CN115960059A - Method for synthesizing furosemide impurity D with high yield and high purity - Google Patents
Method for synthesizing furosemide impurity D with high yield and high purity Download PDFInfo
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- NQRLIXFNJZQNKV-UHFFFAOYSA-N 2,4-bis(furan-2-ylmethylamino)-5-sulfamoylbenzoic acid Chemical compound C1=C(NCC=2OC=CC=2)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 NQRLIXFNJZQNKV-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 238000000034 method Methods 0.000 title claims abstract description 28
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 21
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229960003883 furosemide Drugs 0.000 claims abstract description 27
- 238000010438 heat treatment Methods 0.000 claims abstract description 12
- 239000003446 ligand Substances 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 7
- DDRPCXLAQZKBJP-UHFFFAOYSA-N furfurylamine Chemical compound NCC1=CC=CO1 DDRPCXLAQZKBJP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000011261 inert gas Substances 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 239000012043 crude product Substances 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- WDVGNXKCFBOKDF-UHFFFAOYSA-N dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C1CCCCC1)C1CCCCC1 WDVGNXKCFBOKDF-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- -1 tBuXPos Chemical compound 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- MXFYYFVVIIWKFE-UHFFFAOYSA-N dicyclohexyl-[2-[2,6-di(propan-2-yloxy)phenyl]phenyl]phosphane Chemical compound CC(C)OC1=CC=CC(OC(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 MXFYYFVVIIWKFE-UHFFFAOYSA-N 0.000 claims description 2
- SACNIGZYDTUHKB-UHFFFAOYSA-N ditert-butyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C(C)(C)C)C(C)(C)C SACNIGZYDTUHKB-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 2
- 235000011009 potassium phosphates Nutrition 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000012535 impurity Substances 0.000 abstract description 17
- 238000000746 purification Methods 0.000 abstract description 11
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- 239000002994 raw material Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 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 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
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- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
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- 229910052757 nitrogen Inorganic materials 0.000 description 3
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- 206010030113 Oedema Diseases 0.000 description 2
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
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- 239000005711 Benzoic acid Substances 0.000 description 1
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- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 1
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- 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
Abstract
The invention discloses a method for synthesizing furosemide impurity D with high yield and high purity, which comprises the following steps: firstly, dissolving furosemide and furfuryl amine by using a solvent; then adding inorganic base and ligand, adding catalyst, and replacing with inert gas; heating and reacting for a period of time; and then recrystallizing twice to obtain the furosemide impurity D. The furosemide impurity D has the characteristics of high yield (the yield is more than 65%), simple purification mode and high purity (the purity is more than 97%), can conveniently obtain a large amount of furosemide impurity D reference substances, and can provide convenience for impurity analysis and research of furosemide bulk drugs and preparations thereof.
Description
Technical Field
The invention relates to the technical field of synthesizing furosemide impurities, in particular to a method for synthesizing furosemide impurity D with high yield and high purity.
Background
Furosemide is a loop diuretic widely used for the treatment of congestive heart failure and edema, is in the form of white or off-white, almost tasteless crystalline powder, is readily soluble in N, N-dimethylformamide, is slightly soluble in methanol, is slightly soluble in ethanol, and is almost insoluble in water. Furosemide mainly inhibits the reabsorption of Cl-and Na + by the medulla part and cortex of the kidney, thereby promoting the massive excretion of Cl-, na +, K + and water and promoting diuresis. The diuretic has strong and short diuretic effect, is a powerful diuretic, can be clinically used for treating cardiac edema, renal edema, ascites due to cirrhosis, pulmonary edema, cerebral edema, acute renal failure or peripheral edema caused by vascular wall disorder, and the like, and particularly has important application value for other cases in which the diuretic is ineffective. Currently, furosemide is usually synthesized by heating and substituting 2, 4-dichloro-5-sulfonamide benzoic acid and furfuryl amine as main raw materials. The furosemide prepared by the method usually contains more impurities, most typically disubstituted furfuryl amine furosemide impurity D, and the impurities seriously affect the quality and the using effect of the furosemide product. The European pharmacopoeia also clearly indicates that the furosemide contains furosemide impurity D, and the impurity is not necessarily detected.
The chemical name of the furosemide impurity D is as follows: 2, 4-bis (furfurylamino) -5-aminosulfonylbenzoic acid, CAS No.: 5046-19-5, formula: C17H17N3O6S, molecular weight: 391.084. structural formula (xvi):
the published reported route of the patent WO 2008052190 for synthesizing the furosemide impurity D is as follows:
the method has a series of problems of low yield (less than 8%), difficult purification mode (two times of column separation and purification), low purity and the like.
For the field of drug development, the main work is not only how to obtain high-quality raw material drug (API) and develop high-efficiency synthesis process, but also more importantly, how to research the types and sources of impurities in the raw material drug and how to control the generation of process impurities. In contrast, impurities generated in the synthesis process are usually oriented, and then an efficient impurity synthesis route is developed so as to obtain a large amount of impurity reference substances and ensure the development of quality detection work (such as impurity HPLC positioning, impurity content measurement and the like) of each batch of raw material medicines. Therefore, the inventor considers that the preparation of the high-yield and high-purity furosemide key impurity D and the purification method thereof have important significance.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a method for synthesizing furosemide impurity D with high yield and high purity, and the obtained furosemide impurity D has the characteristics of high yield (the yield is more than 65%), simple purification mode and high purity (the purity is more than 97%).
In order to achieve the above object, the present invention provides a method for synthesizing furosemide impurity D with high yield and high purity, comprising the steps of:
step S1, dissolving furosemide and furfuryl amine with a solvent;
s2, adding inorganic base and ligand, adding a catalyst, and replacing with inert gas;
s3, heating and reacting for a period of time;
and S4, recrystallizing twice to obtain the furosemide impurity D.
Preferably, the solvent in step S1 is selected from one or more of toluene, dioxane, tetrahydrofuran, DMF, and DMA tert-butanol.
Preferably, the volume of the solvent in the step S1 is 12 to 50 times of the mass of furosemide.
Preferably, the ligand in step S2 is selected from one or more of XPhos, davePhos, john Phos, adBrettPhos, bippyPhos, BINAP, tBuXPs, brettPhos, SPhos, xantPhos, ruPhos, me3 (OMe) tBuXPhos, t-BuBrettPhos, vincophos.
Preferably, the molar ratio of the ligand to the furosemide in the step S2 is 2 to 30 percent
Preferably, the inorganic base in step S2 is selected from one or more of potassium carbonate, potassium phosphate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, LIHMDS; the molar ratio of the inorganic base to the furosemide in the step S2 is 1.5-5.
Preferably, the catalyst in step S2 is selected from one or more of palladium acetate, tris (dibenzylideneacetone) dipalladium; the molar ratio of the catalyst to furosemide in the step S2 is 1-20%.
Preferably, the reaction temperature in the step S3 is 80-120 ℃, and the reaction time is 3-10h.
Preferably, the solvent for recrystallization in step S4 is selected from one or more of ethyl acetate, ethanol, isopropanol, tert-butanol, methyl tert-butyl ether, diethyl ether, acetonitrile, petroleum ether, and water.
Preferably, the specific steps of twice recrystallization in step S4 are:
step S401, filtering the hot reaction solution in the step I, and adjusting the pH value to 3-4 by hydrochloric acid;
step S402, extracting with ethyl acetate, and washing twice with saturated sodium chloride aqueous solution;
step S403, drying the obtained organic phase with anhydrous sodium sulfate, and concentrating; the residue was purified with 1: separating and purifying the ethyl acetate by a fast column for one time to remove most of black substances to obtain a crude product containing the furosemide impurity D;
s404, dispersing the crude product with isopropanol, heating to dissolve the crude product, naturally cooling, crystallizing, filtering, and drying a filter cake under reduced pressure to obtain a product;
and step S405, repeating the operation of the step S404 by using isopropanol again to obtain the furosemide impurity D with the yield of more than 65% and the purity of more than 97%.
By adopting the technical scheme of the invention, the invention has the following beneficial effects: the furosemide impurity D has the characteristics of high yield (the yield is more than 65%), simple purification mode and high purity (the purity is more than 97%), can conveniently obtain a large amount of furosemide impurity D reference substances, and can provide convenience for impurity analysis and research of furosemide bulk drugs and preparations thereof.
Drawings
FIG. 1 is a diagram showing the synthesis of the palladium-catalyzed Buchwald-Hartwig C-N coupling reaction according to the present invention;
FIG. 2 shows the HPLC purity results of furosemide impurity D in example 1 of the present invention;
FIG. 3 shows the HPLC purity results of furosemide impurity D in example 2 of the present invention;
FIG. 4 shows the HPLC purity results of furosemide impurity D in example 3 of the present invention;
FIG. 5 shows furosemide impurity D of the present invention 1 And (5) HNMR mapping results.
Detailed Description
The invention is further described below with reference to the following figures and specific examples.
Referring to fig. 1 to 5, the present invention provides a method for synthesizing furosemide impurity D with high yield and high purity, and the obtained furosemide impurity D has the characteristics of high yield (yield greater than 65%, simple purification method and high purity (purity greater than 97%).
Example 1:
this example 1 provides a high yield, high purity method for synthesizing furosemide impurity D:
putting 1.5g of furosemide into a 100ml single-neck bottle, stirring and dissolving by using 30ml of dioxane, adding 1.6g of potassium tert-butoxide, 65mg of Brettphos ligand and 42mg of tris (dibenzylideneacetone) dipalladium, fully replacing by using a nitrogen ball, heating to 100 ℃ for reaction for 3 hours, sampling TLC (thin layer chromatography) to confirm that the raw materials are completely reacted, filtering the reaction solution while the reaction solution is hot, pouring the filtrate into 100ml of water, adjusting the pH to about 3-4 by using 1M hydrochloric acid, extracting by using 30ml of ethyl acetate, washing by using 80ml of saturated sodium chloride aqueous solution twice, drying and concentrating the obtained organic phase by using anhydrous sodium sulfate, and using petroleum ether as a residue: ethyl acetate =1, and the most of black substances are removed by flash column separation and purification once to obtain 1.6g of crude product containing the impurity D; dispersing the crude product by using 12ml of isopropanol, heating to 80 ℃ to enable the crude product to be dissolved clearly, naturally cooling, crystallizing and filtering, then drying a filter cake under reduced pressure to obtain 1.4g of a product with the purity of 92.3%, repeating the crystallization operation by using 10ml of isopropanol again, filtering, and drying the obtained filter cake under reduced pressure to obtain the furosemide impurity D1.22g with the purity of 98.3% and the yield of 68.6%.
Referring to fig. 5: MS (m/z): 392 (M + H) +,414 (M + Na) +
1 HNMR(400MHz，DMSO-d6):δ:8.92(1H，s)，8.18(1H，s)，7.61(2H，dd)，7.51(1H，s)，7.11(2H，s)，6.56(1H，t)，6.41(1H，t)，6.31(2H，dd)，5.98(1H，s)，4.43(4H，t)
Example 2:
example 2 provides a high yield, high purity method for synthesizing furosemide impurity D:
putting 1.5g of furosemide into a 100ml single-mouth bottle, stirring and dissolving by using 30ml of dioxane, adding 1.6g of potassium tert-butoxide, 82mg of XantPhos ligand and 84mg of tris (dibenzylideneacetone) dipalladium, fully replacing by using a nitrogen ball, and heating to 100 ℃ for reaction for 3 hours; sampling TLC to confirm that the reaction of the raw materials is finished, filtering the reaction solution while the reaction solution is hot, pouring the filtrate into 100ml of water, adjusting the pH to be about 3-4 by using 1M hydrochloric acid, extracting by using 30ml of ethyl acetate, and washing twice by using 80ml of saturated sodium chloride aqueous solution; the organic phase obtained is dried over anhydrous sodium sulfate, concentrated and the residue is purified with petroleum ether: ethyl acetate =1, and the most of black substances are removed by flash column separation and purification once to obtain 1.7g of crude product containing the impurity D; dispersing the crude product with 13ml of isopropanol, heating to 80 ℃ to enable the crude product to be dissolved clearly, naturally cooling for crystallization, filtering, and drying the obtained filter cake under reduced pressure to obtain 1.55g of product with the purity of 93.5%; the crystallization was repeated again using 10ml of isopropanol, and the filtration was carried out, and the obtained cake was dried under reduced pressure to obtain furamel impurity D1.30g with a purity of 97.9% and a yield of 73.1%.
Referring to fig. 5: MS (m/z): 392 (M + H) +,414 (M + Na) +
1 HNMR(400MHz，DMSO-d6):δ:8.92(1H，s)，8.18(1H，s)，7.61(2H，dd)，7.51(1H，s)，7.11(2H，s)，6.56(1H，t)，6.41(1H，t)，6.31(2H，dd)，5.98(1H，s)，4.43(4H，t)
Example 3:
this example provides a high yield, high purity method for synthesizing furosemide impurity D:
putting 1.5g of furosemide into a 100ml single-mouth bottle, stirring and dissolving by using 30ml of dioxane, then adding 1.6g of potassium tert-butoxide, 97mg of Brettphos ligand and 24mg of palladium acetate, fully replacing by using a nitrogen ball, and heating to 100 ℃ for reaction for 3 hours; sampling TLC to confirm that the reaction of the raw materials is finished, filtering the reaction solution while the reaction solution is hot, pouring the filtrate into 100ml of water, adjusting the pH to be about 3-4 by using 1M hydrochloric acid, extracting by using 30ml of ethyl acetate, and washing twice by using 80ml of saturated sodium chloride aqueous solution; the organic phase obtained is dried over anhydrous sodium sulfate, concentrated and the residue is purified with petroleum ether: ethyl acetate =1, and the most of black substances are removed by flash column separation and purification once to obtain 1.8g of crude product containing the impurity D; dispersing the crude product by using 14ml of isopropanol, heating to 80 ℃ to enable the crude product to be dissolved clearly, naturally cooling, crystallizing, filtering, and drying the obtained filter cake under reduced pressure to obtain 1.5g of a product with the purity of 91.8%; the crystallization operation was repeated again using 12ml of isopropyl alcohol, and the obtained cake was filtered and dried under reduced pressure to obtain furosemide impurity d1.33g having a purity of 98.8% and a yield of 74.8%.
Referring to FIG. 5: MS (m/z): 392 (M + H) +,414 (M + Na) +
1 HNMR(400MHz，DMSO-d6):δ:8.92(1H，s)，8.18(1H，s)，7.61(2H，dd)，7.51(1H，s)，7.11(2H，s)，6.56(1H，t)，6.41(1H，t)，6.31(2H，dd)，5.98(1H，s)，4.43(4H，t)
From the above examples 1 to 3, it can be seen that the furosemide impurity D of the present invention has characteristics of high yield (yield greater than 65%), simple purification method and high purity (purity greater than 97%), which can conveniently obtain a large amount of reference samples of the furosemide impurity D, and provide convenience for impurity analysis and research of furosemide bulk drug and preparations thereof.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention, and all modifications and equivalents of the present invention, which are made by the contents of the present specification and the accompanying drawings, or directly/indirectly applied to other related technical fields, are included in the scope of the present invention.
Claims (10)
1. A method for synthesizing furosemide impurity D with high yield and high purity is characterized by comprising the following steps:
step S1, dissolving furosemide and furfuryl amine with a solvent;
s2, adding inorganic base and ligand, adding a catalyst, and replacing with inert gas;
s3, heating and reacting for a period of time;
and S4, recrystallizing twice to obtain the furosemide impurity D.
2. The method for synthesizing furosemide impurity D with high yield and high purity according to claim 1, wherein the solvent in step S1 is selected from one or more of toluene, dioxane, tetrahydrofuran, DMF, and DMA tert-butanol.
3. The method for synthesizing furosemide impurity D with high yield and high purity according to claim 2, wherein the volume of the solvent in step S1 is 12-50 times of the mass of furosemide.
4. The method for high yield and high purity synthesis of furosemide impurity D according to claim 1, wherein the ligand in step S2 is selected from one or more of XPhos, davePhos, johnPhos, adBrettPhos, bippyPhos, BINAP, tBuXPos, brettPhos, SPhos, xantpos, ruPhos, me3 (OMe) tBuXPhos, t-BuBrettPhos, vincePhos.
5. The method for synthesizing furosemide impurity D in high yield and high purity according to claim 4, wherein the molar ratio of the ligand to furosemide in step S2 is 2-30%.
6. The method for synthesizing furosemide impurity D with high yield and high purity as claimed in claim 5, wherein the inorganic base in step S2 is selected from one or more of potassium carbonate, potassium phosphate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, LIHMDS; the molar ratio of the inorganic base to the furosemide in the step S2 is 1.5-5.
7. The method for synthesizing furosemide impurity D with high yield and high purity according to claim 6, wherein the catalyst in step S2 is selected from one or more of palladium acetate, tris (dibenzylideneacetone) dipalladium; the molar ratio of the catalyst to the furosemide in the step S2 is 1-20%.
8. The method for synthesizing furosemide impurity D with high yield and high purity according to claim 1, wherein the reaction temperature in step S3 is 80-120 ℃ and the reaction time is 3-10h.
9. The method for synthesizing furosemide impurity D with high yield and high purity according to claim 1, wherein the solvent for recrystallization in the step S4 is selected from one or more of ethyl acetate, ethanol, isopropanol, tert-butanol, methyl tert-butyl ether, diethyl ether, acetonitrile, petroleum ether and water.
10. The method for synthesizing furosemide impurity D with high yield and high purity according to claim 9, wherein the steps of two-time recrystallization in the step S4 are as follows:
step S401, filtering the hot reaction solution in the step I, and adjusting the pH value to 3-4 by hydrochloric acid;
step S402, extracting with ethyl acetate, and washing twice with saturated sodium chloride aqueous solution;
step S403, drying the obtained organic phase with anhydrous sodium sulfate, and concentrating; the residue was extracted with 1: separating and purifying the ethyl acetate by a rapid column for one time to remove most of black substances to obtain a crude product containing the furosemide impurity D;
s404, dispersing the crude product by using isopropanol, heating to dissolve the crude product, naturally cooling to crystallize, filtering, and drying a filter cake under reduced pressure to obtain a product;
and S405, repeating the operation of the step S404 by using isopropanol again to obtain the furosemide impurity D with the yield of more than 65% and the purity of more than 97%.
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