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Preparation method of Noxafil

The technology of a posaconazole and a purification method is applied in the field of preparation of posaconazole, can solve the problems of many by-products, low total yield, complicated operation, etc., and achieves few reaction by-products, no heavy metal residues, and simple operation. safe effect

Pending Publication Date: 2019-12-20
SHANGHAI BOCIMED PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The technical problem to be solved by the present invention is in order to overcome the complex operation of the preparation method of posaconazole in the prior art, many reaction steps, many by-products, low conversion rate, low total yield, poor product purity and production cost. High, unsuitable for industrialized production and other defects and provide a kind of preparation method of posaconazole

Method used

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  • Preparation method of Noxafil
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  • Preparation method of Noxafil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Embodiment 1: Preparation of phenyl (4-(4-(4-hydroxyl)-1-piperazinyl) phenyl) carbamate (V)

[0030]

[0031] Add 4.00kg of 1-(4-aminophenyl)-4-(4-hydroxyphenyl)piperazine (VII) and 35.57kg of tetrahydrofuran into a 100L glass reactor, start stirring, and cool down to 0-10°C. Keep the temperature below 25°C and add 2.56 kg of phenyl chloroformate (VIII) dropwise, and the dropwise addition is completed in 0.5-1 hour, and the reaction is continued for 0.5-1.0 hour under temperature control at 20-25°C. The reaction was monitored by TLC. After the reaction was completed, the temperature was lowered to 0-10°C, and saturated aqueous sodium bicarbonate solution (2.00 kg of sodium bicarbonate dissolved in 38 kg of purified water) was added, followed by 20 kg of purified water, and stirred for 10-20 min. Centrifugal filter until almost no solvent flows out, then rinse with 8kg of purified water, and centrifugal filter until basically no solvent flows out.

[0032]The whole b...

Embodiment 2

[0033] Example 2: 2-((2S,3S)-2-(benzyl)-3-pentyl)-4-(4-(4-(4-hydroxyl)-1-piperazine)phenyl)-2 , Preparation of 4-dihydro-3-hydro-1,2,4-triazol-3-one (III)

[0034]

[0035] Add 4.36kg N'-((2S,3S)-2-benzyloxy)pentyl-3-formylhydrazide oxalate (VI) and 45.36kg dioxane into a 100L glass reactor, start stirring, Add 3.45 kg N,N-diisopropylethylamine. After stirring for 1-1.5 hours, 5.47 kg of phenyl (4-(4-(4-hydroxy)-1-piperazinyl)phenyl)carbamate (V) was added. After the addition, the temperature was raised to 80±5°C for 24-30 hours. TLC monitoring. After the reaction was completed, the temperature of the system was lowered to 15-25° C., 57.79 kg of dichloromethane and 21.81 kg of pure water were added, stirred for 10-20 minutes, and the layers were separated. The lower organic phase was collected, and the aqueous phase was discarded. The organic phase was transferred to a 100L glass reactor, and 21.81 kg of purified water was added to the reactor, stirred for 10-20 minutes...

Embodiment 3

[0036] Example 3: 4-(4-(4-(4-(((3R,5R)-5-((1-hydrogen-1,2,4-l-1-triazolyl)methyl)-5 -(2,4-Difluorophenyl)-3-tetrahydrofuryl)methoxy)phenyl)-1-piperazinyl)phenyl)-2-((2S,3S)-2-(benzyl) Preparation of -3-pentyl)-2,4-dihydro-3-hydro-1,2,4-triazol-3-one (II)

[0037]

[0038] With 35.01kg dimethyl sulfoxide, mass concentration is 50% sodium hydroxide aqueous solution (sodium hydroxide 1.24kg is dissolved in pure water 1.24kg, and described mass concentration refers to that the quality of sodium hydroxide accounts for the total mass of sodium hydroxide aqueous solution %), added to a 50L glass reactor, stirred to dissolve, then added 5.31kg of compound (III), stirred for 20 to 30 minutes, added 4.60Kg (3S,5R)-toluene-4-sulfonic acid 5-(2, 4-difluorophenyl)-5-(1H-1,2,4-triazol-1-yl)methyltetrahydrofuran-3-ylmethyl ester (IV). After the feeding is completed, the temperature is controlled at 25±5°C for 8-12 hours. TLC monitors the reaction, after the reaction is complete. Contr...

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Abstract

The invention discloses a preparation method of Noxafil. The preparation method of Noxafil I comprises the following step of performing a hydrolysis reaction on a compound II in the presence of an inorganic protonic acid so as to obtain Noxafil I. The preparation method has simple and safe operation, no requirements for special equipment, no heavy metal residues, few reaction byproducts and high yield, the product has high purity, and the chiral purity is greater than 99.90%; the purity of related substances is greater than 99.50%, all impurities are less than 0.1%, and standard requirements of crude drugs can be met; and the production cost is low, environmental protection is achieved, and the preparation method is suitable for industrial production.

Description

[0001] This application is a divisional application of a patent with the application number 201611026296.X, the application date is November 22, 2016, and the invention name is "a preparation method of posaconazole". technical field [0002] The invention relates to a preparation method of posaconazole. Background technique [0003] Posaconazole (CAS number: 171228-49-2; chemical name: 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl) -5-(1,2,4-Triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[( 2S,3S)-2-hydroxypentyl-3-yl]-1,2,4-triazol-3-one) is a triazole antifungal drug, the structure is as shown in formula I: [0004] [0005] Posaconazole (trade name Noxafil) is a third-generation antifungal drug developed by Schering-Plough Pharmaceutical Co., Ltd. It was first launched in Germany in December 2005, and it was launched in the UK in March 2006 until September 18, 2006. Received FDA approval. Posaconazole has a wide range of antibacterial properties...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/14
CPCC07D405/14
Inventor 应述欢皮红军刘振峰陈健乔岩河
Owner SHANGHAI BOCIMED PHARMA CO LTD
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