Synthesis method of posaconazole key intermediate

Abstract

The invention provides a preparation method of a posaconazole key intermediate I. The method comprises the following steps: by taking a compound II as a raw material, carrying out chiral catalytic substitution reaction to obtain a compound III, carrying out bromination and cyclization on dibromohydantoin to obtain a compound IV, and hydrolyzing to obtain the target compound I. The compound is the key intermediate of an antifungal drug posaconazole. The method disclosed by the invention is simple to operate, mild in condition, high in reaction yield, obviously reduced in cost, more environment-friendly and suitable for large-scale industrial production. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and particularly relates to a method for synthesizing a key intermediate of posaconazole. Background Art

[0002] Posaconazole is a derivative of itraconazole and a second-generation triazole antifungal drug. Posaconazole exerts its antifungal activity by inhibiting the biosynthesis of ergosterol and is mainly used to treat Candida infections. It has the advantages of good efficacy and significant safety. ((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methanol is a key intermediate in the synthesis of posaconazole. Its quality and cost play a vital role in the synthesis of this drug.

[0003] The methods for preparing ((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methanol reported so far mainly include the following methods:

[0004] From the literature Tetrahedron Letters (1995), 36 (11), 1787-90, the synthesis route is as follows:

[0005]

[0006] This route is the original synthesis route of posaconazole developed by Schering-Plough. This route uses 2'-bromo-2,4-difluoroacetophenone as the raw material and obtains ((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methanol through a series of reactions.

[0007] However, this reaction has a long synthesis process, a low yield in each step, and iodine is used in the reaction process, which produces iodine vapor that is polluting to the environment. The economic and environmental benefits are poor.

[0008] The synthesis route disclosed in patent CN101824009A is as follows:

[0009]

[0010] This route uses 1-chloro-2,4-difluoroacetophenone as raw material and obtains the target compound through Wittig reaction, Sharpless epoxidation, substitution, condensation, reduction and other reactions.

[0011] The reaction steps of this synthesis scheme are also lengthy, and column chromatography is used to purify intermediates in multiple steps, which is costly and results in low yields, making it unfavorable for industrial production.

[0012] The route in patent US2014343285A1 of Indian MSN Laboratories Limited is as follows:

[0013]

[0014] This route uses m-difluorobenzene as a starting material, and obtains the target compound through Friedel-Crafts acylation, Wittig reaction, amide condensation, hydroxymethylation, halogenation cyclization, reduction reaction, aminoalkylation, and esterification.

[0015] However, the reaction of this scheme is relatively complicated and is prone to produce intramolecular ring-closed impurities, which requires the addition of a post-processing process, which will significantly increase the cost. In addition, the process uses a strong base butyl lithium, which is flammable and has an impact on safe production. The process also uses titanium tetrachloride, which is highly corrosive. Therefore, this process is not suitable for large-scale industrial production.

[0016] In summary, there is a need in the art for a new method for preparing the key intermediate of posaconazole, ((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methanol. Summary of the invention

[0017] In view of the shortcomings of the above-mentioned prior art, the purpose of the present invention is to provide a method for synthesizing a key intermediate of posaconazole, which has the advantages of simple operation, mild conditions, high total yield and significantly reduced cost, and is suitable for industrial production.

[0018] To achieve the above object, the present invention adopts the following technical solution:

[0019] A method for preparing a key intermediate of posaconazole, wherein the structural formula of the intermediate is shown in Compound I,

[0020]

[0021] The synthetic route of compound I is:

[0022]

[0023] The preparation method comprises the following steps:

[0024] S1: Under nitrogen protection, add the reaction solvent, add compound II with stirring, then add anhydrous sodium sulfate with stirring, then add the catalyst Novozym435, cool to -5 to -10°C, add isobutyric anhydride, control the temperature at -5 to -10°C to react for 15 to 20 hours, after the reaction is completed, filter, and rinse the filter cake with dichloromethane solution to obtain a solution of compound III.

[0025] S2: Add potassium carbonate to the solution of compound III, cool to -15 to -10°C, add dibromohydantoin, react for 8 to 10 hours, then heat to 15 to 20°C and react for 3 hours, add sodium sulfite aqueous solution and stir for 30 minutes, add dichloromethane and stir, let stand to separate the liquids, wash the organic phase with water, dry it, and concentrate under reduced pressure to obtain compound IV.

[0026] S3: Add DMSO to compound IV and stir to dissolve, add sodium triazole and heat to 85-90°C, keep the temperature for reaction for 20 hours, cool to 15-20°C, add sodium hydroxide aqueous solution and stir, then add water, add concentrated hydrochloric acid to adjust the pH to 1-2, add toluene to extract, wash the organic phase with sodium chloride aqueous solution, concentrate under reduced pressure, and crystallize with ethyl acetate / n-heptane at -5 to -0°C to obtain compound I.

[0027] Furthermore, in S1, the mass ratio of compound II to catalyst Novozym 435 is 30:1, and the catalyst Novozym 435 comprises 50% each of new Novozym 435 and recycled Novozym 435.

[0028] Furthermore, in S1, the reaction solvent is acetonitrile or acetone, or a combination thereof, preferably acetonitrile.

[0029] Furthermore, in S1, the molar ratio of isobutyric anhydride to compound II is 1.1:1.0 to 1.0:1.0.

[0030] Furthermore, in S2, the molar ratio of dibromohydantoin to compound II is 1.2:1.0 to 1.1:1.0.

[0031] Furthermore, in S3, the molar ratio of sodium triazole to compound II is 1.2:1.0 to 1.1:1.0.

[0032] Furthermore, in S3, the mass ratio of ethyl acetate to n-heptane is 1.0:1 to 2.0:1.

[0033] Compared with the prior art, the advantages of the present invention are:

[0034] (1) A method for preparing a key intermediate of posaconazole is provided. By brominating compound III, a new cyclization method for preparing compound IV is provided, which improves the product yield and avoids the environmental impact of using elemental iodine. In addition, the reaction conditions are mild, the yield is higher, and the product quality is better, which is suitable for large-scale commercial production.

[0035] (2) In S1 of the method of the present invention, the catalyst Novozym 435 is mixed with new and old catalysts, which reduces the use of catalysts, improves reaction efficiency, and reduces production costs. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 The compound I prepared in Example 3 1 H-NMR spectrum; DETAILED DESCRIPTION

[0037] In order to better understand the technical solution of the present invention, further description is made in conjunction with specific embodiments of the present invention so that those skilled in the art can better understand the present invention, but it is not intended to be limiting.

[0038] Example 1

[0039] S1: Under nitrogen protection, add 80g of compound II to 400g of acetonitrile, add 22kg of anhydrous sodium sulfate, 44kg of sodium bicarbonate, cool to below -10°C, add 1.3g of recovered A73-435 catalyst and 1.3g of new A73-435 catalyst, control the temperature at -15°C to -10°C to react for 10 to 12h, filter after the reaction is completed, add 160g of dichloromethane, stir and separate the liquids to obtain a dichloromethane solution of compound III.

[0040] S2: Add 105g of dibromohydantoin to the dichloromethane solution of the above compound III, and react at -15 to -10℃ for 8 to 10h after addition; then slowly heat to 15 to 20℃ and react for 3h. After the reaction is completed, add the pre-prepared sodium sulfite solution of 4.4g sodium sulfite / 792g water, stir at 20 to 25℃ for 30min, separate the liquids, add 20g sodium bicarbonate / 160g water sodium bicarbonate solution to the organic phase, wash with water and separate the liquids, dry the organic phase with 20g anhydrous sodium sulfate, filter, and concentrate to obtain 144g of compound IV as an oil.

[0041] S3: Add 720 g DMSO and 144 g sodium triazole to 144 g compound IV, raise the temperature to 85-90°C, keep the temperature to react for 20 hours, and after the reaction is completed, cool down to 15-20°C. Add 47g sodium hydroxide / 52g water sodium hydroxide solution, stir for 2h, then add 1600g water and 400g hydrochloric acid to the system, adjust pH=1-2, stir for 20min, add 720g toluene, stir for 20min, stand for 30min, separate, adjust the aqueous phase to pH=10 with sodium hydroxide aqueous solution, extract with 1200g methyl tert-butyl ether, add 100g anhydrous sodium sulfate to the organic phase, dry, filter, concentrate the filtrate under reduced pressure at 45-50°C, add 137g ethyl acetate to the system when solid precipitates, heat to 65-70°C to completely dissolve the solid, cool to -5-0°C, add 274kg n-heptane, keep warm for 4h, filter and dry to obtain 78.9g solid of compound I. The purity is 99.4%, and the ee value is 99.6%.

[0042] Comparative Example 1

[0043] The difference between this comparative example and Example 1 is that this comparative example uses a brand-new A73-435 catalyst, and the other operations are the same as Example 1. Similarly, according to the operating procedures of Examples 2 and 3, this comparative example obtains 77.1 g of solid compound I with a purity of 99.5% and an ee value of 99.3%.

[0044] Comparative Example 2

[0045] The difference between this comparative example and Example 2 is that in this comparative example, elemental iodine is used as the iodine reagent when preparing compound IV, and the other operations are the same as those in Example 2. After the operation process of Example 3, this comparative example obtains 67.1 g of compound I solid with a purity of 98.5% and an ee value of 97.3%.

[0046] From the data of the above embodiments and comparative examples, it can be seen that the yields of compound I obtained by using half of the recycled and half of the new A73-435 catalysts in Example 1 are similar, but the use of recycled A73-435 has more cost advantages; in Comparative Example 2, elemental iodine was used as the iodine reagent when preparing compound IV. Compared with Example 2, the risk of using elemental iodine on the environment is significantly increased, and the yield, quality and ee value are significantly reduced compared with the present invention.

[0047] Although the present invention has been described through the embodiments of the present invention, other embodiments that can be thought of by those skilled in the art and that involve variations of the present invention are also included in the intended scope of the present invention and are interpreted and defined by the claims of the present invention.

Claims

1. A method for preparing a key intermediate of posaconazole, characterized in that: Compound I is obtained by three-step reaction using compound II as raw material. The synthetic route is: Features: Step S1: under nitrogen protection, add a solvent, add compound II with stirring, then add anhydrous sodium sulfate with stirring, then add catalyst Novozym435, cool to -5 to -10°C, add isobutyric anhydride, control the temperature at -5 to -10°C to react for 15 to 20 hours, filter after the reaction, and rinse the filter cake with a dichloromethane solution to obtain a dichloromethane solution of compound III; The solvent is any one of acetonitrile and acetone or a combination thereof. Step S2: Add potassium carbonate to the solution of compound III, cool to -15--10°C, add dibromohydantoin, react for 8-10 hours, then heat to 15-20°C and react for 3 hours, add sodium sulfite aqueous solution and stir for 30 minutes, add dichloromethane and stir, stand and separate, wash the organic phase with water, dry it, and concentrate under reduced pressure to obtain compound IV; Step S3: Add DMSO to compound IV and stir to dissolve, add sodium triazole and heat to 85-90°C, keep the temperature for reaction for 20 hours, cool to 15-20°C, add sodium hydroxide aqueous solution and stir, then add water, add concentrated hydrochloric acid to adjust the pH to 1-2, add toluene for extraction, wash the organic phase with sodium chloride aqueous solution, concentrate under reduced pressure, and crystallize with ethyl acetate / n-heptane at -5 to -0°C to obtain compound I.

2. The preparation method according to claim 1, characterized in that In the step S1, the mass ratio of compound II to catalyst Novozym 435 is 30:

1.

3. The preparation method according to claim 1, characterized in that The mass ratio of the recovered Novozym 435 to the new Novozym 435 in the catalyst Novozym 435 in step S1 is 1:

1.

4. The preparation method according to claim 1, characterized in that In the step S1, the molar ratio of isobutyric anhydride to compound II is 1.1:1.0 to 1.0:1.

0.

5. The preparation method according to claim 1, characterized in that In the step S2, the molar ratio of dibromohydantoin salt to compound II is 1.2:1.0 to 1.1:1.

0.

6. The preparation method according to claim 1, characterized in that In the step S3, the molar ratio of sodium triazole to compound II is 1.2:1.0 to 1.1:1.

0.

7. The preparation method according to claim 1, characterized in that The mass ratio of ethyl acetate to n-heptane in step S3 is 1.0:1 to 2.0:1.

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