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Prepartion method of itraconazole

An itraconazole and compound technology, applied in the field of preparation of itraconazole, can solve the problems of affecting the internal quality control of itraconazole products, the price of cis-bromoester is relatively expensive, the process operation is complicated and tedious, and the The effect of high reaction selectivity and purity, environmental friendliness and high purity

Active Publication Date: 2016-11-23
SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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  • Abstract
  • Description
  • Claims
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AI Technical Summary

Problems solved by technology

[0015] The above-mentioned synthesis method has the following deficiencies: (1) The process operation is complicated and cumbersome, and it needs to be synthesized through three steps such as first preparing triazole sodium, then N-alkylating with cis-bromoester, and finally being synthesized by three steps such as sodium hydroxide alkali hydrolysis Triazoles, long production cycle
(2) The raw material cis-bromoester is more expensive
(3) The yield is low, only 50% to 60%, and the isomer impurity content is relatively high, about 15%. Excessive isomer impurity content will lead to a high content of related substances in the itraconazole finished product, or even exceed the standard , seriously affected the internal quality control of itraconazole products

Method used

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  • Prepartion method of itraconazole
  • Prepartion method of itraconazole
  • Prepartion method of itraconazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0043] Embodiment 1-1: the synthesis of trityl-glycidyl ether (1)

[0044]Trityl chloride (139.4g, 0.5mol) was dissolved in 5000mL of dichloromethane, 4-diaminopyridine (DMAP, 3g, 25mmol) and triethylamine (100mL) were added, and (±)-epoxypropylene was dropped under stirring Dichloromethane solution (500mL) of alcohol (37g, 0.5mol) was reacted at room temperature for 3 hours; a large amount of white solid was precipitated, the solid was filtered off, the solution was washed with saturated sodium chloride solution (300mL), dried over anhydrous sodium sulfate, and concentrated Recrystallized from absolute ethanol and dried to obtain a white solid (109.6 g, 1), with a yield of 69.3%.

Embodiment 1-2

[0045] Embodiment 1-2: the synthesis of trityl-glycidyl ether (1)

[0046] Trityl chloride (153.3g, 0.55mol) was dissolved in 5000mL chloroform, 4-diaminopyridine (DMAP, 3g, 25mmol) and triethylamine (120mL) were added, and (±)-glycidyl alcohol ( 37g, 0.5mol) in chloroform solution (500mL), reacted at room temperature for 5 hours; a large amount of white solid was precipitated, the solid was filtered out, the solution was washed with saturated sodium chloride solution (300mL), dried over anhydrous sodium sulfate, concentrated and then washed with absolute ethanol Recrystallized and dried to obtain a white solid (119.0 g, 1), with a yield of 75.2%.

Embodiment 2-1

[0047] Embodiment 2-1: Preparation of compound 2

[0048] Sodium hydride (50% in mineral oil, 0.7 mol) was washed twice with 1 L of hexane, then dried under nitrogen. Dry dimethylformamide (0.5 L) was added. Then, keeping the temperature below 50°C, benzyl alcohol (140 mL) was added dropwise at a certain rate, and the dropwise addition was completed within 2 hours. Compound 1 (110.7g, 0.35mol) was added dropwise for 0.5 hours, cooled to keep the temperature below 40°C, stirred at 20°C for 16 hours, and then stirred at 50°C for 2.5 hours. Evaporate under reduced pressure to remove dimethylformamide, dissolve the oily residue with 1L of ether, and use 0.5L of water, 0.5L of 2% hydrochloric acid solution, 0.5L of 1% sodium bicarbonate solution, and 0.35 L was washed with brine, dried over anhydrous sodium sulfate, and concentrated to give a brown oil (compound 2, 104.5 g), with a yield of 70.5%.

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Abstract

The invention discloses a preparation method of itraconazole. Raceme-glycidol which is cheap and easy to obtain is adopted as raw materials, hydroxyls at the two ends are protected by trityl and benzyl and then esterified by 2,4-dichlorobenzene formyl chloride, then, a silylation Grignard addition reaction and a beta-silicyl alcohol elimination reaction are adopted for reducing carbonyl into carbon-carbon double bonds, iodine is adopted for performing an olefin addition reaction and a stereoselectivity ring-closure reaction, triazole replacement and debenzylation are performed, and tosyl is introduced to obtain a compound 9; the compound and a compound 10 are subjected to a condensastion reaction to obtain itraconazole; the overall synthesis process is small in pollution, easy to process, few in by-product, high in reaction selectivity and purity, environmentally friendly, low in production cost and suitable for industrial production; the defects that in the prior art, the selectivity is poor, multiple by-products are produced, the yield is low, and expensive catalysts and reagents with large environmental pollution are avoided are avoided.

Description

technical field [0001] The invention relates to the technical field of medicine and chemical industry, in particular to a preparation method of itraconazole. Background technique [0002] Itraconazole is currently a broad-spectrum triazole antifungal drug with good efficacy and few side effects. It has a broad antibacterial spectrum in vitro. It can be injected into the lung infection site for the treatment of pulmonary Aspergillus infection. Its English name is Itraconazole, and its Chinese chemical name is cis-4-[4-[4-[4-[[-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-three Azol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2'S)-1-methyl propyl]-1,2,4-triazol-3-one. Its chemical structural formula is as follows: [0003] [0004] Itraconazole has 3 chiral carbon atoms, and there are 8 optical isomers in total. The clinical use is a mixture of 4 cis isomers on the dioxolane ring in its structure, corresponding to 2S, 4R, 2 'R-Itraconazole (A), 2S,4R,2...

Claims

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Application Information

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IPC IPC(8): C07D405/14C07D405/06C07D317/24C07C67/14C07C69/76C07C41/18C07C43/178C07B53/00
CPCY02P20/55C07D405/14C07B53/00C07B2200/07C07C41/18C07C67/14C07D317/24C07D405/06C07C69/76C07C43/178
Inventor 刘新泉郑苏苏刘伟
Owner SHANDONG LUOXIN PHARMA GRP HENGXIN PHARMA CO LTD
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