CN114920729A - Synthetic method and application of voriconazole intermediate - Google Patents
Synthetic method and application of voriconazole intermediate Download PDFInfo
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- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 title claims abstract description 34
- 229960004740 voriconazole Drugs 0.000 title claims abstract description 33
- 238000010189 synthetic method Methods 0.000 title claims abstract description 10
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims abstract description 12
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- 238000003756 stirring Methods 0.000 claims abstract description 10
- 238000000746 purification Methods 0.000 claims abstract description 6
- 238000006555 catalytic reaction Methods 0.000 claims abstract 3
- 239000003054 catalyst Substances 0.000 claims abstract 2
- 238000001308 synthesis method Methods 0.000 claims description 7
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- 238000000034 method Methods 0.000 abstract description 14
- 230000008569 process Effects 0.000 abstract description 7
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- 239000001257 hydrogen Substances 0.000 abstract description 5
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- 229910052757 nitrogen Inorganic materials 0.000 description 33
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- 230000000843 anti-fungal effect Effects 0.000 description 6
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- 230000002194 synthesizing effect Effects 0.000 description 4
- LKTGVRWVTAJGMS-UHFFFAOYSA-N 4-chloro-6-ethyl-5-fluoropyrimidine Chemical compound CCC1=NC=NC(Cl)=C1F LKTGVRWVTAJGMS-UHFFFAOYSA-N 0.000 description 3
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 3
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- 241001337994 Cryptococcus <scale insect> Species 0.000 description 1
- 241000221204 Cryptococcus neoformans Species 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
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- MSFSPUZXLOGKHJ-UHFFFAOYSA-N Muraminsaeure Natural products OC(=O)C(C)OC1C(N)C(O)OC(CO)C1O MSFSPUZXLOGKHJ-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a synthetic method of voriconazole intermediate, which comprises the steps of reacting an initial raw material intermediate 2 with ammonium formate and 10% palladium-carbon under the catalysis of a catalyst, wherein the reaction condition temperature is 25-30 ℃, and the reaction time is 1 hour; distilling at 50-60 deg.C under reduced pressure, and stirring with water at 25-30 deg.C to obtain intermediate 3; wherein the molar ratio of the intermediate 2 to ammonium formate is 1: 2-4; the molar ratio of the intermediate 2 to water is 1: 2-5; the mass ratio of the intermediate 2 to 10 percent palladium-carbon is 20: 0.5-1. The synthetic route avoids using high-pressure hydrogen as a reducing agent, and has the characteristics of simple process, convenient operation, no need of column chromatography purification, high yield and the like.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a synthetic method and application of a voriconazole intermediate.
Background
Voriconazole (Voriconazole) is developed by the american pfizer company, a second-generation triazole antifungal new drug marketed in the united states in 2002, and is mainly used for treating acute or chronic deep fungal infection clinically, and is sold under the trade name Vfend. Compared with the existing fungi drugs, voriconazole as a fluconazole derivative has wider antibacterial spectrum and better safety, can be orally taken and injected, has good curative effect on invasive aspergillus infection in particular, and is mainly used for treating candidiasis of blood stasis, deep subcutaneous tissue and abdomen, kidney, bladder wall and wound. Voriconazole has become a new market by the characteristics of high efficiency and low toxicity, and has great economic value and market prospect, so that the synthetic process of voriconazole needs to be optimized, the voriconazole is more favorable for industrial production, and the voriconazole has better economic benefit
The structural formula of voriconazole is as follows:
fungal infections are a serious problem facing the clinic and are one of the common diseases endangering human health. The type of fungal infection can be divided into superficial and deep fungal infections, depending on the site of infection. The superficial fungal infection has high morbidity and strong infectivity, mainly attacks the epidermis, hair, nails and other parts of the body, but generally does not cause serious consequences, accounts for more than 90 percent of patients with fungal infection, and can be treated by external or internal antifungal drugs; while deep fungal infections mainly invade internal organs and blood and bones, although less common than superficial fungal infections, they are more harmful and have a high mortality rate. Statistically, deep fungal infections are most common in digestive and respiratory infections, accounting for 40.5% and 33.7% of deep fungal infections, respectively. Fungi have a more complex structure than bacteria, have a nucleus, are eukaryotes, have a thicker cell wall, mainly consist of polysaccharides and proteins, and do not contain peptidoglycan. Fungi widely exist in nature, most of the fungi are not pathogenic, and are divided into unicellular fungi and multicellular fungi according to different morphological structures, wherein the unicellular fungi are circular or oval, such as saccharomycetes, cryptococcus and candida; the multicellular fungi have two parts of hypha and spore, which are interwoven into a cluster, and the common fungi have skin filamentous fungi and the like. In recent years, dysbacteriosis caused by abuse of antibiotics, and immune function reduction caused by abuse of hormones, immunosuppressants, anticancer drugs and HIV infection cause that the fungal infection rate is obviously increased, deep fungal infection becomes one of the more clinically problematic problems, so that the search for new and more ideal antifungal drugs becomes a hot spot of people.
The antifungal drugs currently used clinically can be roughly classified into 3 types that interfere with fungal cell membranes, affect fungal nucleic acid synthesis and function, and destroy fungal cell walls according to the mechanism of action. Wherein Fluconazole (Fluconazole) interfering fungal cell membranes is marketed in the United states in 1990 but is marketed earlier in Europe, and has a wide antifungal spectrum, a long half-life (30H), good oral bioavailability, low liver and kidney toxicity and light adverse reaction, and is not affected by food, antacids and H2 receptor blockers. Has good antibacterial activity against Candida, Cryptococcus neoformans, Microsporum, Trichophyton, Epidermophyton, Blastomyces dermatitidis, Coccidioides, etc., but is not sensitive to some filamentous fungi such as Aspergillus. Can be used for treating cryptococcal meningitis, while ketoconazole can hardly penetrate blood brain barrier. The in vitro antibacterial activity of fluconazole is obviously lower than that of ketoconazole, but the in vivo antibacterial activity of fluconazole is obviously higher than that of ketoconazole, and the in vivo antifungal activity of fluconazole is 10-20 times stronger than that of ketoconazole. The major obstacle in the application of fluconazole is the slow development of intravenous drug administration dosage form, and the drug resistance rate of fungi such as candida is increased for years in clinical application.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a method for simply synthesizing voriconazole intermediate 3.
In order to achieve the purpose, the invention provides the following technical scheme:
voriconazole intermediate 3 it has the following structure:
the synthetic method of the voriconazole intermediate comprises the following steps:
the intermediate 2 of the starting material reacts with ammonium formate under the conditions of 25-30 ℃ and 1 hour; carrying out reduced pressure distillation, and stirring with water to obtain an intermediate 3; the molar ratio of the intermediate 2 to the ammonium formate is 1: 2-4; the molar ratio of the intermediate 2 to water is 1: 2-5; the mass ratio of the intermediate 2 to 10 percent palladium-carbon is 20: 0.5-1.
The invention further discloses application of the voriconazole intermediate 3 prepared by the synthesis method in improving product yield and simplifying purification equipment. The experimental results show that: the key intermediate has high purity, the synthetic route avoids using high-pressure hydrogen as a reducing agent, and the method has the characteristics of simple process, convenient operation, no need of column chromatography purification, high yield and the like.
The invention is described in more detail below:
the synthetic method of the voriconazole intermediate mainly comprises the following steps:
1) the intermediate 2 of the starting material reacts with ammonium formate under the conditions of 25-30 ℃ and 1 hour; carrying out reduced pressure distillation, and stirring with water to obtain an intermediate 3; the molar ratio of the intermediate 2 to the ammonium formate is 1: 2-4; the molar ratio of the intermediate 2 to water is 1: 2-5; the mass ratio of the intermediate 2:10% palladium-carbon is 20: 0.5-1;
the invention further discloses application of the preparation intermediate 3 in the production of voriconazole. Experimental results show that the synthetic method is simple and effective. The adopted method for synthesizing voriconazole can effectively provide the defects of low purity and yield of key intermediates for production and strict requirements on purification equipment.
The typical synthesis method of the intermediate 3 of the invention is as follows:
1) sequentially taking the initial intermediate 2, ammonium formate, 10% palladium-carbon and 95% ethanol for reaction, and carrying out reduced pressure distillation and agitation washing to obtain an intermediate 3; the molar ratio of the intermediate 2 to the ammonium formate is 1: 2-4; the molar ratio of the intermediate 2 to water is 1: 2-5; the mass ratio of the intermediate 2 to 10 percent palladium-carbon is 20: 0.5-1.
The synthetic route of voriconazole is as follows:
1) sequentially taking the initial intermediate 2, ammonium formate, 10% palladium-carbon and 95% ethanol for reaction, and carrying out reduced pressure distillation and agitation washing to obtain an intermediate 3;
in the synthesis method, the reaction condition temperature in the step 1) is preferably 25-30 ℃ and the time is preferably 1 hour.
In the synthesis method of the invention, the reduced pressure distillation temperature in the step 1) is preferably 50-60 ℃.
In the synthesis method, the preferred temperature of the agitation washing in the step 1) is 25-30 ℃. The synthetic method for producing the voriconazole intermediate disclosed by the invention has the positive effects that:
the invention provides a simple synthetic method of voriconazole intermediate. The adopted method for synthesizing the voriconazole intermediate has the advantages of high purity of the key intermediate, simple process, convenient operation, no need of column chromatography purification, high yield and the like, and the synthetic route avoids using high-pressure hydrogen as a reducing agent. Provides a powerful support for the large-scale industrial production of voriconazole.
Detailed Description
For the sake of simplicity and clarity, descriptions of well-known techniques are omitted appropriately below to avoid unnecessary detail affecting the description of the present solution. The synthesis of voriconazole intermediate 3 according to the present invention is further illustrated below with reference to the preferred examples, in which ammonium formate, 10% palladium on carbon, and 95% ethanol are commercially available.
Example 1
1) Intermediate 2 was synthesized with a yield of 65% starting from 4-chloro-6-ethyl-5-fluoropyrimidine (reference US6586594B 1).
2) To a 500L tank, 130.4kg 95% ethanol was pumped in, 20.6kg ammonium formate, 55.0kg intermediate 2 was added, the batch port was sealed, and the batch was dissolved for 10 minutes. Opening a tank vacuum valve, vacuumizing to the gauge pressure of-0.06 MPa, closing the vacuum valve, opening a nitrogen valve, filling nitrogen to the gauge pressure of +0.06MPa, and closing the nitrogen valve. And slowly opening a reflux valve to release nitrogen pressure. Opening a feed port, pouring a paste stirred by 10.0kg of 95% ethanol and 0.96kg of 10% palladium-carbon in a stainless steel barrel into a reaction tank under the protection of a small nitrogen flow, washing the barrel by 10.0kg of 95% ethanol, pouring a washing solution into the tank, sealing the feed port, closing a nitrogen valve, and closing a reflux valve. Slowly opening a vacuum valve of the reaction tank, vacuumizing to gauge pressure of-0.06 MPa, closing the vacuum valve, opening a nitrogen valve, slowly filling nitrogen to gauge pressure of +0.06MPa, closing the nitrogen valve, and observing for 1 minute to confirm no leakage; the operation was repeated 2 more times while replacing the air with nitrogen 3 times. The temperature was maintained at 25 ℃ for 1 hour.
And (3) carrying out pressure filtration by using nitrogen under the stirring operation state, introducing steam to heat the mixture until the internal temperature is 50 ℃ after the filtrate is completely pressurized, pumping 20.0kg of drinking water when the volume of the mixture is about one third, continuing distillation until no liquid drops, and ending the distillation.
220.0kg of drinking water is pumped in under stirring, the temperature is heated to 30 ℃ in a water bath, and the temperature is kept for 3 hours. The filter cake was rinsed off with 22.0kg of drinking water (28 ℃ C.). After the centrifugal separation, the machine is stopped after 30 minutes of delay. The filter cake was dried at 50 ℃ for 8 hours to give 35.46kg of hydride (intermediate 3) in 96.1% yield and 96.3% HPLC.
Example 2
1) Intermediate 2 was synthesized in 65% yield starting from 4-chloro-6-ethyl-5-fluoropyrimidine (reference US6586594B 1).
2) To a 500L tank, 130.4kg 95% ethanol was pumped in, 24.72kg ammonium formate and 55.0kg intermediate 2 were added, the feed port was sealed and the batch was taken for 10 minutes. Opening a tank vacuum valve, vacuumizing to gauge pressure of-0.06 MPa, closing the vacuum valve, opening a nitrogen valve, filling nitrogen to gauge pressure of +0.06MPa, and closing the nitrogen valve. And slowly opening a reflux valve to release nitrogen pressure. Opening a feed port, pouring a paste stirred by 10.0kg of 95% ethanol and 0.96kg of 10% palladium-carbon in a stainless steel barrel into a reaction tank under the protection of a small nitrogen flow, washing the barrel by 10.0kg of 95% ethanol, pouring a washing solution into the tank, sealing the feed port, closing a nitrogen valve, and closing a reflux valve. Slowly opening a vacuum valve of the reaction tank, vacuumizing to gauge pressure of-0.06 MPa, closing the vacuum valve, opening a nitrogen valve, slowly filling nitrogen to gauge pressure of +0.06MPa, closing the nitrogen valve, and observing for 1 minute to confirm no leakage; the operation was repeated 2 more times while replacing the air with nitrogen 3 times. The temperature was maintained at 28 ℃ for 1 hour.
And (3) carrying out pressure filtration by using nitrogen under the stirring operation state, introducing steam to heat the mixture until the internal temperature is 55 ℃ after the filtrate is completely pressurized, pumping 20.0kg of drinking water when the volume of the mixture is about one third, continuing distillation until no liquid drops, and ending the distillation.
200.0kg of drinking water is pumped in under stirring, the temperature is heated to 35 ℃ in a water bath, and the temperature is kept for 3 hours. The filter cake is rinsed by a centrifuge and 20.0kg of drinking water (25-30 ℃). After the centrifugal separation, the machine is stopped after 30 minutes of delay. The filter cake was dried at 55 ℃ for 8 hours to give 35.61kg of hydride (intermediate 3) in 96.5% yield and 96.9% HPLC.
Example 3
1) Intermediate 2 was synthesized in 65% yield starting from 4-chloro-6-ethyl-5-fluoropyrimidine (reference US6586594B 1).
2) To a 500L tank, 130.4kg 95% ethanol was pumped in, 28.84g ammonium formate, 55.0kg intermediate 2 were added, the feed port was sealed, and the batch was taken for 10 minutes. Opening a tank vacuum valve, vacuumizing to gauge pressure of-0.06 MPa, closing the vacuum valve, opening a nitrogen valve, filling nitrogen to gauge pressure of +0.06MPa, and closing the nitrogen valve. And slowly opening a reflux valve to release nitrogen pressure. Opening a feed port, pouring a paste stirred by 10.0kg of 95% ethanol and 0.96kg of 10% palladium-carbon in a stainless steel barrel into a reaction tank under the protection of small nitrogen flow, then washing the barrel by 10.0kg of 95% ethanol, pouring the washing liquid into the tank, sealing the feed port, closing a nitrogen valve, and closing a reflux valve. Slowly opening a vacuum valve of the reaction tank, vacuumizing to gauge pressure of-0.06 MPa, closing the vacuum valve, opening a nitrogen valve, slowly filling nitrogen to gauge pressure of +0.06MPa, closing the nitrogen valve, and observing for 1 minute to confirm that no leakage exists; the operation was repeated 2 more times while replacing the air with nitrogen 3 times. The temperature was maintained at 30 ℃ for 1 hour.
And (3) under the stirring operation state, performing pressure filtration by using nitrogen, after the filtrate is completely pressed, introducing steam to heat the mixture until the internal temperature is 60 ℃, pumping 20.0kg of drinking water when about one third of the volume of the mixture is remained, continuing distillation until no liquid drops, and ending the distillation.
110.0kg of drinking water is pumped in under stirring, the temperature is heated to 40 ℃ in a water bath, and the temperature is kept for 3 hours. The filter cake was rinsed off with 11.0kg of drinking water (25 ℃ C.). After the centrifugal separation, the machine is stopped after 30 minutes of delay. The filter cake was dried at 60 ℃ for 8 hours to give 35.83kg of hydride (intermediate 3) in 97.1% yield and 97.3% HPLC.
1 H NMR(CDCl 3 )δ1.11(d,3H),7.83(q,1H),4.17(d,1H), 4.81(d,1H), 6.57(s,1H), 6.82(m, 2H), 7.43(d, 1H),7.51(m,1H), 7.61(s, 1H),7.92(s,1H), 8.77(d,1H), 9.16(s,1H). [M+H] + =349.94。
The intermediate 3 can be efficiently synthesized according to the formula. The yield reaches more than 96 percent, and the product has high purity and high operability. Provides a practical synthesis method for producing voriconazole.
Example 4
Comparative experiment
And (4) conclusion: the voriconazole generally needs high-pressure hydrogen in the conventional process reaction, the post-treatment is complicated, and the yield is low. Developing a new process for synthesizing voriconazole, improving the reaction yield and optimizing the synthesis process; the conversion rate and the selectivity of the reaction are improved, the occurrence of side reactions is reduced, and the quality is improved; the environmental pollution is reduced, the generation of waste liquid and waste gas is reduced, and the cost is reduced, so that the method has important significance for the industrial production of the voriconazole.
Example 5
Voriconazole is further synthesized by using the intermediate 3 prepared by the invention (the method is shown in a reference document US6586594B 1), and the hydrogen spectrum and the mass spectrum of the synthesized voriconazole are consistent with those reported in a document US6586594B 1.
It will be apparent to those skilled in the art that various changes and modifications can be made in the above embodiments without departing from the spirit and scope of the invention, and it is intended that all such changes and modifications as fall within the true spirit and scope of the invention be interpreted in accordance with the principles of the invention. And the invention is not limited to the example embodiments set forth in the description.
Claims (2)
1. A synthetic method of voriconazole intermediate is characterized by comprising the following steps:
under the catalysis of a catalyst, the starting material intermediate 2 reacts with ammonium formate under the catalysis of 10% palladium-carbon, the reaction condition is that the temperature is 25-30 ℃, and the time is 1 hour; distilling at 50-60 deg.C under reduced pressure, and stirring with water at 25-30 deg.C to obtain intermediate 3; the molar ratio of the intermediate 2 to the ammonium formate is 1: 2-4; the molar ratio of the intermediate 2 to water is 1: 2-5; the mass ratio of the intermediate 2 to 10 percent palladium-carbon is 20: 0.5-1.
2. Use of voriconazole prepared by the synthesis method of claim 1 for improving product yield and simplifying purification equipment.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632267A (en) * | 2016-11-09 | 2017-05-10 | 中国科学院成都生物研究所 | Method for synthesizing voriconazole |
| CN112079819A (en) * | 2020-09-24 | 2020-12-15 | 南京易亨制药有限公司 | Improved voriconazole racemate preparation method |
| CN114057699A (en) * | 2021-07-13 | 2022-02-18 | 陕西丽彩药业有限公司 | Preparation method of voriconazole intermediate raceme |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106632267A (en) * | 2016-11-09 | 2017-05-10 | 中国科学院成都生物研究所 | Method for synthesizing voriconazole |
| CN112079819A (en) * | 2020-09-24 | 2020-12-15 | 南京易亨制药有限公司 | Improved voriconazole racemate preparation method |
| CN114057699A (en) * | 2021-07-13 | 2022-02-18 | 陕西丽彩药业有限公司 | Preparation method of voriconazole intermediate raceme |
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Application publication date: 20220819 |