阅读说明：本技术 一种泊沙康唑的制备方法 (Preparation method of posaconazole ) 是由 徐晓晓 于 2019-11-20 设计创作，主要内容包括：本发明公开了一种泊沙康唑的精制方法。本发明提供了一种泊沙康唑的精制方法,其包以下步骤：将泊沙康唑粗品与溶剂形成的溶液,析晶,得到纯化后的泊沙康唑；所述的溶剂为酯类溶剂、或酯类溶剂与卤代烃类溶剂的混合溶剂；所述的泊沙康唑粗品的HPLC纯度达到85％以上。本发明的精制方法操作简单、方便、收率高、制得的产品纯度高、杂质含量低、能够达到原料药标准、生产成本低、适合于工业化。(The invention discloses a refining method of posaconazole. The invention provides a refining method of posaconazole, which comprises the following steps: crystallizing a solution formed by the crude product of posaconazole and a solvent to obtain purified posaconazole; the solvent is an ester solvent or a mixed solvent of the ester solvent and a halogenated hydrocarbon solvent; the HPLC purity of the crude posaconazole product reaches more than 85 percent. The refining method provided by the invention is simple and convenient to operate, high in yield, high in purity of the prepared product, low in impurity content, capable of reaching the standard of raw material medicines, low in production cost and suitable for industrialization.)

1. A refining method of posaconazole is characterized by comprising the following steps: crystallizing a solution formed by the crude product of posaconazole and a solvent to obtain purified posaconazole; the solvent is an ester solvent or a mixed solvent of the ester solvent and a halogenated hydrocarbon solvent; the HPLC purity of the crude posaconazole product reaches more than 85 percent.

2. The refining process of posaconazole as claimed in claim 1, wherein: in the refining method of posaconazole, the ester solvent is one or more of ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, n-pentyl acetate and n-hexyl acetate; and/or in the refining method of posaconazole, the halogenated hydrocarbon solvent is a chlorinated hydrocarbon solvent; and/or in the refining method of posaconazole, the volume-mass ratio of the solvent to the crude posaconazole product is 3 mL/g-15 mL/g; and/or in the refining method of posaconazole, the temperature of the solution formed by the crude posaconazole product and the solvent is 30-70 ℃; and/or in the refining method of posaconazole, the crystallization temperature is-5 ℃ to 15 ℃ and/or in the refining method of posaconazole, the crystallization time is 1 hour to 4 hours; and/or in the refining method of posaconazole, the crystallization is stirred crystallization.

3. The refining process of posaconazole as claimed in claim 2, wherein: in the refining method of posaconazole, the chlorinated hydrocarbon solvent is dichloromethane and/or, and in the refining method of posaconazole, the temperature of a solution formed by a posaconazole crude product and the solvent is 40-70 ℃; and/or in the refining method of posaconazole, the stirring speed is 60-180 rpm.

4. The refining process of posaconazole as claimed in claim 3, wherein: in the refining method of posaconazole, when a mixed solvent of an ester solvent and a halogenated hydrocarbon solvent is adopted, the volume ratio of the ester solvent to the halogenated hydrocarbon solvent is 1-10; and/or, in the refining method of posaconazole, when a mixed solvent of an ester solvent and a halogenated hydrocarbon solvent is adopted, the mixed solvent of the ester solvent and the halogenated hydrocarbon solvent is a mixed solvent of ethyl acetate and dichloromethane, a mixed solvent of isopropyl acetate and dichloromethane, a mixed solvent of n-propyl acetate and dichloromethane, a mixed solvent of n-butyl acetate and dichloromethane, a mixed solvent of n-pentyl acetate and dichloromethane, or a mixed solvent of n-hexyl acetate and dichloromethane.

5. The refining process of posaconazole as claimed in claim 1, wherein: in the refining method of posaconazole, the solution formed by the posaconazole crude product and the solvent is prepared by mixing and heating the posaconazole crude product and the solvent until the posaconazole crude product is dissolved.

6. The refining process of posaconazole as claimed in claim 5, wherein the mixing is stirred mixing; and/or the heating temperature is 30-70 ℃; and/or the dissolving time is 1-4 hours.

7. The refining process of posaconazole as claimed in claim 6, wherein: the heating temperature is 40-70 ℃; and/or the stirring speed is 60 rpm-180 rpm.

Technical Field

The invention relates to a refining method of posaconazole.

Background

Posaconazole (posaconazole) was approved by the FDA in the united states for marketing in 2007 for immunocompromised patients or patients with other antifungal agents such as amphotericin b (amphothericin b), fluconazole, itraconazole are ineffective, and patients intolerant to these antibacterial agents. The antifungal spectrum includes: invasive fungal infections caused by Candida, Mucor, Aspergillus, Fusarium and Coccidioides provide a new treatment option for the prevention and treatment of deep fungal infections.

The chemical name of posaconazole is 2, 5-anhydro-1, 3, 4-trideoxy-2-C- (2, 4-difluorophenyl) -4- [ [4- [4- [1- [ (1- [ (1S, 2S) -1-ethyl-2-hydroxypropyl ] -1, 5-dihydro-5-oxo-4H-1, 2, 4-triazol-4-yl ] phenyl ] -1-piperazinyl ] phenoxy ] methyl ] -1- (1H-1, 2, 4-triazol-1-yl) -D-threo-pentitol, which has the following structure:

the use of organic compounds as pharmaceuticals in clinical settings requires very high purity, the control of various types of impurities in pharmaceutical compounds below pharmacopoeial standards, and the compliance with marketing standards is a complex and elaborate process.

The structure of posaconazole is complex, 4 chiral centers are involved in molecules, the compound can be obtained through multi-step chemical reactions, and a series of impurities are introduced in the synthetic process, wherein the impurities comprise:

1. an unreacted intermediate;

2. impurities introduced in the starting materials and intermediates;

3. impurities generated by side reactions during the synthesis process;

4. intermediates and degradation impurities of posaconazole.

The prior art does not disclose a specific purification method therefor, and it is necessary to further purify such an unqualified product or crude product to improve the yield and purity of the product. There is an urgent need in the art to develop a refining method of posaconazole with low cost and high yield, which is suitable for mass production, so as to overcome the above disadvantages.

The technical problem to be solved by the invention is to overcome the defects of the prior art and provide a method for purifying posaconazole, which has the advantages of simplicity, high product purity, high yield and easy industrial production.

Disclosure of Invention

The invention aims to solve the technical problems that the refining method of posaconazole in the prior art is complex in operation, low in total yield, poor in purity of the prepared product, not capable of reaching the standard of raw material medicines, high in production cost, not suitable for industrial production and the like. The refining method provided by the invention is simple and convenient to operate, high in yield, high in purity of the prepared product, low in impurity content, capable of reaching the standard of raw material medicines, low in production cost and suitable for industrialization.

The invention provides a refining method of posaconazole, which comprises the following steps: crystallizing a solution formed by the crude product of posaconazole and a solvent to obtain purified posaconazole; the solvent is an ester solvent or a mixed solvent of the ester solvent and a halogenated hydrocarbon solvent; the HPLC purity of the crude posaconazole product reaches more than 85 percent.

In the refining method of posaconazole, the purity of the posaconazole crude product is preferably 90-100%, and the purity refers to HPLC purity; for example 97.38%, 94.37%, 92.44% or 90.56%. If the purity of the crude posaconazole product is less than 85%, the posaconazole product can be refined by the method disclosed by the invention or by the method in the prior literature to the purity of more than 85%.

In the refining method of posaconazole, the ester solvent is preferably one or more of ethyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, n-pentyl acetate and n-hexyl acetate.

In the refining method of posaconazole, the halogenated hydrocarbon solvent is preferably a chlorinated hydrocarbon solvent; the chlorinated hydrocarbon solvent is preferably dichloromethane.

In the refining method of posaconazole, when a mixed solvent of an ester solvent and a halogenated hydrocarbon solvent is adopted, the volume ratio of the ester solvent to the halogenated hydrocarbon solvent is preferably 1-10, such as 1, 3, 7 or 10.

In the refining method of posaconazole, when a mixed solvent of an ester solvent and a halogenated hydrocarbon solvent is adopted, the mixed solvent of the ester solvent and the halogenated hydrocarbon solvent is preferably a mixed solvent of ethyl acetate and dichloromethane, a mixed solvent of isopropyl acetate and dichloromethane, a mixed solvent of n-propyl acetate and dichloromethane, a mixed solvent of n-butyl acetate and dichloromethane, a mixed solvent of n-pentyl acetate and dichloromethane or a mixed solvent of n-hexyl acetate and dichloromethane.

In the refining method of posaconazole, the volume-mass ratio of the solvent to the crude posaconazole product is preferably 3mL/g to 15mL/g, such as 3mL/g, 5mL/g, 6mL/g, 8mL/g, 10mL/g or 15 mL/g.

In the refining method of posaconazole, the temperature of the solution formed by the crude posaconazole and the solvent is preferably 30-70 ℃, more preferably 40-70 ℃, for example 40 ℃, 60 ℃ or 70 ℃.

In the refining method of posaconazole, the 'solution formed by the posaconazole crude product and the solvent' is preferably prepared by mixing the posaconazole crude product and the solvent and heating until the mixture is dissolved. The mixing is preferably stirred. The stirring speed is preferably 60rpm to 180rpm, for example 60rpm, 120rpm or 180 rpm. The stirring time is preferably 1 hour to 5 hours, for example 1 hour, 2 hours, 3 hours or 4 hours. The heating temperature is preferably 30 to 70 ℃, more preferably 40 to 70 ℃, for example 40 ℃, 60 ℃ or 70 ℃. The dissolving time is preferably 1 to 4 hours; for example 1 hour, 2 hours, 3 hours or 4 hours.

In the refining method of posaconazole, the crystallization temperature is preferably-5-15 ℃; for example-5 deg.C, 0 deg.C, 5 deg.C, 10 deg.C or 15 deg.C.

In the refining method of posaconazole, the time for crystallization is preferably 1 to 4 hours; for example 1 hour, 2 hours, 3 hours or 4 hours.

In the refining method of posaconazole, the crystallization is preferably performed by stirring, and the stirring speed is preferably 60rpm to 180rpm, for example, 60rpm, 120rpm or 180 rpm.

The refining method of posaconazole preferably further comprises the following steps: and (3) adjusting the pH of the solution formed by the purified posaconazole and the alkali to 1-7 to obtain the refined posaconazole.

The crude posaconazole product can be prepared by the method disclosed in patent document CN201610755734. X; the other starting materials or reagents are all commercially available.

In the invention, the room temperature refers to the ambient temperature and is 10-35 ℃.

The positive progress effects of the invention are as follows: the refining method provided by the invention is simple and safe to operate, does not need special equipment, is high in yield, is high in purity of the prepared product (the purity of related substances is more than 99.0%, the purity of chenodeoxycholic acid is less than 0.5%, and all other impurities are less than 0.1%, and reach the standard of raw material medicines), is low in production cost, is environment-friendly, and is suitable for industrial production.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

Example 1: synthesis of posaconazole intermediate (see patent cn201610755734. x).

(1) The reaction kettle structure with the built-in stirrer comprises:

the reaction kettle is a 100L enamel reaction kettle with the height of 120cm and the diameter of 50 cm. The stirring device is a standard component and comprises a stirring shaft arranged along the axial direction of the reaction kettle and two groups of stirring blade groups uniformly distributed along the axial direction of the stirring shaft, wherein each group of stirring blade groups are arranged in parallel, each group of stirring blade group comprises two stirring blades uniformly distributed along the circumferential direction of the stirring shaft, and the length of each stirring blade along the radial direction of the reaction kettle is 8 cm; baffle group is including highly being 60cm, and the width is 5cm, and thickness is 1 cm's 4 baffles, and the length direction of each baffle is along being on a parallel with the axis direction setting of agitator (one side is fixed on reation kettle's the diapire), width direction follow reation kettle's radial direction sets up, and each baffle is fixed along the direction that its width extends (one side) on reation kettle's the lateral wall, the opposite side orientation the position of agitator extends, and each baffle with the axis of agitator is perpendicular well separated time and is the circumference and distributes.

(2) Synthesis of posaconazole

Into the above 100L enamel reactor, 60L of methanol, 4kg of the compound represented by the formula II, 4L of hydrochloric acid having a concentration of 36.5% by weight, 320g of 10% palladium on carbon catalyst (containing 50% water) were charged, the reactor was sealed, and the stirrer was turned on (stirring speed: 350 rpm). Replacing the air in the kettle with nitrogen for 3 times, then replacing with hydrogen for 3 times, keeping the pressure of the hydrogen at 0.1 MPa (gauge pressure), heating to 50 ℃, monitoring the reaction by HPLC, and finishing the reaction for 2 hours. Cooling, replacing 3 times with nitrogen, and filtering to obtain 10% palladium-carbon catalyst. Pouring the filtrate into another 200L enamel reaction kettle, adding ice blocks, cooling to 0-5 ℃, dropwise adding 2mol/L NaOH solution into the filtrate, adjusting the pH to 11, separating out a large amount of solids, stirring for 2h, centrifuging, washing the filter cake for 3 times by water, and drying the solids in a 55 ℃ forced air drying oven to obtain 3.32 kg of a product, namely the required posaconazole, wherein the yield of the product is 93.6% and the HPLC purity is 99.754% by calculation.

Example 2: refining of posaconazole

15.04 Kg of crude posaconazole (prepared in example 1 and having an HPLC purity of 99.7%), 82L of n-butyl acetate and 8.2L of dichloromethane were taken, heated to 40 ℃ and stirred (120rpm) for 2 hours to completely dissolve the posaconazole, and then cooled to 5 ℃ within 3 hours and stirred (120rpm) for 2 hours. And (4) performing centrifugal filtration to obtain a white solid, and performing vacuum drying (-0.01 to-0.1 MPa, 45 to 55 ℃) for 12 hours to obtain 12.44 Kg of purified posaconazole. HPLC purity: 99.98%, 0.002% (other max monohetero).

Example 3: refining of posaconazole

210g of crude posaconazole (prepared as described in example 1 and having an HPLC purity of 99.7%), 1.26L of isopropyl acetate and 0.42L of dichloromethane were taken, heated to 40 ℃ and stirred (180rpm) for 3 hours to completely dissolve the crude posaconazole, and then cooled to 0 ℃ within 3 hours and stirred (180rpm) for 1 hour. And filtering to obtain a white solid, and performing vacuum drying (-0.01-0.1 MPa, 45-55 ℃) for 12 hours to obtain 155.7 g of purified posaconazole. HPLC purity: 99.95%, 0.03% (other max monohetero).