CN114478391A - Ornidazole ester prodrug, pharmaceutical composition, preparation method and application thereof - Google Patents

Ornidazole ester prodrug, pharmaceutical composition, preparation method and application thereof Download PDF

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CN114478391A
CN114478391A CN202011152826.1A CN202011152826A CN114478391A CN 114478391 A CN114478391 A CN 114478391A CN 202011152826 A CN202011152826 A CN 202011152826A CN 114478391 A CN114478391 A CN 114478391A
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CN114478391B (en
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沙向阳
郑枫
孙蕴哲
叶仕春
尹德艳
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members 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
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Abstract

The invention discloses an ornidazole ester prodrug, a pharmaceutical composition, a preparation method and application thereof. The hydroxyl of racemic ornidazole is subjected to derivatization, a series of ornidazole ester prodrugs are designed and prepared, and in vitro plasma tests show that the compound has good pharmacokinetic properties. And the physical and chemical stability of the compound is high, for example, the purity of the compound is basically kept unchanged in a high-temperature test (standing for 6-13 days at 60 ℃).

Description

Ornidazole ester prodrug, pharmaceutical composition, preparation method and application thereof
Technical Field
The invention relates to an ornidazole ester prodrug, a pharmaceutical composition, a preparation method and application thereof, and belongs to the field of pharmaceutical chemistry.
Background
Ornidazole (Ornidazole) is a third-generation nitroimidazole antibiotic developed by Roche, and has an inhibiting effect on anaerobic bacteria infection, protozoan infection, trichomonas infection and the like. The ornidazole has long drug effect duration, the half-life period of plasma elimination is 14.4 hours, which is higher than 8.4 hours of the ornidazole and 12.7 hours of the tinidazole, the frequency of taking the drug by a patient can be reduced, and the ornidazole is convenient to use; after the ornidazole is introduced into clinic, researchers find that compared with nitroimidazoles such as tinidazole, metronidazole and the like, the product has more obvious anti-infection advantages. The mutagenic and teratogenic effects are lower than those of metronidazole and tinidazole; in the aspect of resisting anaerobic bacteria infection, the minimum bacteriostatic concentration and the minimum bactericidal concentration are both less than metronidazole and tinidazole, and the curative effect of the medicine is better than that of the metronidazole and tinidazole.
The preparation of the l-ornidazole as an injection is researched and developed by Nanjing Sheng and pharmaceutical industry in 2009 bottom, the l-ornidazole is an l-form body of the ornidazole, is a type 1 new medicament independently researched and developed in China, and has better anti-anaerobe and anti-protozoan effects. At present, the oral solid preparation of the levoornidazole is also on the market.
The disodium levoornidazole phosphate is the sodium salt of the L-isomer phosphate derivative of ornidazole, and is a prodrug of the marketed levoornidazole. The problem of poor water solubility of the levoornidazole is solved by the disodium levoornidazole phosphate, but the disodium levoornidazole phosphate is unstable in an aqueous solution and can only be prepared into a freeze-dried preparation to solve the stability of the preparation in storage, but the stability in use cannot be solved; the literature reports that the problem of pain at the injection site is not solved by the preparation of the disodium levoornidazole phosphate, probably because the local sodium ion concentration is too high or the high-concentration levoornidazole is generated by the rapid hydrolysis of the disodium levoornidazole phosphate, and the aim of improvement is not achieved. Therefore, on the basis of the research of the existing levoornidazole, the necessity of further modifying the levoornidazole exists.
Disclosure of Invention
The invention aims to provide an ornidazole ester prodrug, a pharmaceutical composition, a preparation method and application thereof.
The invention is mainly realized by the following technical scheme:
in the invention, a series of ester prodrugs are designed and prepared by derivatizing the hydroxyl of the racemic ornidazole or the levoornidazole and are prepared into the fat emulsion injection preparation, thereby overcoming some problems in the existing clinical application of ornidazole, and achieving the purposes of prolonging half-life period, improving stability, improving drug effect or reducing toxic and side effects and the like.
One of the purposes of the invention is to provide an ornidazole ester prodrug, namely a compound with a structure shown in a structural formula (1), a racemate, a stereoisomer, a pharmaceutically acceptable salt or a solvate thereof,
Figure BDA0002741706670000021
in the formula (1), R1，R2And R3Identical or different, independently of one another, from hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-8Cycloalkyl, 5-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl; wherein said C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C1-10Alkoxy radical, C3-8Cycloalkyl radical, C3-8Cycloalkyloxy, 5-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl groups may optionally be substituted with one, two or more halogen, hydroxy, amino, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Alkoxy, optionally substituted by C1-10Alkyl substituted C6-10Aryl or optionally substituted by C1-10Alkyl-substituted 5-10 membered heteroaryl; 0 ≦ n ≦ 6, n being an integer.
According to an embodiment of the present invention, in the structural formula (1), R1，R2And R3Identical or different, independently of one another, from hydrogen, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-8Cycloalkyl, 5-8 membered heterocyclyl, C6-8Aryl and 5-8 membered heteroaryl; wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radicalBase, C3-8Cycloalkyl radical, C3-8Cycloalkyloxy, 5-8 membered heterocyclyl, C6-8Aryl and 5-8 membered heteroaryl groups may optionally be substituted with one, two or more halogen, hydroxy, amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, optionally substituted by C1-6Alkyl substituted C6-8Aryl or optionally substituted by C1-6Alkyl-substituted 5-8 membered heteroaryl.
According to an embodiment of the present invention, in the structural formula (1), R1，R2And R3Identical or different, independently of one another, from hydrogen, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and C1-6Alkoxy, wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and C1-6Alkoxy groups may optionally be substituted by one, two or more fluorine, chlorine, bromine, iodine, hydroxy, amino or optionally by C1-6Alkyl substituted phenyl substituted.
According to an embodiment of the present invention, in the structural formula (1), R1Is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl; r2Hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl; r is3Is methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, methoxy, ethoxy, isopropoxy, tert-butoxy, isobutoxy.
According to an embodiment of the invention, the compound represented by structural formula (1) is selected from the following compounds:
Figure BDA0002741706670000031
according to an embodiment of the present invention, the compound represented by the structural formula (1) is further preferably selected from the following compounds and levorotatory enantiomer thereof, i.e., an isomer having the S configuration at the carbon at position 1. The levorotatory enantiomer of the compound is shown below:
Figure BDA0002741706670000032
the other purpose of the invention is to provide a preparation method of the ornidazole derivative.
The invention provides a preparation method of a compound shown in a structural formula (1), and a racemate, a stereoisomer, a pharmaceutically acceptable salt or a solvate thereof.
According to an embodiment of the present invention, the preparation of the compound represented by structural formula (1) includes the step of reacting compound 1 with compound 2, which is represented by the following reaction formula:
Figure BDA0002741706670000041
wherein, the compound 1 is selected from racemic ornidazole with R configuration or S configuration; the compound 2 is a halogenated organic carbonate structure, R1、R2、R3Are each independently defined as hereinbefore; x is selected from chlorine, bromine or iodine.
The synthesis method comprises the following steps:
at a certain temperature, a certain amount of ornidazole and an acid-binding agent are put into a reaction vessel, a proper amount of reaction solvent is added for mixing, then the compound 2 is slowly added into the reaction vessel, and after the addition is finished, the reaction liquid is stirred and reacts for a period of time at a certain temperature. And during post-reaction treatment, extracting the reaction solution, washing, drying, concentrating and performing column chromatography to obtain the target compound.
The invention also provides a preparation method of the compound 2, when X in the structure of the compound 2 is chlorine or iodine, R1Is alkyl, R2Is hydrogen, R3When the alkoxy is adopted, the reaction formula is as follows:
Figure BDA0002741706670000042
the synthesis method comprises the following steps:
a) reacting the compound 2-1 with triphosgene to obtain a compound 2-2 in the form of chloroformate;
b) transformingCompound 2-2 with alcohol R3-OH reaction to give a chlorinated organic carbonate, compound 2(X ═ Cl);
c) reacting compound 2(X ═ Cl) with NaI to give iodoorganic carbonate, compound 2(X ═ I);
when X in the structure of the compound 2 is bromine, R1Is alkyl, R2Is hydrogen, R2When the alkoxy is adopted, the reaction formula is as follows:
Figure BDA0002741706670000043
the synthesis method comprises the following steps:
a) compound 2-3 (organic carbonic acid diester) is reacted with dibromohydantoin to give a bromo organic carbonate, compound 2(X ═ Br).
According to an embodiment of the present invention, the reaction may be carried out in the presence of a solvent; the solvent is at least one selected from acetone, dichloromethane, trichloromethane, carbon tetrachloride and diethyl ether;
according to embodiments of the invention, the reaction may be carried out in the presence of an acid-binding agent, such as a base; the acid-binding agent is selected from pyridine, triethylamine, DIEA, DBU, NaOH, KOH, K2CO3、KHCO3、NaCO3And NaHCO3At least one of (1).
According to an embodiment of the present invention, the reaction time of the preparation method is 0.5 to 3 hours, for example, 1 to 2 hours.
According to an embodiment of the invention, in said step a), compound 2-1 is placed in a low temperature environment and in N2And (3) carrying out reaction under protection. Further, the method comprises the steps of extracting under reduced pressure (absorbing the extracted gas with alkali liquor) and concentrating the residual solution under reduced pressure at room temperature to remove the solvent, and then obtaining the compound 2-2 by a distillation method.
According to an embodiment of the present invention, in said step b), the compound 2-2 is reacted with an alcohol under anhydrous and oxygen-free solvent conditions. Preferably, under ice bath conditions, an acid-binding agent is added thereto to obtain compound 2.
According to an embodiment of the invention, the method further comprises a post-treatment step. For example, the reaction solution is washed, dried and concentrated under reduced pressure to obtain compound 2.
According to an embodiment of the present invention, the preparation of the compound represented by structural formula (1) includes a step of reacting compound 3 with compound 4 or compound 5, which is represented by the following reaction formula:
Figure BDA0002741706670000051
the synthesis method comprises the following steps:
at a certain temperature, taking a certain amount of compound 3 into a reaction container, adding a proper amount of reaction solvent for dissolving, replacing air in the reaction container by gases such as argon or nitrogen for 2-3 times, slowly adding DIABL-H, stirring for a period of time after the addition is finished, then slowly and sequentially adding an acid-binding agent and compound 4 or 5, and stirring for a period of time at a certain temperature after the addition is finished. And during post-reaction treatment, extracting the reaction solution, washing, drying, concentrating and performing column chromatography to obtain the target compound.
According to an embodiment of the invention, the reaction temperature of the preparation method is-80-50 ℃, for example-80-30 ℃; the reaction time is 1 to 16 hours, for example 2 to 6 hours.
According to an embodiment of the invention, the preparation method further comprises a post-treatment step. Such as concentrating the reaction solution to remove the solvent, washing, concentrating or distilling to obtain the product.
According to an embodiment of the invention, the acid scavenger used may be an inorganic base such as NaOH, KOH, K2CO3、KHCO3、NaCO3、NaHCO3Or an organic base such as one or more of triethylamine, pyridine, DMAP, DIEA, DBU; the reaction solvent can be one or more of acetone, dichloromethane, trichloromethane, carbon tetrachloride, tetrahydrofuran, acetonitrile, DMF, DMAc or diethyl ether; the phase transfer catalyst used may be tetrabutylammonium bromide, 18-crown-6, etc.
The present invention also provides a process for producing compound 3, comprising the step of reacting compound 1 with compound 3-1 or compound 3-2, according to the following reaction formula:
Figure BDA0002741706670000061
wherein, the compound 1 is selected from racemic ornidazole with R configuration or S configuration; r1Is alkyl, R3Is an alkyl group; x is selected from chlorine or bromine.
The synthesis method comprises the following steps:
at a certain temperature, a certain amount of ornidazole and an acid-binding agent are put into a reaction vessel, a proper amount of reaction solvent is added for mixing, gas such as argon or nitrogen replaces the air in the reaction vessel for 2-3 times, then, a compound 3-1 or 3-2 is slowly added into the reaction vessel, and after the addition is finished, the reaction solution is stirred and reacts for a period of time at a certain temperature. And during post-reaction treatment, extracting the reaction solution, washing, drying, concentrating and performing column chromatography to obtain the target compound 3.
According to an embodiment of the present invention, an acylation catalyst such as DMAP or the like may be added to the above reaction or heating may be performed to accelerate the progress of the reaction.
According to an embodiment of the invention, the reaction temperature of the preparation method is-5 to 80 ℃, for example 0 to 50 ℃; the reaction time is 1 to 8 hours, for example, 2 to 6 hours.
According to an embodiment of the invention, the preparation method further comprises a post-treatment step. Such as concentrating the reaction solution to remove the solvent, washing, concentrating or distilling to obtain the product.
According to an embodiment of the invention, the acid scavenger used may be an inorganic base such as NaOH, KOH, K2CO3、KHCO3、NaCO3、NaHCO3Or an organic base such as one or more of triethylamine, pyridine, DMAP, DIEA, DBU; the reaction solvent can be one or more of acetone, dichloromethane, trichloromethane, carbon tetrachloride, tetrahydrofuran, acetonitrile, DMF, DMAc or diethyl ether; the phase transfer catalyst used may be tetrabutylammonium bromide, 18-crown-6, etc.
The invention also provides application of the compound shown in the structural formula (1), racemate, stereoisomer, pharmaceutically acceptable salt or solvate thereof, or solvate of pharmaceutically acceptable salt thereof in preparation of medicines.
According to an embodiment of the invention, the medicament may be used for the treatment of one or more of the following diseases: the medicine is used for treating bacteroides fragilis, bacteroides dieldii, bacteroides ovatus, bacteroides thetaiotaomicron, bacteroides vulgatus, clostridium, eubacterium, digestive coccus and digestive streptococcus, helicobacter pylori, bacteroides melanosporum, clostridium, CO2And a plurality of infectious diseases caused by sensitive anaerobes such as the bacteriophage phagocytosis and the gingival bacteroides.
The fourth purpose of the invention is to provide a pharmaceutical composition containing the compound shown in the structural formula (1), racemate, stereoisomer, pharmaceutically acceptable salt or solvate thereof, or pharmaceutically acceptable salt solvate thereof.
According to an embodiment of the invention, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient. The pharmaceutical composition can be oral preparations, such as tablets, capsules, granules and the like, and can also be injections, eye drops, gels, creams, ointments, cataplasms and the like.
The pharmaceutical composition of the present invention may be administered by injection route. The injection route comprises intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection and the like. The pharmaceutical composition can be prepared into preparations suitable for injection administration, such as injection, injection emulsion, powder injection and the like; the injection emulsion can be fat emulsion injection.
The present invention also provides a fat emulsion injection comprising: a compound shown in a structural formula (1), a racemate, a stereoisomer, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt solvate thereof, an oily substance and an emulsifier.
Suitable oily substances for use in the present invention are injectable oil esters selected from soybean oil, safflower oil, cottonseed oil, olive oil, sesame oil, coconut oil, castor oil, sea buckthorn oil, evening primrose oil, corn oil, brucea javanica oil, perilla oil, grape seed oil, tea oil, palm oil, peanut oil, medium chain oil (medium chain triglycerides), long chain triglycerides, ethyl oleate, acetylated monoglycerides, propylene glycol diesters, glycerol linoleate or glycerol laureate polyethylene glycol, or a combination of two or more thereof.
According to an embodiment of the invention, the emulsifier is selected from natural emulsifiers, such as soya lecithin, egg lecithin, hydrogenated lecithin, saturated and unsaturated C12-18One, a combination of two or more of fatty acyl phosphatidylcholines; egg yolk lecithin and/or soybean lecithin, or synthetic nonionic emulsifier such as Tween-80, poloxamer-188 or their combination.
According to the embodiment of the invention, other pharmaceutically acceptable auxiliary materials such as a co-emulsifier, an osmotic pressure regulator, a pH regulator, an antioxidant, a stabilizer, a metal chelating agent and the like can be further added into the fat emulsion injection according to needs.
The coemulsifier is oleic acid, sodium oleate, cholesterol, cholic acid, sodium cholate, sodium deoxycholate, sodium glycocholate or egg yolk phosphatidylglycerol (EPG), or a combination of two or more thereof.
The isotonicity adjusting agent is selected from glycerol, sorbitol, glucose, maltose, mannitol or propylene glycol, or a combination of two or more thereof.
The pH adjuster is selected from sodium hydroxide, hydrochloric acid, phosphoric acid, phosphate, citric acid, citrate, citric acid, acetic acid, acetate, glycine, or lysine, or a combination of two or more thereof; according to the embodiment of the invention, the pH value is adjusted to be between 5.5 and 8.5 by the pH adjusting agent, and is preferably between 6.0 and 8.0.
The antioxidant is selected from sodium sulfite, sodium bisulfite or sodium metabisulfite, or a combination of two or more thereof.
The stabilizer is one or a combination of two or more selected from oleic acid, phosphatidylglycerol and sodium oleate.
The metal chelating agent is Ethylene Diamine Tetraacetic Acid (EDTA) or ethylene diamine tetraacetic acid sodium salt (EDTA-Na), in particular ethylene diamine tetraacetic acid disodium salt.
According to an embodiment of the present invention, the fat emulsion injection may be a fat emulsion injection or a lyophilized milk. Wherein the fat emulsion injection further comprises water for injection. Freeze-drying the fat emulsion injection to obtain freeze-dried emulsion; before freeze drying, a freeze-drying protective agent can be added into the fat emulsion injection, and the freeze-drying protective agent can be one, two, three or more of lactose, sucrose, mannitol, dextran 20, dextran 40, dextran 70, xylitol, sorbitol and trehalose.
The fat emulsion injection prepared by the invention is suitable for being administrated by a parenteral administration mode, and the parenteral administration comprises intravenous injection, intra-arterial injection, subcutaneous injection, intraperitoneal injection or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intracerebroventricular, administration. The administration may be parenteral in a single bolus form, or may be by, for example, a continuous infusion pump. Or intracranial, e.g., intrathecal or intracerebroventricular, administration; common containers for injections include glass ampoules, vial vials, plastic ampoules, pre-filled syringes, and the like.
The fat emulsion injection contains 0.01-400 mg of active ingredients per milliliter; preferably 5 to 300 mg of active ingredient per ml; most preferred are unit mass preparations containing 10 to 200 mg of active ingredient per ml.
The average particle size of the fat emulsion injection is within the range of 10-1000nm, such as 20-800nm, 30-500nm, 40-400nm, 50-300nm and the like.
The invention also provides a preparation method of the fat emulsion injection, which comprises the following steps: uniformly mixing a compound shown in a structural formula (1), a racemate, a stereoisomer, a pharmaceutically acceptable salt or a solvate thereof, or a pharmaceutically acceptable salt solvate and an emulsifier with an oil phase substance to obtain an oil phase; dispersing optional coemulsifier, osmotic pressure regulator, antioxidant, stabilizer, metal chelating agent and freeze-drying protective agent into a proper amount of water for injection to obtain a water phase; mixing the oil phase and the water phase, and emulsifying to obtain primary emulsion; and then, adding water for injection to fix the volume, further emulsifying, and adding a pH regulator to regulate the pH to obtain the fat emulsion injection.
According to an embodiment of the present invention, the method for preparing the fat emulsion injection further optionally comprises the step of freeze-drying the fat emulsion injection to obtain a freeze-dried milk.
Has the advantages that:
(1) the hydroxyl of racemic ornidazole is subjected to derivatization, a series of ornidazole ester prodrugs are designed and prepared, and in vitro plasma tests show that the compound can be converted into active ingredient levoornidazole faster than a control compound within 24 hours, so that the compound has good pharmacokinetic properties.
(2) The main pharmacological activity of ornidazole comes from l-ornidazole, the l-ornidazole is used as a raw material to directionally synthesize a (1S) configuration l-ornidazole derivative, namely a prodrug, and further tests show that the l-corresponding isomer of the ornidazole prodrug can keep high stability of related substances in an oil phase in a high-temperature test (standing at 60 ℃ for 6-13 days).
(3) Further tests show that the compound Tween 80 physiological saline solution is mainly degraded to generate the levoornidazole in the process of placing at room temperature and 40 ℃, compared with the compound, the compound levoornidazole disodium phosphate Tween 80 physiological saline solution is mainly degraded to generate unknown impurities in the process of placing at room temperature and 40 ℃, which indicates that the aqueous solution is poor in stability and is degraded at room temperature, so that the medication safety is influenced.
(4) The side chains of the ornidazole derivatives prepared by the invention contain alkyl carboxylate and alkyl carbonate structures, so that the fat solubility is improved; the structural compound has certain lipid solubility, can be dissolved in oily substances to prepare fat emulsion injection, and the injection routes comprise intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, acupoint injection and the like.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of Compound N1 (S).
FIG. 2 is a graph showing the degradation of related compounds in human plasma.
FIG. 3 is a graph showing the levels of the corresponding active metabolites produced by the metabolism of related compounds in human plasma.
FIG. 4 is a liquid chromatogram of a sample taken from a Tween physiological saline solution at 40 ℃ for 1 day, which is prepared by dissolving Compound N1(S) of the present invention in the solution.
Fig. 5 is a liquid chromatogram of the levoornidazole and the disodium levoornidazole phosphate (the retention time of the levoornidazole relative to the disodium levoornidazole phosphate is 1.1).
FIG. 6 is a liquid chromatogram of the sample for detecting the related substances when the disodium levoornidazole phosphate is placed in the Tween physiological saline solution for 1 day at 40 ℃.
Detailed Description
The present invention is further described in detail below with reference to specific examples and figures, which are intended to be illustrative, not limiting, and are not intended to limit the scope of the invention, as the materials used may be commercially or commercially available without further elaboration.
Abbreviations used in this context have the following meanings: DCM: dichloromethane; py: pyridine; DMAP: 4-dimethylaminopyridine; DCC: dicyclohexylcarbodiimide; TBAB: 4-butylammonium bromide.
Example 1 synthesis of compound N1 (S):
Figure BDA0002741706670000101
compound N1(S) intermediate 1 was synthesized first: levoornidazole (5.036g,22.93mmol) was weighed into a bottle, 20ml of DCM was added and dissolved under stirring at room temperature, Py (3.609g,45.62mmol) and DMAP (2.811g,23.01mmol) were weighed into a reaction bottle in turn, finally acetic anhydride (3.514g,34.42mmol) was weighed and slowly dropped into the reaction bottle, stirring was maintained for 1h, and TLC was monitored until the starting material disappeared. After-treatment, 50ml of water and 30ml of DCM are added for extraction and liquid separation, an organic layer is extracted and then is respectively added with 50ml of saturated NaHCO3Washing with saturated salt solution, anhydrous Na2SO4Drying and then concentration under reduced pressure gave a white solid (4.367g,16.69mmol) with a yield of 72.8%.
Synthesis of compound N1 (S): weighing compound 1, intermediate 1(1.056g,4.04mmol) and adding into a bottle, adding DCM6ml and stirring to dissolve at room temperature, replacing reaction bottle with Ar gas for 3 times, and reactingMoving the flask into a cold trap, stirring at-78 ℃, slowly dropping (1.162g,8.17mmol) diisobutylaluminum hydride into the reaction flask, keeping stirring for 1h after dropping, weighing Py (0.965g,12.20mmol), DMAP (1.004g,8.22mmol) respectively, diluting with 2ml DCM, slowly dropping into the reaction flask, weighing acetic anhydride (2.496g,24.45mmol) into the reaction flask, keeping stirring for 20h, starting the post-treatment, adding DCM 40ml and saturated NH4Extracting with Cl 50ml, separating, collecting organic layer, washing the organic layer with 50ml water and saturated salt water, and collecting anhydrous Na2SO4Drying, rotary steaming to obtain oily substance, separating with silica gel column chromatography, using n-hexane: ethyl acetate 4: 1, and concentrating by rotary evaporation to obtain the final product (0.272g,0.89mmol) g with the yield of 22.0%.
1H NMR(400MHz,CDCl3)δ7.97(d,1H,J＝11.3Hz),δ5.82-5.44(m,1H),δ4.73-4.60(m,1H),δ4.38-4.09(m,2H),δ3.76-3.64(m,2H),δ2.53(s,3H),δ1.90(d,3H,J＝95.0Hz),δ1.25(dd,3H,J＝5.3Hz，J＝69.2Hz)；
ESI-MS m/z＝306.0,[M+H]+
Example 2 synthesis of compound N3 (S):
Figure BDA0002741706670000111
compound N3(S) intermediate 1 was synthesized first: weighing levoornidazole (6.012g,27.37mmol), adding DCM 20ml, stirring and dissolving at room temperature, weighing Py (4.319g,54.60mmol) and DMAP (3.313g,27.12mmol) and sequentially adding into a reaction bottle, finally weighing propionic anhydride (5.310g,40.80mmol) and slowly dropping into the reaction bottle, keeping stirring for 1h, and monitoring by TLC until the raw materials disappear. After-treatment, 50ml of water and 30ml of DCM are added for extraction and separation, an organic layer is extracted and then is respectively added with 50ml of saturated NaHCO3Washing with saturated salt solution, anhydrous Na2SO4Drying and then concentration under reduced pressure gave a white solid (5.571g,20.21mmol) with a yield of 73.8%.
Synthesis of compound N3 (S): weighing compound 2, adding intermediate 1(1.104g,4.00mmol) into a bottle, adding DCM6ml, stirring and dissolving at room temperature, replacing the reaction bottle with Ar gas for 3 times, moving the reaction bottle into a cold trap, and stirring at-78 DEG CStirring, slowly dropping (1.145g,8.05mmol) diisobutylaluminum hydride into a reaction flask, keeping stirring for 1h after dropping, weighing Py (0.956g,12.09mmol) and DMAP (0.997g,8.16mmol) respectively, diluting with 2ml DCM, slowly dropping into the reaction flask, weighing acetic anhydride (2.439g,23.89mmol) again after dropping, keeping stirring for 20h, starting aftertreatment, adding DCM 40ml and saturated NH4Extracting with Cl 50ml, separating, collecting organic layer, washing the organic layer with 50ml water and saturated salt water, and collecting anhydrous Na2SO4Drying, rotary steaming to obtain oily substance, separating with silica gel column chromatography, using n-hexane: ethyl acetate 4: 1, and concentrating by rotary evaporation to obtain the final product (0.325g,1.02mmol) g with a yield of 25.5%.
1H NMR(400MHz,CDCl3)δ7.97(d,1H,J＝11.2Hz),δ5.78-5.42(m,1H),δ4.71-4.58(m,1H),δ4.36-4.07(m,2H),δ3.74-3.62(m,2H),δ2.53(s,3H),δ1.90(d,3H,J＝95.0Hz),δ1.38-1.16(m,2H),δ0.95-0.89(m,3H)；
ESI-MS m/z＝320.0,[M+H]+
Example 3 synthesis of compound N7 (S):
Figure BDA0002741706670000112
compound N7(S) intermediate 1 was synthesized first: levoornidazole (5.036g,22.93mmol) was weighed into a bottle, 20ml of DCM was added and dissolved under stirring at room temperature, Py (3.609g,45.62mmol) and DMAP (2.811g,23.01mmol) were weighed into a reaction bottle in turn, finally acetic anhydride (3.514g,34.42mmol) was weighed and slowly dropped into the reaction bottle, stirring was maintained for 1h, and TLC was monitored until the starting material disappeared. After-treatment, 50ml of water and 30ml of DCM are added for extraction and separation, an organic layer is extracted and then is respectively added with 50ml of saturated NaHCO3Washing with saturated salt solution, anhydrous Na2SO4Drying and then concentration under reduced pressure gave a white solid (4.367g,16.69mmol) with a yield of 72.8%.
Synthesis of compound N7 (S): weighing compound 3, adding intermediate 1(1.214g,4.64mmol) into a bottle, adding DCM6ml, stirring and dissolving at room temperature, replacing reaction bottle with Ar gas for 3 times, moving reaction bottle into a cold trap, stirring at-78 deg.C, adding (1.324g,9.31mmol) bisSlowly dropping isobutylaluminum hydride into the reaction bottle, keeping stirring for 1h after dropping, weighing Py (1.104g,13.96mmol), DMAP (1.141g,9.34mmol) respectively diluting with 2ml DCM, slowly dropping propionic anhydride (3.717g,28.56mmol), dropping propionic anhydride into the reaction bottle, keeping stirring for 20h, starting after-treatment, adding DCM 40ml, saturated NH4Extracting with Cl 50ml, separating to obtain organic layer, washing the organic layer with 50ml water and saturated salt water, and collecting anhydrous Na2SO4Drying, rotary steaming to obtain oily substance, separating with silica gel column chromatography, using n-hexane: ethyl acetate 4: 1, and concentrating by rotary evaporation to obtain the final product (0.356g,1.11mmol) g with a yield of 24.0%.
1H NMR(400MHz,CDCl3)δ7.96(d,1H,J＝11.1Hz),δ5.82-5.43(m,1H),δ4.75-4.62(m,1H),δ4.38-4.09(m,2H),δ3.76-3.64(m,2H),δ2.55(s,3H),δ2.03-1.77(m,2H,J＝95.0Hz),δ1.27(dd,2H,J＝5.4Hz，J＝69.8Hz),δ1.12-1.06(m,3H)；
ESI-MS m/z＝320.0,[M+H]+
Example 4 synthesis of compound N8 (S):
Figure BDA0002741706670000121
compound N8(S) intermediate 1 was synthesized first: weighing levoornidazole (6.012g,27.37mmol), adding DCM 20ml, stirring and dissolving at room temperature, weighing Py (4.319g,54.60mmol) and DMAP (3.313g,27.12mmol) and sequentially adding into a reaction bottle, finally weighing propionic anhydride (5.310g,40.80mmol) and slowly dropping into the reaction bottle, keeping stirring for 1h, and monitoring by TLC until the raw materials disappear. After-treatment, 50ml of water and 30ml of DCM are added for extraction and separation, an organic layer is extracted and then is respectively added with 50ml of saturated NaHCO3Washing with saturated salt solution, anhydrous Na2SO4Drying and then concentration under reduced pressure gave a white solid (5.571g,20.21mmol) with a yield of 73.8%.
Synthesis of compound N8 (S): weighing compound 4, intermediate 1(1.078g,3.91mmol), adding into a bottle, adding DCM6ml, stirring and dissolving at room temperature, replacing the reaction bottle with Ar gas for 3 times, moving the reaction bottle into a cold trap, stirring at-78 ℃, and adding (1.119g,7.87mmol) diisobutylSlowly dropping aluminum hydride into the reaction bottle, keeping stirring for 1h after dropping, weighing Py (0.929g,11.75mmol), DMAP (0.965g,7.90mmol) respectively diluting with 2ml DCM, slowly dropping into the reaction bottle, weighing propionic anhydride (3.065g,23.55mmol) again after dropping, keeping stirring for 20h, starting after-treatment, adding DCM 40ml and saturated NH4Extracting with Cl 50ml, separating, collecting organic layer, washing the organic layer with 50ml water and saturated salt water, and collecting anhydrous Na2SO4Drying, rotary distilling to obtain oily substance, separating with silica gel column chromatography, and separating with n-hexane: ethyl acetate 4: 1, and concentrating by rotary evaporation to obtain the final product (0.404g,1.21mmol) with a yield of 30.9%.
1H NMR(400MHz,CDCl3)δ7.98(d,1H,J＝11.1Hz),δ5.84-5.45(m,1H),δ4.76-4.63(m,1H),δ4.39-4.11(m,2H),δ3.77-3.66(m,2H),δ2.56(s,3H),δ2.05-1.80(m,2H,J＝96.1Hz),δ1.40-1.18(m,2H),δ1.14-1.08(m,3H),δ0.99-0.92(m,3H)；
ESI-MS m/z＝334.1,[M+H]+
Example 5 synthesis of compound N9 (S):
Figure BDA0002741706670000131
synthesis of 1-iodoethyl ethyl carbonate: 1-chloroethyl ethyl carbonate (2.064g,13.53mmol) was weighed into a dry 100ml two-necked reaction flask, and anhydrous NaI (1.704g,11.37mmol), TBAB (0.087g,0.27mmol), anhydrous CaCl were added2(0.494g,4.45mmol) and ethyl acetate 10ml, heated to 80 ℃ and reacted under reflux for 3 h. Adding water into a reaction bottle, shaking, separating liquid, washing an EA layer with saturated salt solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain brown oily substance which is directly used for the next reaction without purification.
Synthesis of compound N9 (S): levoornidazole (1.627g,7.41mmol) is weighed and added into a bottle, 10ml of acetone is used for stirring and dissolving, 1-iodoethyl ethyl carbonate (2.701g,11.07mmol), anhydrous potassium carbonate (0.820g,5.93mmol) and TBAB (0.048g,0.15mmol) are added, and the mixture is transferred to a water bath at 40 ℃ after the addition is finished and stirred for 5 hours. Post-treating, adding 50ml water and 50ml ethyl acetate, extracting to obtain organic layerThen 5% NaHCO was used3Washing with water and saturated salt water, drying with anhydrous sodium sulfate, rotary steaming to obtain oily substance, separating with silica gel column chromatography, and separating with n-hexane: ethyl acetate 4: 1, and concentrating by rotary evaporation to obtain the final product (1.027g,3.06mmol) with a yield of 41.3%.
1H NMR(400MHz,CDCl3)δ7.96(s,1H),δ6.67-6.51(m,1H),δ5.67-5.56(m,1H),δ4.79-4.47(m,2H),δ4.15-4.09(m,2H),δ3.91-3.79(m,2H),δ2.53(s,3H),δ2.07-2.02(m,3H),δ1.36-1.32(m,3H)；
ESI-MS m/z＝336.1,[M+H]+
Example 6 synthesis of compound N10 (S):
Figure BDA0002741706670000141
synthesis of 1-iodoethyl isopropyl carbonate: 1-chloroethyl isopropyl carbonate (2.046g,12.28mmol) was weighed into a dry 100ml two-necked reaction flask, and anhydrous NaI (1.706g,11.38mmol), TBAB (0.087g,0.27mmol), anhydrous CaCl were added2(0.517g,4.66mmol) and 10ml of ethyl acetate, and heated to 80 ℃ for reflux reaction for 3 hours. Adding water into a reaction bottle, shaking, separating liquid, washing an EA layer with saturated salt solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain brown oily substance which is directly used for the next reaction without purification.
Synthesis of compound N10 (S): weighing levoornidazole (1.586g and 7.22mmol), adding into a bottle, stirring with 10ml acetone to dissolve, adding 1-iodoethyl isopropyl carbonate (2.516g and 9.75mmol), anhydrous potassium carbonate (0.815g and 5.90mmol) and TBAB (0.058g and 0.18mmol), and moving to 40 ℃ water bath to stir for 5h after the addition is finished. Post-treatment, adding 50ml water and 50ml ethyl acetate, extracting to obtain organic layer, and adding 5% NaHCO into the organic layer3Washing with water and saturated salt water, drying with anhydrous sodium sulfate, rotary steaming to obtain oily substance, separating with silica gel column chromatography, and separating with n-hexane: ethyl acetate 4: 1, and concentrating by rotary evaporation to obtain the final product (0.990g,2.83mmol) with a yield of 39.2%.
1H NMR(400MHz,CDCl3)δ7.95(s,1H),δ6.68-6.52(m,1H),δ5.67-5.56(m,1H),δ4.79-4.48(m,2H),δ4.23-4.16(m,1H),δ3.90-3.78(m,2H),δ2.54(s,3H),δ2.11-2.05(m,3H),δ1.43-1.38(m,6H)；
ESI-MS m/z＝350.1,[M+H]+
Example 7 synthesis of compound N11 (S):
Figure BDA0002741706670000142
firstly, 1-chloropropyl chloroformate is synthesized by weighing triphosgene (10.030g,33.70mmol) and 100ml of three-necked reaction flask, adding 15ml of anhydrous dichloromethane, replacing the reaction flask with Ar gas for 3 times, and moving the reaction flask to a cold trap at-20 ℃ to stir continuously. Py (0.540g,6.83mmol) was measured, diluted with 5ml of methylene chloride, and charged into a reaction flask. Then n-propionaldehyde (4.602g,79.20mmol) was weighed and slowly added into the reaction flask, after dropping, the cold trap temperature was set to-20 ℃ and the reaction was continued for 20 h. The reaction flask containing the aqueous KOH solution was pumped down for 5min, then removed from the cold trap, concentrated under reduced pressure to remove DCM, and then distilled to give 3.91g of a colorless to pale yellow oil in 73.2% yield.
And (2) weighing 1-chloropropyl chloroformate (0.868g,5.53mmol) in a dry two-neck reaction bottle, adding 10ml of anhydrous DCM (DCM) and continuously stirring, weighing ethanol (0.310g,7.75mmol) and adding into the reaction bottle, transferring the reaction bottle into an ice-water bath and continuously stirring, weighing pyridine (0.522g,6.60mmol) and slowly adding into the reaction bottle, wherein white solid appears in the dropwise adding process, and after the dropwise adding is finished, moving the reaction bottle to room temperature and reacting for 1 h. 10ml of water was added to the reaction flask, the solution was separated, and the DCM layer was washed with 5% KHSO4Washing until the pH value is 3-4, then washing with water until the pH value is close to neutral, washing with saturated salt water, and drying with anhydrous sodium sulfate. Vacuum concentrating to obtain colorless oil 0.727g, and directly carrying out the next reaction without purification;
synthesis of 1-iodopropylethyl carbonate: 1-chloropropylethyl carbonate (0.727g,4.36mmol) was weighed into a dry 100ml two-neck reaction flask, added anhydrous NaI (0.579g,3.86mmol), TBAB (0.032g,0.10mmol), anhydrous CaCl2(0.171g,1.54mmol) and ethyl acetate 5ml, and heated to 80 ℃ for reflux reaction for 3 h. Adding water into a reaction bottle, shaking, separating liquid, washing an EA layer with saturated salt solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain brown oily substance which is directly used for the next reaction without purification.
Synthesis of compound N11 (S): weighing and adding the levoornidazole (0.602g,2.74mmol) into a bottle, stirring and dissolving the levoornidazole with 5ml of acetone, adding 1-iodopropyl ethyl carbonate (1.061g,4.11mmol), anhydrous potassium carbonate (0.303g,2.19mmol) and TBAB (0.026g,0.08mmol), and moving to a water bath at 40 ℃ after the addition is finished, and stirring for 5 hours. Post-treatment, adding water 25ml and ethyl acetate 25ml, extracting to obtain organic layer, and adding 5% NaHCO into the organic layer3Washing with water and saturated salt water, drying with anhydrous sodium sulfate, rotary steaming to obtain oily substance, separating with silica gel column chromatography, and separating with n-hexane: ethyl acetate 4: 1, and concentrating by rotary evaporation to obtain the final product (0.392g,1.12mmol) with a yield of 40.9%.
1H NMR(400MHz,CDCl3)δ7.96(s,1H),δ6.67-6.51(m,1H),δ5.69-5.59(m,1H),δ4.77-4.44(m,2H),δ4.16-4.11(m,2H),δ3.91-3.79(m,2H),δ2.54(s,3H),δ2.18-2.12(m,2H),δ1.37-1.31(m,3H)δ0.99-0.93(m,3H)；
ESI-MS m/z＝350.1,[M+H]+
Example 8 synthesis of compound N12 (S):
Figure BDA0002741706670000161
firstly, 1-chloropropyl chloroformate is synthesized by weighing triphosgene (10.030g,33.70mmol) and 100ml of three-necked reaction flask, adding 15ml of anhydrous dichloromethane, replacing the reaction flask with Ar gas for 3 times, and moving the reaction flask to a cold trap at-20 ℃ to stir continuously. Py (0.540g,6.83mmol) was measured, diluted with 5ml of methylene chloride, and charged into a reaction flask. Then n-propionaldehyde (4.602g,79.20mmol) was weighed and slowly added into the reaction flask, after dropping, the cold trap temperature was set to-20 ℃ and the reaction was continued for 20 h. The reaction flask containing the aqueous KOH solution was pumped down for 5min, then removed from the cold trap, concentrated under reduced pressure to remove DCM, and then distilled to give 3.91g of a colorless to pale yellow oil in 73.2% yield.
And (2) weighing 1-chloropropyl chloroformate (0.815g and 5.19mmol) in a dry two-neck reaction bottle, adding 10ml of anhydrous DCM (DCM) and continuously stirring, weighing isopropanol (0.453g and 7.54mmol) and adding the isopropanol into the reaction bottle, transferring the reaction bottle into an ice-water bath and continuously stirring, weighing pyridine (0.522g and 6.60mmol) and slowly adding the pyridine into the reaction bottle, wherein white solid appears in the dropwise adding process, and after the dropwise adding is finished, moving the reaction bottle to room temperature and reacting for 1 hour. The reaction flask was charged with 10ml of water, separated, and the DCM layer was washed with 5% KHSO4 to reach pH 3 to 4, then washed with water to near neutral, washed with saturated brine, and dried over anhydrous sodium sulfate. Vacuum concentrating to obtain colorless oily substance 0.746g, and directly carrying out next reaction without purification;
synthesis of 1-iodopropylethyl carbonate: 1-chloropropylethyl carbonate (0.746g,4.13mmol) was weighed into a dry 100ml two-necked reaction flask, anhydrous NaI (0.564g,3.76mmol), TBAB (0.032g,0.10mmol), anhydrous CaCl2(0.162g,1.46mmol) and ethyl acetate 5ml were added, and the mixture was heated to 80 ℃ for reflux reaction for 3 h. Adding water into a reaction bottle, shaking, separating liquid, washing an EA layer with saturated salt solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain brown oily substance which is directly used for the next reaction without purification.
Synthesis of compound N12 (S): weighing levoornidazole (0.560g,2.55mmol), adding into a bottle, stirring with 5ml acetone to dissolve, adding 1-iodopropyl ethyl carbonate (1.056g,3.88mmol), anhydrous potassium carbonate (0.290g,2.10mmol), TBAB (0.032g,0.10mmol), transferring to 40 deg.C water bath after adding, and stirring for 5 h. Post-treatment, adding water 25ml and ethyl acetate 25ml, extracting to obtain organic layer, and adding 5% NaHCO into the organic layer3Washing with water and saturated salt water, drying with anhydrous sodium sulfate, rotary steaming to obtain oily substance, separating with silica gel column chromatography, and separating with n-hexane: ethyl acetate 4: 1, and concentrating by rotary evaporation to obtain the final product (0.433g,1.22mmol) with a yield of 47.8%.
1H NMR(400MHz,CDCl3)δ7.95(s,1H),δ6.67-6.51(m,1H),δ5.69-5.59(m,1H),δ4.75-4.41(m,2H),δ4.14-4.07(m,2H),δ3.92-3.79(m,2H),δ2.55(s,3H),δ2.21-2.13(m,2H),δ1.54-1.48(m,2H)δ1.08-1.00(m,3H),δ0.89-0.83(m,3H)；
ESI-MS m/z＝364.1,[M+H]+
Example 9 synthesis of compound N13 (S):
Figure BDA0002741706670000171
synthesis of 1-chloro-1-methyl-ethyl ester isopropyl carbonate: chloroformate (2.514g,20.86mmol) was dissolved in 20ml of dry DCM, and isopropanol (1.262g,21.01mmol) and pyridine (1.754g,22.01mmol) were added in sequence to react at room temperature for 2 hours. The system was poured into 20ml of ice water, the organic phase was dried over sodium sulfate, filtered and the filtrate evaporated to dryness to give a colorless transparent liquid. To this liquid was added l0ml diethyl ether, then 50ml of 4N hydrochloric acid/diethyl ether was slowly added dropwise, and after the addition was completed, the mixture was stirred at room temperature overnight to distill off a colorless liquid (1.203g,6.66 mmol).
Synthesis of 1-iodo-1-methyl-ethyl ester isopropyl carbonate: 1-chloro-1-methyl-ethyl ester isopropyl carbonate (1.203g,6.66mmol) was weighed into a dry 100ml two-necked reaction flask and anhydrous NaI (838g,5.59mmol), TBAB (0.043g,0.15mmol), anhydrous CaCl were added2(0.250g,2.25mmol) and ethyl acetate 10ml, heated to 80 ℃ and reacted under reflux for 3 h. Adding water into a reaction bottle, shaking, separating liquid, washing an EA layer with saturated salt solution, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain brown oily substance which is directly used for the next reaction without purification.
Synthesis of compound N13 (S): levoornidazole (0.681g,3.10mmol) was weighed out and added to a bottle, dissolved with 10ml acetone under stirring, and 1-iodo-1-methyl-ethyl ester isopropyl carbonate (1.268g,4.66mmol), anhydrous potassium carbonate (0.815g,5.90mmol), TBAB (0.032g,0.10mmol) and after addition, transferred to a 40 ℃ water bath and stirred for 5 h. Post-treatment, adding 50ml water and 50ml ethyl acetate, extracting to obtain organic layer, and adding 5% NaHCO into the organic layer3Washing with water and saturated salt water, drying with anhydrous sodium sulfate, rotary evaporating to obtain oily substance, separating with silica gel column chromatography, and separating with n-hexane: ethyl acetate 4: 1, and concentrating by rotary evaporation to obtain the final product (0.320g,0.88mmol) with 28.4% yield.
1H NMR(400MHz,CDCl3)δ7.97(s,1H),δ6.82-6.61(m,1H),δ5.68-5.57(m,1H),δ4.80-4.48(m,2H),δ4.23-4.16(m,1H),δ3.90-3.78(m,2H),δ2.54(s,3H),δ2.22-2.14(m,6H),δ1.43-1.38(m,6H)；
ESI-MS m/z＝364.1,[M+H]+
Comparative example 1
Patent GB1453417A discloses a class of ornidazole derivatives, the general structure of which is as follows:
Figure BDA0002741706670000181
wherein R can be selected from alkyl, alkoxy, phenoxy, benzyloxy and the like.
The present invention is selected from the group consisting of comparative compound 1, wherein R is isopropyloxy, i.e., compound N2' (S), having the following structural formula:
Figure BDA0002741706670000182
synthesis of compound N2' (S): levoornidazole (2.010g,9.152mmol) was weighed into a bottle and dissolved with dichloromethane 15ml with stirring under argon. The mixture was transferred to an ice-water bath, triethylamine (1.843g,18.243mmol) was added, isopropyl chloride (1.606g,13.102mmol) was gradually added dropwise, and after the addition was completed, the mixture was transferred to room temperature and stirred for reaction for 1 hour. After-treatment, 50ml of water and 20ml of dichloromethane are added, the organic layer is extracted and then 5% NaHCO is added to the organic layer3The resulting mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to remove a part of the solvent, whereby a reddish brown liquid was obtained. Using n-hexane: the column was washed with a mixed solvent of ethyl acetate 3:1, and concentrated by rotary evaporation to give pale yellow crystals (2.187g,7.154mmol) with a yield of 78.1%.
1H NMR(400MHz,CDCl3)δ7.96(s,1H),δ5.27-5.33(m,1H),δ4.78-4.82(m,1H),δ4.70-4.76(m,1H),δ4.39-4.45(m,1H),δ3.83-3.88,1H),δ2.53(s,3H),δ1.18-1.26(m,6H)
Comparative example 2
The method disclosed in patent CN108409786A is used to prepare a disodium levoornidazole phosphate hydrate, which is a control compound 2 of the compound of the present invention, and the structural formula is as follows:
Figure BDA0002741706670000191
test example 1 metabolism study of the compound of the present invention in human plasma:
1.1 Experimental procedures: the compound N1(S) prepared in the examples and the control compound 1 prepared in comparative example 1 were used as controls to perform an enzymatic kinetics experiment in human plasma, the experimental procedure was as follows:
(1) preparing a pure acetonitrile stock solution of 40mM of the compound NX (X represents different compound numbers) of the invention and a pure acetonitrile stock solution of 40mM of a control compound 1;
(2) mixing human plasma of 1ml of ornidazole stock solution, vortexing for 30s, sampling 200 μ L, adding acetonitrile 800 μ L to settle protein, vortexing for 1min to stop reaction, and using as ornidazole control; 40mM of a compound of the invention, 40mM of a control compound 1 stock solution diluted 200-fold as a prodrug control;
(4) adding 100 mu L of the compound of the invention and a reference compound 1 pure acetonitrile stock solution into 4ml of human plasma, mixing, whirling for 30s, and placing in a constant-temperature oscillating water bath heater at 37 ℃ for 200rpm oscillation;
(5) sampling 200 μ L at different time points (0,30,60,120min), sampling 3 times at each time point, adding 800 μ L acetonitrile to settle protein, and vortexing for 1min to terminate the reaction; and making blank plasma contrast by the same method;
(6) centrifuging at 12000rpm at 4 deg.C for 10min, collecting supernatant 400ul, adding purified water 200ul, introducing sample 30 μ L (filtering membrane), and recording peak area change;
(7) the hydrolysis rates of compound NX of the invention and control compound 1 were observed and analyzed, and appropriate compounds of the invention were screened according to the data.
1.2 Experimental results: experimental studies found that the degradation rate was N1(S) > N2' (S); control compound 1 was hardly degraded in plasma; from the level of the compound metabolizing to generate the active metabolite S-ornidazole, the compound N1(S) of the invention is proved to be converted into the active ingredient levoornidazole faster than a control compound within 24h by an in vitro plasma test, and the compound has good pharmacokinetic property.
Test example 2 oil solution stability examination of Compound N1(S) of the present invention
2.1 protocol: a medium-chain triglyceride (MCT) solution containing a compound N1(S) and a soybean oil solution are prepared, the obtained sample is placed at 60 ℃ and sampled for detecting the generation of the related substances at 0 day, 6 days and 13 days respectively.
2.2 test methods: the samples were prepared as in Table 2 and each sample was individually dispensed according to the loft volume4And (6) lofting the bottles.
Table 2 oil solution stability survey sample recipe
Figure BDA0002741706670000201
Preparation of compound N1(S) MCT solution: compound N1(S) was weighed in the prescribed amount, MCT was added in the prescribed amount, and mixed well by magnetic stirring for 20 minutes.
② preparation of soybean oil solution of compound N1 (S): compound N1(S) was weighed, added to soybean oil, and mixed well by magnetic stirring for 20 minutes.
The split charging is reserved:
respectively filling MCT solution containing compounds and soybean oil solution into 4 penicillin bottles (2.5 g/bottle), covering with rubber plugs, rolling covers, and making name and batch number marks.
Storing each batch of penicillin bottle samples in a shading box, keeping the samples in an electric heating constant temperature air blast drying oven at 60 ℃, and sampling and detecting the generation condition of related substances in 0 day, 6 days and 13 days respectively.
2.3 measurement of related substances according to high performance liquid chromatography (2015 version of Chinese pharmacopoeia 0512).
The method comprises the following steps of: the column was a Welch Xtimate C18 column, 4.6mm X250 mm, 5 μm, mobile phase: taking water as a mobile phase A and acetonitrile as a mobile phase B, and carrying out gradient elution according to the following table;
Figure BDA0002741706670000202
the detection wavelength is 318 nm; the flow rate was 1.0ml per minute; the column temperature was 35 ℃;
the method comprises the following steps: taking a proper amount of the product, precisely weighing, adding a diluent [ absolute ethyl alcohol ] to shake and dissolve, quantitatively diluting to prepare a solution containing about 0.4mg per 1ml, filtering by a PTFE filter membrane (0.22 μm, Jinteng), and taking a subsequent filtrate as a test solution. Precisely measuring 10 mu l of the solution, injecting the solution into a liquid chromatograph, and recording a chromatogram; and if an impurity peak exists in the chromatogram of the test solution, calculating according to a peak area normalization method to obtain the product.
The test results are shown in table 3:
TABLE 3
Figure BDA0002741706670000211
According to test results, the compound N1(S) is placed in MCT and soybean oil for 13 days at 60 ℃, and the content of the levoornidazole is 0.02% and 0.04% in sequence; the total impurities are 0.66 percent and 0.52 percent in sequence, and compared with the initial impurities, the total impurities are stable without obvious change; the number of auxiliary material peaks of the blank soybean oil and the blank MCT is large, but the main peak detection of the sample is not interfered.
Test example 2 examination of stability of aqueous solution of Compound N1(S) of the present invention
2.1 protocol:
in order to compare the stability of the compound N1(S) ester compound and the levo-ornidazole disodium phosphate in an aqueous solution, a compound N1(S) Tween 80 sodium chloride solution is prepared and is respectively placed at room temperature for 0h, 1h, 4h, 6h, 8h and 26h, and then sampling is carried out to detect the growth trend of related substances.
2.2 test methods:
prescription:
compound (I) N1(S) Tween 80 Physiological saline
Amount of the composition 80mg 6g 34g
2.3 test procedure:
1. compound N1(S), tween 80 and normal saline in the above prescribed amounts were weighed into a 50mL Erlenmeyer flask and sheared at high speed for 3min to mix them uniformly. Feeding a sample for analysis, detecting the generation condition of the related substances within 0h, and sampling and detecting the generation condition of the related substances after the sample is reserved for 1h, 4h, 6h, 8h and 26h at room temperature after the sample is detected;
2. weighing 1.5g of Tween 80 and 8.5g of normal saline, placing in a 25mL conical flask, magnetically stirring for 3min, and completely dissolving by visual inspection to serve as a blank control for detecting related substances;
3. and transferring the sample remained at room temperature to a 40 ℃ drug stabilization box for sample remaining within 0-1 h, and sampling after 1d and 4d respectively to detect the generation condition of related substances.
The test results are shown in table 4:
TABLE 4
Time Levo ao Miao Xiao (Miao Xiao)Azole (%) Total hetero (%) Purity (%)
0h 0.09 0.55 99.45
1h 0.34 0.78 99.22
2h 0.47 0.89 99.11
4h 0.69 1.10 98.90
5h 0.80 1.22 98.78
26h 3.61 4.07 95.93
24h/40℃ 15.05 15.51 84.49
4d/40℃ 43.58 44.11 55.89
And (4) conclusion: the blank tween 80 normal saline does not interfere the detection of the sample, the compound N1(S) tween 80 normal saline solution is placed at room temperature for 26h, and the content of the levoornidazole is gradually increased from 0.09% to 3.61%. When the ornidazole is placed at 40 ℃ for 24 hours, the increase of the ornidazole is obvious compared with 0 hour, and the increase is from 0.09% to 15.05%. The compound N1(S) Tween 80 physiological saline solution is mainly degraded to generate the levoornidazole during the process of placing at room temperature and 40 ℃.
Test example 3: control Compound 2 disodium Ornidazole phosphate solution stability study
3.1 protocol:
in order to compare the stability of the N1(S) ester compound and the stability of the disodium levonidazole phosphate, a disodium levonidazole phosphate Tween 80 sodium chloride solution is prepared, and the solution is respectively placed at room temperature for 0h, 1h, 4h, 6h, 8h and 26h, and then is sampled to detect the growth trend of related substances.
3.2 test methods:
prescription:
compound (I) Levoornidazole disodium phosphate Tween 80 Physiological saline
Amount of the composition 40mg 3g 17g
2.3 test procedure:
1. weighing the above-mentioned prescription amount of the disodium levoornidazole phosphate, the tween 80 and the normal saline in a 50mL conical flask, and shearing at high speed for 3min to mix them uniformly. Feeding a sample for analysis, detecting the generation condition of the related substances within 0h, and sampling and detecting the generation condition of the related substances after the sample is reserved for 1h, 4h, 6h, 8h and 26h at room temperature after the sample is detected;
2. weighing 1.5g of Tween 80 and 8.5g of normal saline, placing in a 25mL conical flask, magnetically stirring for 3min, and completely dissolving by visual inspection to serve as a blank control for detecting related substances;
3. and transferring the sample remained at room temperature to a 40 ℃ drug stabilization box for sample remaining within 0-1 h, and sampling after 1d and 4d respectively to detect the generation condition of related substances.
The test results are shown in table 5:
TABLE 5
Time Levoornidazole (%) Total impurities (%) Purity (%)
0h / 2.07 97.93
1h / 2.20 97.80
2h / 2.31 97.69
4h / 2.56 97.44
5h 0.02 2.69 97.31
26h 0.09 6.07 93.93
24h/40℃ 0.03 33.38 66.62
4h/40℃ 0.04 72.91 27.09
And (4) conclusion: the blank tween 80 physiological saline does not interfere with the detection of the sample, the contrast compound 2, disodium l-ornidazole phosphate tween 80 physiological saline is placed at room temperature for 26 hours, and the content of the l-ornidazole is gradually increased from 2.07 percent to 6.07 percent. After being placed at 40 ℃ for 24h, the total impurities are increased from 2.07 percent to 33.38 percent compared with 0 h. The contrast compound 2, disodium levoornidazole phosphate tween 80, a physiological salt solution, is mainly degraded to generate unknown impurities in the process of being placed at room temperature and 40 ℃, which indicates that the aqueous solution is poor in stability and is degraded at room temperature, and the medication safety is influenced.

Claims (8)

1. A compound shown as a structural formula (1), a racemate, a stereoisomer, a pharmaceutically acceptable salt or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof,
Figure 557034DEST_PATH_IMAGE001
structural formula (1)
Wherein R is1，R2And R3Identical or different, independently of one another, from hydrogen, C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C3-8Cycloalkyl, 5-10 membered heterocyclyl, C6-10Aryl and 5-10 membered heteroaryl; wherein said C1-10Alkyl radical, C2-10Alkenyl radical, C2-10Alkynyl, C1-10Alkoxy radical, C3-8Cycloalkyl radical, C3-8Cycloalkyloxy, 5-to 10-membered heterocyclic group, C6-10Aryl and 5-10 membered heteroaryl groups may optionally be substituted with one, two or more halogen, hydroxy, amino, C1-8Alkyl radical, C2-8Alkenyl radical, C2-8Alkynyl, C1-8Alkoxy, optionally substituted by C1-10Alkyl substituted C6-10Aryl or optionally substituted by C1-10Alkyl-substituted 5-10 membered heteroaryl;
preferably, R1，R2And R3Identical or different, independently of one another, from hydrogen, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, alkynyl,C3-8Cycloalkyl, 5-8 membered heterocyclyl, C6-8Aryl and 5-8 membered heteroaryl; wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy radical, C3-8Cycloalkyl radical, C3-8Cycloalkyloxy, 5-8 membered heterocyclyl, C6-8Aryl and 5-8 membered heteroaryl groups may optionally be substituted with one, two or more halogen, hydroxy, amino, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Alkoxy, optionally substituted by C1-6Alkyl substituted C6-8Aryl or optionally substituted by C1-6Alkyl-substituted 5-8 membered heteroaryl;
preferably, R1，R2And R3Identical or different, independently of one another, from hydrogen, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and C1-6Alkoxy, wherein said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl and C1-6Alkoxy groups may optionally be substituted by one, two or more fluorine, chlorine, bromine, iodine, hydroxy, amino or optionally by C1-6Alkyl substituted phenyl substituted.
2. A compound of claim 1, wherein R is1Is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl; r2Hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl; r3Is methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, methoxy, ethoxy, isopropoxy, tert-butoxy, isobutoxy.
3. The compound of claim 2, wherein the compound of formula (1) is selected from the following structures:
Figure 840248DEST_PATH_IMAGE002
preferably, the compound of formula (1), preferably the levorotatory enantiomer thereof, is selected from the following structures:
Figure 928289DEST_PATH_IMAGE003
。
4. the method for preparing a compound according to claim 1, wherein the compound of formula (1) is prepared by reacting compound 1 with compound 2, according to the following reaction formula:
Figure 664164DEST_PATH_IMAGE004
wherein R is1、R2、R3Each having the meaning as defined in any one of claims 1 to 5; x is selected from chlorine, bromine or iodine; the compound 1 is selected from racemic ornidazole with R configuration or S configuration;
the synthesis method comprises the following steps:
putting ornidazole and an acid-binding agent into a reaction vessel, adding a reaction solvent for mixing, then slowly adding the compound 2 into the reaction vessel, and stirring the reaction solution for reaction after the addition is finished; during post-reaction treatment, extracting, washing, drying, concentrating and performing column chromatography on the reaction solution to obtain a target compound;
when X in the structure of the compound 2 is chlorine or iodine, R1Is alkyl, R2Is hydrogen, R3When the alkoxy is adopted, the reaction formula is as follows:
Figure 66327DEST_PATH_IMAGE005
the synthesis method comprises the following steps:
a) reacting the compound 2-1 with triphosgene to obtain a compound 2-2 in the form of chloroformate;
b) compound 2-2 with alcohol R3-OH reaction to give a chlorinated organic carbonate, compound 2(X = Cl);
c) reacting compound 2(X = Cl) with NaI to give an iodoorganic carbonate, compound 2(X = I);
when X in the structure of the compound 2 is bromine, R1Is alkyl, R2Is hydrogen, R2When the alkoxy is adopted, the reaction formula is as follows:
Figure 204047DEST_PATH_IMAGE006
the synthesis method comprises the following steps:
a) reacting the compound 2-3 (organic carbonic diester) with dibromohydantoin to obtain bromo-organic carbonate, namely compound 2(X = Br);
or the like, or, alternatively,
the preparation of the compound represented by the structural formula (1) comprises the step of reacting a compound 3 with a compound 4 or a compound 5, which has the following reaction formula:
Figure 164787DEST_PATH_IMAGE007
wherein R is1、R3Has the meaning as defined in any one of claims 1 to 5; x is selected from chlorine, bromine or iodine;
the synthesis method comprises the following steps:
placing the compound 3 into a reaction vessel, adding a reaction solvent for dissolving, replacing air in the reaction vessel with gases such as argon or nitrogen for 2-3 times, slowly adding DIABL-H, stirring for reaction after the addition is finished, then slowly and sequentially adding an acid-binding agent and the compound 4 or 5, and stirring for reaction for a period of time after the addition is finished; and during post-reaction treatment, extracting the reaction solution, washing, drying, concentrating and performing column chromatography to obtain the target compound.
5. A process for the preparation of a compound according to claim 4, wherein the acid scavenger is selected from the group consisting of inorganic bases such as NaOH, KOH, K2CO3、KHCO3、NaCO3、NaHCO3Or an organic base such as one or more of triethylamine, pyridine, DMAP, DIEA, DBU.
6. The method for preparing the compound according to claim 4, wherein the reaction solvent is selected from one or more of acetone, dichloromethane, trichloromethane, carbon tetrachloride, tetrahydrofuran, acetonitrile, DMF, DMAc or diethyl ether; the phase transfer catalyst used is one or more selected from tetrabutylammonium bromide and 18-crown-6.
7. Use of a compound of formula (1) according to any one of claims 1 to 3, a racemate, a stereoisomer, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament; preferably, the medicament is for the treatment of a disease caused by bacteroides fragilis, bacteroides dieldii, bacteroides ovatus, bacteroides thetaiotaomicron, bacteroides vulgatus, clostridium sp2And a plurality of infectious diseases caused by sensitive anaerobes such as the bacteriophage phagocytosis and the gingival bacteroides.
8. A pharmaceutical composition comprising a compound represented by the structural formula (1) according to any one of claims 1 to 3, a racemate, a stereoisomer, a pharmaceutically acceptable salt or solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof; preferably, the pharmaceutical composition is an oral preparation, such as a tablet, a capsule, a granule, an injection, an eye drop, a gel, a cream, an ointment or a cataplasm, for example, a fat emulsion injection.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1453417A (en) * 1974-03-04 1976-10-20 Hoffmann La Roche Nitroimidazoles
CN1044280A (en) * 1989-01-19 1990-08-01 赫彻斯特股份公司 Cephalosporins derivatives and preparation method thereof
JPH0672965A (en) * 1992-08-31 1994-03-15 Eisai Co Ltd Production of 1-iodoalkyl carbonate ester
WO1999061017A1 (en) * 1998-05-22 1999-12-02 Bristol-Myers Squibb Company Water-soluble prodrugs of azole compounds
CN101723969A (en) * 2009-12-08 2010-06-09 陕西合成药业有限公司 Nitro imidazole derivate used for treatment
CN108409786A (en) * 2018-02-10 2018-08-17 扬子江药业集团南京海陵药业有限公司 A kind of industrialized preparing process of phosphoric acid l-ornidazole ester disodium hydrate
WO2020176868A1 (en) * 2019-02-28 2020-09-03 Puretech Lyt, Inc. Lipid prodrugs of btk inhibitors and uses thereof

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1453417A (en) * 1974-03-04 1976-10-20 Hoffmann La Roche Nitroimidazoles
CN1044280A (en) * 1989-01-19 1990-08-01 赫彻斯特股份公司 Cephalosporins derivatives and preparation method thereof
JPH0672965A (en) * 1992-08-31 1994-03-15 Eisai Co Ltd Production of 1-iodoalkyl carbonate ester
WO1999061017A1 (en) * 1998-05-22 1999-12-02 Bristol-Myers Squibb Company Water-soluble prodrugs of azole compounds
US20010012843A1 (en) * 1998-05-22 2001-08-09 Hudyma Thomas W. Water soluble prodrugs of azole compounds
CN101723969A (en) * 2009-12-08 2010-06-09 陕西合成药业有限公司 Nitro imidazole derivate used for treatment
CN108409786A (en) * 2018-02-10 2018-08-17 扬子江药业集团南京海陵药业有限公司 A kind of industrialized preparing process of phosphoric acid l-ornidazole ester disodium hydrate
WO2020176868A1 (en) * 2019-02-28 2020-09-03 Puretech Lyt, Inc. Lipid prodrugs of btk inhibitors and uses thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
JASTI, RAMESH: "Racemization in Prins Cyclization Reactions" *
V. V. N. K. V.PRASADA RAJU 等: "A facile synthesis of potent antiherpes drug substance, ganciclovir, 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine, using a new masked glycerol derivative" *
姚元海 等: "头孢泊肟酯的合成" *

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