CN115448912B - Preparation method of posaconazole intermediate - Google Patents
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Abstract
The application discloses a preparation method of a posaconazole intermediate, the structural formula of the posaconazole intermediate is shown as a compound A,the synthetic route of the compound A is as follows,
Description
Technical Field
The application belongs to the field of medicines, and particularly relates to a preparation method of a posaconazole intermediate.
Background
Posaconazole (posaconazole) is a derivative of itraconazole, a second-generation triazole antifungal drug marketed in the FDA in 2006. The structural formula of the posaconazole intermediate is shown in a compound A:
whereas the general preparation route for compound E for compound a is shown below,
the application patent with application number 201310063736.9 discloses that a compound B is esterified with isobutyric anhydride at the temperature of minus 40-0 ℃ in an aprotic solvent under the protection of nitrogen and under the catalysis of Lewis acid to obtain a crude product of a compound C, and the crude product is recrystallized to obtain the compound C; the Lewis acid is one or a mixture of more than one of ZnCl2, alCl3, feCl3, snCl4 and MnCl 2; the aprotic solvent is dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetone, acetonitrile, benzene, toluene, carbon tetrachloride or ethylene glycol monomethyl ether. The yield of the process is low, not more than 70%, and the product loss is too large due to recrystallization of the process.
The application patent application number 201180024633.0 discloses a preparation method of a compound C and a compound D. Compound C: compound B was dissolved in toluene and cooled to-15 ℃, sodium hydrogencarbonate, enzyme and isobutyric anhydride were added, after the reaction, the solid was filtered off and the filtrate was washed with aqueous sodium hydrogencarbonate solution, then washed with water, and the solvent of the obtained organic layer was removed by distillation under reduced pressure to obtain the desired product compound C as an oil, and then the oily compound C was recrystallized to obtain colorless crystals in a yield of 70%. Compound D: compound C was dissolved in ethyl acetate, iodine and sodium bicarbonate were added at low temperature, quenched in aqueous sodium sulfite after the completion of the reaction of compound C, separated, washed with aqueous sodium sulfite solution for an organic layer, then washed with water, and the solvent for washing the organic layer was removed by distillation under reduced pressure to obtain the title compound as an oil in 95.0% yield. In the method, pure acetonitrile is used as a reaction solvent when the compound C is prepared, however, acetonitrile has high toxicity, production waste liquid is not friendly to the environment, and the yield of the obtained compound C is too low.
Disclosure of Invention
In order to solve the problems, the application provides a preparation method of a posaconazole intermediate.
In order to achieve the above purpose, the present application adopts the following technical scheme:
a preparation method of a posaconazole intermediate, wherein the structural formula of the posaconazole intermediate is shown as a compound A,
the synthetic route of the compound A is as follows:
the preparation method comprises the following steps:
s1: under the protection of inert gas, dissolving a compound B in a reaction solvent, adding compound lipase and Tween 80, cooling the system to-10 ℃ to-15 ℃, then adding isobutyric anhydride, and keeping the temperature of-10 ℃ to-15 ℃ to react for about 20-24 hours; filtering after the reaction is finished, collecting filtrate, and then washing the filtrate with pure water to obtain a solution containing a compound C; the compound lipase consists of Novozym435 lipase and Chiralzyme IM-100, and the reaction solvent consists of ethyl acetate and acetonitrile;
s2: cooling the solution obtained in the step S1 to the temperature of between minus 15 and minus 12 ℃, adding iodine and sodium bicarbonate, maintaining the system temperature for reaction for 5 to 7 hours, quenching the reaction system in sodium sulfite aqueous solution, washing an organic layer by sodium sulfite aqueous solution, washing the organic layer by water, and removing the solvent from the organic layer to obtain a product containing a compound D;
s3: dissolving the product containing the compound D obtained in the step S2 in a DMF solvent, adding sodium triazole, heating a reaction system to 90-100 ℃ for reaction for 20-24 hours, cooling to room temperature, adding a sodium hydroxide aqueous solution, fully hydrolyzing, adding pure water for dilution, adding methyl tertiary butyl ether for fully stirring, separating liquid and collecting an organic layer, washing the organic layer with water, adding dilute hydrochloric acid into the organic layer, fully stirring, collecting a water phase, adding triethylamine into the water phase, adding methyl tertiary butyl ether for extraction, washing the organic phase with pure water, then carrying out rotary evaporation on the organic phase to obtain a solid, stirring the solid in n-heptane at 50-60 ℃, and cooling to separate out a solid to obtain the compound E;
s4: dissolving the compound E obtained in the step S3 in dichloromethane, adding triethylamine, adding p-toluenesulfonyl chloride at the temperature of between-2 ℃ and 2 ℃, adding water for quenching after the reaction is completed, separating liquid, collecting an organic phase, drying, concentrating and crystallizing to obtain the compound A.
According to the technical scheme, the reaction solvent used in S1 is the mixed solvent composed of ethyl acetate and acetonitrile, so that the use of pure acetonitrile with high toxicity as the reaction solvent is avoided, and because the polarity of ethyl acetate is low, the use of pure ethyl acetate as the reaction solvent is large in dosage and unfavorable for reaction, the product yield is low. In addition, the main solvents used in the S1 and the S2 are all ethyl acetate, so after the reaction in the S1 is finished, the S2 can be carried out by simple filtration (removing the compound lipase in the system) and pure water washing (washing away tween 80 and most acetonitrile in the system), complicated post-reaction treatment is not needed, the residual acetonitrile (not more than 3%) in the pure water washing does not influence the S2, and the feeding amount of the sodium bicarbonate in the S2 is the conventional technology. Analysis of the solid obtained by post-treatment of the solution containing compound C obtained in S1 reveals that it contains not more than 4% of diester impurities, which enter the subsequent reaction without further purification of the product obtained in S1, but because of the low activity of the diester impurities, they cannot react with iodine in S2 and with sodium triazol in S3, the direct feeding of the solution containing compound C obtained in S1 into S2 is totally unproblematic, whereas S4 requires the obtaining of the target product, and therefore a purification treatment in S3. Firstly, using methyl tertiary butyl ether as an extractant to extract a compound E and other byproduct impurities (including diester, which can be hydrolyzed under alkaline conditions but does not affect the extraction of the hydrolyzed product into an organic phase) which can be dissolved in the methyl tertiary butyl ether into the methyl tertiary butyl ether, as primary purification, then adding dilute hydrochloric acid to enable the compound E to form hydrochloride and enter a water phase to be separated from impurities in the organic phase, adding triethylamine into the water phase to enable the compound E to be free, then using the compound E for methyl tertiary butyl ether extraction, and evaporating the solvent in the rotary evaporation process to obtain a solid, wherein the solid also contains some isomer impurities, and thus, recrystallizing to obtain the purified compound E.
Further, in S1, the mass ratio of the compound B to the compound lipase is 20:1; in the composite lipase, the mass fraction of Novozym435 lipase is 80% -90%.
Further, in the reaction solvent, the volume ratio of ethyl acetate to acetonitrile is 9:1.
Further, in S1, the dosage of Tween 80 is 10-12mg/mL.
Further, in S1, the molar ratio of the isobutyric anhydride to the compound B is 1-1.1:1.
Further, in S2, the amount of iodine is such that the molar ratio of iodine to compound B is 1-1.1:1.
In the S3, the dosage of the sodium triazole is that the molar ratio of the sodium triazole to the compound B is 1-1.1:1.
Compared with the prior art, the application has the beneficial effects that:
(1) In the method S1, the tween 80 is added into the mixed solvent of ethyl acetate and acetonitrile as a reaction solvent, and the synergistic effect of the tween 80 and the compound lipase is achieved, so that the use of a toxic reagent in the production process is greatly reduced on the premise of ensuring the yield of the product, meanwhile, the ee value of the product obtained in the step S1 is improved to 99.8%, and the dosage of the compound lipase is small;
(2) In the application, in the S1, only simple post-treatment operation of pure water washing is carried out after the reaction is finished, and the step S2 is directly carried out after the pure water washing is finished, so that excessive and tedious post-treatment after the reaction in the S1 is avoided, meanwhile, the direct loss of a target product compound C in the post-treatment process is avoided, and the problem that S2 is influenced by solvent residues caused by the selection of different solvents in the S1 and the S2 is also avoided; the ethyl acetate used in the S1 is directly used as the solvent of the S2, so that the use of the solvent is saved;
(3) In S1 to S3, only the purification is carried out in S3, the product loss caused by multi-step purification is avoided while the process operation is reduced, and the total yield of three steps from S1 to S3 is more than 75%.
Detailed Description
The present application is further described below in conjunction with embodiments, which are merely some, but not all embodiments of the present application. All other embodiments, which can be made by those skilled in the art without making any inventive effort, are intended to be within the scope of the present application.
Example 1
S1: under the protection of nitrogen, 5g of compound B is dissolved in 30mL of reaction solvent, 250mg of compound lipase and 300mg of Tween 80 are added, the system is cooled to the temperature ranging from minus 10 ℃ to minus 15 ℃, 3.5g of isobutyric anhydride is added, and the temperature ranging from minus 10 ℃ to minus 15 ℃ is kept for reaction for about 20 to 24 hours until the compound B is reacted; filtering after the reaction is finished, collecting filtrate, and then washing the filtrate with pure water to obtain a solution containing a compound C; 25mg of Novozym435 lipase 225mg,Chiralzyme IM-100 lipase in the composite lipase, and the volume ratio of ethyl acetate to acetonitrile in the reaction solvent is 9:1;
s2: cooling the solution obtained in the step S1 to the temperature of between minus 15 and minus 12 ℃, adding 5.6g of iodine and sodium bicarbonate, keeping the temperature of the system to react for 5 to 7 hours within the range of between minus 15 and minus 12 ℃, quenching the reaction system in sodium sulfite aqueous solution, washing an organic layer by sodium sulfite aqueous solution, washing the organic layer by water, and removing the solvent by rotary evaporation to obtain a product containing the compound D;
s3: dissolving the product containing the compound D obtained in the step S2 in 50mL of DMF solvent, adding 2g of sodium triazole, heating a reaction system to 90-100 ℃ for reacting for 20-24 hours, cooling to room temperature, adding aqueous sodium hydroxide solution, fully hydrolyzing, adding pure water for dilution, adding methyl tertiary butyl ether for fully stirring, separating liquid to collect an organic layer, washing the organic layer with water, collecting the organic layer, adding dilute hydrochloric acid into the organic layer, fully stirring, collecting an aqueous phase, adding triethylamine into the aqueous phase, adding methyl tertiary butyl ether for extraction, washing the organic phase with pure water, then carrying out rotary evaporation on the organic phase to obtain 5.8g of solid, stirring the solid in n-heptane at 50-60 ℃, and cooling to precipitate solid, thereby obtaining the compound E5 g with the yield of 77.3% and the purity of 99.5%;
s4: 5g of compound E is dissolved in methylene dichloride, 1.8g of triethylamine is added, 3.3g of p-toluenesulfonyl chloride is added between-2 ℃ and 2 ℃, water is added for quenching after the reaction is completed, then an organic phase is collected by liquid separation, and the compound A7.3g with the purity of 99.3 percent is obtained by drying, concentrating and crystallizing.
Example 2
S1: under the protection of nitrogen, 100g of compound B is dissolved in 600mL of reaction solvent, 5g of compound lipase and 6000mg of Tween 80 are added, the system is cooled to the temperature ranging from minus 10 ℃ to minus 15 ℃, 70g of isobutyric anhydride is added, and the temperature ranging from minus 10 ℃ to minus 15 ℃ is kept for reaction for about 20 to 24 hours; filtering after the reaction is finished, collecting filtrate, and then washing the filtrate with pure water to obtain a solution containing a compound C; in the composite lipase, the volume ratio of ethyl acetate to acetonitrile in the reaction solvent is 9:1, wherein the Novozym435 lipase is 4.5g,Chiralzyme IM-100 lipase which is 0.5 g;
s2: cooling the solution obtained in the step S1 to the temperature of between minus 15 and minus 12 ℃, adding 112g of iodine and sodium bicarbonate, keeping the system temperature to react for 5 to 7 hours within the range of between minus 15 and minus 12 ℃, quenching the reaction system in sodium sulfite aqueous solution, washing an organic layer by sodium sulfite aqueous solution, washing the organic layer by water, and removing the solvent by rotary evaporation to obtain a product containing the compound D;
s3: dissolving the product containing the compound D obtained in the step S2 in 1000mL of DMF solvent, then adding 40g of sodium triazole, heating a reaction system to 90-100 ℃ for reacting for 20-24 hours, then cooling to room temperature, adding aqueous sodium hydroxide solution, fully hydrolyzing, adding pure water for dilution, then adding methyl tertiary butyl ether for fully stirring, separating liquid and collecting an organic layer, washing the organic layer with water, collecting the organic layer, adding dilute hydrochloric acid into the organic layer, fully stirring, collecting an aqueous phase, adding triethylamine into the aqueous phase, adding methyl tertiary butyl ether for extraction, washing the organic phase with pure water, then carrying out rotary evaporation on the organic phase to obtain 116.7g of solid, stirring the solid in 50-60 ℃ n-heptane, and cooling to precipitate solid, thereby obtaining 103.3g of compound E with the yield of 79.8% and the purity of 99.3%;
s4: 100g of compound E is dissolved in methylene dichloride, 35g of triethylamine is added, 65g of p-toluenesulfonyl chloride is added between-2 ℃ and 2 ℃, water is added for quenching after the reaction is completed, then an organic phase is collected by liquid separation, and the compound A146.4g is obtained by drying, concentration and crystallization, and the purity is 99.1%.
In the two examples, in example 1, the total yield of three steps S1 to S3 was 77.3%; in example 2, the overall yield of three steps S1 to S3 was 79.8%. Example 2 is a 20-fold amplification test of example 1, and from the results, the yield of the first three steps of example 1 is lower than that of the first three steps of example 2, and it is hypothesized that the scale of example 1 is too small, and even if materials are scattered only a little during the reaction, larger errors are caused, whereas the occasional errors are greatly reduced by the amplification test of example 2, which is reflected in that the yield of S1 to S3 is increased, and the method has stable process and is suitable for factory amplification production.
Example 3
In order to verify the catalytic capability of the composite lipase, only the S1 step reaction is carried out, and the compound C is obtained by post-treatment after the S1 step is completed, specifically as follows:
under the protection of nitrogen, 10g of compound B is dissolved in 60mL of reaction solvent (the volume ratio of ethyl acetate to acetonitrile in the reaction solvent is 9:1), 500mg of composite lipase and 600mg of Tween 80 are added, 50mg of Novozym435 lipase 450mg,Chiralzyme IM-100 lipase is added, the system is cooled to the temperature ranging from minus 10 ℃ to minus 15 ℃, 7g of isobutyric anhydride is added, and the reaction is kept at the temperature ranging from minus 10 ℃ to minus 15 ℃ for about 20-24 hours; filtering after the reaction is finished, collecting filtrate, and then washing the filtrate with pure water; the filtrate was concentrated in vacuo to give an oil, which was then dissolved in 50-60 ℃ n-heptane, cooled to solids precipitation, the filter cake collected and dried in vacuo at room temperature to give 12g of product in 91.8% yield, which was assayed at 99.3% purity and 99.8% ee.
Example 4:
this example differs from example 3 in that in this example, 100mg of Novozym435 lipase 400mg,Chiralzyme IM-100 lipase was used as the complex lipase, and the other operations were the same as those in example 3.
11.8g of the product is obtained in this example, the yield is 90.2%, the purity of the product is 99.4% and the ee value is 99.7% by detection analysis.
Example 5
This example is different from example 3 in that in this example, the addition amount of Tween 80 was 720mg, that is, the concentration of Tween 80 was 12mg/mL, and the other operations were the same as in example 3.
This example gave 12.1g of the product in 92.5% yield, which was analyzed to detect a product having a purity of 99.1% and an ee value of 99.8%.
From the data of examples 3 to 5, it was intended to obtain solid compound C, and good yields and higher ee values of the products could be achieved within the scope of the present application.
Comparative example 1
This comparative example was different from example 3 in that tween 80 was not added thereto, and the other operations were the same as in example 3.
This comparative example gave 9.4g of product in 71.8% yield and the product was analyzed to have a purity of 96.6% and an ee value of 94.2%.
Comparative example 2
This comparative example differs from example 3 in that the solvent of this comparative example is pure ethyl acetate, and the other operations are the same as in example 3.
This comparative example gave 4.2g of the product in a yield of 32.1% and the product was analyzed to give a purity of 93.1% and an ee value of 91.4%.
Comparative example 3
This comparative example differs from example 3 in that instead of using a complex lipase, 500mg of Novozym435 lipase was used alone, and the other operations were the same as in example 3.
This comparative example gave 8.2g of product in 62.7% yield and the product was analyzed to have a purity of 98.2% and an ee value of 99.2%.
Comparative example 4
This comparative example differs from example 3 in that instead of using a complex lipase, 500mg of a single Chiralzyme IM-100 lipase was used, and the other operations were the same as in example 3.
This comparative example gave 4.4g of the product in 33.7% yield and the product was analyzed to give a purity of 83.7% and an ee value of 97.6%.
From the data of example 3 and comparative example 1 above, tween 80 affects the selectivity of the enzyme-catalyzed reaction; from the data of example 3 and comparative example 2, it is understood that even with tween 80, good yields and ee values are not achieved if the solvent is not suitable; the data of comparative example 3, comparative example 4 and example 3 show that the catalytic efficiency of the single lipase is low, and the product yield is far less than that of the complex lipase.
Claims (4)
1. The structural formula of the posaconazole intermediate is shown as a compound A,the synthetic route of the compound A is as follows,
it is characterized in that the method comprises the steps of,
s1: under the protection of inert gas, dissolving a compound B in a reaction solvent, adding compound lipase and Tween 80, cooling the system to-10 ℃ to-15 ℃, then adding isobutyric anhydride, and keeping the temperature of-10 ℃ to-15 ℃ for reaction for 20-24 hours; filtering after the reaction is finished, collecting filtrate, and then washing the filtrate with pure water to obtain a solution containing a compound C; the compound lipase consists of Novozym435 lipase and Chiralzyme IM-100, and the reaction solvent consists of ethyl acetate and acetonitrile;
s2: cooling the solution obtained in the step S1 to the temperature of between minus 15 and minus 12 ℃, adding iodine and sodium bicarbonate, maintaining the system temperature for reaction for 5 to 7 hours, quenching the reaction system in sodium sulfite aqueous solution, washing an organic layer by sodium sulfite aqueous solution, washing the organic layer by water, and removing the solvent from the organic layer to obtain a product containing a compound D;
s3: dissolving the product containing the compound D obtained in the step S2 in a DMF solvent, adding sodium triazole, heating a reaction system to 90-100 ℃ for reaction for 20-24 hours, cooling to room temperature, adding a sodium hydroxide aqueous solution, fully hydrolyzing, adding pure water for dilution, adding methyl tertiary butyl ether for fully stirring, separating liquid and collecting an organic layer, washing the organic layer with water, adding dilute hydrochloric acid into the organic layer, fully stirring, collecting a water phase, adding triethylamine into the water phase, adding methyl tertiary butyl ether for extraction, washing the organic phase with pure water, then carrying out rotary evaporation on the organic phase to obtain a solid, stirring the solid in n-heptane at 50-60 ℃, and cooling to separate out a solid to obtain the compound E;
s4: dissolving the compound E obtained in the step S3 in dichloromethane, adding triethylamine, adding p-toluenesulfonyl chloride at the temperature of between-2 ℃ and 2 ℃, adding water for quenching after the reaction is completed, separating liquid, collecting an organic phase, drying, concentrating and crystallizing to obtain a compound A;
the mass ratio of the compound B to the compound lipase is 20:1; in the composite lipase, the mass fraction of Novozym435 lipase is 80% -90%;
the volume ratio of the ethyl acetate to the acetonitrile is 9:1;
the dosage of Tween 80 is 10-12mg/mL.
2. The process for the preparation of posaconazole intermediate according to claim 1, wherein the molar ratio of isobutyric anhydride to compound B is 1-1.1:1.
3. The process for the preparation of posaconazole intermediate according to claim 1, wherein the molar ratio of iodine to compound B is 1-1.1:1.
4. The method for preparing posaconazole intermediate according to claim 1, wherein the molar ratio of sodium triazole to compound B is 1-1.1:1.
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| Raymond G. Lovey 等.PPL-catalyzed enzymic asymmetrization of a 2-substituted prochiral 1,3-diol with remote chiral functionality: improvements toward synthesis of the eutomers of SCH 45012.Tetrahedron Letters.1994,第35卷(第33期),6047-6050. * |
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