CN111116503A

CN111116503A - Preparation method of high-purity micafungin intermediate

Info

Publication number: CN111116503A
Application number: CN201911361521.9A
Authority: CN
Inventors: 杨博; 海威
Original assignee: Nanjing Chico Pharmaceutical Co ltd
Current assignee: Nanjing Chico Pharmaceutical Co ltd
Priority date: 2019-12-25
Filing date: 2019-12-25
Publication date: 2020-05-08

Abstract

The application belongs to the field of drug synthesis, relates to a preparation method of a high-purity micafungin intermediate, and particularly relates to a preparation method of a micafungin intermediate compound shown in a formula A-4. The synthesis method is simple to operate, has high yield and can meet the requirement of industrial production.

Description

Preparation method of high-purity micafungin intermediate

Technical Field

The invention belongs to the field of drug synthesis, and relates to a preparation method of a high-purity micafungin intermediate, in particular to a preparation method of 4- [5- (4-pentyloxyphenyl) isoxazol-3-yl ] benzoic acid.

Background

Micafungin (Micafungin) is a novel echinocandin antifungal drug obtained by modifying a natural product of Coleophoma empetri and chemically synthesizing; it has good inhibitory activity against Candida, such as Candida albicans, Candida glabrata, Candida thermonatns, Candida krusei and Candida parapsilosis, and also has good in vitro inhibitory activity against Aspergillus, but has no inhibitory activity against Cryptococcus neoformans, Fusarium, Zygomycetes and Trichosporon baijiensis. Micafungin (Micafungin) was developed by japan tenzier, marketed in japan in 12 months 2002, under the trade name Fungusrd, approved by the FDA in 2005, and is currently approved for prophylactic treatment of esophageal candida infection, bone marrow transplantation, and neutropenia in ADS patients.

Many conventional methods for synthesizing micafungin are disclosed in the documents, for example, in patent nos. CN103917531A and CN103145810B, N' -dicyclohexylcarbodiimide (DCC, EDCl) and the like, and further, N-hydroxybenzotriazolyl ester (HOBt) as an auxiliary reagent is added to prevent racemization, such as Butyl Octyl Phthalate (BOP) and benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate (PyBOP). The post-treatment purification needs to be carried out by adopting ion exchange resin and a column chromatography method. These processes have the disadvantage that the reagents used are relatively expensive, that more spent solvent is produced and that the product obtained is of lower purity.

The application provides a preparation method of a high-purity micafungin intermediate 4- [5- (4-pentyloxyphenyl) isoxazol-3-yl ] benzoic acid, which is simple to operate, the obtained product has high purity, the maximum single impurity content is less than 0.5%, the isomer impurity content is less than 0.1%, and the preparation method is suitable for industrial production.

Disclosure of Invention

The application provides a preparation method of a high-purity micafungin intermediate compound shown as a formula A-4, which comprises the following steps:

1) reacting the compound A with the compound B in the presence of alkali to obtain a compound A-1,

2) reacting the compound A-1 with the compound A-2 in the presence of alkali to obtain a compound A-3,

3) reacting the compound A-3 in the presence of TsNHOH and alkali to obtain a compound A-4,

the above preparation method, wherein in step 1), the base is selected from potassium carbonate.

In some embodiments, wherein in step 1), the mass ratio of the compound of formula B, the compound of formula A and the base is 1: 1.58: 1.2.

The above preparation method, wherein the reaction in step 1) is carried out in DMF solvent. In some embodiments, the reaction temperature of step 1) above is 60 ℃.

The above production method, wherein in the step 2), the base is selected from sodium hydroxide.

In some embodiments, wherein in step 2), the mass ratio of the compound of formula A-1, the compound of formula A-2, and the base is 1: 0.33.

The above production method, wherein the reaction in the step 2) is carried out in a mixed solvent of ethanol and water. In some embodiments, the volume ratio of ethanol to water is 1: 2.5. In some embodiments, the reaction temperature of step 2) above is 40 ℃.

The above production method, wherein in the step 3), the base is selected from sodium hydroxide.

In some embodiments, wherein in step 3), the mass ratio of the compound of formula A-3, TsNHOH to base is 1: 4.1: 0.93.

The above production method, wherein the reaction in step 3) is carried out in a mixed solvent of methanol and water. In some embodiments, the volume ratio of methanol to water is 4: 1. In some embodiments, the reaction temperature of step 3) above is 43 ℃.

The reaction in the step 3) and the post-treatment process comprise a purification method of pulping by adopting ethanol; in some embodiments, the ethanol pulping operation is repeated twice.

The solvents and reagents used in this application are all commercially available products and are used directly in the reaction without purification.

The scheme of the invention is simple to operate, the obtained product has high purity, and the HPLC content of the final product compound of formula A-4 is 99.1%, the maximum single impurity HPLC content is less than 0.8%, and the isomer impurity is less than 0.1%. Is suitable for industrial production.

Detailed Description

EXAMPLE 1 preparation of Compound A-1

5g of p-hydroxyacetophenone (compound of formula B), 7.9g of iodopentane (compound of formula A) and 6g of anhydrous potassium carbonate were added to 50ml of DMF, and the mixture was stirred at 60 ℃ for 4 hours. Detecting the reaction, cooling to room temperature after the reaction is finished, and sequentially adding petroleum ether (50mL) and water (50mL) to keep a petroleum ether layer. The petroleum ether layer was washed successively with 0.5mol/L sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give 7g in total of compound A-1, yield 93% and HPLC purity 95%.

EXAMPLE 2 preparation of Compound A-3

Compound A-1(4g), p-aldehyde benzoic acid (4.1g, compound of formula A-2), and sodium hydroxide (1.3 g) were added to water (20ml) and ethanol (8ml) in this order, and stirred at 40 ℃ for 4 hours. After the reaction, the reaction solution was cooled in an ice bath, 10% diluted hydrochloric acid was added to adjust the pH to 2, and the solid was collected by filtration. The solid was stirred in 45ml ethanol at room temperature and filtered to give compound A-3(5.5g) in 85% yield and 95.7% HPLC purity.

EXAMPLE 3 preparation of Compound A-4

Compound A-3(2.7g), TsNHOH (N-p-toluenesulfonylhydroxylamine, 11g), sodium hydroxide (2.5g) were dissolved in 50ml of a mixed solution of methanol and water (volume ratio: 4: 1). After completion of the reaction, the reaction mixture was stirred at 43 ℃ for 35 hours, cooled in ice water, and then 10% diluted hydrochloric acid was added thereto to adjust the pH to 2, followed by filtration. Adding 80ml ethanol into the obtained solid, stirring and pulping at room temperature, washing a filter cake, filtering to obtain a compound A-4, further adding the compound into 60ml ethanol, pulping at room temperature, filtering and drying to obtain the compound A-4(2.2g), wherein the yield is 80%. HPLC content 98.5%, maximum monohybrid HPLC content < 0.8%, isomer impurities < 0.1%.

Claims

1. A preparation method of a micafungin intermediate compound shown as a formula A-4 comprises the following steps:

2. the method of claim 1, wherein in step 1), the base is selected from potassium carbonate.

3. The method according to claim 1, wherein the mass ratio of the compound of formula B to the compound of formula A to the base in step 1) is 1: 1.58: 1.2.

4. The preparation process according to claim 1, wherein the reaction in step 1) is carried out in DMF solvent at a temperature of 60 ℃.

5. The method according to claim 1, wherein in step 2), the base is selected from sodium hydroxide.

6. The production process according to claim 1, wherein in the step 2), the mass ratio of the compound of the formula A-1, the compound of the formula A-2 and the base is 1: 0.33.

7. The preparation method according to claim 1, wherein the reaction in step 2) is carried out in a mixed solvent of ethanol and water, the volume ratio of ethanol to water is 1: 2.5, and the reaction temperature is 40 ℃.

8. The method according to claim 1, wherein in step 3), the base is selected from sodium hydroxide.

9. The preparation process according to claim 1, wherein in step 3), the mass ratio of the compound of formula a-3, TsNHOH and base is 1: 4.1: 0.93.

10. The preparation method as set forth in claim 1, wherein the reaction in the step 3) is carried out in a mixed solvent of methanol and water in a volume ratio of 4: 1 at a reaction temperature of 43 ℃, and the post-treatment process comprises a purification method using beating of ethanol, which is repeated twice.