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Preparation method of posaconazole main ring intermediate

A technology for the main ring and intermediates of posaconazole, which is applied in the field of medicinal chemistry synthesis, can solve the problems of reducing the reaction conversion rate, high cost, not conforming to the concept of green chemistry, etc., and achieves reducing the generation of by-products, improving yield, The effect of reducing production costs

Pending Publication Date: 2022-06-28
ZHANGJIAKOU GERUI HIGH TECH
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  • Description
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Problems solved by technology

1-[1-(bromomethyl)ethylene]-2,4-difluoro-benzene is an indispensable important intermediate for preparing the economical process route of the main ring of posaconazole, and its molecular formula C 9 h 7 BrF 2 , molecular weight 233.05, structural formula see Figure 4 , but currently the cost of synthesizing 1-[1-(bromomethyl)ethylene]-2,4-difluoro-benzene is relatively high, and the synthesis process is often accompanied by the formation of isomers of the target product, which greatly reduces the reaction The conversion rate is not in line with the concept of green chemistry

Method used

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  • Preparation method of posaconazole main ring intermediate
  • Preparation method of posaconazole main ring intermediate
  • Preparation method of posaconazole main ring intermediate

Examples

Experimental program
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Embodiment 1

[0060] Embodiment 1 A kind of preparation method of posaconazole main ring intermediate

[0061] The present embodiment is a preparation method of a posaconazole main ring intermediate, including the following steps performed in sequence:

[0062] Preparation of S1.2-(2,4-difluorophenyl)propan-2-ol

[0063] Take 100.0kg of methyl tertiary butyl ether and place it in a 300L reaction kettle. Under the protective gas nitrogen environment, start the temperature control system to make the temperature of the reaction kettle to -5°C, and add 3mol / L methyl bromide at 85 rpm. 80.0kg of magnesium tetrahydrofuran solution, control the temperature of the system at 3°C, add 20.0kg of 2,4-difluoroacetophenone dropwise, and control the temperature of the system to be 0-5°C during the dropwise addition. After the completion of the dropwise addition, the temperature of the system in the reaction process was controlled to be 15 to 20°C, and the reaction process was monitored by TLC method. Aft...

Embodiment 2-7

[0103] Embodiment 2-7 The preparation method of posaconazole main ring intermediate

[0104] Embodiments 2-7 are respectively a preparation method of a posaconazole main ring intermediate, and their steps are basically the same as those of embodiment 1, and the difference is only in the amount of raw materials and process parameters, and the amount of raw materials in different embodiments is specific. See Table 2 for details, and see Table 3 for various process parameters of different preparation steps.

[0105] Table 2 Raw Material Consumption Table in Examples 2 to 7

[0106]

[0107]

[0108] Table 3 step process parameter table in embodiment 2~7

[0109]

[0110] Example 2-7 A summary table of the yields of 1-[1-(bromomethyl)ethylene]-2,4-difluoro-benzene that finally obtains the target product with 2,4-difluoroacetophenone as a raw material, The specific data are shown in Table 4.

[0111] Table 4 target product yield summary table

[0112]

[0113] As ca...

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Abstract

The invention discloses a preparation method of a posaconazole main ring intermediate, which comprises the following steps: sequentially preparing 2-(2, 4-difluorobenzene) propane-2-alcohol, 1-(1-propylene-2-yl)-2, 4-difluorobenzene and 1-bromine-2-(2, 4-difluorobenzene)-isopropanol, and finally preparing a target product 1-[1-(bromomethyl) ethylene]-2, 4-difluorobenzene. The preparation method comprises the following steps: firstly, synthesizing 1-[(1E)-1-bromopropyl-1-ene-2-yl]-2, 4-difluoro-benzene and an isomer 1-[(1E)-1-bromopropyl-1-ene-2-yl]-2, 4-difluoro-benzene, and then converting the isomer 1-[(1E)-1-bromopropyl-1-ene-2-yl]-2, 4-difluoro-benzene into a target product. According to the preparation method provided by the invention, the relatively economical solvent and catalyst are selected, and the isomer is converted into the target product, so that the yield of the target product can be improved, and the production cost can be reduced. The method can be used for preparing the posaconazole main ring intermediate, and the prepared posaconazole main ring intermediate is further applied to production of posaconazole.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemical synthesis, and relates to a preparation method of a posaconazole intermediate, in particular to a preparation method of a posaconazole main ring intermediate. Background technique [0002] Posaconazole (Posaconazole) is a derivative of itraconazole. It is the second-generation triazole antifungal drug with high lipophilicity, which was first introduced and marketed in Germany on October 25, 2005. Low and broad antibacterial spectrum and other advantages. Posaconazole oral suspension and posaconazole enteric-coated tablets were successfully approved to enter the Chinese market in June 2013 and December 2018, respectively. At present, posaconazole is a first-line drug with a very large clinical demand in my country. [0003] Posaconazole, its API chemical name is 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...

Claims

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Application Information

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IPC IPC(8): C07C17/358C07C17/35C07C25/24
CPCC07C17/358C07C17/35C07C29/64C07C29/40C07C25/24C07C33/46Y02P20/55
Inventor 孙文王毅仝海云李君
Owner ZHANGJIAKOU GERUI HIGH TECH
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