CN108329304B - Preparation method of itraconazole derivative - Google Patents
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Abstract
The invention discloses a preparation method of an itraconazole derivative, which takes 1-acetyl-4- (4-hydroxyphenyl) piperazine as a raw material to realize the synthesis of the itraconazole derivative through six-step reaction. The preparation method provided by the invention has the advantages of reasonable process design, strong operability, mild reaction conditions and high yield, and can realize industrial production. The itraconazole derivative prepared by the invention can provide important basis for scientific evaluation of itraconazole quality, safety and efficacy, has good pharmacological activity, can be used for developing medicaments for treating fungal infection caused by various reasons, and has important application value.
Description
Technical Field
The invention relates to a preparation method of a compound, in particular to a preparation method of an itraconazole derivative.
Technical Field
Itraconazole is a synthesized broad-spectrum antifungal drug, is a triazole derivative, and is invented in 1984, and the drug can be orally taken or injected intravenously. Effective against dermatophytes (trichophyton, microsporum, epidermophyton floccosum), yeasts [ cryptococcus neoformans, pityrosporum, candida (including candida albicans, candida glabrata, and candida krusei), aspergillus, histoplasma, paracoccidiopsis brasiliensis, trichosporon, chromomyces, cladosporium, blastomyces dermatitidis, and various other yeast and fungal infections. In vitro studies have demonstrated that the product inhibits the synthesis of ergosterol, a major component of fungal cell membranes, thereby exerting antifungal effects.
It is the basic drug list of the world health organization, and is the most important drug in the basic health system. Compared with fluconazole, itraconazole has a wider activity range. It can also be used for treating cystic disease, sporular disease, histoplasmosis, and onychomycosis. Itraconazole has more than 99% of protein, and hardly permeates into cerebrospinal fluid. Therefore, it should not be used to treat meningitis or other central nervous system infections. It is also used for systemic infections such as aspergillosis, candidiasis and cryptococcosis. Itraconazole has also been reported to be useful in the treatment of basal cell carcinoma, non-small cell lung cancer and prostate cancer.
With the progress of the times and the improvement of the technological level, people have more sufficient understanding on the importance of scientific evaluation of the quality, safety and efficacy of the medicine before the medicine is on the market, and the control of the derivative contained in the medicine is closely related to the quality of the medicine. Derivatives are often associated with drug safety and in a few cases also with efficacy. Therefore, controlling the level of derivatives is becoming more and more important to medical workers in the process of drug development and research.
The synthetic method of the itraconazole derivative provided by the invention is not reported, and the itraconazole derivative is possibly provided with better medicinal prospect by performing related researches on pharmacology, pharmacokinetics and the like on the itraconazole derivative.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to overcome the defects in the prior art and provide a method for synthesizing a novel drug molecule itraconazole derivative, which has the advantages of reasonable process design, high yield and convenient and controllable operation process.
The technical scheme is as follows: in order to achieve the above purpose, the invention adopts the technical scheme that:
a preparation method of itraconazole derivatives comprises the following steps:
(1) dissolving 1-acetyl-4- (4-hydroxyphenyl) piperazine I in a polar aprotic solvent, adding alkali, then adding a compound X, and heating and stirring to react to obtain a compound II;
(2) dissolving the compound II in an organic solvent, adding alkali, heating, stirring, reacting, and recrystallizing, purifying and separating to obtain a compound III;
(3) dissolving a compound III in a polar aprotic solvent, adding p-nitrohalogenated benzene and inorganic base in an ice bath, and reacting to obtain a compound IV;
(4) dissolving the compound IV in an organic solvent, and adding a reducing agent to reduce to obtain a compound V;
(5) suspending the compound V in pyridine and triethylamine, adding diformylhydrazine under the ice bath condition, reacting overnight, cooling, and separating to obtain a compound VI;
(6) and suspending the compound VI in an organic solvent, adding iodosec-butyl alkane, and performing reflux reaction to obtain a compound VII, namely the itraconazole derivative.
As a preferable mode, the preparation method of the itraconazole derivative comprises the following steps:
(1) dissolving 1-acetyl-4- (4-hydroxyphenyl) piperazine I in a polar aprotic solvent, adding an alkali, adding a compound X at 0-20 ℃, and heating and stirring for 2-4 hours to obtain a compound II;
(2) dissolving the compound II in an organic solvent, adding alkali, heating and stirring at 50-120 ℃ for 20h, and then recrystallizing, purifying and separating to obtain a compound III;
(3) dissolving a compound III in a polar aprotic solvent, adding p-nitrohalogenated benzene and inorganic base in an ice bath, and reacting at 110 ℃ for 18 hours to obtain a compound IV;
(4) dissolving the compound IV in an organic solvent, and adding a reducing agent for reduction to obtain a compound V;
(5) suspending the compound V in pyridine and triethylamine, adding diformylhydrazine under the ice bath condition, reacting at 100 ℃ overnight, cooling, and separating by column chromatography to obtain a compound VI;
(6) and suspending the compound VI in an organic solvent, adding iodosec-butyl alkane, and refluxing for 20 hours to react to obtain a compound VII, namely the itraconazole derivative.
The itraconazole derivative prepared by the invention has the chemical name of 4- (4- (4- (4- (((2R,4S) -2- ((1H-1,2, 4-triazole-1-yl) methyl) -2- (2, 4-dichlorophenyl) -1, 3-dioxa-4-yl) methoxyl) phenyl) piperazine-1-yl) phenyl) -1- (sec-butyl) -1H-1,2, 4-triazole-4-iodine molecular weight of 817.55, and the molecular formula of C35H39Cl2IN8O3The structural formula is as follows:
preferably, in the preparation method of itraconazole derivatives described above, the polar aprotic solvent in step (1) is dimethyl sulfoxide, dimethylformamide, dimethylacetamide, or acetonitrile.
Preferably, in the preparation method of itraconazole derivatives described above, the base in step (1) is sodium hydride, sodium hydroxide or potassium hydroxide; the reaction time is 2 to 4 hours.
Preferably, in the preparation method of itraconazole derivatives described above, the organic solvent in step (2) is methanol, ethanol, isopropanol, tetrahydrofuran or acetone.
Preferably, in the preparation method of itraconazole derivatives described above, the base in step (2) is sodium hydroxide or potassium hydroxide.
Preferably, in the method for preparing itraconazole derivatives, the polar aprotic solvent in step (3) is dimethyl sulfoxide, dimethylformamide, dimethylacetamide or acetonitrile.
Preferably, in the preparation method of itraconazole derivatives described above, the inorganic base in step (3) is potassium carbonate or cesium carbonate.
Preferably, in the preparation method of itraconazole derivatives, the organic solvent in step (4) is ethanol, methanol, isopropanol, tetrahydrofuran or ethyl acetate.
In the preferable embodiment, in the preparation method of itraconazole derivatives, the reducing agent in step (4) is iron powder, zinc powder, palladium on carbon or stannous chloride.
Preferably, in the preparation method of itraconazole derivatives described above, the organic solvent in step (6) is acetonitrile, acetone or 2-butanone.
Preferably, in the method for preparing the itraconazole derivative, the compound X in the step (1) is cis-methanesulfonic acid- [2- (2, 4-dichlorophenyl) -2- (1H-1,2, 4-triazol-1-ylmethyl) -1, 3-dioxolan-4-yl ] methyl ester.
Has the advantages that: the preparation method of the itraconazole derivative provided by the invention has the following advantages:
1. the synthesis method of the novel drug molecule itraconazole derivative provided by the invention has the advantages of reasonable process design, simple operation method, easily obtained raw materials, high synthesis efficiency, scalable production process, high purity, controllable reaction process and good environmental protection effect.
2. The itraconazole derivative prepared by the invention can provide important basis for scientific evaluation of the quality, safety and efficacy of itraconazole, can be used for developing medicaments for treating fungal infection caused by various reasons, and has important application value.
Drawings
Fig. 1 is a flow chart of a preparation process of itraconazole derivatives provided by the present invention.
Detailed Description
The following examples are intended to illustrate the invention in detail, but are not intended to limit the invention.
Example 1
As shown in fig. 1: the preparation method of the itraconazole derivative specifically comprises the following steps:
(1) preparation of compound ii:
dissolving 1-acetyl-4- (4-hydroxyphenyl) piperazine (compound I) (22.00g,96mmol) in dimethyl sulfoxide (500mL), dropwise adding a dimethyl sulfoxide solution of sodium hydroxide (2.5g) in an ice bath, continuously stirring for one hour in an ice bath after the addition is finished, adding a compound X (30g), stirring for reaction for two hours after the addition is finished and the temperature is raised to 90 ℃, cooling, adding water for dilution, extracting with ethyl acetate, drying an extract, concentrating, purifying by silica gel column chromatography (the volume ratio of an eluent is dichloromethane-methanol is 50:1) to obtain a compound II (35g), and the yield is 89.0%.
Of compounds II1H NMR(400MHz,CDCl3):8.23(s,1H),7.92(s,1H),7.60～7.59(d,1H),7.50(d,1H),6.98～6.96(d,2H),6.83～6.80(d,2H),4.86～4.75(dd,2H),4.52(br,2H),4.38～4.35(m,1H),3.94～3.92(t,1H),3.90～3.80(m,2H),3.52～3.50(m,1H),3.50～3.40(m,4H),3.30～3.25(m,4H),2.10(s,3H).MS:532.2[M-H]+。
(2) Compound III is prepared by suspending compound II (23g,43mmol) in methanol (350mL), adding 230mL of 3N NaOH solution, reacting at 68 ℃ for 20 hours, concentrating to 50mL, adding water, extracting with dichloromethane (500mLx 2), combining the organic phases, drying, concentrating, and slurrying with n-hexane to obtain 19g of compound III as a white solid with a yield of 89.7%.
Of compounds III1H NMR(400MHz,CDCl3):8.21(s,1H),7.90(s,1H),7.59～7.57(d,1H),7.48(d,1H),6.96～6.94(d,2H),6.82～6.80(d,2H),4.86～4.75(dd,2H),4.52(br,2H),4.38～4.35(m,1H),3.94～3.92(t,1H),3.90～3.80(m,2H),3.52～3.50(m,1H),3.50～3.40(m,4H),3.30～3.25(m,4H).MS:490.2[M-H]+。
(3) The compound IV is prepared by dissolving a compound III (19g, 39mmol) in dimethyl sulfoxide (190mL), adding p-chloronitrobenzene (6.3g, 39mmol) and potassium carbonate (11g, 77mmol) under the condition of ice bath for reaction at 110 ℃ for 18 hours, cooling to room temperature, pouring into ice water to obtain a light yellow suspension, filtering, washing with water, and drying under vacuum to obtain 22g of a yellow solid compound IV with the yield of 92.8%.
Of compounds IV1H NMR(400MHz,CDCl3):8.25(s,1H),7.90(s,1H),7.59～7.57(d,1H),7.48(d,1H),7.29～7.25(m,2H),7.08～7.05(d,2H),6.96～6.94(d,2H),6.82～6.80(d,2H),4.86～4.75(dd,2H),,4.38～4.35(m,1H),3.94～3.92(t,1H),3.90～3.80(m,2H),3.52～3.50(m,1H),3.50～3.40(m,4H),3.30～3.25(m,4H).MS:611.2[M-H]+。
(4) Preparation of Compound V Compound IV (11g,18mmol) is suspended in ethanol (180mL) and water (40mL), iron powder (11g) and ammonium chloride (4g) are added, reaction is carried out at 110 ℃ for 3 hours, suction filtration is carried out while hot, and 11g of Compound V is obtained as a light brown solid after filtrate is dried by spinning, with the yield of 100%.
Of compound V1H NMR(400MHz,CDCl3):8.24(s,1H),7.90(s,1H),7.59～7.57(d,1H),7.48(d,1H),7.29～7.25(m,2H),7.08～7.05(d,2H),6.96～6.94(d,2H),6.82～6.80(d,2H),4.86～4.75(dd,2H),4.52(br,2H),4.38～4.35(m,1H),3.94～3.92(t,1H),3.90～3.80(m,2H),3.52～3.50(m,1H),3.50～3.40(m,4H),3.30～3.25(m,4H).MS:581.2[M-H]+。
(5) Preparation of compound VI Compound V (7.5g,13mmol) was suspended in pyridine (180mL) and triethylamine (45mL), added with diformylhydrazine (3.43g, 39mmol) under ice bath conditions, reacted at 100 ℃ for 22 hours, cooled in ice bath, added with saturated brine, extracted with ethyl acetate (300mLx 3), combined organic phases, dried, and then purified with dichloromethane in a volume ratio of 10: 1: the column chromatography was performed using methanol as the eluent to obtain 8.01g of a pale yellow solid compound VI with a yield of 97.9%.
Of compounds VI1H NMR(400MHz,CDCl3):8.40(s,2H),8.21(s,1H),7.90(s,1H),7.59～7.57(d,1H),7.48(d,1H),7.29～7.25(m,2H),7.08～7.05(d,2H),6.96～6.94(d,2H),6.82～6.80(d,2H),4.86～4.75(dd,2H),4.38～4.35(m,1H),3.94～3.92(t,1H),3.90～3.80(m,2H),3.52～3.50(m,1H),3.50～3.40(m,4H),3.30～3.25(m,4H).MS:633.2[M-H]+。
(6) Preparation of Compound VII Compound VI (3.6g, 6mmol) was suspended in acetonitrile (100mL), and sec-butyl iodide (2.5g, 12mmol) was added at room temperature and reacted at 90 ℃ for 24 hours to form a pale yellow suspension. The reaction solution was cooled to room temperature, filtered, washed with methanol, and dried under vacuum to give a off-white solid compound VII (99.77% HPLC) with a yield of 91.0%.
Of compounds VII1H NMR(400MHz,CDCl3):12.2(s,1H),8.54(s,1H),8.21(s,1H),7.90(s,1H),7.75(d,2H),7.60(d,2H),7.48(s,1H),7.27(d,1H),7.10(d,2H),6.90(d,2H),6.80(d,2H),5.15～5.30(m,1H),4.70～4.90(dd,2H),4.30～4.40(m,1H),3.80～4.0(m,3H),3.4～3.60(m,6H),3.21(m,4H),2.0～2.2(m,2H),1.74(d,3H),0.98(t,3H).MS:689.2[M-H]+。
EXAMPLE 2 antifungal experiments
1. The experimental method comprises the following steps:
preparation of bacterial liquid
Before experiment, after the experimental bacteria are activated, the microzyme is cultured on a Sabourgeon weak agar medium (SDA) for 48 hours at the temperature of 30 ℃; culturing filamentous fungi in Potato Dextrose Agar (PDA) culture medium at 26 deg.C for 7-10 days; preparing into suspension with sterile normal saline, counting with a blood ball counter, diluting with 2% glucose RMPI-1640 liquid culture medium to obtain 1.0 × 10% Candida albicans3cfu/mL; the other filamentous fungi are prepared into 2.5 × 104cfu/mL. 0.1mL of each of the bacterial solutions was added to each well with a medium containing the compound VII prepared in example 1, 11 wells were used as a medium control, and 12 wells were used as a medium control. The vehicle control well was filled with 0.1mL of diluted vehicle and the control well was filled with 0.1mL of distilled water. After the sample is added, the mixture is placed on a plate shaking machine at the rotating speed of 100r/min multiplied by 10min so as to lead the medicines and the bacteria to be mixedThe liquids are in full contact. Liquid medium containing 2% glucose RMPI-1640 without any antibiotic was used as the basal medium.
2. Method for determining experimental result
80% minimum inhibitory concentration (80% MIC): taking the growth of blank control and solvent control poriferous bacteria as reference, the bacteria in the drug-based holes only grow 80% to show that the bacteria have bacteriostasis, and the bacteria grow to show that the bacteria have no bacteriostasis. The specific experimental results are shown in table 1:
TABLE 1 results of 80% MIC determination of itraconazole derivatives for fungi
The experimental results show that the itraconazole derivative prepared by the method provided by the invention has a certain antifungal effect.
Claims (1)
1. A preparation method of itraconazole derivatives is characterized by comprising the following steps:
(1) dissolving 1-acetyl-4- (4-hydroxyphenyl) piperazine in a polar aprotic solvent, adding alkali, adding a compound X at the temperature of 0-20 ℃, and heating and stirring for 2-4 hours to obtain a compound II;
(2) dissolving the compound II in an organic solvent, adding alkali, heating and stirring at 50-120 ℃ for 20h, and then recrystallizing, purifying and separating to obtain a compound III;
(3) dissolving a compound III in a polar aprotic solvent, adding p-nitrohalogenated benzene and inorganic base in an ice bath, and reacting at 110 ℃ for 18 hours to obtain a compound IV;
(4) dissolving the compound IV in an organic solvent, and adding a reducing agent for reduction to obtain a compound V;
(5) suspending the compound V in pyridine and triethylamine, adding diformylhydrazine under the ice bath condition, reacting overnight at 100 ℃, cooling, and separating by column chromatography to obtain a compound VI;
(6) suspending the compound VI in an organic solvent, adding iodosec-butyl alkane, and refluxing for reaction for 20 hours to obtain a compound VII, namely the itraconazole derivative
The polar aprotic solvent in the step (1) is dimethyl sulfoxide, dimethylformamide, dimethylacetamide or acetonitrile; the alkali in the step (1) is sodium hydride, sodium hydroxide or potassium hydroxide;
the molar using amount ratio of the 1-acetyl-4- (4-hydroxyphenyl) piperazine to the compound X is 1: 1-1: 1.5; the compound X is cis-methanesulfonic acid- [2- (2, 4-dichlorophenyl) -2- (1H-1,2, 4-triazole-1-ylmethyl) -1, 3-dioxolan-4-yl]Methyl ester; the structural formula is as follows:
the organic solvent in the step (2) is methanol, ethanol, isopropanol, tetrahydrofuran or acetone; the alkali in the step (2) is sodium hydroxide or potassium hydroxide;
the polar aprotic solvent in the step (3) is dimethyl sulfoxide, dimethylformamide, dimethylacetamide or acetonitrile; the inorganic base is potassium carbonate or cesium carbonate;
the organic solvent in the step (4) is ethanol, methanol, isopropanol, tetrahydrofuran or ethyl acetate; the reducing agent is iron powder, zinc powder or stannous chloride;
the molar use ratio of the compound V to the diformylhydrazine in the step (5) is 1: 1-1: 5;
the organic solvent in the step (6) is acetonitrile, acetone or 2-butanone; the molar using amount ratio of the compound VI to the iodo-sec-butyl alkane is 1: 1-1: 3.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4267179A (en) * | 1978-06-23 | 1981-05-12 | Janssen Pharmaceutica, N.V. | Heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US4267179A (en) * | 1978-06-23 | 1981-05-12 | Janssen Pharmaceutica, N.V. | Heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)methyl-1H-imidazoles and 1H-1,2,4-triazoles |
Non-Patent Citations (2)
| Title |
|---|
| Antimycotic Azoles. 7. Synthesis and Antifungal Properties of a Series of Novel Triazol-3-ones;J. Heeres et al.;《J. Med. Chem.》;19841231;第27卷(第10期);第894-900页 * |
| Cardiotonic Agents. 2. Synthesis and Structure-Activity Relationships of 4,5-Dihydro-6-[4-( 1H-imidazol-l-yl)phenyl]-3(2H)-pyridazinones: A New Class of Positive Inotropic Agents";Ila Sircar et al.;《J. Med. Chem.》;19851231;第28卷(第10期);第1405-1413页 * |
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