CN111362873B - Synthetic method of gatifloxacin metabolite - Google Patents
Synthetic method of gatifloxacin metabolite Download PDFInfo
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- CN111362873B CN111362873B CN202010340273.6A CN202010340273A CN111362873B CN 111362873 B CN111362873 B CN 111362873B CN 202010340273 A CN202010340273 A CN 202010340273A CN 111362873 B CN111362873 B CN 111362873B
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- C—CHEMISTRY; METALLURGY
- 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 a gatifloxacin metabolite, belongs to the field of biomedicine, and provides a method for synthesizing the gatifloxacin metabolite, which has the advantages of reasonable route, strong operability and easy purification of a 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 medicines are on the market, the quality, safety and efficacy of the medicines are scientifically evaluated, and the gatifloxacin metabolite provides a test sample for the biological metabolism of gatifloxacin and can be applied to the research on the aspect of clinical pharmacokinetics so as to more accurately understand the metabolic process of gatifloxacin in organisms.
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 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;
the reaction in the step (2) is as follows: dissolving the compound II prepared in the step (1) in a solvent, adding 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 that of the mixture, 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)
In the step (2), the reaction solvent is dry THF or dry chloroform, preferably dry THF, the molar ratio of the compound II to methylsulfonyl chloride or p-toluenesulfonyl chloride is preferably 1;
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;
the tertiary phosphine in the step (4) is triphenylphosphine or tributylphosphine, preferably triphenylphosphine, the molar ratio of the compound IV to the tertiary phosphine is preferably 1.
Has the advantages that: the synthetic 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 method can be used for researching the metabolic process of the gatifloxacin in a living body, and the 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, displaying complete reaction by TLC (thin layer chromatography), directly concentrating and evaporating reaction liquid, 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, indicating that the reaction is complete by TLC, cooling the reaction solution, washing with water, drying the organic phase, concentrating to obtain 7g of compound III, and carrying out MS:451[M+Na + ]Yield 86%;
and (3): preparation of Compound V
Dissolving 7g of compound III in 70mL of DMSO, adding 8.3g of trimethylsilylazide, stirring overnight at 40 ℃, completely performing plate reaction, cooling the reaction solution, adding water, continuing to extract twice with ethyl acetate, drying sodium sulfate, concentrating, and crystallizing with ethanol to obtain 4g of 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 the reaction solution and evaporating 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, and after 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
1.7g of Compound V are dissolved in 17mL of methanol, 1g of tributylphosphine are added, stirring is carried out at 70 ℃ for 2 hours, and the crude product is concentratedPurifying with chromatographic column to obtain 0.8g of gatifloxacin metabolite VI, MS:350[ mu ] M + H + ]Yield 42%.
HPLC:99.5％, 1 H 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(-NH 2 ,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 (8)
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 organic base, reacting with methylsulfonyl chloride or p-toluenesulfonyl chloride for 2 hours at room temperature, wherein the molar dosage ratio of the compound (II) to the methylsulfonyl chloride or the p-toluenesulfonyl chloride is 1 (1-5), and the molar dosage ratio of the compound (II) to the organic base is 1 (1-6), and treating to obtain a methylsulfonate compound (III) or a p-toluenesulfonate active ester compound;
(3) Mixing the compound (III) or 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) or p-toluenesulfonic acid active ester compound to trimethylsilylazide is 1 (2-8), and reacting at 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. 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 a gatifloxacin metabolite according to claim 1, wherein the reaction solvent in the step (2) is dry THF or dry chloroform, the organic base is triethylamine or diisopropylethylamine, and the molar ratio of the compound (ii) to methanesulfonyl chloride or p-toluenesulfonyl chloride is 1.
5. The method for synthesizing a gatifloxacin metabolite according to claim 4, wherein the reaction solvent in the step (2) is dry THF.
6. The method for synthesizing a gatifloxacin metabolite according to claim 1, wherein the molar ratio of the compound (iii) to the trimethylsilylazide in the step (3) is 1.
7. 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 ℃.
8. The method for synthesizing gatifloxacin metabolite according to claim 7, wherein the tertiary phosphine in step (4) is triphenylphosphine, the molar ratio of the compound (iv) to the tertiary phosphine is 1.
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Non-Patent Citations (3)
| Title |
|---|
| A digitized impurity database analysis method for determining the impurity profiles of gatifloxacin in bulk materials and injections;Zhang Dousheng，等;《Pharmazie》;20121231;827-833 * |
| Single- and Multiple-Dose Pharmacokinetics of AM-1155, a New 6-Fluoro-8-Methoxy Quinolone, in Humans;MITSUYOSHI NAKASHIMA，等;《ANTIMICROBIAL AGENTS AND CHEMOTHERAPY》;19951231;2635-2640 * |
| Spectral correlation of high-performance liquid chromatography-diode array detection data from two independent chromatographic runs Peak tracking in pharmaceutical impurity profiling;Wei Li，等;《Journal of Chromatography A》;20080306;141-149 * |
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