CN108084049B - Preparation method of posaconazole intermediate - Google Patents

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of a posaconazole intermediate. The method comprises the steps of etherification, reduction, oxidation, condensation and alkylation to obtain a compound 2. Compared with the existing synthesis method, the method provided by the invention has the characteristics of cheap and easily available raw materials, high yield and the like.

Description

Preparation method of posaconazole intermediate

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a posaconazole intermediate

The preparation method of (1).

Background

Posaconazole (Structure as follows)

The compound is a novel 2, 2, 4-trisubstituted tetrahydrofuran derivative antifungal agent, has good safety and tolerance, provides a new choice for preventing and treating deep fungal infection, is firstly marketed in Europe at 10-25 th 2005, and is approved by the FDA (food and drug administration) at 9-15 th 2009 in USA for treating deep fungal infection. The sustained release tablet is approved again in 2013, 11 and 25 months.

The formyl hydrazine derivative shown as the compound 1 is used as a key intermediate for further synthesizing the posaconazole. Since Compound 1 is an oil at room temperature, Compound 1 is prepared

As key intermediates, a number of problems are encountered in production. First, purification is difficult and requires separation and purification by a chromatographic column to obtain high chemical purity. Second, the optical purity is low and cannot be purified by conventional means. Thirdly, the solvent residue is not easy to control, and the subsequent reaction is influenced. The above problems all affect the quality of the final product posaconazole.

The synthesis process of compound 1 also has some problems, and the following two methods have been publicly reported for preparing compound 1:

1. the process disclosed in world patent wo96/33178 (see scheme 1):

the biggest disadvantage of this method is the need for resolution and the low yield of resolution. The method is difficult to control in the formylation process and is easy to generate the double formylation product, and although the subsequent reaction is not influenced, the process becomes complicated, and the cost is increased.

2. A more compact method is reported in Tetredron Letter (45) 8249-8251 (see scheme 2):

compared with wo96/33178, the method is greatly improved, and the second chirality is generated by inducing the ortho chirality of the substrate, but most of intermediates in the process are liquid at room temperature, are not easy to purify, and have poor process stability.

The key point of the invention is to find a more excellent intermediate for synthesizing posaconazole and develop a method with cheap raw materials, simple and convenient synthesis process and higher yield to prepare the intermediate.

Disclosure of Invention

The content of the invention is that the compound 2 is used as a key intermediate for preparing posaconazole, and a synthetic process for preparing the compound 2 is developed, and the scheme is shown as follows:

the technical scheme of the invention specifically comprises the following steps:

in the first step, hydroxyl of L-lactate is protected by 4-chloro-benzhydrol in an inert solvent under the catalysis of Lewis acid to obtain a compound 3

；

Secondly, reducing the ester group in the compound 3 into hydroxyl by using a metal hydride reducing agent in an alcohol or ether solvent to obtain a compound 4

；

Thirdly, oxidizing hydroxyl in the compound 4 into aldehyde group by using sodium hypochlorite under the action of TEMPO and a sodium bromide catalyst, and then neutralizing the aldehyde group by using a mixed solvent and adding sodium bisulfite to obtain a compound 5;

fourthly, condensing the compound 5 and the formylhydrazine into a compound 6 under the catalysis of Lewis acid

；

Fifthly, reacting the compound 6 with ethyl magnesium chloride or ethyl magnesium bromide in an ether solvent to generate a target compound 2

。

The method has three advantages: the first compound 2 is solid at room temperature and can be improved in chemical purity and optical purity by solvent crystallization, which is very beneficial to the quality control of the final target product posaconazole. Secondly, the introduction of a protective agent with large steric hindrance at the 2-hydroxyl of the L-lactic acid can improve the induction in the process of forming a second chiral center, thereby improving the optical purity of the compound 2. The isolation of the aldehyde as a solid sulfonate by the third compound 5 greatly improves the intermediate quality.

Detailed Description

Adding 100ml of L-ethyl lactate (0.847 mol) and 100ml of dichloromethane into a 1000ml three-neck flask, cooling the reaction liquid to-10 ℃ to-15 ℃, adding 10ml of boron trifluoride diethyl etherate, dripping 400ml of dichloromethane solution of 203g (0.913 mol) of 4-chlorobenzhydrol into the reaction liquid for about 4 hours, dripping 200ml of water into the reaction system after the reaction is finished, raising the temperature of the reaction liquid to room temperature, standing for layering, washing the organic layer once with 500ml of clear water, drying the organic layer after layering, and evaporating to dryness to obtain a compound 3 which is directly used in the next step.

Adding the compound 3 obtained in the previous step and 400ml of ethanol into a 500ml three-necked bottle, cooling the reaction liquid to 0-5 ℃ under stirring, adding 16g of sodium borohydride (0.424 mol) and 16g of anhydrous calcium chloride, preserving the temperature for reaction for 3 hours, monitoring the reaction by TLC (ethyl acetate: n-hexane =1: 5), pouring the reaction liquid into 500ml of water after the reaction is finished, adding 200ml of dichloromethane, stirring for 10 minutes, separating an organic layer, drying and evaporating, adding 300ml of isopropyl ether, stirring and crystallizing at 0-5 ℃ for 3 hours, performing suction filtration, washing a solid with 100ml of n-hexane, and drying the solid at normal pressure of 30-35 ℃ for 24 hours to obtain 4163 g of a white compound.

4100 g (0.364 mol) of the compound, 700ml of dichloromethane, 1g of TEMPO, 2g of sodium bromide and 30ml of water are added into a 1000ml three-necked bottle, the reaction solution is cooled to 0-5 ℃, 360ml of sodium hypochlorite is added into 18g of sodium bicarbonate to be stirred, dissolved and cleared, then the mixture is slowly dripped into the cooled reaction solution, TLC (ethyl acetate: n-hexane =1: 2) monitors the reaction, after the reaction is finished, standing and demixing are carried out, an aqueous layer is discarded, an organic layer is washed by water, and the solvent is evaporated under reduced pressure. To the resulting oil, 160ml of ethyl acetate, 80ml of ethanol, 40ml of water and 30g (0.291 mol) of sodium hydrogen sulfite were added, stirred at room temperature for 5 hours, filtered under suction, washed with 25ml of ethyl acetate to give a white solid, and the solid was dried at normal pressure at 50 to 60 ℃ for 24 hours to give 5103 g of a white compound in a yield of 75%.

560 g (0.155 mol) of compound and 150ml of dichloromethane are added into a 500ml three-necked bottle, 12ml (0.170 mol) of trimethylchlorosilane is dripped into the three-necked bottle at room temperature, the mixture is stirred and reacted for 1 hour, then 11g (0.170 mol) of formylhydrazine and 150ml of methanol are added, 600ml of water is added after the reaction is finished by stirring for 30 minutes, an organic phase is separated, 100ml of dichloromethane is used for extracting a water layer, the organic layer is combined, 80ml of ethanol and 80ml of isopropyl ether are added after the drying and the evaporation, the mixture is stirred and crystallized for 2 hours, the filtration is carried out, the washing is carried out by 20ml of isopropyl ether, and the drying is carried out at the normal pressure of 40-.

321ml of 1.0mol/L ethyl magnesium chloride tetrahydrofuran solution is added into a 1000ml three-necked flask, then the mixture is cooled to 5-10 ℃, 645 g (0.107 mol) of the compound is dissolved into 100ml of tetrahydrofuran, the mixture is slowly dripped into the cooled Grignard solution under cooling, and after the dripping is finished, the reaction is stirred for 5 hours. After the reaction, adding 300ml of dichloromethane, dropwise adding 40ml of concentrated hydrochloric acid, standing for layering, discarding a water layer, washing an organic layer with 400ml of 1% hydrochloric acid aqueous solution, drying and evaporating the organic layer to obtain the product, adding 200ml of isopropyl ether, stirring and crystallizing for 2 hours. Suction filtration, normal pressure drying at 40-45 deg.C to obtain 232.9 g of compound with 89% yield.

Claims (3)

1. Compound 2

Use as an intermediate in the preparation of posaconazole.

2. The preparation method of the compound 2 is characterized by comprising the following five steps:

A. protecting the hydroxyl group of the L-lactate by 4-chloro-benzhydrol in an inert solvent under the catalysis of Lewis acid to obtain a compound 3

；

B. Reducing the ester group in the compound 3 into hydroxyl group by using metal hydride reducing agent in alcohol or ether solvent to obtain a compound 4

；

C. Oxidizing hydroxyl in the compound 4 with sodium hypochlorite under the action of TEMPO and sodium bromide catalyst to obtain aldehyde group, and adding sodium bisulfite in mixed solvent to obtain compound 5

；

D. Condensing compound 5 and formylhydrazine under the catalysis of Lewis acid to form compound 6

；

E. And reacting the compound 6 with ethyl magnesium chloride or ethyl magnesium bromide in an ether solvent to generate a target compound 2.

3. The process for the preparation of compound 2 according to claim 2, wherein the lewis acid used in step a is boron trifluoride etherate.