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Preparation method of intermediate compound for synthesizing posaconazole and intermediate compound prepared by preparation method

A posaconazole intermediate and compound technology, applied in the field of medicinal chemistry, can solve problems such as not being suitable for large-scale production and affecting yield, and achieve the effects of easy large-scale production, less impurity content, and low cost

Pending Publication Date: 2022-06-07
ZHEJIANG AUSUN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] However, this synthetic scheme is prone to produce intramolecular ring-closing impurities, which can be removed but affect the yield
And this process used flammable, expensive n-butyllithium and titanium tetrachloride which is easy to absorb moisture and corroded when preparing 2-oxazolidinone lithium salt, which is not suitable for large-scale production

Method used

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  • Preparation method of intermediate compound for synthesizing posaconazole and intermediate compound prepared by preparation method
  • Preparation method of intermediate compound for synthesizing posaconazole and intermediate compound prepared by preparation method
  • Preparation method of intermediate compound for synthesizing posaconazole and intermediate compound prepared by preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0145] Example 1: Preparation of compounds of formula VI

[0146]

[0147] Under nitrogen protection, 40 g of the compound of formula X and 200 g of toluene were added to a 500 mL reaction flask, and stirred to dissolve. Use liquid nitrogen to cool down to about -80°C, add 90g of 1.5M toluene solution of diisobutylaluminum hydride (DIBAL-H) ​​dropwise, and keep the reaction for about 2.0h after dropping. Then control the temperature in the range of -5~20℃, slowly add the reaction solution to 400g 3M hydrochloric acid solution for quenching, stir for 3.0h after quenching, let stand for stratification, wash the organic layer twice with 80g×2 water, A toluene solution of the compound of formula VI is obtained. The obtained solution was directly used in the next reaction without concentration.

Embodiment 2

[0148] Example 2: Preparation of Chiral Catalyst (R-PDD-TMS)

[0149]

[0150] Add 40g R-diphenylprolinol (R-PDD), 400mL dichloromethane and 32.2g imidazole to a 500mL reaction flask, stir to dissolve, cool down to 0°C, and dropwise add 50mL trimethylchlorosilane (TMSCl) , after dripping, the temperature was raised to 25 °C for 12 h and the reaction was incubated for 12 h. After the insulation was completed, 1000 mL of methyl tert-butyl ether was added, and after stirring for 30 minutes, the filtrate was filtered. 2 SO 4 It was dried and concentrated under reduced pressure to obtain 50 g of oil. Yield 97%, HPLC purity 98%.

Embodiment 3

[0151] Example 3: Preparation of compounds of formula V

[0152]

[0153] 1.5g of chiral catalyst R-PDD-TMS and 2.0g of KH were added to the toluene solution of the compound of formula VI prepared in Example 1 above. 2 PO 4 and 3.1g K 2 HPO 4 And stir for 10 ~ 15min. Then, 15 g of 37% formaldehyde solution was added, the temperature was raised to an internal temperature of about 20° C., and the reaction was maintained for 12 h. 100 g of water was added to the reaction solution, stirred, and the layers were separated. The aqueous layer was extracted with 50 g of toluene. The aqueous layer was discarded. The organic phases were combined and concentrated to dryness under reduced pressure to obtain 40 g of the compound of formula V. Yield: 88%, HPLC purity: 85%.

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Abstract

The invention relates to a preparation method of an intermediate compound for synthesizing medicine posaconazole and the intermediate compound prepared by the preparation method. The preparation method of the compound as shown in the formula I comprises the following steps: by taking 4-(2, 4-difluorophenyl)-4-enylpentanoic acid methyl ester or a reduction product thereof 4-(2, 4-difluorophenyl)-4-enylpentanecarboxaldehyde as an initial raw material, reacting with formaldehyde or paraformaldehyde in the presence of a chiral catalyst, and then carrying out characteristic oxidation, esterification reaction and halogenation cyclization reaction to obtain the compound as shown in the formula I. The compound as shown in the formula I is prepared by the following steps of: reacting the initial raw material with methyl 4-(2, 4-difluorophenyl)-4-enylpentanoic acid methyl ester or the reduction product thereof. And finally carrying out hydrolysis and acid treatment. The preparation method has the advantages of mild reaction conditions, simple reaction process, high total yield of target products, high purity and the like, and is suitable for industrial production.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, and more particularly to a method for preparing a compound that is an intermediate of posaconazole and an intermediate compound prepared by these methods. Background technique [0002] As a second-generation antifungal drug, Posaconazole is used in immunocompromised patients or in patients who fail to respond to other antifungal agents such as amphotericin B, fluconazole, and itraconazole, as well as in patients with patients with intolerance to these antimicrobials. Posaconazole was first listed in Europe on October 25, 2005, and was subsequently approved by the US FDA on September 15, 2006. The compound of the following formula IX is the key intermediate of the synthetic drug posaconazole (referred to herein as "posaconazole key intermediate", and can obtain posaconazole through further transformation, and the reaction scheme is as follows: [0003] [0004] At present, some pate...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/24C07D405/06C07D319/06C07C67/11C07C51/31C07C45/41C07C69/732C07C59/56C07C49/235
CPCC07D307/24C07D405/06C07D319/06C07C67/11C07C51/31C07C45/41C07C69/732C07C59/56C07C49/235Y02P20/55
Inventor 代春光朱保云张利荣蒲学灿余官能李运峰郑志国
Owner ZHEJIANG AUSUN PHARMA
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