CN113004328A - Voriconazole phosphocholine inner salt intermediate, preparation method and method for preparing voriconazole phosphocholine inner salt - Google Patents

Voriconazole phosphocholine inner salt intermediate, preparation method and method for preparing voriconazole phosphocholine inner salt Download PDF

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CN113004328A
CN113004328A CN202110254997.3A CN202110254997A CN113004328A CN 113004328 A CN113004328 A CN 113004328A CN 202110254997 A CN202110254997 A CN 202110254997A CN 113004328 A CN113004328 A CN 113004328A
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voriconazole
phosphocholine
inner salt
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reaction
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许华侨
王威
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Chongqing Simirui Pharmaceutical Technology Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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    • C07—ORGANIC CHEMISTRY
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Abstract

The invention relates to the field of pharmaceutical chemicals, and discloses a plurality of voriconazole phosphocholine inner salt intermediates, voriconazole phosphocholine inner salts and a preparation method thereof, and specifically comprises the following steps: carrying out oxidation reaction on the compound shown in the formula II to prepare a formula IV; dissolving the intermediate shown in the formula IV in a reaction solvent, and controlling the temperature to react for a certain time; then adding a hydrolytic agent, and purifying to obtain a voriconazole phosphocholine inner salt intermediate V shown in the formula V; the intermediate shown in the formula V is used for preparing the voriconazole phosphocholine inner salt shown in the formula I under the action of an acid-binding agent. The intermediate obtained by the invention has good purity and high yield; the finally prepared finished product of the voriconazole phosphocholine inner salt has high yield and high purity of over 99.5 percent; the preparation method of the intermediate is simple and convenient to operate, mature and reliable, short in reaction route, easy in obtaining of raw materials and suitable for large-scale industrial production.

Description

Voriconazole phosphocholine inner salt intermediate, preparation method and method for preparing voriconazole phosphocholine inner salt
Technical Field
The invention relates to the field of pharmaceutical chemical production, and particularly relates to a voriconazole phosphocholine inner salt intermediate, a preparation method thereof and a method for preparing voriconazole phosphocholine inner salt by using the intermediate.
Background
Voriconazole is a broad-spectrum triazole antifungal drug with the following indications: invasive aspergillosis; candidemia in non-neutropenic patients; severe invasive infections caused by fluconazole-resistant candida species (including candida krusei); severe infections caused by podophyllotoxins and fusarium. Primarily for the treatment of patients suffering from progressive, potentially life-threatening infections.
Due to poor water solubility of voriconazole, hydroxypropyl beta-cyclodextrin is required to be wrapped to increase solubility during injection preparation, and the preparation difficulty is high. In addition, hydroxypropyl beta-cyclodextrin has a good solubilizing effect on various insoluble drugs, but documents show that the auxiliary material has certain hemolysis, nephrotoxicity and carcinogenicity, other unidentified toxic and side effects possibly exist, and hydroxypropyl beta-cyclodextrin is used in a few preparations (such as drugs for treating severe infection and tumors) which are on the market and have special indications abroad. Therefore, intensive research and observation should be continued on such an adjuvant, and it should not be widely used as a conventional adjuvant in injections.
Chinese patent application No. CN201410224332.8 discloses a method for preparing high-purity voriconazole phosphate, which mainly comprises the following steps: (1) dissolving voriconazole and organic weak base in an organic solvent, dropwise adding a phosphorus trichloride solution, and stirring at room temperature for reaction after dropwise adding; (2) cooling the reaction system obtained in the previous step, hydrolyzing the ice-water mixture, and evaporating the organic solution after hydrolysis to obtain an intermediate conazole phosphite ester; (3) dissolving crude voriconazole phosphite and inorganic weak base in water, dropwise adding an oxidant aqueous solution, stirring in an ice bath for reaction, filtering, adjusting the pH value of the filtrate until a large amount of solid is separated out, and filtering to obtain the solid, namely the high-purity voriconazole phosphate. The method has low stability, low purity of the obtained product and low economic benefit, only obtains the target product, and does not produce stable intermediate which can be used in the middle; the acidic voriconazole phosphate compound is prepared by the method to increase the solubility of voriconazole, but the preparation needs to be prepared into salt for reuse when being subsequently prepared into an injection preparation, which brings inconvenience to the preparation of voriconazole into the injection preparation.
Disclosure of Invention
Aiming at the defects in the prior art, the first purpose of the invention is to provide a voriconazole phosphocholine inner salt intermediate and a preparation method thereof, wherein the obtained intermediate has good purity and high yield; the preparation method has the advantages of simple operation, maturity, reliability, short reaction route, easily obtained raw materials and suitability for large-scale industrial production;
the second purpose of the invention is to provide voriconazole phosphocholine inner salt prepared by using the intermediate and a preparation method thereof, wherein the yield of the finished product of the voriconazole phosphocholine inner salt is up to more than 90%, and the purity of the finished product of the voriconazole phosphocholine inner salt is up to more than 99.0%; the preparation method has the advantages of mild reaction conditions, simple process, low cost, high yield, high purity, environmental friendliness and good economic benefit, and is suitable for industrial production.
In order to achieve the above purpose, the solution adopted by the invention is as follows:
a method for synthesizing voriconazole phosphorylcholine ester inner salt comprises the steps of preparing a finished product voriconazole phosphorylcholine ester inner salt from an intermediate V; in particular, intermediate V can be prepared from intermediate IV; intermediate IV can be prepared from intermediate II; the method comprises the steps of taking ionized choline as a starting material, and then reacting with voriconazole to obtain a key intermediate II of voriconazole phosphocholine inner salt shown in a formula II.
Specifically, the invention provides four methods for synthesizing voriconazole phosphocholine ester inner salt I, which are respectively as follows:
the method comprises the following steps of taking choline chloride as a starting material to react with 2 cyanoethyl dichlorophosphate, then reacting with voriconazole, hydrolyzing to obtain a choline chloride compound, and then adjusting alkali to obtain voriconazole phosphocholine inner salt I, wherein the technical process comprises the following steps:
Figure BDA0002967803870000031
secondly, synthesizing choline chloride phosphoester 2 cyanoethyl ester by choline chloride, then reacting with voriconazole to obtain a compound II, hydrolyzing to obtain a choline chloride compound, and then adjusting alkali to obtain voriconazole phosphocholine inner salt I, wherein the technical process comprises the following steps:
Figure BDA0002967803870000032
thirdly, the method takes di (diisopropylamino) 2 cyano phosphorus ethoxylate as a starting material, then the di (diisopropylamino) 2 cyano phosphorus ethoxylate reacts with voriconazole, then the di (diisopropylamino) phosphorus ethoxylate is condensed with ionized choline (preferably choline chloride) to obtain an intermediate II, then the intermediate II is oxidized to obtain a compound IV, the compound IV is hydrolyzed to obtain a choline chloride compound V, and then alkali is adjusted to obtain voriconazole phosphorylcholine ester inner salt I, wherein the technical process is as follows:
Figure BDA0002967803870000041
the invention also provides a fourth method for synthesizing voriconazole phosphocholine inner salt, which comprises the following steps: directly taking ionized choline (preferably choline chloride) as a starting material to synthesize an intermediate III, and then reacting the intermediate III with voriconazole to obtain a key intermediate II of voriconazole phosphocholine inner salt shown in a formula II; carrying out oxidation reaction on the intermediate II under the condition of an oxidant to obtain an intermediate IV, then carrying out hydrolysis reaction on the intermediate IV to obtain an intermediate V, refining the intermediate V, and then adjusting alkali to obtain a finished product of voriconazole phosphorylcholine ester inner salt I with high purity, wherein the process comprises the following steps:
Figure BDA0002967803870000051
in a specific fourth synthesis process, the detailed steps are as follows:
1) reacting ionized choline with (diisopropyl) amino 2 cyanoethoxy phosphorus chloride to obtain a compound shown in a formula III:
Figure BDA0002967803870000052
2) preparing an intermediate II shown in the formula II by further condensation reaction of the compound shown in the formula III and voriconazole:
Figure BDA0002967803870000053
3) and (3) preparing the intermediate shown in the formula II in an oxidizing agent to obtain the compound shown in the formula IV:
Figure BDA0002967803870000061
4) the compound shown as the formula IV is subjected to shape hydrolysis reaction under the action of a hydrolytic agent to prepare the voriconazole phosphocholine ester inner salt intermediate shown as the formula V:
Figure BDA0002967803870000062
5) the intermediate of voriconazole phosphorylcholine ester inner salt shown in the formula V is desalted in an acid-binding agent to prepare the compound shown in the formula I of voriconazole phosphorylcholine ester inner salt:
Figure BDA0002967803870000063
specifically, in the step 1), choline chloride is used as a starting material to react with (diisopropyl) amino (2-cyanoethoxy) phosphorus chloride, and a condensation reagent shown in a formula III is synthesized under the action of an acid-binding agent.
Preferably, the acid scavenger described in this step 1) is selected from: organic bases such as triethylamine and DIPEA, inorganic bases such as ammonia water and sodium carbonate, and the like; the anion of the ionized choline can be halide, sulfate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like. The halide ions include: chlorine, bromine, iodine, preferably chloride.
Preferably, the reaction temperature in the step 1) is-10-40 ℃, and the optimal reaction temperature is-5 ℃; the reaction time is 1-12 hours, and the optimal reaction time is 4-6 hours; the molar ratio of the acid-binding agent to the ionized choline is 1-20: 1, and the optimal molar ratio is 1-2.5: 1; the reaction solvent is selected from: dichloromethane, ethyl acetate, isopropyl acetate, methyl tert-ether or toluene, etc.
Specifically, in the step 2), the condensation reagent shown in the formula III reacts with voriconazole to obtain a key intermediate II of voriconazole phosphocholine inner salt shown in the formula II.
Preferably, in the step 2), voriconazole and a condensation reagent III are subjected to condensation reaction under the action of 1H-tetrazole to synthesize an intermediate II, the reaction temperature is controlled to be-10-70 ℃, the reaction time is 1-16 hours, the optimal reaction time is 2-6 hours, and the reaction solvent is as follows: dichloromethane, acetonitrile, ethyl acetate, isopropyl acetate, methyl tert-ether or toluene.
Preferably, the molar ratio of intermediate III, 1H-tetrazole to voriconazole is 1-10:1-10:1, preferably 2-5:1-2.5: 1.
Specifically, in the step 3), dissolving the intermediate shown in the formula II in a reaction solvent, and reacting for a certain time at controlled temperature; then adding an oxidant, and purifying to obtain the voriconazole phosphocholine inner salt intermediate shown in the formula IV.
Preferably, said oxidizing agent in this step 3) is selected from: hydrogen peroxide solution, peracetic acid solution, m-chloroperoxybenzoic acid, urea peroxide, sodium percarbonate, t-butyl peroxy-butanol, or the like.
Preferably, the reaction temperature of the oxidation reaction in the step 3) is-10 ℃ to 50 ℃, and the optimal reaction temperature is-10 ℃ to 10 ℃; the reaction time of the oxidation reaction is 1-12 hours, and the optimal reaction time is 3-6 hours; the molar ratio of the oxidant to the intermediate (II) is 1-20: 1, and the optimal molar ratio is 1-5: 1.
specifically, in the step 4), dissolving the intermediate shown in the formula IV in a reaction solvent, and controlling the temperature to react for a certain time; then adding a hydrolytic agent, and purifying to obtain the voriconazole phosphocholine inner salt intermediate V shown in the formula V.
Preferably, the hydrolysing agent in step 4) is selected from: and organic bases such as ammonia, anionic resins, and triethylamine, and aqueous solutions of inorganic bases such as sodium carbonate.
Preferably, the reaction temperature of the hydrolysis reaction in the step 4) is-10 ℃ to 100 ℃, and the optimal reaction temperature is-5 ℃ to 5 ℃; the reaction time is 0.5-12 hours, and the optimal reaction time is 2-5 hours; the molar ratio of the hydrolytic agent to the Intermediate (IV) is 1-20: 1, and the optimal molar ratio is 1-2.5: 1; the reaction solvent is selected from methanol, ethanol, isopropanol, tert-butanol, tetrahydrofuran, acetonitrile, water mixtures of the above solvents, ethyl acetate, isopropyl acetate, dichloromethane, methyl tert-butyl ether, ethyl acetate and petroleum ether mixtures, and mixtures of the above solvents.
Specifically, in the step 5), the acid-binding agent is selected from: ammonia water, an organic base such as an anionic resin or triethylamine, an aqueous solution of sodium hydroxide, an aqueous solution of an inorganic base such as sodium hydrogen carbonate or sodium carbonate, or the like.
Preferably, in the step 5), the intermediate shown in the formula V is dissolved in an acid binding agent, and the temperature is controlled to react for a certain time; purifying to obtain the voriconazole phosphocholine inner salt product shown in the formula I.
Preferably, the reaction temperature in the step 5) is-10-40 ℃, and the optimal reaction temperature is-10 ℃; the reaction time is 0.5-4 hours, and the optimal reaction time is 1-2 hours; the molar ratio of the acid-binding agent to the intermediate (V) is 1-20: 1, and the optimal molar ratio is 1-2: 1.
preferably, the step 5) comprises: before the step 5), refining and purifying the compound shown in the formula V prepared in the step 4) by using a solvent, wherein the solvent is selected from methanol, ethanol, isopropanol, tert-butyl alcohol, tetrahydrofuran, acetonitrile, ethyl acetate, isopropyl acetate, dichloromethane, methyl tert-butyl ether, ethyl acetate, petroleum ether mixture, mixtures of the above solvents and the like.
The invention has the beneficial effects that:
1. the invention provides a plurality of intermediates for preparing voriconazole phosphocholine inner salt and a preparation method thereof, the preparation method of each intermediate is simple and convenient to operate, mature and reliable, the reaction route is short, the raw materials are easy to obtain, and the method is suitable for large-scale industrial production; the obtained intermediates have good purity and high yield, stable voriconazole phosphocholine inner salt products can be more easily obtained, and meanwhile, each obtained intermediate can realize stable economic benefits.
2. The aqueous solution of voriconazole phosphocholine ester inner salt prepared by the invention is nearly neutral, the preparation is more uniform, the solubility is obviously improved, and the preparation difficulty is reduced; the pH of the solution is moderate, and the solution can be quickly hydrolyzed in plasma in vivo, thereby being more beneficial to intravenous drip.
3. The invention provides a method for preparing voriconazole phosphorylcholine ester inner salt, the preparation process has high conversion rate and low cost of raw materials, the obtained voriconazole phosphorylcholine ester inner salt has high purity, the HPLC detection purity is more than 99.5%, and the method is suitable for large-scale production conversion.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The present invention will be described in further detail with reference to the following examples.
Example 1:
Figure BDA0002967803870000101
the method comprises the following steps of taking choline chloride as a starting material to react with 2 cyanoethyl dichlorophosphate, then reacting with voriconazole, hydrolyzing to obtain a choline chloride compound, and then adjusting alkali to obtain voriconazole phosphocholine inner salt I, wherein the specific steps are as follows:
1.1 condensation reagent (diisopropyl) amino 2 cyanoethoxy phosphorus chloride:
keeping the temperature at about 0 ℃, introducing nitrogen for protection, adding 600ml of DCM, 279.3g (2.00mol) of choline chloride and 376.0g (2.00mol) of 2-cyanoethyl dichlorophosphate into a 3000ml reaction bottle, stirring for 0.5 hour, cooling to-5 ℃, slowly dropwise adding 222.6g (2.20mol) of triethylamine, keeping the temperature at-5-0 ℃ for reaction for 6 hours after dropwise adding is finished, and keeping the solution for later use.
1.2, preparation of intermediate IV:
174.7g (0.50mol) of voriconazole, 35.0g (0.50mol) of 1H-tetrazole and 450ml of dry tetrahydrofuran are added into a 3000ml four-mouth reaction bottle, 174.7g of a 3A molecular sieve is added, the temperature is reduced to 0 ℃, 145.6g (0.50mol) of the corresponding DCM solution of the condensation reagent (diisopropyl) amino 2 cyanoethoxy phosphorus chloride prepared in the example 1.1 is dropwise added under mechanical stirring, the dropwise adding temperature is controlled to be between-3 ℃ and 3 ℃, after the dropwise adding is finished, the temperature is kept at about 0 ℃ for reaction for 3.5 hours, and then the temperature is increased to 25 ℃ for reaction for 8 hours. After the reaction, the molecular sieve was filtered off, the solution was quenched by adding 550ml of water, stirred for 2 hours, then allowed to stand for 1 hour, separated, and extracted by adding 430ml of × 3 dichloromethane to the aqueous phase. The dichloromethane layers were combined, washed with 250g × 3 water, then the dichloromethane layer was dried over anhydrous sodium sulfate, filtered under suction, and the organic solvent was evaporated off to give 254.7g of condensation intermediate IV, 84.3% molar yield, 95.2% HPLC purity.
1.3 preparation of intermediate V:
255.0g (422.2mmol) of the intermediate IV prepared in the step 1.2 is dissolved in 1050g of methanol in a reaction bottle, the temperature is reduced to 0 ℃, 37.8g of 20 percent ammonia methanol solution is dropwise added under the condition of stirring, the temperature is increased to 25 ℃, and the reaction is carried out for 4 hours. After the reaction is completed, carrying out decompression bubbling to remove redundant ammonia, carrying out decompression steaming in a water bath at 45 ℃ until the flow is cut off, adding 200g of isopropanol, pulping, mechanically stirring for 2 hours, carrying out suction filtration, and carrying out decompression drying to obtain 203.5g of a voriconazole phosphocholine ester inner salt intermediate V, wherein the molar yield is as follows: 87.5% and 99.1% HPLC purity.
1.4, voriconazole phosphocholine inner salt I:
dissolving 203.5g (369.4mmol) of the intermediate V prepared in example 1.3 in 520g of methanol in a reaction bottle, controlling the temperature to be 25 ℃, dropwise adding 369.4g (369.4mmol) of 4% NaOH aqueous solution under mechanical stirring, then keeping the temperature for reaction for 1 hour, then cooling to 0 ℃, keeping the temperature for stirring for 4 hours, carrying out suction filtration, washing a filter cake with 35g of absolute ethanol to obtain 173.3g of voriconazole phosphorylcholine ester inner salt I, wherein the molar yield is as follows: 91.2% and 99.6% HPLC purity.
Example 2:
Figure BDA0002967803870000121
the method comprises the steps of firstly synthesizing choline chloride phosphoester 2 cyanoethyl ester by choline chloride, then reacting with voriconazole to obtain a compound II, then hydrolyzing to obtain a choline chloride compound, and then adjusting alkali to obtain voriconazole phosphocholine inner salt I, wherein the technical process comprises the following steps:
2.1, condensing reagent choline chloride phosphoester 2 cyanoethyl chloride:
keeping the temperature at about 0 ℃, introducing nitrogen for protection, adding 600ml of DCM, 279.3g (2.00mol) of choline chloride and 344.0g (2.00mol) of 2-cyanoethyl dichlorophosphite into a 3000ml reaction bottle, stirring for 1.5 hours, cooling to-5 ℃, slowly dropwise adding 212.5g (2.10mol) of triethylamine, keeping the temperature at-5-0 ℃ for reaction for 6 hours after dropwise adding is finished, and keeping the solution for later use.
2.2, preparation of condensation intermediate II:
174.7g (0.50mol) of voriconazole, 35.0g (0.50mol) of 1H-tetrazole and 450ml of dry tetrahydrofuran are added into a 3000ml four-mouth reaction bottle, 174.7g of 4A molecular sieve is added, the temperature is reduced to 0 ℃, the corresponding DCM solution of 151.4g (0.55mol) of condensation reagent choline chloride phosphite chloride 2 cyanoethyl ester prepared in the example 2.1 is dripped under mechanical stirring, the dripping temperature is controlled between-3 ℃ and 3 ℃, after the dripping is finished, the temperature is kept at about 0 ℃ for reaction for 3.5 hours, and then the temperature is increased to 25 ℃ for reaction for 8 hours. After the reaction, the molecular sieve was filtered off, the solution was quenched by adding 550ml of water, stirred for 2 hours, then allowed to stand for 1 hour, separated, and extracted by adding 430ml of × 3 dichloromethane to the aqueous phase. The dichloromethane layers were combined, washed with 250g × 3 water, and then the dichloromethane layer was dried over anhydrous sodium sulfate, filtered with suction, and the organic solvent was evaporated to give 283.5g of condensation intermediate II, 96.4% molar yield, and 94.8% HPLC purity.
2.3, preparation of condensation intermediate IV:
265.3g (451.2mmol) of the condensation intermediate II prepared in the example 2.2 and 1300ml of isopropyl acetate are added into a three-mouth reaction bottle, the temperature is reduced to minus 10 ℃, 153.5g (1.35mol) of 30 percent hydrogen peroxide is dripped under mechanical stirring, the dripping temperature is controlled to minus 10 ℃ to 10 ℃, and the temperature is kept at about 0 ℃ for reaction for 3 hours after the dripping is finished. Adding 300ml of water, adding 5% sodium bisulfite aqueous solution for quenching, preparing a system hydrogen peroxide by using starch potassium iodide test paper, stirring for 1 hour, testing by using precise hydrogen peroxide test paper until the system hydrogen peroxide is quenched, separating liquid, extracting an aqueous phase by using 250ml multiplied by 3 of isopropyl acetate, combining isopropyl acetate layers, washing by using 200g multiplied by 3 of water, evaporating the isopropyl acetate under reduced pressure, adding 400ml of methyl tert-butyl ether for pulping after evaporation, and performing suction filtration to obtain an intermediate IV 255.0g, wherein the molar yield is 93.6%, and the HPLC purity is 95.0%.
2.4, preparation of condensation intermediate V:
255.0g (422.2mmol) of intermediate IV prepared in example 2.3 is dissolved in 1050g of methanol in a reaction bottle, the temperature is reduced to 0 ℃, 37.8g of 20% ammonia methanol solution is dropwise added under stirring, the temperature is raised to 25 ℃, and the reaction is carried out for 4 hours. After the reaction is completed, carrying out decompression bubbling to remove redundant ammonia, carrying out decompression steaming in a water bath at 45 ℃ until the flow is cut off, adding 200g of isopropanol, pulping, mechanically stirring for 2 hours, carrying out suction filtration, and carrying out decompression drying to obtain 203.5g of a voriconazole phosphocholine ester inner salt intermediate V, wherein the molar yield is as follows: 87.5% and 99.1% HPLC purity.
2.5, voriconazole phosphocholine inner salt I:
dissolving 203.5g (369.4mmol) of voriconazole phosphocholine inner salt intermediate V prepared in example 2.4 in 520g of methanol in a reaction bottle, controlling the temperature to be 25 ℃, dropwise adding 369.4g (369.4mmol) of 4% NaOH aqueous solution under mechanical stirring, then preserving heat for reacting for 1 hour, then cooling to 0 ℃, preserving heat for stirring for 4 hours, performing suction filtration, washing a filter cake with 35g of absolute ethyl alcohol to obtain 173.3g of voriconazole phosphocholine inner salt I, wherein the molar yield is as follows: 91.2% and 99.6% HPLC purity.
Example 3:
Figure BDA0002967803870000141
the method comprises the following steps of taking bis (diisopropylamino) 2 cyanoethoxylation phosphorus as a starting material, reacting with voriconazole, condensing with ionized choline to obtain an intermediate II, oxidizing to obtain a compound IV, hydrolyzing to obtain a choline chloride compound V, and adjusting alkali to obtain voriconazole phosphocholine inner salt I, wherein the process comprises the following steps:
3.1 condensation reagent bis (diisopropylamino) 2 cyanoethoxylated phosphorus:
keeping the temperature at about 0 ℃, introducing nitrogen for protection, adding 600ml DCM, 404.8g (2.00mol) of diisopropylamine and 344.0g (2.00mol) of dichloro 2-cyano ethyl phosphite into a 3000ml reaction bottle, stirring for 1.0 hour, cooling to 0 ℃, slowly dripping 222.6g (2.20mol) of triethylamine, reacting for 6 hours at-5-0 ℃ after dripping is finished, and keeping the temperature at the end of reaction for standby.
3.2, preparation of condensation intermediate II:
174.7g (0.50mol) of voriconazole, 35.0g (0.50mol) of 1H-tetrazole and 450ml of dry tetrahydrofuran are added into a 3000ml four-mouth reaction bottle, 174.7g of a 3A molecular sieve is added, the temperature is reduced to 0 ℃, 180.8g (0.60mol) of corresponding DCM solution of the condensation reagent bis (diisopropylamino) 2 cyanoethoxylation phosphorus prepared in the example 3.1 is dropwise added under mechanical stirring, the dropwise adding temperature is controlled to be between-3 ℃ and 3 ℃, after the dropwise adding is finished, the temperature is kept at about 0 ℃ for reaction for 3.5 hours, and then the temperature is increased to 25 ℃ for reaction for 8 hours. After the reaction, the molecular sieve was filtered off, the solution was quenched by adding 550ml of water, stirred for 2 hours, then allowed to stand for 1 hour, separated, and extracted by adding 430ml of × 3 dichloromethane to the aqueous phase. The dichloromethane layers are combined, washed by 250g multiplied by 3 water, then the dichloromethane layer is dried by anhydrous sodium sulfate, filtered by suction and the organic solvent is removed by evaporation; keeping the temperature at about 0 ℃, introducing nitrogen for protection, adding 1200ml of THF and 139.7g (1.00mol) of choline chloride into a 3000ml reaction bottle, stirring for 4.5 hours, then heating to 45 ℃, keeping the temperature for reaction for 6 hours, sampling and controlling the reaction, obtaining a condensation intermediate II THF solution after the reaction is finished, obtaining 285.4g of condensation intermediate, wherein the molar yield is 86.6 percent, and the HPLC purity is 96.1 percent.
3.3, preparation of condensation intermediate IV:
265.3g (451.2mmol) of the intermediate II prepared in the example 3.2 and 1300ml of isopropyl acetate are added into a three-mouth reaction bottle, the temperature is reduced to minus 10 ℃, 153.5g (1.35mol) of 30 percent hydrogen peroxide is dripped under mechanical stirring, the dripping temperature is controlled to minus 10 ℃ to 10 ℃, and the temperature is kept at about 0 ℃ for reaction for 3 hours after the dripping is finished. Adding 300ml of water, adding 5% sodium bisulfite aqueous solution for quenching, preparing a system hydrogen peroxide by using starch potassium iodide test paper, stirring for 1 hour, testing by using precise hydrogen peroxide test paper until the system hydrogen peroxide is quenched, separating liquid, extracting an aqueous phase by using 250ml multiplied by 3 of isopropyl acetate, combining isopropyl acetate layers, washing by using 200g multiplied by 3 of water, evaporating the isopropyl acetate under reduced pressure, adding 400ml of methyl tert-butyl ether for pulping after evaporation, and performing suction filtration to obtain an intermediate IV 255.0g, wherein the molar yield is 93.6%, and the HPLC purity is 95.0%.
3.4, preparation of condensation intermediate V:
255.0g (422.2mmol) of intermediate IV prepared in example 3.3 is dissolved in 1050g of methanol in a reaction flask, the temperature is reduced to 0 ℃, 37.8g of 20% ammonia methanol solution is dropwise added under stirring, the temperature is raised to 25 ℃ and the reaction is carried out for 4 hours. After the reaction is completed, carrying out decompression bubbling to remove redundant ammonia, carrying out decompression steaming in a water bath at 45 ℃ until the flow is cut off, adding 200g of isopropanol, pulping, mechanically stirring for 2 hours, carrying out suction filtration, and carrying out decompression drying to obtain 203.5g of a voriconazole phosphocholine ester inner salt intermediate V, wherein the molar yield is as follows: 87.5% and 99.1% HPLC purity.
3.5, voriconazole phosphocholine inner salt I:
dissolving 203.5g (369.4mmol) of the intermediate V prepared in example 3.4 in 520g of methanol in a reaction bottle, controlling the temperature to be 25 ℃, dropwise adding 369.4g (369.4mmol) of 4% NaOH aqueous solution under mechanical stirring, then keeping the temperature for reaction for 1 hour, then cooling to 0 ℃, keeping the temperature for stirring for 4 hours, carrying out suction filtration, washing a filter cake with 35g of absolute ethanol to obtain 173.3g of voriconazole phosphorylcholine ester inner salt I, wherein the molar yield is as follows: 91.2% and 99.6% HPLC purity.
Example 4:
Figure BDA0002967803870000171
the method comprises the steps of synthesizing III by taking choline chloride as a starting material, then reacting with voriconazole to obtain a compound II, oxidizing to obtain a compound, hydrolyzing to obtain a choline chloride compound, and then adjusting alkali to obtain voriconazole phosphocholine inner salt I. The process comprises the following steps:
4.1, preparation of condensation reagent III:
choline chloride is used as an initial raw material to react with (diisopropyl) amino 2 cyanoethoxy phosphorus chloride, and a condensation reagent III is synthesized under the action of an acid-binding agent:
Figure BDA0002967803870000172
keeping the temperature at about 0 ℃, introducing nitrogen for protection, adding 500ml of DCM, 279.3g (2.00mol) of choline chloride and 222.6g (2.20mol) of triethylamine into a 3000ml reaction bottle, stirring for 0.5 hour, cooling to-5 ℃, slowly dropwise adding 473.4g (2.00mol) of 5 (diisopropyl) amino 2 cyanoethoxy phosphorus chloride dissolved in 500ml of DCM, after dropwise adding, keeping the temperature at-5-0 ℃ for reaction for 5 hours to obtain a condensation reagent III.
4.2 preparation of intermediate II
The condensation reagent III prepared in the example 4.1 is reacted with voriconazole to obtain a key intermediate II of voriconazole phosphocholine inner salt:
Figure BDA0002967803870000181
174.7g (0.50mol) of voriconazole, 35.0g (0.50mol) of 1H-tetrazole and 500ml of acetonitrile are added into a 3000ml four-mouth reaction bottle, 174.7g of 4A molecular sieve is added, the temperature is reduced to 0 ℃, the mixture is stirred and dissolved, 339.9g (1.00mol) of corresponding DCM solution of the condensation reagent III prepared in the example 1 is dripped, the dripping temperature is controlled to be between-5 ℃ and 5 ℃, the temperature is kept at about 0 ℃ for reaction for 4 hours after the dripping is finished, and then the temperature is increased to 25 ℃ for reaction for 6 hours. After the reaction, the molecular sieve is filtered out, the solution is added with 500ml of water for quenching, stirred for 2 hours, then kept stand for 1 hour, separated, and added with 400ml of multiplied by 3 dichloromethane for extraction. The dichloromethane layers were combined, washed with 200g × 3 water, then the dichloromethane layer was dried over anhydrous sodium sulfate, filtered under suction, and the organic solvent was evaporated off to give 265.3g of condensation intermediate II, 90.2% molar yield, 97.0% purity by HPLC.
4.3, preparation of condensation intermediate IV:
265.3g (451.2mmol) of the intermediate II prepared in the example 4.2 and 1300ml of isopropyl acetate are added into a three-mouth reaction bottle, the temperature is reduced to minus 10 ℃, 153.5g (1.35mol) of 30 percent hydrogen peroxide is dripped under mechanical stirring, the dripping temperature is controlled to minus 10 ℃ to 10 ℃, and the temperature is kept at about 0 ℃ for reaction for 3 hours after the dripping is finished. Adding 300ml of water, adding 5% sodium bisulfite aqueous solution for quenching, preparing a system hydrogen peroxide by using starch potassium iodide test paper, stirring for 1 hour, testing by using precise hydrogen peroxide test paper until the system hydrogen peroxide is quenched, separating liquid, extracting an aqueous phase by using 250ml multiplied by 3 of isopropyl acetate, combining isopropyl acetate layers, washing by using 200g multiplied by 3 of water, evaporating the isopropyl acetate under reduced pressure, adding 400ml of methyl tert-butyl ether for pulping after evaporation, and performing suction filtration to obtain an intermediate IV 255.0g, wherein the molar yield is 93.6%, and the HPLC purity is 95.0%.
4.4, preparation of condensation intermediate V:
255.0g (422.2mmol) of intermediate IV prepared in example 4.3 is dissolved in 1050g of methanol in a reaction flask, the temperature is reduced to 0 ℃, 37.8g of 20% ammonia methanol solution is dropwise added under stirring, the temperature is raised to 25 ℃ and the reaction is carried out for 4 hours. After the reaction is completed, carrying out decompression bubbling to remove redundant ammonia, carrying out decompression steaming in a water bath at 45 ℃ until the flow is cut off, adding 200g of isopropanol, pulping, mechanically stirring for 2 hours, carrying out suction filtration, and carrying out decompression drying to obtain 203.5g of a voriconazole phosphocholine ester inner salt intermediate V, wherein the molar yield is as follows: 87.5% and 99.1% HPLC purity.
4.5, voriconazole phosphocholine inner salt I:
dissolving 203.5g (369.4mmol) of the intermediate V prepared in example 4.4 in 520g of methanol in a reaction bottle, controlling the temperature to be 25 ℃, dropwise adding 369.4g (369.4mmol) of 4% NaOH aqueous solution under mechanical stirring, then keeping the temperature for reaction for 1 hour, then cooling to 0 ℃, keeping the temperature for stirring for 4 hours, carrying out suction filtration, washing a filter cake with 35g of absolute ethanol to obtain 173.3g of voriconazole phosphorylcholine ester inner salt I, wherein the molar yield is as follows: 91.2% and 99.6% HPLC purity.
1H-NMR(400MHz,DCCl3):δ8.83(s,1H),8.71(s,1H),8.23(d,1H),8.00(s,1H),7.29～7.21(m,1H),6.95～6.80(m,2H),6.24(d,1H),5.23(d,1H),4.48～4.40(m,2H),4.13～4.03(m,1H),3.79～3.75(m,1H),3.33(s,9H),1.20(d,3H)；ESI+MS:515.17。
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (12)

1. Voriconazole phosphocholine inner salt intermediate V, characterized by the following formula:
Figure FDA0002967803860000011
2. voriconazole phosphocholine inner salt intermediate IV, characterized by the following formula:
Figure FDA0002967803860000012
3. the preparation method of the voriconazole phosphocholine inner salt intermediate V is characterized by comprising the following steps:
carrying out hydrolysis reaction on the voriconazole phosphorylcholine ester inner salt intermediate IV in the presence of a hydrolyzing agent to obtain a voriconazole phosphorylcholine ester inner salt intermediate V; the reaction formula is as follows:
Figure FDA0002967803860000021
4. the process for preparing voriconazole phosphocholine ester inner salt intermediate V according to claim 3, wherein the hydrolyzing agent is an organic base or an aqueous inorganic base.
5. The preparation method of voriconazole phosphocholine ester inner salt intermediate V according to claim 4, wherein the molar ratio of the hydrolysis agent to intermediate IV is 1-20: 1.
6. the preparation method of the voriconazole phosphocholine inner salt intermediate IV is characterized by comprising the following two methods:
the method A comprises the steps of reacting choline chloride serving as a starting material with 2-cyanoethyl dichlorophosphate, and then reacting with voriconazole to prepare a voriconazole phosphocholine inner salt intermediate IV; the reaction formula is as follows:
Figure FDA0002967803860000031
or the method B, reacting the voriconazole phosphocholine inner salt intermediate shown in the formula II with an oxidant to prepare a voriconazole phosphocholine inner salt intermediate IV; the reaction formula is as follows:
Figure FDA0002967803860000032
7. the process for the preparation of voriconazole phosphocholine ester intermediate IV according to claim 6, wherein the oxidizing agent in process B is: hydrogen peroxide solution, peracetic acid solution, m-chloroperoxybenzoic acid, urea peroxide, sodium percarbonate or t-butanol peroxide.
8. The process for the preparation of voriconazole phosphocholine ester inner salt intermediate IV according to claim 7, wherein the molar ratio of the oxidant to intermediate II in process B is 1-20: 1.
9. the preparation method of voriconazole phosphocholine inner salt is characterized by comprising the following steps:
preparing voriconazole phosphorylcholine ester inner salt I from the intermediate V of voriconazole phosphorylcholine ester under the action of an acid-binding agent; the reaction formula is as follows:
Figure FDA0002967803860000041
10. the method for preparing voriconazole phosphocholine ester inner salt according to claim 9, wherein the acid-binding agent is an organic base or an inorganic base aqueous solution.
11. The preparation method of voriconazole phosphocholine ester inner salt according to claim 10, wherein the molar ratio of the acid-binding agent to voriconazole phosphocholine ester inner salt intermediate V is 1-20: 1.
12. voriconazole phosphocholine inner salt prepared by the preparation method of any one of claims 9 to 11.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102439018A (en) * 2009-03-19 2012-05-02 塞普斯制药有限公司 Fosfluconazole derivatives, synthesis, and use in long acting formulations
US20150071861A1 (en) * 2012-05-23 2015-03-12 Canon Kabushiki Kaisha Polymer, contrast agent for nuclear magnetic resonance analysis or magnetic resonance imaging using the polymer, compound and method of nuclear magnetic resonance analysis and method of magnetic resonance imaging using the polymer
CN106432339A (en) * 2015-08-08 2017-02-22 陕西合成药业股份有限公司 Voriconazole derivative, synthesis thereof, and use thereof in long-acting preparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102439018A (en) * 2009-03-19 2012-05-02 塞普斯制药有限公司 Fosfluconazole derivatives, synthesis, and use in long acting formulations
US20150071861A1 (en) * 2012-05-23 2015-03-12 Canon Kabushiki Kaisha Polymer, contrast agent for nuclear magnetic resonance analysis or magnetic resonance imaging using the polymer, compound and method of nuclear magnetic resonance analysis and method of magnetic resonance imaging using the polymer
CN106432339A (en) * 2015-08-08 2017-02-22 陕西合成药业股份有限公司 Voriconazole derivative, synthesis thereof, and use thereof in long-acting preparation

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