2 atm, and after about 14 hours, the pressure in the kettle is not changed, thereby indicating that the hydrogen absorption is finished. Discharging, filtering to recover palladium carbon, adding 6g of active carbon into filtrate, refluxing and decoloring for 10min, filtering, dripping the obtained filtrate into 2400ml of water, precipitating solid, filtering, washing a filter cake with water, and pumping to obtain 64g of white solid, namely bumetanide, with the yield of 90%. The HPLC purity was 96.59% and the EP impurity D was 1.87%, and the HPLC chart thereof was shown in FIG. 5.
The above description of the present invention is further illustrated in detail and should not be taken as limiting the practice of the present invention. It is within the scope of the present invention for those skilled in the art to make simple deductions or substitutions without departing from the concept of the present invention.
Claims (3)
1. The preparation method of bumetanide is characterized by taking 4-chloro-3-nitro-5-sulfonamide benzoic acid as a raw material and comprising the following steps of:
1) Etherification reaction: carrying out etherification reaction on 4-chloro-3-nitro-5-sulfonamide benzoic acid and a phenoxy reagent at 70-80 ℃ under the condition of an alkaline salt catalyst, wherein the molar feed ratio of the 4-chloro-3-nitro-5-sulfonamide benzoic acid to the phenoxy reagent is 1 (2.0-5.0), and the molar feed ratio of the alkaline salt catalyst to the phenoxy reagent is 1 (1.0-1.6); after the etherification reaction is completed, extracting and crystallizing to obtain 3-nitro-4-phenoxy-5-sulfonamide benzoate;
2) Reduction reaction: the 3-nitro-4-phenoxy-5-sulfonamide benzoate obtained in the step 1) undergoes a reduction reaction under the condition of an inorganic base catalyst, and is hydrolyzed to obtain 3-amino-4-phenoxy-5-sulfonamide benzoic acid;
3) Amination reaction: the 3-amino-4-phenoxy-5-sulfonamide benzoic acid obtained in the step 2) and n-butyraldehyde are subjected to amination reaction at 20-30 ℃ under the condition of an organic acid catalyst, and then hydrogenation reduction is carried out to obtain a crude product of bumetanide;
4) And (3) crystallization: dissolving the crude product of the bumetanide obtained in the step 3) in an organic solvent, and then washing and crystallizing to obtain a bumetanide finished product;
Wherein, the etherification reaction conditions in the step 1) are as follows: the alkaline salt catalyst is at least one of sodium bicarbonate, sodium carbonate and potassium carbonate; the phenoxy reagent is at least one of phenol, potassium phenoxide and sodium phenoxide; the extractant is at least one of n-heptane, toluene, ethyl acetate and methylene dichloride;
The amination conditions of step 3) are: the feeding mole ratio of the organic acid catalyst to the 3-amino-4-phenoxy-5-sulfonamido benzoic acid to the n-butyraldehyde is (0.4-1.2): 1:1.1-1.3; the organic acid catalyst is at least one selected from formic acid, acetic acid, butyric acid, propionic acid and maleic acid.
2. The method according to claim 1, wherein the inorganic base catalyst in the step 2) is at least one selected from the group consisting of lithium hydroxide, sodium hydroxide and potassium hydroxide.
3. The preparation method according to claim 1 or 2, wherein the organic solvent in the step 4) is at least one selected from the group consisting of methanol, ethanol, acetonitrile, ethyl acetate, water and dichloromethane.
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