CN115368369A - Synthesis method of demethylation impurity of danofloxacin mesylate - Google Patents
Synthesis method of demethylation impurity of danofloxacin mesylate Download PDFInfo
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- CN115368369A CN115368369A CN202210979666.0A CN202210979666A CN115368369A CN 115368369 A CN115368369 A CN 115368369A CN 202210979666 A CN202210979666 A CN 202210979666A CN 115368369 A CN115368369 A CN 115368369A
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- demethylated
- danofloxacin
- danofloxacin mesylate
- mesylate
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- 239000012535 impurity Substances 0.000 title claims abstract description 68
- MYDXUJMODAZBGN-UHFFFAOYSA-N 6-bromo-5-methyl-2-methylsulfanyl-1h-[1,2,4]triazolo[1,5-a]pyrimidin-7-one Chemical compound CC1=C(Br)C(=O)N2NC(SC)=NC2=N1 MYDXUJMODAZBGN-UHFFFAOYSA-N 0.000 title claims abstract description 62
- 229960004745 danofloxacin mesylate Drugs 0.000 title claims abstract description 62
- 230000017858 demethylation Effects 0.000 title claims abstract description 17
- 238000010520 demethylation reaction Methods 0.000 title claims abstract description 17
- 238000001308 synthesis method Methods 0.000 title abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 44
- QMLVECGLEOSESV-RYUDHWBXSA-N Danofloxacin Chemical compound C([C@@H]1C[C@H]2CN1C)N2C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=CC=1N2C1CC1 QMLVECGLEOSESV-RYUDHWBXSA-N 0.000 claims abstract description 13
- 229960004385 danofloxacin Drugs 0.000 claims abstract description 13
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 12
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 239000007800 oxidant agent Substances 0.000 claims abstract description 8
- 230000001590 oxidative effect Effects 0.000 claims abstract description 6
- 238000003756 stirring Methods 0.000 claims abstract description 3
- 238000001914 filtration Methods 0.000 claims description 25
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 21
- 239000012043 crude product Substances 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 14
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- 239000011630 iodine Substances 0.000 claims description 7
- 230000003647 oxidation Effects 0.000 claims description 4
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 239000003125 aqueous solvent Substances 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 7
- 238000003786 synthesis reaction Methods 0.000 claims 7
- 238000011160 research Methods 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 6
- 239000007858 starting material Substances 0.000 abstract description 3
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 125000004122 cyclic group Chemical group 0.000 abstract description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 239000003513 alkali Substances 0.000 description 12
- 238000001816 cooling Methods 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- HQQSBEDKMRHYME-UHFFFAOYSA-N pefloxacin mesylate Chemical compound [H+].CS([O-])(=O)=O.C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCN(C)CC1 HQQSBEDKMRHYME-UHFFFAOYSA-N 0.000 description 4
- APFDJSVKQNSTKF-FXMYHANSSA-N Danofloxacin mesylate Chemical group CS(O)(=O)=O.C([C@@H]1C[C@H]2CN1C)N2C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=CC=1N2C1CC1 APFDJSVKQNSTKF-FXMYHANSSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- PLUBXMRUUVWRLT-UHFFFAOYSA-N Ethyl methanesulfonate Chemical compound CCOS(C)(=O)=O PLUBXMRUUVWRLT-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 2
- ZSPLOATUDIRNAS-PPHPATTJSA-N levofloxacin mesylate Chemical compound CS(O)(=O)=O.C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 ZSPLOATUDIRNAS-PPHPATTJSA-N 0.000 description 2
- 244000144972 livestock Species 0.000 description 2
- 229960001808 pefloxacin mesylate Drugs 0.000 description 2
- 244000144977 poultry Species 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229940007526 advocin Drugs 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000315 carcinogenic Toxicity 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- MBABOKRGFJTBAE-UHFFFAOYSA-N methyl methanesulfonate Chemical compound COS(C)(=O)=O MBABOKRGFJTBAE-UHFFFAOYSA-N 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- SWWHCQCMVCPLEQ-UHFFFAOYSA-N propan-2-yl methanesulfonate Chemical compound CC(C)OS(C)(=O)=O SWWHCQCMVCPLEQ-UHFFFAOYSA-N 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A40/00—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production
- Y02A40/70—Adaptation technologies in agriculture, forestry, livestock or agroalimentary production in livestock or poultry
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application provides a synthesis method of demethylation impurities of danofloxacin mesylate, belonging to the technical field of heterocyclic compounds which contain nitrogen atoms as only heterocyclic atoms in condensed ring systems. The danofloxacin is used as a starting material, water is used as a solvent, an oxidant is added, after the oxidation reaction is completed by stirring, the danofloxacin mesylate is crystallized, purified, filtered and dried to obtain a pure product of demethylation impurities of the danofloxacin mesylate. The application is applied to the quality research of active ingredients of medicaments, the quality of danofloxacin mesylate can be effectively improved, and the synthesized impurity has higher yield and purity.
Description
Technical Field
The application relates to a synthesis method of demethylated impurities of danofloxacin mesylate, belonging to the technical field of heterocyclic compounds containing nitrogen atoms as only heterocyclic atoms in condensed ring systems.
Background
The danofloxacin mesylate is a fluoroquinolone drug special for the third generation animals. The product is firstly introduced by the American pfeire company, the CA registration number is 119478-55-6, the product is marketed in countries such as Mexico in 1990, the product name is Advocin, the product is mainly used for treating respiratory tract infection of livestock and poultry, and the product has the characteristics of wide antimicrobial spectrum, strong antimicrobial activity, no drug resistance, small adverse reaction, high oral bioavailability, convenient use and the like.
The chemical name of danofloxacin mesylate (danofloxacin) is: 1-cyclopropyl-6-fluoro-7- [ (1S, 4S) -5-methyl-2, 5-diazabicyclo [2.2.1] heptan-2-yl ] -1, 4-dihydro-4-oxoquinoline-3-carboxylic acid methanesulfonate, as a 1.5 water crystal, the structural formula is as follows:
the danofloxacin mesylate has good water solubility, can be administered by various ways, is quickly absorbed, has high bioavailability, has high drug concentration in animal lung tissues, has good antibacterial effect on main respiratory pathogenic bacteria, and is an ideal drug for treating respiratory system infection of livestock.
There are a number of journal articles for determination and research of pefloxacin mesylate and levofloxacin mesylate, such as: the content determination methods of carcinogenic components such as methyl methanesulfonate, ethyl methanesulfonate, isopropyl methanesulfonate and the like included in the Chinese pharmacopoeia (ChP) and European Pharmacopoeia (EP), and the research on determination of methanesulfonate impurity in pefloxacin methanesulfonate by GC-MS method (Yi Da et al, chinese antibiotic impurity, 2017,42 (6), p 521-525), "comparison of detection methods of pefloxacin methanesulfonate related substances in Chinese pharmacopoeia and European pharmacopoeia (Yu, chinese antibiotic impurity, 2017,42 (6), p 526-530), HPLC method for measuring the content of pefloxacin mesylate tablets and related substances (Liqun et al, J pediatric pharmacy, 2009,15 (3), p 49-51), high performance liquid chromatography for measuring the content of danofloxacin mesylate (Lucyanine, chinese poultry, 2001,23 (13), p 20), gas chromatography-mass spectrometry for measuring the content of ethyl methanesulfonate in levofloxacin mesylate tablets (Houjin Feng et al, chinese medicine guide, 2018,15 (3), p 126-129), and optical rotation method for measuring the content of danofloxacin mesylate (Lidayan, J Chinese veterinary medicine, 2004,38 (1), p 30-31).
However, in the research on related substances of danofloxacin mesylate, related pharmacopoeias do not record the product, related journal researches are less, the currently determined main impurity is demethylation impurity, the previous synthesis method of the impurity is complex, the impurity undergoes multi-step reaction from the starting material L-hydroxyproline, the purification is difficult, the difficulty is brought to the quality research, and the demethylation impurity which is simple to synthesize and has higher purity is provided, which is a problem to be solved urgently at present.
Disclosure of Invention
In view of this, the present application provides a method for synthesizing a demethylated impurity of danofloxacin mesylate, which is shown in the following structure:
The impurity is used as a reference substance for the quality research of Active Pharmaceutical Ingredients (API), and can well improve the quality of danofloxacin mesylate as a raw material.
Specifically, the method is realized through the following scheme:
a synthetic method of demethylation impurities of danofloxacin mesylate comprises the following steps:
(1) The danofloxacin is used as a starting material, water is used as a solvent, the pH value is adjusted to be alkaline by using alkali liquor, an oxidant is added, after the oxidation reaction is completed by stirring for a specified time at a certain temperature (the alkali liquor is required to be added in the reaction process to maintain the pH value to be alkaline until the pH value is unchanged), the pH value is adjusted by using hydrochloric acid, and the crude product of demethylation impurities of the danofloxacin mesylate is obtained by filtering and drying.
(2) And (2) adding the crude product of the demethylation impurity of the danofloxacin mesylate obtained in the step (1) into a water-containing solvent, and crystallizing and purifying the methanesulfonic acid to obtain the demethylation impurity methanesulfonate of the danofloxacin mesylate with higher purity.
(3) And (3) adding water into the high-purity danofloxacin mesylate demethylation impurity mesylate obtained in the step (2), adjusting the pH value to 7 to 7.5 by using alkali liquor, filtering and drying to obtain a pure danofloxacin mesylate demethylation impurity.
The process takes water as a solvent, realizes the conversion of the danofloxacin into a demethylated impurity crude product by means of the addition of an oxidant and the control of pH, and then finishes the purity improvement of the impurities step by step in the modes of crystallization purification and pH adjustment. The method is simple to operate, and the related reagents are only water, an oxidizing agent, a water-containing solvent, a pH adjusting reagent and the like, so that the cost is low; the purity of the obtained impurity HPLC reaches more than 95%, and the yield reaches more than 30%.
Further, it is preferable that:
in the step (1), the ratio (w/w) of the danofloxacin to the water is 1 to 3 to 8, preferably 1.
In the step (1), adjusting the pH value of the solution to 10 to 11 by using an alkali liquor.
In the step (1), the oxidant is iodine, and the dosage ratio (n/n) of the danofloxacin to the iodine is (n/n) 1.
In the step (1), the oxidation temperature is 40 to 60 ℃, preferably 50 to 55 ℃ in the oxidation reaction process.
In the step (1), in the oxidation reaction process, the oxidation reaction time is 2 to 6 hours, preferably 4 hours.
In the step (1), the pH value of the solution is adjusted to 7.8 to 8.3 by hydrochloric acid.
In the step (2), the water-containing solvent is methanol, the water content is 10-30%, preferably 20%, and after salifying, the impurity removal effect and the certain yield level are ensured by the certain water content in the solvent.
In the step (2), the dosage ratio (w/w) of the crude demethylated impurity of danofloxacin mesylate to the aqueous solvent is 1 to 8 to 12 times, preferably 1.
In the step (2), the dosage ratio (w/w) of the crude product of the demethylated impurity of danofloxacin mesylate to methanesulfonic acid is (1) 0.27 to 0.54, preferably (1).
According to the preparation method of the danofloxacin mesylate demethylated impurity, the reaction can be carried out under the isothermal condition at room temperature or at medium or low temperature, the danofloxacin mesylate obtains a crude product of the danofloxacin mesylate demethylated impurity by an oxidation method, and then obtains a high-purity pure product of the danofloxacin mesylate demethylated impurity by a salifying crystallization method, wherein the HPLC purity is more than 95%.
Detailed Description
Example 1
500 40.0 g (0.11 mol) of danofloxacin and 120 g of water are added into a mL four-neck flask, the pH value is adjusted to 10.2 by using alkali liquor, 55.9 g (0.22 mol) of iodine is added, the temperature is raised to 40 ℃, the temperature is kept for reaction for 2 hours (the pH value is maintained at 10.2 by adding alkali liquor in the reaction process). After the reaction is finished, 2 spoons of activated carbon are added, and the mixture is stirred for 0.5 hour for decolorization and filtration. And (3) adjusting the filtrate to 7.9 by hydrochloric acid, cooling to 20 ℃, filtering, rinsing with a large amount of water, and drying to obtain 23.43 g of crude product of demethylated impurities of danofloxacin mesylate.
500 And adding 20.0g of the obtained crude product of the demethylated impurities of danofloxacin mesylate in the previous step into a mL four-neck flask, adding 5.4g of methanesulfonic acid and 160 g of methanol with 10% of water, heating to reflux and fully dissolving, adding 2 spoons of activated carbon, preserving heat for 0.5 hour, filtering, cooling the filtrate to 20 ℃, and filtering. Putting the filter cake into a 500mL four-neck flask, adding 200 g of water, adjusting the pH value to 7.0 by using an alkali liquor, filtering, rinsing by using a large amount of water, and drying to obtain 12.37 g of the demethylated impurity of danofloxacin mesylate, wherein the HPLC content is 95.22%, and the yield is about 30.9% (12.37/40).
Example 2
500 40.0 g (0.11 mol) of danofloxacin and 160 g of water are added into a mL four-neck flask, the pH value is adjusted to 10.8 by using alkali liquor, 55.9 g (0.22 mol) of iodine is added, the temperature is raised to 45 ℃, and the reaction is kept for 3 hours (the pH value is maintained at 10.8 by adding alkali liquor in the reaction process). After the reaction is finished, 2 spoons of activated carbon are added, and the mixture is stirred for 0.5 hour, decolorized and filtered. And (3) adjusting the filtrate to 8.0 by hydrochloric acid, cooling to 20 ℃, filtering, rinsing with a large amount of water, and drying to obtain 24.81 g of crude demethylated impurities of danofloxacin mesylate.
500 And adding 20.0g of the obtained crude product of the demethylated impurities of danofloxacin mesylate in the previous step into a mL four-neck flask, adding 180 g of methanol containing 15% of water and 5.4g of methanesulfonic acid, heating to reflux and fully dissolving, adding 2 spoons of activated carbon, preserving the temperature for 0.5 hour, filtering, cooling the filtrate to 20 ℃, and filtering. Putting the filter cake into a 500mL four-neck flask, adding 200 g of water, adjusting the pH value to 7.0 by using alkaline liquor, filtering, rinsing by using a large amount of water, and drying to obtain 12.84 g of the demethylated impurity of danofloxacin mesylate, wherein the HPLC content is 95.68%, and the yield is about 32.1% (12.84/40).
Example 3
500 40.0 g (0.11 mol) of danofloxacin and 200 g of water are added into a mL four-neck flask, the pH value is adjusted to 10.5 by using alkaline liquor, 83.82 g (0.33 mol) of iodine is added, the temperature is raised to 50 ℃, and the reaction is kept for 4 hours (the pH value is maintained to be 10.5 by adding alkaline liquor in the reaction process). After the reaction is finished, 2 spoons of activated carbon are added, and the mixture is stirred for 0.5 hour, decolorized and filtered. And (3) adjusting the filtrate to 7.9 by hydrochloric acid, cooling to 20 ℃, filtering, rinsing with a large amount of water, and drying to obtain 25.02 g of crude product of demethylated impurities of danofloxacin mesylate.
500 And adding 20.0g of the obtained crude product of the demethylated impurities of danofloxacin mesylate in the previous step into a mL four-neck flask, adding 200 g of methanol with 20% of water and 8.0 g of methanesulfonic acid, heating to reflux and fully dissolving, adding 2 spoons of activated carbon, preserving the temperature for 0.5 hour, filtering, cooling the filtrate to 20 ℃, and filtering. Putting the filter cake into a 500mL four-neck flask, adding 200 g of water, adjusting the pH value to 7.0 by using an alkali liquor, filtering, rinsing by using a large amount of water, and drying to obtain 14.25 g of the demethylated impurity of danofloxacin mesylate, wherein the HPLC content is 97.13%, and the yield is about 35.6% (14.25/40).
Example 4
1000 40.0 g (0.11 mol) of danofloxacin and 280g of water are added into a mL four-neck flask, the pH value is adjusted to 10.8 by using alkaline liquor, 96.52 g (0.38 mol) of iodine is added, the temperature is raised to 55 ℃, and the reaction is kept for 5 hours (the pH value is maintained to be 10.8 by adding alkaline liquor in the reaction process). After the reaction is finished, 2 spoons of activated carbon are added, and the mixture is stirred for 0.5 hour, decolorized and filtered. And (3) adjusting the filtrate to 8.2 by hydrochloric acid, cooling to 20 ℃, filtering, rinsing with a large amount of water, and drying to obtain 22.42 g of crude demethylated impurities of danofloxacin mesylate.
500 And adding 20.0g of the obtained crude product of the demethylated impurities of danofloxacin mesylate obtained in the previous step into a mL four-neck flask, adding 220 g of methanol with 25% of water and 10.8 g of methanesulfonic acid, heating to reflux and fully dissolving, adding 2 spoons of activated carbon, preserving heat for 0.5 hour, filtering, cooling the filtrate to 20 ℃, and filtering. Putting the filter cake into a 500mL four-neck flask, adding 200 g of water, adjusting the pH to 7.0 by using an alkali liquor, filtering, rinsing by using a large amount of water, and drying to obtain 12.56 g of demethylated impurity of danofloxacin mesylate, wherein the HPLC content is 93.94%, and the yield is about 31.4% (12.56/40).
Example 5
1000 40.0 g (0.11 mol) of danofloxacin and 320g of water are added into a mL four-neck flask, the pH value is adjusted to 10.2 by using alkaline liquor, 111.7 g (0.44 mol) of iodine is added, the temperature is raised to 60 ℃, and the reaction is kept for 6 hours (the pH value is maintained to be 10.2 by adding alkaline liquor in the reaction process). After the reaction is finished, 2 spoons of activated carbon are added, and the mixture is stirred for 0.5 hour, decolorized and filtered. And (3) adjusting the filtrate to 8.0 by hydrochloric acid, cooling to 20 ℃, filtering, rinsing with a large amount of water, and drying to obtain 21.05 g of crude product of demethylated impurities of danofloxacin mesylate.
500 And adding 20.0g of the crude product of the demethylated impurities of danofloxacin mesylate obtained in the previous step into a mL four-neck flask, adding 240 g of methanol containing 30% of water and 10.8 g of methanesulfonic acid, heating to reflux and fully dissolving, adding 2 spoons of activated carbon, preserving the temperature for 0.5 hour, filtering, cooling the filtrate to 20 ℃, and filtering. Putting the filter cake into a 500mL four-neck flask, adding 200 g of water, adjusting the pH to 7.0 by using an alkali liquor, filtering, rinsing by using a large amount of water, and drying to obtain 11.75 g of demethylated impurity of danofloxacin mesylate, wherein the HPLC content is 91.17%, and the yield is about 29.4% (11.75/40).
The active ingredient quality research is carried out by taking the demethylated impurity of danofloxacin mesylate obtained in the above embodiment as a reference substance, and the result shows that: the prepared demethylation impurity of the danofloxacin mesylate meets the purity requirement of impurities and is used as an impurity reference substance.
Claims (10)
1. A method for synthesizing demethylated impurities of danofloxacin mesylate is characterized by comprising the following steps:
(1) Adjusting the pH value of the solution to 10 to 11 with water as a solvent as an initial raw material, adding an oxidant, stirring to complete an oxidation reaction, adjusting the pH value to 7.8 to 8.3, filtering and drying to obtain a crude product of demethylated impurities of danofloxacin mesylate;
(2) Adding methanesulfonic acid and a water-containing solvent into the crude product of the demethylation impurity of danofloxacin mesylate obtained in the step (1) for crystallization and purification to obtain the demethylation impurity methanesulfonate of danofloxacin mesylate;
(3) And (3) adding water into the danofloxacin mesylate demethylation impurity mesylate obtained in the step (2), adjusting the pH value to 7-7.5, filtering and drying to obtain a pure danofloxacin mesylate demethylation impurity product.
2. The process for the synthesis of a demethylated impurity of danofloxacin mesylate according to claim 1, wherein: in the step (1), the mass ratio of the danofloxacin to the water is 1 to 3-8.
3. The process for the synthesis of a demethylated impurity of danofloxacin mesylate according to claim 1, wherein: in the step (1), the molar ratio of the danofloxacin to the oxidizing agent is 1 to 2-4.
4. The process for the synthesis of a demethylated impurity of danofloxacin mesylate according to claim 1, wherein: the oxidant is iodine.
5. The process for the synthesis of a demethylated impurity of danofloxacin mesylate according to claim 1, wherein: in the oxidation reaction, the oxidation temperature is 40 to 60 ℃, and the oxidation reaction time is 2 to 6 hours.
6. The process of synthesizing a demethylated impurity of danofloxacin mesylate according to claim 5, wherein: the oxidation temperature is 50 to 55 ℃.
7. The process for the synthesis of a demethylated impurity of danofloxacin mesylate according to claim 1, wherein: in the step (2), the addition amount of the aqueous solvent is 1 to 8 to 12 times of the mass of the crude product of the demethylated impurity of danofloxacin mesylate.
8. The process for the synthesis of a demethylated impurity of danofloxacin mesylate according to claim 1, wherein: in the step (2), the water-containing solvent is methanol, and the water content is 10 to 30 percent.
9. The process for the synthesis of a demethylated impurity of danofloxacin mesylate according to claim 1, wherein: in the step (2), the mass ratio of the crude demethylated impurity of danofloxacin mesylate to methanesulfonic acid is 1: 0.27-0.54.
10. The method for synthesizing the danofloxacin mesylate demethylated impurity according to claim 1, wherein the structure of the danofloxacin mesylate demethylated impurity is as follows:
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0215650A2 (en) * | 1985-09-18 | 1987-03-25 | Pfizer Inc. | Substituted bridged-diazabicycloalkyl quinolone carboxylic acids |
| CN101703469A (en) * | 2009-11-24 | 2010-05-12 | 东北农业大学 | Preparation method and products of danofloxacin mesylate liposome |
-
2022
- 2022-08-16 CN CN202210979666.0A patent/CN115368369A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0215650A2 (en) * | 1985-09-18 | 1987-03-25 | Pfizer Inc. | Substituted bridged-diazabicycloalkyl quinolone carboxylic acids |
| US4775668A (en) * | 1985-09-18 | 1988-10-04 | Pfizer Inc. | Substituted bridged-diazabicycloalkyl quinolone carboxylic acids and anti-bacterial use thereof |
| CN101703469A (en) * | 2009-11-24 | 2010-05-12 | 东北农业大学 | Preparation method and products of danofloxacin mesylate liposome |
Non-Patent Citations (1)
| Title |
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| Y CHEN 等: "Microbial models of soil metabolism: biotransformations of danofloxacin", 《JOURNAL OF INDUSTRIAL MICROBIOLOGY & BIOTECHNOLOGY》 * |
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Application publication date: 20221122 |