CN112679445A - Preparation method of posaconazole intermediate - Google Patents
Preparation method of posaconazole intermediate Download PDFInfo
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Abstract
The invention discloses a preparation method of a posaconazole intermediate shown in a formula I, which is characterized in that p-bromonitrobenzene and anhydrous piperazine are used as raw materials to prepare a target product through condensation reaction, reduction reaction, monoacylation reaction, cyclization reaction and diazotization hydrolysis reaction. Compared with the prior art of synthesizing by taking 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine as the starting material, the preparation method provided by the invention has the advantages of easily obtained raw materials, high reaction efficiency, mild reaction conditions, high yield of target products, simplicity, convenience, high efficiency and low cost.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of posaconazole intermediate 2- ((2S,3S) -2- (benzyloxy) -3-pentyl) -4- (4- (4- (4-hydroxyphenyl) piperazine-1 yl) phenyl) -2, 4-dihydro-1, 2, 4-triazole-3 (4H) -ketone.
Background
Posaconazole is an antifungal drug developed by the company pionsliaea for infections caused by candida, aspergillus and other pathogenic fungi, and its intravenous injection is approved by the FDA to be on the market in 3 months 2014. The posaconazole has the characteristics of good curative effect and low toxicity, and the clinical application range of posaconazole is wide, so the development and research on the synthesis process of posaconazole are increased year by year. The compound 2- ((2S,3S) -2- (benzyloxy) -3-pentyl) -4- (4- (4- (4-hydroxyphenyl) piperazine-1-yl) phenyl) -2, 4-dihydro-1, 2, 4-triazole-3 (4H) -ketone shown as the formula I is an important intermediate for synthesizing posaconazole.
At present, in the prior art, methods disclosed in patents WO9633178 and WO2013042138 are mostly adopted for synthesizing posaconazole intermediates shown in formula i, that is, the posaconazole intermediates are prepared from 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine, and specific preparation processes are shown as follows:
the process for preparing posaconazole intermediate shown in formula i disclosed in chinese patent CN109824612A is as follows:
the above-disclosed prior art requires preparation of posaconazole intermediate represented by formula i from compound 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine, but the synthesis conditions of compound 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine are severe, and as shown in the synthesis methods disclosed in patents CN101824009A and CN111362886A, 3-step reaction or 4-step reaction is required to obtain 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine, and strong acid such as hydrobromic acid or boron trichloride is required to perform demethylation, which has the disadvantages of severe reaction conditions, multiple reaction steps and low yield.
In order to overcome the defects of the prior art, the application provides a method for synthesizing the posaconazole intermediate shown in the formula I, the method prepares a target product by using p-bromonitrobenzene and anhydrous piperazine as starting materials, and the product yield is obviously improved compared with the prior art. In addition, compared with 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine, the method has the advantages of less reaction steps for synthesizing 1, 4-bis (4-aminophenyl) piperazine, mild conditions and green and high-efficiency synthesis.
Disclosure of Invention
The invention aims to provide a preparation method of posaconazole intermediate 2- ((2S,3S) -2- (benzyloxy) -3-pentyl) -4- (4- (4- (4-hydroxyphenyl) piperazine-1-yl) phenyl) -2, 4-dihydro-1, 2, 4-triazole-3 (4H) -ketone aiming at the defects of the prior art, and the method obtains a target product by synthesizing p-bromonitrobenzene and anhydrous piperazine as raw materials and has the advantages of simplicity, convenience, high efficiency and low cost.
In a first aspect, the present invention provides a method for preparing a posaconazole intermediate represented by formula i, comprising the steps of:
the synthetic route is shown as the following formula:
(1) under the protection of nitrogen, dissolving p-bromonitrobenzene and anhydrous piperazine in a molar ratio of 2-3:1 in a solvent, violently stirring in the presence of alkali, heating and refluxing for 16-20h at the temperature of 100-;
(2) under the protection of nitrogen, dissolving 1, 4-bis (4-nitrophenyl) piperazine obtained in the step (1) in an ethanol aqueous solution, adding a reducing agent, heating and refluxing for 10-12h, cooling to room temperature, extracting an organic phase, washing with water, drying, concentrating, and recrystallizing to obtain 1, 4-bis (4-aminophenyl) piperazine (compound V).
(3) Under the protection of nitrogen, dissolving 1, 4-bis (4-aminophenyl) piperazine in a solvent, adding an alkali, cooling to-10-0 ℃, dropwise adding phenyl chloroformate according to the molar ratio of 1:1-1.2 of the 1, 4-bis (4-aminophenyl) piperazine to the phenyl chloroformate, stirring and reacting for 20-24h at 0 ℃, washing with a saturated sodium bicarbonate solution, and concentrating under reduced pressure to obtain 4- (4- (4- (4-aminophenyl) piperazin-1 yl) phenyl) -phenyl carbamate (compound III);
(2) under the protection of nitrogen, dissolving N' - ((2S,3S) -2-benzyloxy) pentyl-3-formhydrazide (compound IV) in a solvent, adding alkali, stirring uniformly, adding 4- (4- (4- (4-aminophenyl) piperazine-1 yl) phenyl) -carbamic acid phenyl ester obtained in the step (1), heating and refluxing at the temperature of 20-200 ℃ for 20-24H, concentrating under reduced pressure, adding water for crystallization, and recrystallizing to obtain 2- ((2S,3S) -2- (benzyloxy) -3-pentyl) -4- (4- (4- (4-aminophenyl) piperazine-1 yl) phenyl) -2, 4-dihydro-1, 2, 4-triazole-3 (4H) -ketone (compound II);
(3) under the protection of nitrogen, dissolving 2- ((2S,3S) -2- (benzyloxy) -3-pentyl) -4- (4- (4- (4-aminophenyl) piperazine-1 yl) phenyl) -2, 4-dihydro-1, 2, 4-triazole-3 (4H) -ketone in an acid solution, cooling to below 5 ℃, dropwise adding a sodium nitrite aqueous solution, stirring for 0.5-1H at the temperature of-10-10 ℃, dropwise adding the obtained solution into water at the temperature of 80 ℃, preserving the temperature for 1-2H after adding, cooling to room temperature, adjusting the pH value to be neutral to precipitate a solid, filtering, drying and recrystallizing to obtain a target product (compound I).
Preferably, the solvent used in step (1) is one or a combination of two or more of dimethyl sulfoxide, N-dimethylformamide and N, N-dimethylacetamide. In the most preferred embodiment of the present invention, the solvent is N, N-dimethylacetamide.
Preferably, the reducing agent in step (2) is selected from one or a combination of more than two of sodium sulfide, ammonium sulfide, sodium hydrosulfide, hydrogen/palladium/carbon, iron powder and zinc powder. More preferably, the reducing agent is one or a combination of two or more of hydrogen/palladium/carbon, sodium hydrosulfide, iron powder and zinc powder.
Preferably, the molar ratio of 1, 4-bis (4-aminophenyl) piperazine to phenyl chloroformate in step (3) is in the range of 1:1 to 1.1. The solvent is one or the combination of more than two of methylene chloride, N-dimethylformamide and toluene. In a preferred embodiment of the invention, the solvent is a combination of dichloromethane and N, N-dimethylformamide. The base used in the reaction is triethylamine, diisopropylethylamine or diethylamine, preferably triethylamine.
Preferably, the solvent in step (4) is one or a combination of two or more selected from dioxane, toluene and xylene. In a preferred embodiment of the invention, the solvent is dioxane. The base used in the reaction is triethylamine, diethylamine or diisopropylethylamine. More preferably, the heating reflux reaction is 80-120 ℃.
Preferably, the acid in step (5) is sulfuric acid, hydrochloric acid or phosphoric acid.
In a second aspect, the present invention provides a posaconazole intermediate of formula i, prepared by the process as described above.
The technical advantages of the invention are as follows: in the prior art, 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine is used as an initial raw material for synthesizing the posaconazole intermediate shown in the formula I, but the 1- (4-aminophenyl) -4- (4-hydroxyphenyl) piperazine is synthesized under severe conditions, usually strong acid such as hydrobromic acid or boron trichloride for demethylation is needed, and the defects of severe reaction conditions and low yield exist. The method for preparing the posaconazole intermediate shown in the formula I takes p-bromonitrobenzene and anhydrous piperazine as starting materials, has high reaction efficiency, mild reaction conditions and high yield of the final target product, and has the advantages of simplicity, convenience, high efficiency and low cost.
Drawings
Figure 1 example the resulting posaconazole intermediate1H nuclear magnetic resonance spectrum.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only some embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
ExamplesSynthesis of posaconazole intermediate shown as formula I
The synthetic route is shown as the following formula:
s1: 5000mL of dimethylacetamide, 100g of anhydrous piperazine, 516g of p-bromonitrobenzene and 353g of potassium carbonate powder are sequentially added into a dry reaction bottle under the protection of nitrogen, the mixture is heated and refluxed for 16h at 200 ℃ under the condition of vigorous stirring, cooled, filtered, the filtrate is decompressed and concentrated, and the residue is recrystallized by acetonitrile to obtain 339g of 1, 4-bis (4-nitrophenyl) piperazine (compound VI), wherein the yield is 89%;
s2: adding 200g of the compound VI prepared in the step S1, 2000mL of ethanol, 330mL of water and 292g of 70% sodium hydrosulfide into a reaction flask under the protection of nitrogen in sequence, heating to 80-90 ℃ for refluxing for 10 hours after the addition is finished, cooling to room temperature, adding 3000mL of water to dilute the reaction solution, extracting the obtained mixture with 3X 1000mL of isopropyl acetate, washing an organic phase with 3X 500mL of water, drying, concentrating under reduced pressure, and recrystallizing the residue with ethanol to obtain 117g of 1, 4-bis (4-aminophenyl) piperazine (compound V) with the yield of 72%;
s3: adding 100g of a compound V, 500mL of dichloromethane, 500mL of N, N-dimethylformamide and 37.7g of triethylamine into a dry reaction bottle under the protection of nitrogen in sequence, stirring for dissolving, cooling to-10-0 ℃, slowly dropwise adding 58.4g of phenyl chloroformate, stirring for reacting for 24h at 0 ℃ after the addition is finished, adding 500mL of dichloromethane, washing the obtained mixture with a saturated sodium bicarbonate aqueous solution, drying an organic phase, concentrating under reduced pressure to obtain a crude product, pulping and washing with isopropanol for 24h to obtain 109g of 4- (4- (4- (4-aminophenyl) piperazin-1 yl) phenyl) -phenyl carbamate (compound III), wherein the yield is 75%;
s4: adding 50.6g of N' - ((2S,3S) -2-benzyloxy) pentyl-3-formylhydrazine (compound IV), 1200mL of dioxane and 30.3g of triethylamine into a dry reaction bottle under the protection of nitrogen in turn, uniformly stirring, adding 90g of the compound III prepared in the step S1, heating the reaction liquid to 80-120 ℃ under stirring after adding, refluxing for 24h, concentrating under reduced pressure until the volume is one fourth of the original volume, adding 1000mL of water for crystallization, filtering to obtain a crude product, drying the crude product, recrystallizing the crude product by using a mixed solvent of methanol/dichloromethane (1: 1) to obtain 2- ((2S,3S) -2- (benzyloxy) -3-pentyl) -4- (4- (4- (4-aminophenyl) piperazin-1 yl) phenyl) -2, 4-dihydro-1, 96g of 2, 4-triazole-3 (4H) -ketone (compound II), and the yield is 82%;
s5: adding 500mL of 20% sulfuric acid into a reaction bottle under the protection of nitrogen in sequence, adding 80g of the compound II prepared in the step S2, cooling to below 5 ℃, slowly dropwise adding a solution formed by dissolving 11.3g of sodium nitrite in 20mL of water, stirring and reacting for 0.5H at 0-5 ℃ after the addition is finished, slowly dropwise adding the obtained solution into 500mL of water at 80 ℃, keeping the temperature for 1H after the addition is finished, cooling to room temperature, adjusting the pH to 7 with a saturated sodium carbonate solution, separating out a solid, filtering, drying to obtain a crude product, recrystallizing the crude product with methanol to obtain 64g of 2- ((2S,3S) -2- (benzyloxy) -3-pentyl) -4- (4- (4-hydroxyphenyl) piperazine-1 yl) phenyl) -2, 4-dihydro-1, 2, 4-triazole-3 (4H) -one (compound I), the yield thereof was found to be 80%.
The prepared compound I is subjected to1H nuclear magnetic identification, determined by Bruker Avance II-600 nuclear magnetic spectrometer, DMSO-d6As solvent and TMS as internal standard1The H nuclear magnetic spectrum is as follows:1H NMR (DMSO-d6,600MHz)δ8.85(s,1H)，8.31(s,1H)，7.46(d,2H)，7.21～7.23 (m,3H)，7.17(dd,2H)，7.10(d,2H)，6.85(d,2H)，6.68(d,2H)，4.53 (d,1H)，4.26(d,1H)，3.71～3.74(m,2H)，3.31(t,4H)，3.11(t,4H)， 1.74(q,2H)，1.22(d,3H)，0.78(t,3H)。
finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.
Claims (10)
1. A preparation method of a posaconazole intermediate shown as a formula I comprises the following steps:
(1) under the protection of nitrogen, dissolving p-bromonitrobenzene and anhydrous piperazine in a molar ratio of 2-3:1 in a solvent, violently stirring in the presence of alkali, heating and refluxing for 16-20h at the temperature of 100-;
(2) under the protection of nitrogen, dissolving 1, 4-bis (4-nitrophenyl) piperazine obtained in the step (1) in an ethanol aqueous solution, adding a reducing agent, heating and refluxing for 10-12h, cooling to room temperature, extracting an organic phase, washing with water, drying, concentrating, and recrystallizing to obtain 1, 4-bis (4-aminophenyl) piperazine;
(3) under the protection of nitrogen, dissolving 1, 4-bis (4-aminophenyl) piperazine in a solvent, adding an alkali, cooling to-10-0 ℃, dropwise adding phenyl chloroformate according to the molar ratio of 1:1-1.2 of the 1, 4-bis (4-aminophenyl) piperazine to the phenyl chloroformate, stirring and reacting for 20-24h at 0 ℃, washing with a saturated sodium bicarbonate solution, and concentrating under reduced pressure to obtain 4- (4- (4- (4-aminophenyl) piperazin-1 yl) phenyl) -phenyl carbamate;
(4) under the protection of nitrogen, dissolving N' - ((2S,3S) -2-benzyloxy) pentyl-3-formhydrazide in a solvent, adding alkali, stirring uniformly, adding the 4- (4- (4- (4-aminophenyl) piperazine-1 yl) phenyl) -carbamic acid phenyl ester obtained in the step (1), heating and refluxing at the temperature of 20-200 ℃ for 20-24H, concentrating under reduced pressure, adding water for crystallization, and recrystallizing to obtain 2- ((2S,3S) -2- (benzyloxy) -3-pentyl) -4- (4- (4- (4-aminophenyl) piperazine-1 yl) phenyl) -2, 4-dihydro-1, 2, 4-triazole-3 (4H) -one;
(5) under the protection of nitrogen, dissolving 2- ((2S,3S) -2- (benzyloxy) -3-pentyl) -4- (4- (4- (4-aminophenyl) piperazine-1 yl) phenyl) -2, 4-dihydro-1, 2, 4-triazole-3 (4H) -ketone in an acid solution, cooling to below 5 ℃, dropwise adding a sodium nitrite aqueous solution, stirring for 0.5-1H at the temperature of-10-10 ℃, dropwise adding the obtained solution into water at the temperature of 80 ℃, preserving the temperature for 1-2H after adding, cooling to room temperature, adjusting the pH value to be neutral to precipitate a solid, filtering, drying and recrystallizing to obtain the target product.
2. The method according to claim 1, wherein the solvent used in step (1) is one or a combination of two or more of dimethylsulfoxide, N-dimethylformamide and N, N-dimethylacetamide.
3. The method according to claim 2, wherein the solvent is N, N-dimethylacetamide.
4. The method of claim 1, wherein the reducing agent in step (2) is selected from one or more of sodium sulfide, ammonium sulfide, sodium hydrosulfide, hydrogen/palladium/carbon, iron powder and zinc powder.
5. The preparation method of claim 4, wherein the reducing agent is one or a combination of two or more of hydrogen/palladium/carbon, sodium hydrosulfide, iron powder and zinc powder.
6. The method according to claim 1, wherein the molar ratio of 1, 4-bis (4-aminophenyl) piperazine to phenyl chloroformate in step (3) is 1:1 to 1.1, the solvent is one or a combination of two or more selected from the group consisting of methylene chloride, N-dimethylformamide and toluene, and the base used in the reaction is triethylamine, diisopropylethylamine or diethylamine.
7. The method according to claim 1, wherein the solvent in step (4) is selected from dioxane, toluene and xylene, and the heating reflux reaction is 80-120 ℃.
8. The method according to claim 7, wherein the solvent is dioxane. The base used in the reaction is triethylamine, diethylamine or diisopropylethylamine.
9. The method according to claim 1, wherein the acid in the step (5) is sulfuric acid, hydrochloric acid or phosphoric acid.
10. An intermediate posaconazole of formula i, prepared according to the process of any one of claims 1 to 9.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115536602A (en) * | 2022-10-12 | 2022-12-30 | 成都海博为药业有限公司 | Preparation method of posaconazole intermediate |
| CN117624155A (en) * | 2024-01-26 | 2024-03-01 | 济南大学 | Preparation method of posaconazole isomer |
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| WO2013042138A2 (en) * | 2011-09-19 | 2013-03-28 | Msn Laboratories Limited | Process for the preparation of triazole antifungal drug, its intermediates and polymorphs thereof |
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| CN108147946A (en) * | 2017-12-04 | 2018-06-12 | 华南农业大学 | A kind of method for preparing 4- phenylphenols |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115536602A (en) * | 2022-10-12 | 2022-12-30 | 成都海博为药业有限公司 | Preparation method of posaconazole intermediate |
| CN117624155A (en) * | 2024-01-26 | 2024-03-01 | 济南大学 | Preparation method of posaconazole isomer |
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