WO2013020460A1 - Atazanavir preparation method - Google Patents

Abstract

The present invention relates to the field of chemical medicaments. Disclosed is an Atazanavir preparation method, with a reaction formula as represented in figure (I). The present invention uses DEPBT as a condensing agent; 1-[4-(pyridine-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2, 5-diamino-6- phenyl-2-azahexane is reacted with N-methoxycarbonyl-L-tertiary leucine in an organic solvent to give the Atazanavir. The condensing agent normally used in the reaction in existing literatures is TPTU, a combination of carbon diimine compounds and benzotriazole compounds, or only the carbon diimine compounds. However, the compounds are expensive, toxic and heavily pollutive. The present invention uses inexpensive, safe and environment-friendly DEPBT as the condensing agent, and provides an economically feasible, safe and environment-friendly Atazanavir preparation method with high yield and easy product separation.

Description

 Method for preparing atazanavir

 This application is submitted to the Chinese Patent Office on August 5, 2011, and the application number is

The priority of the Chinese patent application is hereby incorporated by reference. Technical field

 The invention belongs to the field of chemical medicine, and particularly relates to a preparation method of atazanavir. Background technique

 Atazanavir, the English name Atazanavir, is an open-chain aza-peptidomimetic compound developed by Bristol-Myers Squibb. It is a novel HIV-1 protease inhibitor with the chemical structure shown in the following formula 1.

 The product was marketed in the US and Europe on June 20, 2003 and March 2, 2004, respectively. The pharmaceutical ingredient in the marketed dosage form was atazanavir sulfate (trade name: Reyataz).

U.S. Patent No. 5,489,911 issued by Novartis, Inc. (Application Date: Apr. 9, 1997). Example 46 is the first disclosure of atazanavir and its preparation method, one of which is a method for preparing atazanavir including the following steps,

式 2化合物在缩合剂 0-(l,2-二氢 -2-氧 -1-吡啶基) -Ν,Ν,Ν',Ν，-四甲基鎿 四氟硼酸 (TPTU)作用下， 与式 a化合物 N- (甲氧基羰基 )-(L)-叔亮氨酸缩 合制得式 1阿扎那韦单体。但是该方法中 TPTU价格非常昂贵， 4艮难获得 工业规模的供应， 且其分离提取步骤操作繁杂， 不适合工业化生产。

The compound of formula 2 is treated with the condensing agent 0-(l,2-dihydro-2-oxo-1-pyridyl)-indole, hydrazine, hydrazine, hydrazine, tetramethylphosphonium tetrafluoroborate (TPTU), The compound a-(methoxycarbonyl)-(L)-tert-leucine is condensed to obtain the atazanavir monomer of formula 1. However, the TPTU is very expensive in this method, and it is difficult to obtain an industrial-scale supply, and the separation and extraction steps are complicated and unsuitable for industrial production.

 This reaction is also disclosed in WO9740029, and it is disclosed that the condensing agent may be a carbodiimide such as EDC. Carbodiimides are commonly used activators, but their activation properties are too high for this reaction, resulting in racemization of the amino acids. In order to avoid racemization, the patent uses a carbodiimide in combination with a benzotriazole compound, and the benzotriazole compound used is HOBT. However, HOBT is a dangerous chemical with a high degree of danger. Hazard codes R5 and R11 are very flammable and can cause an explosion due to heating. The transportation is strictly controlled and difficult to obtain, and the method has a large environmental pollution.

 There are different documents such as EP1930324, WO2009002829, WO2005108380, etc., and other carbodiimide compounds such as WSC, DCC, DIC, etc. are used in combination with HOBT, and the above defects are also present.

 WO2010146119 discloses a process for using DIC or DCC as a condensing agent alone, without using HOBT, which has improved safety over the above process, but DIC and DCC are still dangerous chemicals, irritating to eyes and skin, The danger of serious eye damage, and DIC is a very toxic chemical.

DEPBT, 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4-one, CAS No. 165534-43-0, English name

 3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one, US Patent Application US7834043 (Assignee: Abbott, Inc., Application Date: December 9, 2004) DEPBT was released as a condensing agent For the application of the following reactions,

该专利中以 DEPBT为缩合剂，在 THF和 Ν,Ν-二异丙基乙胺中反应， 其收率仅为 55%, 且其产品分离纯化复杂， 需要用层析柱分离， 不适于 工业化生产。

In this patent, DEPBT is used as a condensing agent, and it is reacted in THF and hydrazine, hydrazine-diisopropylethylamine, and its yield is only 55%. The separation and purification of the product is complicated, and it needs to be separated by a chromatography column, which is not suitable for industrialization. produce.

 Therefore, it is necessary to develop a method for preparing atazanavir suitable for industrialization, which is economical, less polluting, safe and environmentally friendly, and has a high yield. Summary of the invention

 The invention overcomes the defects in the prior art mentioned above, and provides a preparation method of atazanavir which is economical, feasible, safe and environmentally friendly, has high yield, and is easy to separate products.

This method will be 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-azetane And N-methoxycarbonyl-L-tert-leucine is reacted in the presence of a condensing agent DEPBT to obtain an atazanavir monomer, and the reaction formula is as follows:

进一步地， 所述阿扎那韦单体的制备方法为： 将 1-[4- (吡啶 -2-基) -苯 基]— 4(S)-羟基 -5(S)-2,5-二氨基 -6-苯基 -2-氮杂己烷溶于有机溶剂， 加入 N- 甲氧羰基 -L-叔亮氨酸和 DEPBT, 搅拌反应得阿扎那韦单体。

Further, the atazanavir monomer is prepared by: 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5- Diamino-6-phenyl-2-azahexane is dissolved in an organic solvent, and N-methoxycarbonyl-L-tert-leucine and DEPBT are added, and the reaction is stirred to obtain atazanavir monomer.

 The organic solvent is a single solvent or a mixed solvent selected from tetrahydrofuran, dichloromethane, chloroform, butanone, triethylamine, N-methylmorpholine or methyl isobutyl ketone. Preferably, the organic solvent is a mixed solvent selected from the group consisting of dichloromethane, tetrahydrofuran, N-methylmorpholine or triethylamine, more preferably a mixed solvent of dichloromethane and N-methylmorpholine or tetrahydrofuran. Mixed solvent with triethylamine. The reaction is carried out at 20 to 40 ° C, preferably at 28 to 35 ° C.

 After the above reaction is completed, the finished product of atazanavir can be obtained through a post-treatment step. The post-treatment step comprises: adding a base to the reaction solution, concentrating under reduced pressure, adding a crystallization solvent to the residual liquid, and heating and cooling to obtain an atazanavir monomer.

 The base comprises: an aqueous solution of sodium hydroxide, sodium hydrogencarbonate or sodium carbonate.

 The crystallization solvent includes a mixed solution of water and methanol, ethanol, isopropanol or a ketone solvent, preferably a mixed solution of ethanol and water.

 Preferably, the post-treatment step is: adding a base to the reaction solution, stirring, standing layering, washing the organic layer with water, adding ethanol, concentrating under reduced pressure, adding ethanol and water to the residual liquid, heating to 60 °C, slowly reduce the temperature to about 0 ° C, stir, suction filtration, baking, to obtain solid atazanavir monomer.

Further, the compound of the formula 2 is 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2 - azahexane from the compound of formula 3 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxyl -5(S)-2,5-bis[(tert-butoxycarbonyl)amino]-6-phenyl-2-azane was obtained by deprotection reaction in an organic solvent. The protecting group is a tert-butoxycarbonyl group on the amino group.

 Preferably, the 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-nitrogen The heterohexane can be prepared by: 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-di[(tert-butoxycarbonyl) Amino] -6-phenyl-2-azahexane is mixed with an organic solvent, and the reaction is kept warm after heating, then the temperature is lowered, the alkali is added, the layer is allowed to stand, and the organic layer is concentrated to obtain 1-[4 - (Pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-azanium solid.

 Wherein the organic solvent is selected from a mixed solvent of one or more of tetrahydrofuran, chloroform, methyl ethyl ketone, dichloromethane or methyl isobutyl ketone.

 The acid includes sulfuric acid, hydrochloric acid, hydrogen chloride, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid.

 The base may be an inorganic base such as an aqueous solution of sodium hydroxide, sodium hydrogencarbonate or sodium carbonate, or an organic base such as pyridine, N-methylmorpholine, triethylamine or diethylamine.

 Further, the atazanavir monomer can be reacted with concentrated sulfuric acid to prepare atazanavir sulfate, and the preparation method comprises the following steps: dissolving the atazanavir monomer in an organic solvent, adding a concentrated sulfuric acid solution, incubating the reaction, and cooling the temperature to 0~5 ° C, stirring to get atazanavir sulfate. The organic solvent is acetone, methyl tert-butyl ether, dichloromethane or isopropanol.

The invention adopts DEPBT as a condensing agent for synthesizing atazanavir monomer, and has the following advantages over the prior art synthesis process of atazanavir: (1) the price of DEPBT is low, and the reaction requires no other auxiliary materials, and the reaction condition is mild. The equipment and operation requirements are relatively low, and can be carried out at 20 ~ 40 °C, which effectively reduces the cost; (2) DEPBT has good safety and produces less pollutants. Environmentally friendly; (3) Operating the cartridge, does not require activation of the carboxylic acid; (4) High product yield, easy to separate and purify, suitable for industrial production. detailed description

 The invention discloses a preparation method of atazanavir, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention. The method of the present invention has been described by the preferred embodiments, and it is obvious that the method and application described herein can be modified or appropriately modified and combined without departing from the scope of the present invention. Invention technology.

 In order to further understand the present invention, the preparation method of atazanavir provided by the present invention will be described in detail below with reference to the examples. It is to be understood that the description of the embodiments of the present invention is intended to be illustrative only and not restrictive of the scope of the invention. Example 1: 1-[4-(Pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-aza Preparation of alkane

To a clean reaction flask, 11.25 g (20 mmol) of 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-di[( Add 9.3 g of hydrochloric acid to t-butoxycarbonyl)amino]-6-phenyl-2-azanone and 45 ml of dichloromethane; dilute and warm to 40-45 ° C for 3 h; TLC analysis and tracking After the reaction was completed, the temperature was lowered to 25 ° C, 13.2 g of N-methylmorpholine was added, and the mixture was stirred at the same temperature for 1 hour, and the organic layer was dried over anhydrous sodium sulfate for 1 hour, filtered, and the filter cake was rinsed with a small amount of solvent. Concentration to dryness under reduced pressure afforded 1-[4-(pyridin-2-yl)-phenyl] -4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2 - 6.76 g of azahexane, yield 95.2%. Example 2: Preparation of atazanavir monomer To a clean reaction flask, add 6.87 g of 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-benzene. Base-2-azane, 50 ml of dichloromethane and 3.83 g of N-methylmorpholine, then 4.16 g (22 mmol) of N-methoxycarbonyl-L-tert-leucine and 7.2 g (24 mmol) DEPBT was stirred at 35 ° C for 2 h, and TLC analysis was followed until the end of the reaction. 40 ml of 2% sodium hydroxide was added dropwise, stirred for 0.5 h, and the mixture was allowed to stand. The organic layer was washed with water 2~40 ml, dichloromethane was evaporated under reduced pressure, and 2~40 ml of ethanol was added, and concentrated to dryness under reduced pressure; Add 45ml ethanol and 55ml water, heat to 60 ° C, slowly reduce to about 0 ° C, stir for 3h, suction filtration, filter cake with 0 ° C ethanol and water (1: 2), the mixture is washed twice (40 ml), drained, and baked to give 11.28 g of solid atazanavir monomer. Yield: 84.1%. Example 3: Preparation of atazanavir

 70.5g of atazanavir monomer was dissolved in 700 acetone at room temperature 25 ° C, while stirring, 5M of 40.4g of concentrated stone was slowly added to the acid, and the temperature was kept at this temperature for 2 hours after the completion of the dropwise addition; At the end, cool down to 0~5 °C and stir for 2h. After suction filtration, the filter cake was washed twice with 150 ml of acetone, and then dried to obtain 77.3 g of atazanavir sulphate, yield 95.4%. Example 4: 1-[4-(Pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-aza Preparation of alkane

To a clean reaction flask, add 225 g (0.4 mol) of 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-di[( 115.2 g of methanesulfonic acid was added dropwise to tert-butoxycarbonyl)amino]-6-phenyl-2-azanone and 1000 ml of tetrahydrofuran; after the dropwise addition, the temperature was raised to reflux for about 2 h, and the reaction was completed by TLC analysis. 200 g of triethylamine was added and stirred at this temperature for 1 h. After cooling to 0 ° C, filtration, the filter cake was rinsed with a small amount of solvent, and the filtrate and washings were combined and concentrated to dryness under reduced pressure. Add 1500 ml of dichloromethane, wash twice with water, dry with anhydrous sodium sulphate, filter, filter cake with a small amount of dichloromethane, combine the filtrate and washings, and concentrate under reduced pressure to dry 1-[4- ( Pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-phenyl-2-azanehexane 134.5 g, yield 93%. Example 5: Preparation of atazanavir monomer

 To a clean reaction flask, add 134.5 g of 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6-benzene. Base-2-azane, 67.5 g of triethylamine, 1000 ml of tetrahydrofuran, 83.3 g (0.44 mmol) of N-methoxycarbonyl-L-tert-leucine and 150 (0.5 mol) of DEPBT,

The reaction was stirred at 28 ° C for 5 h, and the TLC analysis was followed until the end of the reaction. The tetrahydrofuran was removed under reduced pressure, 2*40 ml of ethanol was added, and the mixture was concentrated to dryness under reduced pressure. 400 ml of isopropanol and 600 ml of water were added to the residue, and the mixture was heated to reflux. The mixture was slowly cooled to about 0 ° C, stirred for 3 h, filtered, filtered. The cake was dried with 0 ° C of isopropanol and water (1:1 2 ), and dried to give 240 g of solid atazanavir monomer. Yield: 91.4%. Example 6: Preparation of atazanavir

 70.5g of atazanavir monomer was dissolved in 500ml of isopropanol at room temperature 25 ° C, while stirring, 5M of 40.4 concentrated sulfuric acid was slowly added dropwise, and the temperature was kept at this temperature for 2 hours after the completion of the dropwise addition; , cool down to 0~5 °C, stir for 2h. After suction filtration, the filter cake was washed with a small amount of isopropyl alcohol, and dried to obtain 75 g of atazanavir sulfate, and the yield was 93.4%. The preparation method of atazanavir proposed by the present invention has been described by way of examples, and it is obvious to those skilled in the art that the preparation method of atazanavir described herein can be carried out without departing from the scope, spirit and scope of the present invention. Modifications or appropriate modifications and combinations are employed to implement the techniques of the present invention. It is to be understood that the various alternatives and modifications are obvious to those skilled in the art, and are considered to be included in the spirit, scope and content of the present invention.

Claims

A method for producing atazanavir, characterized in that 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-di Amino-6-phenyl-2-azetane and N-methoxycarbonyl-L-tert-leucine are reacted in the presence of DEPBT in an organic solvent to give atazanavir monomer.  The method according to claim 1, wherein the organic solvent is an option  A single solvent or a mixed solvent of tetrahydrofuran, dichloromethane, chloroform, butanone, triethylamine, N-methylmorpholine or methyl isobutyl ketone. Leeichi The preparation method according to claim 1, wherein the organic solvent is a mixed solvent selected from the group consisting of dichloromethane, tetrahydrofuran, N-methylmorpholine or triethylamine.  The method according to claim 1, wherein the organic solvent is a mixed solvent of methylene chloride and N-methylmorpholine or a mixed solvent of tetrahydrofuran and triethylamine.  The process according to claim 1, wherein 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-diamino-6 -Phenyl-2-azahexane from 1-[4-(pyridin-2-yl)-phenyl]-4(S)-hydroxy-5(S)-2,5-di[(tert-butoxy) The carbonyl)amino]-6-phenyl-2-azene oxide is prepared by a deprotection reaction.  The preparation method according to claim 1, wherein the atazanavir monomer further prepares atazanavir.  The preparation method according to claim 1, wherein after the reaction is completed, the atazanavir monomer is obtained by the following post treatment: a base is added dropwise to the reaction solution, and concentrated under reduced pressure, in the residual liquid. The crystallization solvent is added, and after heating, the crystal is cooled and crystallized to obtain atazanavir monomer.  The method according to claim 7, wherein the base is sodium hydroxide, sodium hydrogencarbonate, sodium carbonate or an aqueous solution thereof.  The production method according to claim 7, wherein the crystallization solvent is a mixed solution of water and methanol, ethanol, isopropanol or a ketone solvent.