阅读说明：本技术 一种非布司他中间体的制备方法 (Preparation method of febuxostat intermediate ) 是由 宋长江 李文芳 于 2020-05-07 设计创作，主要内容包括：本发明属于医药合成技术领域,具体涉及一种非布司他重要中间体的制备方法,本发明以4-异丁氧基间苯二甲酸二甲酯为原料在催化剂作用下将酯基氨解成酰胺基,酰胺基进一步脱水得4-异丁氧基苯-1,3-二腈,该方法以氨解、脱水方式引入氰基,避免使用毒性较大的氰化物,以绿色催化剂代替传统催化剂,反应更加温和、经济环保且收率较高,适于工业化生产。(The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of an important febuxostat intermediate, wherein 4-isobutoxy dimethyl isophthalate is taken as a raw material, an ester group is aminolyzed into an amide group under the action of a catalyst, the amide group is further dehydrated to obtain 4-isobutoxy benzene-1, 3-dinitrile, a cyano group is introduced in the aminolysis and dehydration mode, a cyanide with high toxicity is avoided, a green catalyst is used for replacing a traditional catalyst, the reaction is milder, economic and environment-friendly, the yield is higher, and the preparation method is suitable for industrial production.)

1. A preparation method of febuxostat intermediate compound III is characterized in that compound II reacts with ammonia to obtain intermediate compound III; the synthetic route is as follows:

2. the method of claim 1, comprising the steps of: and adding the compound II into the organic solution, adding a catalyst, introducing ammonia gas, and then controlling the temperature to reflux until the reaction is finished to obtain a compound III.

3. The preparation method according to claim 2, wherein the catalyst is selected from one or a combination of 4-dimethylaminopyridine, triethylamine, pyridine, morpholine and N-methylpyridine.

4. The preparation method according to claim 2, wherein the feeding molar ratio of the compound II to the catalyst is 1: 1.0-2.0.

5. The method according to claim 2, wherein the organic solvent is selected from methanol, ethanol, tetrahydrofuran, and N, N-dimethylformamide, or a combination thereof.

Technical Field

The invention belongs to the technical field of medicine synthesis, and relates to a preparation method of a febuxostat intermediate.

Background

Febuxostat (febuxostat) chemical name: 2- [ 3-cyano-4-isobutoxyphenyl ] -4-methylthiazole-5-carboxylic acid, a non-purine selective Xanthine Oxidase (XO) inhibitor developed by Teijin, japan, for the treatment of hyperuricemia, was approved for febuxostat by the european union at 5 months 2008 and approved for marketing at the us FDA at 3 months 2009, and has the chemical structure shown below:

many studies on the synthesis of febuxostat have been reported, for example, in Japanese patent JP06329647 and Heterocycles,1998,47(2):857, 4-nitrobenzonitrile is used as a starting material, which is subjected to a cyanation reaction with potassium cyanide, then subjected to an etherification reaction with a compound to obtain 4-isobutoxybenzene-1, 3-dinitrile, then subjected to a reaction with thioacetamide to obtain 3-cyano-4-isobutoxythiobenzamide, and then subjected to a cyclization reaction with chloroacetoacetic acid ethyl ester to obtain a precursor compound, and finally hydrolyzed under alkaline conditions and acidified to obtain febuxostat.

Compared with the early synthetic route, the synthetic route is greatly shortened by introducing cyano and ether-forming reaction one-pot synthesis, but the industrial application is limited by using highly toxic cyanide, and the difficulty of industrial production is increased.

The structural formula of the febuxostat intermediate 4-isobutoxy benzene-1, 3-dinitrile is as follows:

as a synthesis of an important intermediate 4-isobutoxy benzene-1, 3-dinitrile of febuxostat, chinese patent application CN102120733 reports that 2, 4-dihalogenophenol is used as a raw material to be alkylated with isobutane with a leaving group L under an alkaline condition to obtain an etherified product 2, and a compound 2 and cuprous cyanide are subjected to a cyanation reaction in a polar aprotic solvent under the catalysis of a cuprous catalyst to obtain a mixture comprising a compound 3 and a hydrolysate thereof, and the route is as follows:

although the process avoids the use of virulent sodium cyanide and potassium cyanide, the cuprous cyanide used still belongs to a highly toxic substance, and the metallic copper catalyst causes environmental pollution and is not in accordance with the concept of green chemical development.

The introduction of an aldehyde group followed by its conversion to a cyano group is reported in the literature (European Journal of Medicinal Chemistry,181,2019,111558) as follows:

the method for introducing the aldehyde group requires that the aldehyde group is introduced firstly, the condition for converting the aldehyde group into the cyano group is harsh, a flammable and corrosive catalyst HMTA is required, and the process is not suitable for industrial mass production.

In conclusion, the preparation method of the febuxostat intermediate 4-isobutoxy benzene-1, 3-dinitrile has the following problems: the use of highly toxic chemical reagents, sodium cyanide and potassium cyanide, is required; high technical requirement, serious environmental pollution and high production cost; therefore, the problem to be solved at present is to explore a process route for 4-isobutoxy benzene-1, 3-dinitrile, which has the advantages of simple operation, short production period, higher yield and more suitability for industrial production.

Disclosure of Invention

In order to solve the problem that in the prior art, highly toxic chemical reagents of sodium cyanide and potassium cyanide are needed in the preparation process of the febuxostat important intermediate 4-isobutoxy benzene-1, 3-dinitrile; the invention provides a preparation method of a new intermediate compound III, which has the advantages of short reaction route, simple and convenient operation, milder reaction, economy, environmental protection, high yield and suitability for industrial production.

The invention is realized by the following technical scheme:

a preparation method of an important intermediate compound III of febuxostat comprises the following steps: reacting the compound II with ammonia solution to obtain an intermediate compound III; the synthetic route is as follows:

preferably, the above steps are described in further detail in the following sections:

preparation of Compound III

And adding the compound II into the organic solution, adding a catalyst, introducing ammonia gas, and then controlling the temperature to reflux until the reaction is finished to obtain a compound III.

Preferably, the catalyst is selected from one or a combination of 4-dimethylamino pyridine, triethylamine, pyridine, morpholine and N-methyl pyridine, wherein 4-dimethylamino pyridine is particularly preferred.

In a preferable embodiment, the feeding molar ratio of the compound II catalyst is 1: 1.0-2.0, and particularly preferably 1: 1.2.

Preferably, the organic solvent is selected from one or a combination of methanol, ethanol, tetrahydrofuran and N, N-dimethylformamide, and particularly preferably methanol.

In a preferred scheme, after the reaction is finished, post-treatment operation is required, and the method specifically comprises the following steps: and (3) decompressing and concentrating the reaction system to remove excessive ammonia and the solvent until the excessive ammonia and the solvent are dried to obtain a white solid, namely the febuxostat intermediate compound III.

The method for preparing the intermediate 4-isobutoxy benzene-1, 3-dinitrile by using the compound III can be implemented according to the following steps: and sequentially adding the compound III and alkali into an organic solvent at room temperature, adding a dehydrating agent into a reaction system under the stirring of an ice bath, and controlling the temperature and stirring to react to obtain an intermediate I.

Preferably, the base is selected from one or a combination of DBU (1, 8-diazabicycloundecen-7-ene), triethylamine, piperidine, N-diisopropylethylamine, and 2-methylpyridine, and DBU is particularly preferred.

Preferably, the dehydration reagent is selected from one or a combination of trifluoroacetic anhydride, phosphorus oxychloride and N, N-Dicyclohexylcarbodiimide (DCC), and particularly preferably trifluoroacetic anhydride.

In a preferred scheme, the feeding molar ratio of the compound III, the alkali and the dehydrating agent is as follows: 1: 4.0-6.0: 1.0-3.0, and particularly preferably 1:5.0: 2.0.

Preferably, the organic solvent is selected from one or a combination of dichloromethane, trichloromethane and 1, 2-dichloroethane, and dichloromethane is particularly preferred.

In a preferred scheme, the reaction temperature is 25-40 ℃.

In a preferred scheme, after the reaction is finished, post-treatment operation is required, specifically, the reaction solution is poured into purified water, reduced pressure suction filtration is carried out, and the precipitated solid is recrystallized to obtain a compound I; the recrystallization solvent is one or the combination of methanol, ethanol, isopropanol and ethyl acetate.

Compared with the prior art, the invention has the following technical effects:

1. the preparation method of the new intermediate compound III is provided, the reaction route for preparing the intermediate 4-isobutoxy benzene-1, 3-dinitrile from the intermediate III is short, the whole synthesis method is simple and convenient to operate, the reaction yield is high, and the purity of the obtained product is high;

2. the invention forms cyano through amide dehydration, has mild condition, avoids using highly toxic limited reagents, and greatly improves the safety and the applicability for industrial production.

Detailed Description

The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.

Example 1

Slowly adding the compound II (266.29g,1.0mol) into 1000mL of methanol, adding 4-dimethylaminopyridine (146.60g, 1.2mol), introducing ammonia gas into the reaction solution for 20min, controlling the temperature and refluxing, detecting the end of the reaction, and concentrating under reduced pressure to remove excessive ammonia and organic solvent until the excessive ammonia and organic solvent are dried to obtain a white solid III.

Adding the obtained compound III and DBU (761.20g, 5.0mol) into dichloromethane (5.0L) for reaction at room temperature for 30min, dropwise adding trifluoroacetic anhydride (420.06g,2.0mol) into the reaction system under the stirring of an ice bath, gradually heating the reaction system to 35 ℃ after the dropwise adding is finished, carrying out heat preservation reaction, pouring the reaction solution into clear water (1.5L) after the detection reaction is finished, separating out a solid, carrying out vacuum filtration to remove a filtrate, recrystallizing the separated solid in methanol (2.0L), and carrying out vacuum drying to obtain the compound I, wherein the yield is 98.5%, and the HPLC purity is 99.92%.

Example 2

Slowly adding the compound II (266.29g,1.0mol) into 1000mL of ethanol, adding 4-dimethylaminopyridine (122.17g, 1.2mol), introducing ammonia gas into the reaction solution for 20min, controlling the temperature and refluxing, detecting the end of the reaction, and concentrating under reduced pressure to remove excessive ammonia and organic solvent until the excessive ammonia and organic solvent are dried to obtain a white solid III.

Adding the obtained compound III and triethylamine (505.95g, 5.0mol) into dichloromethane (5.0L) to react for 30min at room temperature, dropwise adding trifluoroacetic anhydride (420.06g,2.0mol) into the reaction system under the stirring of an ice bath, gradually heating the reaction system to 25 ℃ after the dropwise adding is finished, carrying out heat preservation reaction, pouring the reaction solution into clear water (1.5L) after the detection reaction is finished, separating out a solid, carrying out vacuum filtration to remove a filtrate, recrystallizing the separated solid in ethanol (2.0L), and carrying out vacuum drying to obtain a compound I, wherein the yield is 94.4%, and the HPLC purity is 99.85%.

Example 3

Slowly adding the compound II (266.29g,1.0mol) into 1000mL tetrahydrofuran, adding 4-dimethylaminopyridine (244.34g, 2.0mol), introducing ammonia gas into the reaction solution for 20min, controlling the temperature and refluxing, and after the detection reaction is finished, decompressing and concentrating to remove excessive ammonia and organic solvent until the excessive ammonia and organic solvent are dried to obtain a white solid III.

Adding the obtained compound III and piperidine (425.75g, 5.0mol) into 1, 2-dichloroethane (5.0L) to react for 30min at room temperature, dropwise adding trifluoroacetic anhydride (420.06g,2.0mol) into the reaction system under ice bath stirring, gradually heating the reaction system to 40 ℃ after dropwise adding, carrying out heat preservation reaction, pouring the reaction solution into clear water (1.5L) after detection reaction is finished, separating out a solid, carrying out vacuum filtration to remove a filtrate, recrystallizing the separated solid in isopropanol (2.0L), and carrying out vacuum drying to obtain the compound I, wherein the yield is 92.6%, and the HPLC purity is 99.75%.

Example 4

Slowly adding the compound II (266.29g,1.0mol) into 1000ml of DMF, adding 4-dimethylamino pyridine (280.99g, 2.3mol), introducing ammonia gas into the reaction solution for 20min, controlling the temperature and refluxing, and after the detection reaction is finished, decompressing and concentrating to remove excessive ammonia and organic solvent until the excessive ammonia and organic solvent are dried to obtain a white solid III.

Adding the obtained compound III, N, N-diisopropylethylamine (646.20g, 5.0mol) into dichloromethane (5.0L) to react for 30min at room temperature, dropwise adding trifluoroacetic anhydride (420.06g,2.0mol) into the reaction system under ice-bath stirring, gradually heating the reaction system to 35 ℃ after dropwise adding, carrying out heat preservation reaction, pouring the reaction solution into clear water (1.5L) after detection reaction is finished, separating out a solid, carrying out vacuum filtration to remove a filtrate, recrystallizing the separated solid in methanol (2.0L), and carrying out vacuum drying to obtain the compound I, wherein the yield is 85.0%, and the HPLC purity is 99.65%.

Example 5

Slowly adding the compound II (266.29g,1.0mol) into 1000mL of methanol, adding 4-dimethylaminopyridine (146.60g, 1.2mol), introducing ammonia gas into the reaction solution for 20min, controlling the temperature and refluxing, detecting the end of the reaction, and concentrating under reduced pressure to remove excessive ammonia and organic solvent until the excessive ammonia and organic solvent are dried to obtain a white solid III.

Adding the obtained compound III and DBU (608.96g, 4.0mol) into dichloromethane (5.0L) for reaction at room temperature for 30min, dropwise adding DCC (412.66g,2.0mol) into the reaction system under the stirring of an ice bath, gradually heating the reaction system to 20 ℃ after the dropwise adding is finished, carrying out heat preservation reaction, pouring the reaction solution into clear water (1.5L) after the detection reaction is finished, separating out a solid, carrying out vacuum filtration under reduced pressure to remove a filtrate, recrystallizing the separated solid in methanol (2.0L), and carrying out vacuum drying to obtain a compound I, wherein the yield is 95.0%, and the HPLC purity is 99.86%.

Example 6

Slowly adding the compound II (266.29g,1.0mol) into 1000mL of methanol, adding 4-dimethylaminopyridine (146.60g, 1.2mol), introducing ammonia gas into the reaction solution for 20min, controlling the temperature and refluxing, detecting the end of the reaction, and concentrating under reduced pressure to remove excessive ammonia and organic solvent until the excessive ammonia and organic solvent are dried to obtain a white solid III.

Adding the obtained compound III and DBU (913.44g, 6.0mol) into dichloromethane (5.0L) for reaction at room temperature for 30min, dropwise adding DCC (412.66g,2.0mol) into the reaction system under the stirring of an ice bath, gradually heating the reaction system to 35 ℃ after the dropwise adding is finished, carrying out heat preservation reaction, pouring the reaction solution into clear water (1.5L) after the detection reaction is finished, separating out a solid, carrying out vacuum filtration to remove a filtrate, recrystallizing the separated solid in ethyl acetate (2.5L), and carrying out vacuum drying to obtain the compound I, wherein the yield is 93.9%, and the HPLC purity is 99.76%.

Example 7

Slowly adding the compound II (266.29g,1.0mol) into 1000mL of methanol, adding 4-dimethylaminopyridine (146.60g, 1.2mol), introducing ammonia gas into the reaction solution for 20min, controlling the temperature and refluxing, detecting the end of the reaction, and concentrating under reduced pressure to remove excessive ammonia and organic solvent until the excessive ammonia and organic solvent are dried to obtain a white solid III.

Adding the obtained compound III and DBU (532.84g, 3.5mol) into dichloromethane (5.0L) for reaction at room temperature for 30min, dropwise adding DCC (412.66g,2.0mol) into the reaction system under the stirring of an ice bath, gradually heating the reaction system to 35 ℃ after the dropwise adding is finished, carrying out heat preservation reaction, pouring the reaction solution into clear water (1.5L) after the detection reaction is finished, separating out a solid, carrying out vacuum filtration under reduced pressure to remove a filtrate, recrystallizing the separated solid in methanol (2.0L), and carrying out vacuum drying to obtain a compound I, wherein the yield is 84.8%, and the HPLC purity is 99.67%.

Example 8

Slowly adding the compound II (266.29g,1.0mol) into 1000mL of methanol, adding 4-dimethylaminopyridine (146.60g, 1.2mol), introducing ammonia gas into the reaction solution for 20min, controlling the temperature and refluxing, detecting the end of the reaction, and concentrating under reduced pressure to remove excessive ammonia and organic solvent until the excessive ammonia and organic solvent are dried to obtain a white solid III.

Adding the obtained compound III and DBU (989.56g, 6.5mol) into trichloromethane (5.0L) for reaction at room temperature for 30min, dropwise adding phosphorus oxychloride (306.66g,2.0mol) into the reaction system under the stirring of an ice bath, gradually heating the reaction system to 35 ℃ after the dropwise adding is finished, carrying out heat preservation reaction, pouring the reaction solution into clear water (1.5L) after the detection reaction is finished, separating out a solid, carrying out vacuum filtration to remove a filtrate, recrystallizing the separated solid in methanol (2.0L), and carrying out vacuum drying to obtain the compound I, wherein the yield is 85.4%, and the HPLC purity is 99.63%.

Example 10

Slowly adding the compound II (266.29g,1.0mol) into 1000mL of methanol, adding 4-dimethylaminopyridine (146.60g, 1.2mol), introducing ammonia gas into the reaction solution for 20min, controlling the temperature and refluxing, detecting the end of the reaction, and concentrating under reduced pressure to remove excessive ammonia and organic solvent until the excessive ammonia and organic solvent are dried to obtain a white solid III.

Adding the obtained compound III, 2-methylpyridine (465.65g, 5.0mol) into 1, 2-dichloroethane (5.0L) to react at room temperature for 30min, dropwise adding phosphorus oxychloride (153.33g,1.0mol) into the reaction system under the stirring of an ice bath, gradually heating the reaction system to 50 ℃ after the dropwise adding is finished, carrying out heat preservation reaction, pouring the reaction solution into clear water (1.5L) after the detection reaction is finished, separating out solids, carrying out vacuum filtration to remove filtrate, recrystallizing the separated solids in methanol (2.0L), and carrying out vacuum drying to obtain the compound I, wherein the yield is 94.7%, and the HPLC purity is 99.82%.

Example 11

Slowly adding the compound II (266.29g,1.0mol) into 1000mL of methanol, adding 4-dimethylaminopyridine (146.60g, 1.2mol), introducing ammonia gas into the reaction solution for 20min, controlling the temperature and refluxing, detecting the end of the reaction, and concentrating under reduced pressure to remove excessive ammonia and organic solvent until the excessive ammonia and organic solvent are dried to obtain a white solid III.

Adding the obtained compound III and DBU (761.20g, 5.0mol) into dichloromethane (5.0L) for reaction at room temperature for 30min, adding phosphorus oxychloride (459.99g,3.0mol) into the reaction system under the stirring of an ice bath, gradually heating the reaction system to 35 ℃ after dropwise addition, carrying out heat preservation reaction, pouring the reaction solution into clear water (1.5L) after the detection reaction is finished, separating out a solid, carrying out vacuum filtration to remove a filtrate, recrystallizing the separated out solid in ethanol (2.0L), and carrying out vacuum drying to obtain the compound I, wherein the yield is 92.5%, and the HPLC purity is 99.73%.

Example 12

Slowly adding the compound II (266.29g,1.0mol) into 1000mL of methanol, adding 4-dimethylaminopyridine (146.60g, 1.2mol), introducing ammonia gas into the reaction solution for 20min, controlling the temperature and refluxing, detecting the end of the reaction, and concentrating under reduced pressure to remove excessive ammonia and organic solvent until the excessive ammonia and organic solvent are dried to obtain a white solid III.

Adding the obtained compound III and DBU (761.20g, 5.0mol) into dichloromethane (5.0L) for reaction at room temperature for 30min, adding phosphorus oxychloride (536.66g,3.5mol) into the reaction system under the stirring of an ice bath, gradually heating the reaction system to 35 ℃ after dropwise addition, carrying out heat preservation reaction, pouring the reaction solution into clear water (1.5L) after detection reaction is finished, separating out a solid, carrying out vacuum filtration to remove a filtrate, recrystallizing the separated out solid in isopropanol (2.0L), and carrying out vacuum drying to obtain the compound I, wherein the yield is 86.5%, and the HPLC purity is 99.64%.