CN111362873A - Synthetic method of gatifloxacin metabolite - Google Patents
Synthetic method of gatifloxacin metabolite Download PDFInfo
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- CN111362873A CN111362873A CN202010340273.6A CN202010340273A CN111362873A CN 111362873 A CN111362873 A CN 111362873A CN 202010340273 A CN202010340273 A CN 202010340273A CN 111362873 A CN111362873 A CN 111362873A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
Abstract
The invention discloses a synthesis method of gatifloxacin metabolite, belongs to the field of biomedicine, and provides a method for synthesizing gatifloxacin metabolite, which has reasonable route, strong operability and easy purification of product. The method takes a compound I as a raw material, firstly reacts with isopropanol ammonia, then hydroxyl is prepared into active ester, the active ester is substituted by azide, and finally the azide is reduced to amino to obtain a target molecule. The method has the advantages of reasonable design of the whole route, cheap and easily-obtained raw materials, simple operation, high yield and purity of the obtained product, and the synthesized target molecule provides a test sample for the research of the metabolic mechanism of gatifloxacin, thereby having important application value.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to a synthetic method of a gatifloxacin metabolite.
Background
Gatifloxacin: gatifloxacin, chemical name 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7- (3-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid, trade name Tequin, Zymar, structural formula:
the compound is a fourth-generation quinolone antibacterial drug containing methoxyl, is approved by FDA in the United states and is sold on the market 12 months in 1999, has a wider antibacterial spectrum than other clinical fluoroquinolone antibacterial drugs, particularly enhances the antibacterial activity to gram-positive bacteria and anaerobic bacteria, and simultaneously reduces phototoxicity; is stable in vivo, can be quickly absorbed by oral administration, has good tissue distribution, and is mainly used for treating various mild and moderate infectious diseases caused by sensitive pathogens.
Before the medicine is marketed, the quality, safety and efficacy of the medicine are scientifically evaluated, the gatifloxacin metabolite provides a test sample for the biological metabolism of gatifloxacin, and the test sample can be applied to the research on clinical pharmacokinetics, so that the metabolic process of gatifloxacin in organisms can be more accurately known, but the research on the preparation method of the gatifloxacin metabolite is not reported at present.
Disclosure of Invention
The invention provides a synthesis method of gatifloxacin metabolite, which has reasonable route, strong operability and easy purification of product.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for synthesizing a gatifloxacin metabolite comprises the following steps:
(1) dissolving a raw material I in an organic solvent with the volume ratio of 10-15 times, heating the raw material I and isopropanolamine to react for 5 hours at 80-120 ℃ in the presence of organic base, wherein the molar consumption ratio of the raw material I to the organic base is 1 (1-7), and the molar consumption ratio of the raw material I to the isopropanolamine is 1 (1-5), and treating and purifying to obtain a compound II;
(2) dissolving the compound II prepared in the step (1) in a solvent with the volume ratio of 10-15 times, adding organic base, reacting with methylsulfonyl chloride for 2 hours at room temperature, wherein the molar ratio of the compound II to the methylsulfonyl chloride is 1 (1-5), and the molar ratio of the compound II to the organic base is 1 (1-6), and treating to obtain a methylsulfonate compound III;
(3) mixing the compound III obtained in the step (2) with trimethylsilylazide, dissolving the mixture in an organic solvent with the volume ratio of 10-15 times, wherein the molar use ratio of the compound III to the trimethylsilylazide is 1 (2-8), and heating the mixture at the temperature of 40-80 ℃ for reaction for 12 hours to obtain a compound IV;
(4) dissolving the compound IV obtained in the step (3) in an organic solvent with the volume ratio of 10-15 times, adding tertiary phosphine, wherein the molar use ratio of the compound (IV) to the tertiary phosphine is 1 (0.5-5), reacting for 2 hours at the reaction temperature of 65-85 ℃, reducing azide to amino through a Staudinger reaction, treating and purifying to obtain a target molecule V
In the above steps, the organic base in step (1) is triethylamine or diisopropylethylamine, preferably diisopropylethylamine, the molar ratio of the raw material i to the organic base is preferably 1:2, the molar ratio of the raw material i to the isopropanolamine is preferably 1:3, and the reaction solvent is DMF or dioxane, preferably DMF;
the reaction in the step (2) is as follows: dissolving the compound II prepared in the step (1) in a solvent, adding an organic base, reacting with p-toluenesulfonyl chloride for 2 hours at room temperature, wherein the molar ratio of the compound II to the p-toluenesulfonyl chloride is 1 (1-5), and treating to obtain a p-toluenesulfonate active ester compound; the reaction of the step (3) is as follows: mixing the p-toluenesulfonic acid active ester compound obtained in the step (2) with trimethylsilylazide, dissolving the mixture in an organic solvent with the volume ratio of 10-15 times, wherein the molar ratio of the compound (III) to the trimethylsilylazide is 1 (2-8), and reacting at 40-80 ℃ for 12 hours to obtain a compound (IV)
In the step (2), the reaction solvent is dried THF or dried chloroform, preferably dried THF, the molar dosage ratio of the compound II to methanesulfonyl chloride or p-toluenesulfonyl chloride is preferably 1:3, the organic base is triethylamine or diisopropylethylamine, and the molar dosage ratio of the compound II to the organic base is preferably 1: 3;
in the step (3), the organic solvent is DMSO or DMF, and the molar ratio of the compound III to the trimethylsilylazide is preferably 1: 4;
the tertiary phosphine in the step (4) is triphenylphosphine or tributylphosphine, preferably triphenylphosphine, the molar using ratio of the compound IV to the tertiary phosphine is preferably 1:1, the reaction solvent is THF or methanol, preferably THF, and the reaction temperature is preferably 70 ℃.
Has the advantages that: the synthesis method provided by the invention has the advantages of reasonable route design, low raw material price and simple experimental operation, the optimal reaction conditions and the optimal reaction steps are screened out through a large number of experiments, the purity of the obtained gatifloxacin metabolite is more than 99%, a test sample is provided for the research of the metabolic mechanism of gatifloxacin, the synthesis method can be used for researching the metabolic process of the gatifloxacin in a living body, and the synthesis method has important research value in the clinical pharmacokinetic research.
Drawings
FIG. 1 is a schematic diagram of the synthesis route of gatifloxacin metabolites in the examples of the present invention.
Detailed Description
The invention is described in detail below with reference to the following figures and specific examples:
example 1
As shown in fig. 1, a method for synthesizing a gatifloxacin metabolite comprises the following steps:
step (1): preparation of Compound II
Dissolving 10g of the raw material I and 5.3g of isopropanolamine in 50mL of dioxane, adding 6g of diisopropylethylamine, stirring at 100 ℃ for 5 hours to obtain a light yellow solution, wherein TLC shows that the reaction is complete, directly concentrating and evaporating the reaction solution, and purifying by using a chromatographic column to obtain 9g of a compound II with the yield of 79%;
step (2): preparation of Compound III
Dissolving 9g of compound II in 90mL of dry THF, adding 6.5g of methylsulfonyl chloride and 5.7g of dry triethylamine, reacting at 50 ℃ for 2 hours, reacting completely by TLC, cooling the reaction solution, washing with water, drying the organic phase, and concentrating to obtain 7g of compound III, MS:451[ M + Na ]+]Yield 86%;
and (3): preparation of Compound V
Dissolving 7g of a compound III in 70mL of DMSO, adding 8.3g of trimethyl silicon azide, stirring overnight at 40 ℃, completely dotting the reaction solution, cooling the reaction solution, adding water, continuously extracting with ethyl acetate twice, drying with sodium sulfate, concentrating, and crystallizing with ethanol to obtain 4g of a compound V with a yield of 65%;
and (4): preparation of gatifloxacin metabolite VI
Dissolving 4g of compound V in 45mL of THF, adding 3g of triphenylphosphine, stirring at 70 ℃ for 2 hours, concentrating, adding water, extracting with dichloromethane, drying the organic phase with sodium sulfate, concentrating, purifying the crude product with a chromatographic column to obtain 2g of gatifloxacin metabolite VI, MS:350[ M + H ]+]Yield 49%.
Example 2
Step (1): preparation of Compound II
Dissolving 5g of the raw material I and 2.5g of isopropanolamine in 25mL of DMF, adding 3g of diisopropylethylamine, stirring at 100 ℃ for 6 hours, performing TLC (thin layer chromatography) to show that the reaction is complete, directly concentrating and evaporating the reaction solution to dryness, and purifying by using a chromatographic column to obtain 4g of a compound II with the yield of 70%;
step (2): preparation of Compound III
Dissolving 4g of compound II in 40mL of dry chloroform, adding 4.8g of p-toluenesulfonyl chloride and 2.5g of dry triethylamine, reacting at 50 ℃ for 2 hours, wherein TLC shows that the reaction is complete, cooling the reaction solution, washing with water, drying the organic phase, and concentrating to obtain 3.4g of compound III with the yield of 81%;
and (3): preparation of Compound V
Dissolving 3.4g of a compound III in 35mL of DMSO, adding 3.4g of trimethyl silicon azide, stirring overnight at 40 ℃, completely carrying out plate reaction, cooling the reaction solution, adding water, continuously extracting with ethyl acetate twice, drying sodium sulfate, concentrating, and crystallizing with ethanol to obtain 1.7g of a compound V, wherein the yield is 67%;
and (4): preparation of gatifloxacin metabolite VI
Dissolving 1.7g of compound V in 17mL of methanol, adding 1g of tributylphosphine, stirring at 70 ℃ for 2 hours, concentrating the crude product, and purifying by using a chromatographic column to obtain 0.8g of gatifloxacin metabolite VI, MS:350[ M + H ]+]Yield 42%.
HPLC:99.5％,1H NMR:(400MHz,DMSO-d6):δ1.01-1.13(m,4H),1.24-1.25(dd,3H),3.42-3.55(m,3H),3.72(s,3H),4.16(m,1H),5.07(-NH2,brs,2H),6.49-6.52(m,1H),3.72(s,3H),7.73-7.76(dd,1H),8.65(-Ar,1H),15.16(-COOH,brs,1H)。
The above-described embodiments are preferred embodiments of the present invention, and it should be noted that, for those skilled in the art, various modifications and improvements can be made without departing from the principle of the present invention, and these modifications and improvements should also be construed as the protection scope of the present invention.
Claims (9)
1. A method for synthesizing a gatifloxacin metabolite is characterized by comprising the following steps of:
(1) dissolving a raw material (I) in an organic solvent with the volume ratio of 10-15 times, reacting with isopropanolamine at 80-120 ℃ for 5 hours in the presence of organic base, wherein the molar consumption ratio of the raw material (I) to the isopropanolamine is 1 (1-5), and the molar consumption ratio of the raw material (I) to the organic base is 1 (1-7), and treating and purifying to obtain a compound (II);
(2) dissolving the compound (II) prepared in the step (1) in a solvent with the volume ratio of 10-15 times, adding an organic base, reacting with methylsulfonyl chloride for 2 hours at room temperature, wherein the molar dose ratio of the compound (II) to the methylsulfonyl chloride is 1 (1-5), and the molar dose ratio of the compound (II) to the organic base is 1 (1-6), and treating to obtain a methylsulfonate compound (III);
(3) mixing the compound (III) obtained in the step (2) with trimethylsilylazide, dissolving the mixture in an organic solvent with the volume ratio of 10-15 times, wherein the molar use ratio of the compound (III) to the trimethylsilylazide is 1 (2-8), and reacting at the temperature of 40-80 ℃ for 12 hours to obtain a compound (IV);
(4) dissolving the compound (IV) obtained in the step (3) in an organic solvent with the volume ratio of 10-15 times, adding tertiary phosphine, wherein the molar using amount ratio of the compound (IV) to the tertiary phosphine is 1 (0.5-5), reacting for 2 hours at the reaction temperature of 65-85 ℃, reducing azide to amino through a Staudinger reaction, treating and purifying to obtain a gatifloxacin metabolite (V)
2. The method for synthesizing gatifloxacin metabolite according to claim 1, wherein the organic base in step (1) is triethylamine or diisopropylethylamine, the molar ratio of the raw material (I) to the organic base is 1 (1-7), the reaction solvent is DMF or dioxane, and the molar ratio of the raw material (I) to isopropanolamine is 1: 3.
3. The method for synthesizing gatifloxacin metabolite according to claim 2, wherein the organic base in step (1) is diisopropylethylamine, and the reaction solvent is DMF.
4. The method for synthesizing gatifloxacin metabolite according to claim 1, wherein the reaction in the step (2) is as follows: dissolving the compound (II) prepared in the step (1) in a solvent with the volume ratio of 10-15 times, adding an organic base, reacting with p-toluenesulfonyl chloride at room temperature, wherein the molar dosage ratio of the compound (II) to the p-toluenesulfonyl chloride is 1 (1-5), and treating to obtain a p-toluenesulfonate active ester compound; the reaction of the step (3) is as follows: and (3) mixing the p-toluenesulfonic acid active ester compound obtained in the step (2) with trimethylsilylazide, dissolving the mixture in an organic solvent with the volume ratio of 10-15 times, wherein the molar use ratio of the compound (III) to the trimethylsilylazide is 1 (2-8), and reacting at 40-80 ℃ for 12 hours to obtain a compound (IV).
5. A synthesis method of gatifloxacin metabolite according to claim 1 or 4, characterized in that the reaction solvent in step (2) is dry THF or dry chloroform, the organic base is triethylamine or diisopropylethylamine, and the molar ratio of compound (II) to methanesulfonyl chloride or p-toluenesulfonyl chloride is 1: 3.
6. The method for synthesizing a gatifloxacin metabolite according to claim 5, wherein the reaction solvent in the step (2) is dry THF.
7. The method for synthesizing a metabolite of gatifloxacin according to claim 1 or 4, wherein the molar ratio of compound (iii) to trimethylsilylazide used in step (3) is 1: 4.
8. The method for synthesizing gatifloxacin metabolite according to claim 1, wherein the tertiary phosphine in step (4) is triphenylphosphine or tributylphosphine, the reaction solvent is THF or methanol, and the reaction temperature is 70 ℃.
9. The method for synthesizing gatifloxacin metabolite according to claim 8, wherein the tertiary phosphine in step (4) is triphenylphosphine, the molar ratio of the compound (iv) to the tertiary phosphine is 1:1, and the reaction solvent is THF.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113527288A (en) * | 2020-04-16 | 2021-10-22 | 沈阳药科大学 | Process for preparing quinolone-or naphthyridonecarboxylic acid derivatives |
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Non-Patent Citations (3)
| Title |
|---|
| MITSUYOSHI NAKASHIMA，等: "Single- and Multiple-Dose Pharmacokinetics of AM-1155, a New 6-Fluoro-8-Methoxy Quinolone, in Humans", 《ANTIMICROBIAL AGENTS AND CHEMOTHERAPY》 * |
| WEI LI，等: "Spectral correlation of high-performance liquid chromatography-diode array detection data from two independent chromatographic runs Peak tracking in pharmaceutical impurity profiling", 《JOURNAL OF CHROMATOGRAPHY A》 * |
| ZHANG DOUSHENG，等: "A digitized impurity database analysis method for determining the impurity profiles of gatifloxacin in bulk materials and injections", 《PHARMAZIE》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113527288A (en) * | 2020-04-16 | 2021-10-22 | 沈阳药科大学 | Process for preparing quinolone-or naphthyridonecarboxylic acid derivatives |
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