CN113620832B - Febuxostat Process for the preparation of intermediates - Google Patents

Febuxostat Process for the preparation of intermediates Download PDF

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CN113620832B
CN113620832B CN202010378727.9A CN202010378727A CN113620832B CN 113620832 B CN113620832 B CN 113620832B CN 202010378727 A CN202010378727 A CN 202010378727A CN 113620832 B CN113620832 B CN 113620832B
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CN113620832A (en
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宋长江
李文芳
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Lunan Pharmaceutical Group Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/20—Preparation of carboxylic acid nitriles by dehydration of carboxylic acid amides

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Abstract

The invention belongs to the technical field of medicine synthesis, in particular to a preparation method of an important intermediate of febuxostat, which takes 4-isobutoxymethyl isophthalate as a raw material to carry out ammonolysis on an ester group Cheng Xianan base under the action of a catalyst, the method introduces cyano groups in ammonolysis and dehydration modes, avoids using cyanide with higher toxicity, replaces the traditional catalyst with a green catalyst, has milder reaction, economy and environmental protection and higher yield, and is suitable for industrial production.

Description

Febuxostat Process for the preparation of intermediates
Technical Field
The invention belongs to the technical field of medicine synthesis, and relates to a preparation method of a febuxostat intermediate.
Background
Febuxostat (Febuxosta) chemical name: 2- [ 3-cyano-4-isobutoxyphenyl ] -4-methylthiazole-5-carboxylic acid, a non-purine selective Xanthine Oxidase (XO) inhibitor developed by the company of japan imperial (Teijin) for the treatment of hyperuricemia, was approved by febuxostat in the european union for 5 menstruation in 2008 and was approved by the FDA in the united states in 2009, and the chemical structure is shown below:
There are many studies on the synthetic method of Guan Feibu st, such as Japanese patent JP06329647 and Heteromyces, 1998,47 (2): 857. It is reported that 4-nitrobenzonitrile is used as a starting material to undergo a cyanation reaction with potassium cyanide, then an etherification reaction with a compound is carried out to obtain 4-isobutoxy benzene-1, 3-dinitrile, then a thioacetamide is reacted to obtain 3-cyano-4-isobutoxy thiobenzamide, then a cyclization reaction with ethyl chloroacetoacetate is carried out to obtain a precursor compound, and finally hydrolysis under alkaline conditions is carried out, and then acidification is carried out to obtain febuxostat.
Compared with the early synthetic route, the route leads to cyano and ether forming reaction to be synthesized in one pot, so that the synthetic route is greatly shortened, but the use of the highly toxic cyanide limits the industrialized application, and the difficulty of industrial production is increased.
The structural formula of the febuxostat intermediate 4-isobutoxybenzene-1, 3-dinitrile is as follows:
As an important intermediate of febuxostat, the synthesis of 4-isobutoxybenzene-1, 3-dinitrile, chinese patent application CN102120733 reports that the alkylation reaction of 2, 4-dihalophenol as a raw material with isobutane with a leaving group L under alkaline conditions gives an etherified product 2, and the cyanation reaction of compound 2 with cuprous cyanide in a polar aprotic solvent under the catalysis of a cuprous catalyst gives a mixture comprising compound 3 and its hydrolysate, the route is as follows:
Although the technology avoids the use of extremely toxic sodium cyanide and potassium cyanide, the cuprous cyanide still belongs to highly toxic substances, and the metal copper catalyst can cause environmental pollution and does not accord with the green chemical development concept.
Literature (European Journal of MEDICINAL CHEMISTRY,181,2019,111558) reports the introduction of aldehyde groups followed by the conversion of aldehyde groups to cyano groups, as follows:
the method for introducing the aldehyde group needs to introduce the aldehyde group firstly, the condition of converting the aldehyde group into the cyano group is harsh, a flammable and corrosive catalyst HMTA is needed, and the process is not suitable for industrial mass production.
In summary, the preparation method of the febuxostat intermediate 4-isobutoxybenzene-1, 3-dinitrile has the following problems: sodium cyanide and potassium cyanide, which are highly toxic chemicals, are required; high technical requirements, serious environmental pollution and high production cost; therefore, the exploration of a process route for 4-isobutoxy benzene-1, 3-dinitrile, which is simple and convenient to operate, short in production period, higher in yield and more suitable for industrial production, is still a problem to be solved at present.
Disclosure of Invention
In order to solve the problem that the prior art needs to use highly toxic chemical reagents sodium cyanide and potassium cyanide in the preparation process of the important intermediate 4-isobutoxy benzene-1, 3-dinitrile of febuxostat; the invention provides a novel preparation method of an intermediate compound III, which has the advantages of short reaction route for preparing the intermediate 4-isobutoxy benzene-1, 3-dinitrile, simple and convenient operation, milder reaction, economy, environmental protection and high yield, and is suitable for industrial production.
The invention is realized by the following technical scheme:
the preparation method of the febuxostat important intermediate compound III 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 section:
preparation of Compound III
Adding the compound II into an organic solution, adding a catalyst, introducing ammonia gas, and 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-dimethylaminopyridine, triethylamine, pyridine, morpholine and N-methylpyridine, wherein 4-dimethylaminopyridine is particularly preferred.
In a preferred embodiment, the molar ratio of the catalyst of compound II to the feed is 1:1.0 to 2.0, particularly preferably 1:1.2.
Preferably, the organic solvent is selected from one or a combination of methanol, ethanol, tetrahydrofuran, and N, N-dimethylformamide, wherein methanol is particularly preferred.
Preferably, post-treatment operation is required after the reaction is finished, specifically: concentrating the reaction system under reduced pressure to remove excessive ammonia and solvent until the reaction system is dried to obtain white solid, namely the febuxostat intermediate compound III.
The method for preparing the intermediate 4-isobutoxy benzene-1, 3-dinitrile by the compound III can be as follows: sequentially adding the compound III and alkali into an organic solvent at room temperature, adding a dehydrating agent into a reaction system under ice bath stirring, and carrying out temperature control stirring reaction to obtain an intermediate I.
Preferably, the base is selected from one or a combination of DBU (1, 8-diazabicyclo undec-7-ene), triethylamine, piperidine, N-diisopropylethylamine, 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), particularly preferably trifluoroacetic anhydride.
In a preferred scheme, the feeding mole ratio of the compound III to the alkali to the dehydrating agent is as follows: 1:4.0 to 6.0:1.0 to 3.0, particularly preferably 1:5.0:2.0.
Preferably, the organic solvent is selected from one or a combination of dichloromethane, chloroform and 1, 2-dichloroethane, and particularly preferably dichloromethane.
Preferably, the reaction temperature is 25-40 ℃.
In a preferred scheme, after the reaction is finished, post-treatment operation is needed, 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 a combination of methanol, ethanol, isopropanol and ethyl acetate.
Compared with the prior art, the invention has the technical effects that:
1. the preparation method of the novel intermediate compound III is provided, the reaction route of the intermediate compound III for preparing the intermediate 4-isobutoxy benzene-1, 3-dinitrile 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 method forms cyano by amide dehydration, has mild conditions, avoids using a highly toxic reagent with limited restriction, and greatly improves the safety and applicability for industrial production.
Detailed Description
The invention is further illustrated by the following examples. It should be correctly understood that: the examples of the present invention are intended to be illustrative of the invention and not limiting thereof, so that simple modifications of the invention based on the method of the invention are within the scope of the invention as claimed.
Example 1
Compound II (266.29 g,1.0 mol) was slowly added to 1000mL of methanol, 4-dimethylaminopyridine (146.60 g,1.2 mol) was added, ammonia gas was introduced into the reaction solution for 20min, the reaction solution was refluxed at a controlled temperature, and after completion of the reaction, excess ammonia and organic solvent were removed by concentration under reduced pressure until dryness, to give white solid III.
The compound III, DBU (761.20 g,5.0 mol) obtained above was added to dichloromethane (5.0L) and reacted at room temperature for 30min, trifluoroacetic anhydride (420.06 g,2.0 mol) was added dropwise to the reaction system under stirring in an ice bath, the reaction system was gradually warmed to 35℃after the completion of the dropwise addition, the reaction was kept at a temperature, the reaction was allowed to proceed with a test, the reaction solution was poured into clear water (1.5L) after the completion of the test, solids were precipitated, the filtrate was removed by suction filtration under reduced pressure, the precipitated solids were recrystallized from methanol (2.0L) and dried under vacuum to give compound I in a yield of 98.5% and an HPLC purity of 99.92%.
Example 2
Compound II (266.29 g,1.0 mol) was slowly added to 1000mL of ethanol, 4-dimethylaminopyridine (122.17 g,1.2 mol) was added, ammonia gas was introduced into the reaction solution for 20min, the reaction solution was refluxed at a controlled temperature, and after completion of the reaction, excess ammonia and organic solvent were removed by concentration under reduced pressure until dryness, to give white solid III.
The compound III obtained above, triethylamine (505.95 g,5.0 mol) was added to methylene chloride (5.0L) and reacted at room temperature for 30 minutes, trifluoroacetic anhydride (420.06 g,2.0 mol) was added dropwise to the reaction system under stirring in an ice bath, the reaction system was gradually warmed to 25℃after completion of the addition, the reaction was kept at a constant temperature, the reaction solution was poured into clear water (1.5L) after completion of the detection, solids were precipitated, the filtrate was removed by suction filtration under reduced pressure, and the precipitated solids were recrystallized from ethanol (2.0L) and dried under vacuum to give compound I in a yield of 94.4% and an HPLC purity of 99.85%.
Example 3
Compound II (266.29 g,1.0 mol) was slowly added to 1000mL of tetrahydrofuran, 4-dimethylaminopyridine (244.34 g,2.0 mol) was added, ammonia gas was introduced into the reaction solution for 20min, the reaction solution was refluxed at a controlled temperature, and after completion of the reaction, excess ammonia and organic solvent were removed by concentration under reduced pressure until dryness gave a white solid III.
The compound III obtained above, piperidine (425.75 g,5.0 mol) was added to 1, 2-dichloroethane (5.0L) and reacted at room temperature for 30min, trifluoroacetic anhydride (420.06 g,2.0 mol) was added dropwise to the reaction system under ice bath stirring, the reaction system was gradually warmed to 40℃after the completion of the addition, the reaction was kept at a constant temperature, the reaction solution was poured into clear water (1.5L) after the completion of the detection reaction, solids were precipitated, the filtrate was removed by suction filtration under reduced pressure, and the precipitated solids were recrystallized from isopropanol (2.0L) and dried under vacuum to give compound I in a yield of 92.6% and an HPLC purity of 99.75%.
Example 4
Compound II (266.29 g,1.0 mol) was slowly added to 1000mL of LDMF, 4-dimethylaminopyridine (280.99 g,2.3 mol) was added, ammonia gas was introduced into the reaction solution for 20min, the reaction solution was refluxed at a controlled temperature, and after completion of the reaction, excess ammonia and organic solvent were removed by concentration under reduced pressure until dryness, to give white solid III.
The compound III, N, N-diisopropylethylamine (646.20 g,5.0 mol) obtained above was added to methylene chloride (5.0L) and reacted at room temperature for 30 minutes, trifluoroacetic anhydride (420.06 g,2.0 mol) was added dropwise to the reaction system under stirring in an ice bath, the reaction system was gradually warmed to 35℃after the completion of the addition, the reaction was kept at a constant temperature, the reaction solution was poured into clear water (1.5L) after the completion of the detection, solids were precipitated, the filtrate was removed by suction filtration under reduced pressure, the precipitated solids were recrystallized from methanol (2.0L) and dried under vacuum to give compound I in a yield of 85.0% and an HPLC purity of 99.65%.
Example 5
Compound II (266.29 g,1.0 mol) was slowly added to 1000mL of methanol, 4-dimethylaminopyridine (146.60 g,1.2 mol) was added, ammonia gas was introduced into the reaction solution for 20min, the reaction solution was refluxed at a controlled temperature, and after completion of the reaction, excess ammonia and organic solvent were removed by concentration under reduced pressure until dryness, to give white solid III.
The compound III, DBU (608.96 g,4.0 mol) obtained above was added to dichloromethane (5.0L) and reacted at room temperature for 30min, DCC (412.66 g,2.0 mol) was added dropwise to the reaction system under stirring in an ice bath, the reaction system was gradually warmed to 20℃after the completion of the dropwise addition, reacted at a constant temperature, the reaction solution was poured into clear water (1.5L) after the completion of the detection reaction, solids were precipitated, the filtrate was removed by suction filtration under reduced pressure, and the precipitated solids were recrystallized in methanol (2.0L) and dried under vacuum to give compound I in a yield of 95.0% and an HPLC purity of 99.86%.
Example 6
Compound II (266.29 g,1.0 mol) was slowly added to 1000mL of methanol, 4-dimethylaminopyridine (146.60 g,1.2 mol) was added, ammonia gas was introduced into the reaction solution for 20min, the reaction solution was refluxed at a controlled temperature, and after completion of the reaction, excess ammonia and organic solvent were removed by concentration under reduced pressure until dryness, to give white solid III.
The compound III, DBU (913.44 g,6.0 mol) obtained above was added to dichloromethane (5.0L) and reacted at room temperature for 30min, DCC (412.66 g,2.0 mol) was added dropwise to the reaction system under stirring in an ice bath, the reaction system was gradually warmed to 35℃after the completion of the dropwise addition, the reaction was kept at a constant temperature, the reaction was then carried out after the completion of the detection, the reaction solution was poured into clear water (1.5L) to precipitate a solid, the filtrate was removed by suction filtration under reduced pressure, and the precipitated solid was recrystallized from ethyl acetate (2.5L) and dried under vacuum to give compound I in a yield of 93.9% and an HPLC purity of 99.76%.
Example 7
Compound II (266.29 g,1.0 mol) was slowly added to 1000mL of methanol, 4-dimethylaminopyridine (146.60 g,1.2 mol) was added, ammonia gas was introduced into the reaction solution for 20min, the reaction solution was refluxed at a controlled temperature, and after completion of the reaction, excess ammonia and organic solvent were removed by concentration under reduced pressure until dryness, to give white solid III.
The compound III, DBU (532.84 g,3.5 mol) obtained above was added to dichloromethane (5.0L) and reacted at room temperature for 30min, DCC (412.66 g,2.0 mol) was added dropwise to the reaction system under stirring in an ice bath, the reaction system was gradually warmed to 35℃after the completion of the dropwise addition, the reaction was kept at a constant temperature, the reaction was then carried out, the reaction solution was poured into clear water (1.5L) after the completion of the detection, solids were precipitated, the filtrate was removed by suction filtration under reduced pressure, the precipitated solids were recrystallized in methanol (2.0L) and dried in vacuo to give compound I in a yield of 84.8% and an HPLC purity of 99.67%.
Example 8
Compound II (266.29 g,1.0 mol) was slowly added to 1000mL of methanol, 4-dimethylaminopyridine (146.60 g,1.2 mol) was added, ammonia gas was introduced into the reaction solution for 20min, the reaction solution was refluxed at a controlled temperature, and after completion of the reaction, excess ammonia and organic solvent were removed by concentration under reduced pressure until dryness, to give white solid III.
The compound III, DBU (989.56 g,6.5 mol) obtained above was added to chloroform (5.0L) and reacted at room temperature for 30min, phosphorus oxychloride (306.66 g,2.0 mol) was added dropwise to the reaction system under ice bath stirring, the reaction system was gradually warmed to 35℃after the completion of the dropwise addition, the reaction was kept at a temperature, the reaction solution was poured into clear water (1.5L) after the completion of the detection reaction, solids were precipitated, the filtrate was removed by suction filtration under reduced pressure, and the precipitated solids were recrystallized in methanol (2.0L) and dried under vacuum to give compound I in a yield of 85.4% and an HPLC purity of 99.63%.
Example 10
Compound II (266.29 g,1.0 mol) was slowly added to 1000mL of methanol, 4-dimethylaminopyridine (146.60 g,1.2 mol) was added, ammonia gas was introduced into the reaction solution for 20min, the reaction solution was refluxed at a controlled temperature, and after completion of the reaction, excess ammonia and organic solvent were removed by concentration under reduced pressure until dryness, to give white solid III.
The compound III, 2-methylpyridine (465.65 g,5.0 mol) obtained above was added to 1, 2-dichloroethane (5.0L) and reacted at room temperature for 30 minutes, phosphorus oxychloride (153.33 g,1.0 mol) was added dropwise to the reaction system under stirring in an ice bath, the reaction system was gradually warmed to 50℃after the completion of the addition, the reaction was kept at a constant temperature, the reaction solution was poured into clear water (1.5L) after the completion of the detection, solids were precipitated, the filtrate was removed by suction filtration under reduced pressure, the precipitated solids were recrystallized from methanol (2.0L) and dried under vacuum to give compound I in a yield of 94.7% and an HPLC purity of 99.82%.
Example 11
Compound II (266.29 g,1.0 mol) was slowly added to 1000mL of methanol, 4-dimethylaminopyridine (146.60 g,1.2 mol) was added, ammonia gas was introduced into the reaction solution for 20min, the reaction solution was refluxed at a controlled temperature, and after completion of the reaction, excess ammonia and organic solvent were removed by concentration under reduced pressure until dryness, to give white solid III.
The compound III, DBU (761.20 g,5.0 mol) obtained above was added to methylene chloride (5.0L) and reacted at room temperature for 30min, phosphorus oxychloride (459.99 g,3.0 mol) was added to the reaction system under ice bath stirring, the reaction system was gradually warmed to 35℃after the completion of the dropwise addition, the reaction was kept at a temperature, the reaction was allowed to proceed, the reaction solution was poured into clear water (1.5L) after the completion of the detection, solids were precipitated, the filtrate was removed by suction filtration under reduced pressure, the precipitated solids were recrystallized from ethanol (2.0L) and dried under vacuum to obtain compound I in a yield of 92.5% and an HPLC purity of 99.73%.
Example 12
Compound II (266.29 g,1.0 mol) was slowly added to 1000mL of methanol, 4-dimethylaminopyridine (146.60 g,1.2 mol) was added, ammonia gas was introduced into the reaction solution for 20min, the reaction solution was refluxed at a controlled temperature, and after completion of the reaction, excess ammonia and organic solvent were removed by concentration under reduced pressure until dryness, to give white solid III.
The compound III, DBU (761.20 g,5.0 mol) obtained above was added to methylene chloride (5.0L) and reacted at room temperature for 30min, phosphorus oxychloride (536.66 g,3.5 mol) was added to the reaction system under ice bath stirring, the reaction system was gradually warmed to 35℃after the completion of the dropwise addition, the reaction was kept at a temperature, the reaction was allowed to proceed, the reaction solution was poured into clear water (1.5L) after the completion of the detection, solids were precipitated, the filtrate was removed by suction filtration under reduced pressure, and the precipitated solids were recrystallized in isopropanol (2.0L) and dried under vacuum to give compound I in a yield of 86.5% and an HPLC purity of 99.64%.

Claims (1)

1. The preparation method of the febuxostat intermediate compound I is characterized by comprising the following steps of: 266.29g of compound II is slowly added into 1000mL of methanol, 146.60g of 4-dimethylaminopyridine is added, ammonia gas is introduced into the reaction liquid for 20min, then temperature control reflux is carried out, and after the reaction is finished, excess ammonia and organic solvent are removed through decompression concentration until the reaction liquid is dried, thus obtaining white solid III; adding 761.20g of DBU into 5.0L of dichloromethane, reacting for 30min at room temperature, dropwise adding 420.06g of trifluoroacetic anhydride into a reaction system under ice bath stirring, gradually heating the reaction system to 35 ℃ after the dropwise adding is finished, carrying out heat preservation reaction, pouring the reaction solution into 1.5L of clear water after the detection reaction is finished, precipitating solids, filtering out filtrate under reduced pressure, recrystallizing the precipitated solids in 2.0L of methanol, and carrying out vacuum drying to obtain a compound I; the synthetic route is as follows:
。
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KR102622104B1 (en) * 2015-06-30 2024-01-09 (주)아모레퍼시픽 Preparation method of benzoic acid amide compounds
CN109761836B (en) * 2019-02-21 2020-05-15 中南大学 Preparation method of amide compound

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Publication number Priority date Publication date Assignee Title
CN101080381A (en) * 2004-12-16 2007-11-28 诺瓦提斯公司 Manufacture process of n-substituted salicylamides
CN111100012A (en) * 2019-12-16 2020-05-05 上海交通大学 Method for preparing m-phenylenediamine

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