CN109503513B - One-pot synthesis method of febuxostat intermediate - Google Patents
One-pot synthesis method of febuxostat intermediate Download PDFInfo
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- CN109503513B CN109503513B CN201811640518.6A CN201811640518A CN109503513B CN 109503513 B CN109503513 B CN 109503513B CN 201811640518 A CN201811640518 A CN 201811640518A CN 109503513 B CN109503513 B CN 109503513B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention belongs to the field of drug synthesis, and particularly relates to a one-pot synthesis method of febuxostat intermediate 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-ethyl formate, wherein 2- (4-hydroxyphenyl) -4-methylthiazole-5-ethyl formate is used as a starting raw material, and is subjected to etherification reaction with bromoisobutane under the catalysis of alkali, and then solid-liquid separation is carried out to obtain a filtrate; and (3) dropwise adding phosphorus oxychloride into the filtrate, stirring for reaction, then adding ammonia water and elemental iodine, continuing stirring, quenching for reaction after the reaction is finished, and then extracting and concentrating an organic phase to obtain the phosphorus oxychloride. The method can synthesize the febuxostat key intermediate in series by one pot, and the process can meet the requirement of purity without multiple purifications and has good yield; is suitable for industrial large-scale production.
Description
Technical Field
The invention relates to the technical field of medical technology, in particular to a preparation method of a febuxostat intermediate 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-ethyl formate.
Background
Febuxostat with a molecular formula of C16H16N2O 3S; molecular weight: 316.37
Structural formula (xvi):
febuxostat (Febuxostat), a new generation of drug for treating gout, is used for inhibiting uric acid generation and reducing uric acid concentration in blood, and is a second drug for inhibiting uric acid generation after allopurinol. Developed by the drug of Japanese emperor (T eijin company), is firstly approved to be marketed in France 5.5.2008, and is sold under the name Adenuric for treating gout. FDA approval was obtained 2 months and 16 days 2009 and marketed in the united states under the trade name Uloric. In recent years, a great deal of research on the synthesis of febuxostat at home and abroad is carried out, and a plurality of synthesis methods are proposed.
The febuxostat synthesis route published by the original febuxostat manufacturers emperor in 1994 (JP1994329647) is as follows:
the method comprises the steps of cyclizing an initial material of p-hydroxythiobenzamide (compound I) by alpha-bromoacetoacetic acid ethyl ester to construct a thiazole ring compound II, formylating by hexamethylenetetramine and trifluoroacetic acid to obtain a compound III, etherifying phenolic hydroxyl of the compound to obtain a compound IV, heating the compound IV with hydroxylamine hydrochloride and sodium formate in formic acid to react to obtain a compound V, and finally hydrolyzing to obtain febuxostat.
The method uses trifluoroacetic acid as an aldehyde group on a solvent, and prepares the cyano group in formic acid through reflux, and the two-step reaction has the defects of high corrosion to equipment, long reaction time and the like.
Furthermore, JP1045733 reports the preparation of compound III from polyphosphoric acid and hexamethylenetetramine with compound II, but in this process polyphosphoric acid is used which is disadvantageous for stirring, the yield is low and the treatment of phosphorus-containing acidic waste water is troublesome.
Another febuxostat synthesis route published by Imperial pharmacy (patent publication No. JP2725886B2) is as follows:
the method comprises the steps of taking 3-nitro-4-hydroxybenzaldehyde of a compound VI as a starting material, heating the starting material, hydroxylamine hydrochloride and sodium acetate in formic acid to react to obtain a compound VII, reacting with thioacetamide to obtain a compound VIII, cyclizing the compound VIII with alpha-chloroacetoacetic acid ethyl ester to obtain a compound IX containing a thiazole ring structure, forming phenol ether with bromoisobutane by taking potassium carbonate as an acid-binding agent to obtain a compound X, carrying out hydrogenation reduction on palladium-carbon, diazotization, S and deeyer reaction to obtain a compound V, and finally carrying out alkaline hydrolysis and acidification to obtain febuxostat.
The route uses noble metal catalytic hydrogenation and diazotization reaction, uses highly toxic cyanide, and has higher production cost and operation danger.
Disclosure of Invention
The invention aims to provide a novel series one-pot synthesis route of febuxostat intermediate ethyl 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate for overcoming the defects of corrosive acidic solvent used in formylation reaction and long reaction time.
The invention provides a one-pot synthesis method of febuxostat intermediate 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-ethyl formate, which comprises the following steps:
step (1): taking 2- (4-hydroxyphenyl) -4-methylthiazole-5-ethyl formate as a starting material, carrying out etherification reaction on the starting material and bromoisobutane under the catalysis of a DMF solvent and alkali, and then carrying out solid-liquid separation to obtain a filtrate;
step (2): and (3) dropwise adding phosphorus oxychloride into the filtrate, heating, stirring, reacting, then adding ammonia water and elemental iodine, continuing to react, quenching the reaction after the reaction is finished, and then extracting and concentrating an organic phase to obtain the ethyl 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate.
The invention provides a method for synthesizing a febuxostat main intermediate (2- (4-hydroxyphenyl) -4-methylthiazole-5-ethyl formate) in a one-pot series manner, wherein a reaction circuit is shown as a formula 1; taking 2- (4-hydroxyphenyl) -4-methylthiazole-5-ethyl formate as a starting material (also called a compound II in the invention), obtaining a filtrate through the etherification reaction through simple solid-liquid separation, directly reacting the filtrate with phosphorus oxychloride in advance without purifying the filtrate, then reacting the filtrate with ammonia water and iodine, and finally obtaining the 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-ethyl formate (also called a compound V in the invention) through simple quenching, extraction and concentration operations. The method compresses etherification and cyanation into one-step reaction, does not involve noble metal catalytic hydrogenation, does not involve highly toxic compounds, can effectively control related impurities of an intermediate without operations such as chromatographic purification and the like, can ensure good product yield, and is particularly suitable for industrial amplification.
The invention takes DMF (N, N-dimethylformamide) as an etherification reaction solvent, 2- (4-hydroxyphenyl) -4-methylthiazole-5-ethyl formate, alkali and bromoisobutane are dissolved and/or dispersed in the DMF, and the mixture is stirred for etherification reaction.
Preferably, the mass ratio of DMF to the starting material is 2.5-4.5: 1; more preferably 3.5 to 4.0: 1.
the base used in the etherification reaction is preferably at least one of sodium hydride, n-butyl lithium, sodium amide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate; more preferably potassium carbonate.
In the etherification reaction, the molar ratio of the base to the compound II (i.e., the starting material of the present invention) is preferably 2.0 to 3.6: 1, more preferably 2.5 to 3.6: 1.
preferably, the molar ratio of bromoisobutane (2-methyl-1-bromopropane) to the starting material is 2.0-3.6: 1, more preferably 2.5 to 3.6: 1.
the temperature of the etherification reaction is preferably 70-100 ℃, and more preferably 90-100 ℃.
The etherification reaction time can be determined according to TLC or HPLC control results, and the preferred etherification reaction time is 2-3 h.
After the etherification reaction is completed, the solid portion (for example, excess alkali) in the etherification reaction system is removed by solid-liquid separation. Preferably, the etherification reaction system is cooled to 20-45 ℃ in advance, and more preferably 40-45 ℃ before solid-liquid separation.
The filtrate obtained by solid-liquid separation is directly subjected to the reaction of the subsequent reaction without purifying the filtrate.
Preferably, the filtrate is cooled and then is dropwise added with phosphorus oxychloride, then the temperature is increased and stirred for a period of time, then is cooled, and then ammonia water and elemental iodine are added, and stirring is continued for a period of time until the reaction is finished.
Preferably, the temperature of the filtrate is reduced to 0-5 ℃, and then phosphorus oxychloride is added. That is, the temperature for dropping phosphorus oxychloride is preferably 0-5 ℃.
Preferably, the molar ratio of the phosphorus oxychloride to the compound II is preferably 1.2-1.3: 1.
after the phosphorus oxychloride is added, heating to 50-80 ℃, and preferably stirring to react at 60-70 ℃. It has been found that at this preferred temperature range, the yield and purity of the product can be unexpectedly improved.
The reaction time is preferably 1-3 h; more preferably 2 h.
Reducing the temperature of a system obtained after the reaction of the filtrate and phosphorus oxychloride to 10-20 ℃, and then dropwise adding ammonia water and elemental iodine; and then continuously reacting for 2-4 h at the temperature of 10-20 ℃.
The mol ratio of the ammonia water to the compound II is preferably 20-30: 1.
the molar ratio of the elemental iodine to the compound II is preferably 1.1-1.2: 1.
the preferable febuxostat intermediate ethyl 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate specifically comprises the following steps:
(1) carrying out etherification reaction on the compound II and bromoisobutane under the catalysis of alkali, and directly carrying out the next reaction after the prepared compound XI is cooled and solid is filtered after the reaction is finished;
(2) dropwise adding phosphorus oxychloride into the filtrate obtained in the step (1) at a low temperature, then heating and stirring for a period of time, cooling, adding ammonia water and elemental iodine, and continuously stirring for a period of time. Quenching the reaction by using saturated sodium sulfite aqueous solution, adding ethyl acetate to extract reaction liquid, drying an organic phase by using anhydrous sodium sulfate, filtering, and concentrating filtrate under reduced pressure to obtain the ethyl 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-formate.
In a preferred preparation method, in the step (1), the base is potassium carbonate. The molar ratio of the anhydrous potassium carbonate to the compound II is preferably 2.0-3.6: 1, more preferably 2.5 to 3.6: 1. the mol ratio of the bromoisobutane in the step (1) to the compound II is preferably 2.0-3.6: 1, more preferably 2.5 to 3.6: 1. the mass ratio of the solvent N, N-dimethylformamide in the step (1) to the compound II is preferably 2.5-4.5: 1, more preferably 3.5 to 4.0: 1. the step (1) is preferably carried out at 70-100 ℃, and more preferably at 90-100 ℃. The temperature reduction temperature is preferably 20-45 ℃, and more preferably 40-45 ℃.
In the step (2), the temperature for dripping the phosphorus oxychloride is preferably 0-5 ℃. The mol ratio of the phosphorus oxychloride to the compound II is preferably 1.2-1.3. The reaction temperature of the phosphorus oxychloride is preferably 50-80 ℃, and more preferably 60-70 ℃. The reaction time of the phosphorus oxychloride is preferably 2 h. The reaction temperature is preferably 10-20 ℃ when the ammonia water and the elemental iodine are added dropwise. The mol ratio of the ammonia water to the compound II is preferably 20-30: 1. the molar ratio of the elemental iodine to the compound II is preferably 1.1-1.2: 1. the reaction time of the ammonia and the elementary iodine is preferably 3 hours.
The invention also provides a synthesis method of febuxostat, wherein the synthesis method is adopted to prepare the ethyl 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate, and the ethyl 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate is subjected to ester hydrolysis reaction to obtain the febuxostat.
Advantageous effects
The invention does not need aldehyde group intermediate, and the product of the three-step reaction is prepared by one step through a one-pot method, thereby greatly saving the reaction time and improving the production efficiency. The whole reaction process only needs TLC for central control, so that the reaction time is greatly shortened, and the obtained product has high yield and good quality and is easy for industrial application.
Detailed Description
In order that those skilled in the art will better understand the technical solutions of the present invention, the present invention will be further described with reference to the following detailed description.
Example 1
To a 100ml reaction vessel were added 10g of Compound II (ethyl 2- (4-hydroxyphenyl) -4-methylthiazole-5-carboxylate) and 13.2g of anhydrous potassium carbonate (2.6eqv), followed by addition of 40ml of N, N-dimethylformamide and 13g of bromoisobutane (2.6eqv), and stirring was started. Heating to 75-80 ℃, and carrying out heat preservation reaction for 5 hours at the temperature; TLC is used for central control (developing agent: PE: EA is 4:1), TLC shows that the reaction is complete, then the temperature is reduced to 25 ℃, and potassium carbonate is removed by suction filtration.
Transferring the filtrate into a 500mL reaction kettle, and continuously cooling and stirring. 4.2mL (1.2eqv) of phosphorus oxychloride was added dropwise at 0 ℃ followed by warming to 60 ℃ and stirring for 2 h. The temperature is reduced to 10 ℃, ammonia (25 percent, 57.2ml) is added dropwise, then 10.6g of elementary iodine is added, and the reaction temperature is controlled to be stirred for 2 hours at 20 ℃. TLC was used for medium control (developing solvent: PE: EA: 4:1), and after completion of the reaction, 50mL of saturated aqueous sodium sulfite solution was added to quench the reaction. 40mL of purified water was added to dilute the reaction solution, and 60mL of ethyl acetate was added thereto and extracted three times. 40mL of saturated saline solution is washed, 10g of anhydrous sodium sulfate is dried and filtered, the filtrate is decompressed and concentrated at 50 ℃ to obtain 9.6g of febuxostat intermediate ethyl 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate, the yield is 75%, and the purity HPLC: 95 percent.
Example 2
50g of the compound II and 66g of anhydrous potassium carbonate are added into a 500ml reaction kettle, 200ml of N, N-dimethylformamide and 65g of bromoisobutane are added, and stirring is started. Heating to 90-95 ℃, and reacting for 2-3 h at the temperature; and (4) performing TLC (developing agent: PE: EA is 4:1) to show that the reaction is complete, cooling to 40-45 ℃, and performing suction filtration to remove potassium carbonate.
Transferring the filtrate into a 1000mL reaction kettle, and continuously cooling and stirring. 21mL of phosphorus oxychloride is added dropwise at 0 ℃, and then the temperature is raised to 60 ℃ and the mixture is stirred for 2 hours. And (3) cooling to 10 ℃, dropwise adding ammonia water (25%, 286ml), then adding 53g of elemental iodine, and stirring for 2-3 h at the reaction temperature of 20 ℃. TLC was used for medium control (developing solvent: PE: EA: 4:1), and after completion of the reaction, 50mL of saturated aqueous sodium sulfite solution was added to quench the reaction. The reaction mixture was diluted with 200mL of purified water, and extracted three times with 300mL of ethyl acetate. 200mL of saturated common salt water is washed, 50g of anhydrous sodium sulfate is dried and filtered, the filtrate is decompressed and concentrated at 50 ℃ to obtain 54g of febuxostat intermediate ethyl 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate, the yield is 83%, and the purity HPLC: 96 percent.
Example 3
The main difference compared to example 2 is the addition of POCl3The subsequent reaction temperature was decreased as follows:
10g of the compound II and 13.2g of anhydrous potassium carbonate were added to a 100ml reaction vessel, and then 40ml of N, N-dimethylformamide and 13g of bromoisobutane were added thereto, and stirring was started. Heating to 90-95 ℃, and reacting for 2-3 h at the temperature; TLC is used for central control (developing agent: PE: EA is 4:1), TLC shows that the reaction is complete, then the temperature is reduced to 25 ℃, and potassium carbonate is removed by suction filtration.
Transferring the filtrate into a 500mL reaction kettle, and continuously cooling and stirring. 4.2mL of phosphorus oxychloride is added dropwise at 0 ℃, and then the mixture is heated to 40 ℃ and stirred for 2 hours. The temperature is reduced to 10 ℃, ammonia (25 percent, 57.2ml) is added dropwise, then 10.6g of elementary iodine is added, and the reaction temperature is controlled to be stirred for 2 hours at 20 ℃. TLC was used for medium control (developing solvent: PE: EA: 4:1), and after completion of the reaction, 50mL of saturated aqueous sodium sulfite solution was added to quench the reaction. 40mL of purified water was added to dilute the reaction solution, and 60mL of ethyl acetate was added thereto and extracted three times. 40mL of saturated saline solution is washed, 10g of anhydrous sodium sulfate is dried and filtered, the filtrate is decompressed and concentrated at 50 ℃ to obtain 8.0g of febuxostat intermediate ethyl 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate, the yield is 62%, and the purity HPLC: 87 percent. POCl3The reaction temperature of (a) is low, resulting in a decrease in the purity and yield of the product.
The above embodiments are merely exemplary embodiments adopted to illustrate the principles of the present invention, but the present invention is not limited thereto. It will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope of the invention, and these changes and modifications are also considered to be included in the scope of the invention.
Claims (10)
1. A one-pot synthesis method of febuxostat intermediate is characterized in that 2- (4-hydroxyphenyl) -4-methylthiazole-5-ethyl formate is used as a starting material, and is subjected to etherification reaction with bromoisobutane under the catalysis of a DMF solvent and alkali, and then solid-liquid separation is carried out to obtain a filtrate;
cooling the filtrate to 0-5 ℃, and adding phosphorus oxychloride; after the addition of phosphorus oxychloride is finished, heating to 50-80 ℃, stirring for reaction for 2-3 h, adding ammonia water and elemental iodine, continuing the reaction, quenching the reaction after the reaction is finished, and then extracting and concentrating an organic phase to obtain a febuxostat intermediate 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-ethyl formate;
the molar ratio of the phosphorus oxychloride to the starting material is 1.2-1.3: 1.
2. the synthesis method according to claim 1, wherein the mass ratio of DMF to starting material is 2.5-4.5: 1.
3. the method of claim 1, wherein the base is at least one of sodium hydride, n-butyllithium, sodium amide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide, potassium carbonate, and sodium carbonate.
4. The synthesis method according to claim 1, wherein the molar ratio of the base to the starting material is 2.0 to 3.6: 1.
5. the synthesis method according to claim 1, wherein the molar ratio of bromoisobutane to starting material is 2.0-3.6: 1.
6. the synthesis method according to claim 1, wherein the temperature of the etherification reaction is 70 to 100 ℃.
7. The synthesis method of claim 1, wherein the temperature of a system obtained after the reaction of the filtrate and phosphorus oxychloride is reduced to 10-20 ℃, and ammonia water and elemental iodine are added dropwise; after the dropwise addition is finished, continuously reacting for 2-4 h at the temperature of 10-20 ℃;
the molar ratio of the ammonia water to the starting material is 20-30: 1.
8. the synthesis method according to claim 1, wherein the molar ratio of elemental iodine to starting material is 1.1-1.2: 1.
9. the synthesis method of claim 7 or 8, wherein the reaction is quenched with saturated aqueous sodium sulfite solution, ethyl acetate is added to extract the reaction solution, the organic phase is dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain ethyl 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate.
10. A synthesis method of febuxostat, which is characterized in that the synthesis method of any one of claims 1 to 9 is adopted to prepare ethyl 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate, and the ethyl 2- (3-cyano-4-isobutoxyphenyl) -4-methylthiazole-5-carboxylate is subjected to ester hydrolysis reaction to obtain febuxostat.
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| CN110878064A (en) * | 2019-11-06 | 2020-03-13 | 武汉光谷亚太医药研究院有限公司 | High-yield synthesis method of certain specific impurity of febuxostat |
| CN113072519A (en) * | 2021-04-01 | 2021-07-06 | 福建海西新药创制有限公司 | Method for continuously producing febuxostat by using micro-reaction device |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103539671A (en) * | 2012-07-17 | 2014-01-29 | 北京万生药业有限责任公司 | Method for preparing roflumilast intermediate |
| CN105452228A (en) * | 2013-08-07 | 2016-03-30 | 法尔玛赞公司 | A novel process for the preparation of febuxostat |
| CN106478500A (en) * | 2015-09-02 | 2017-03-08 | 广东东阳光药业有限公司 | Carboxylic acid-substituted（Miscellaneous）Aromatic ring analog derivative and its production and use |
-
2018
- 2018-12-29 CN CN201811640518.6A patent/CN109503513B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103539671A (en) * | 2012-07-17 | 2014-01-29 | 北京万生药业有限责任公司 | Method for preparing roflumilast intermediate |
| CN105452228A (en) * | 2013-08-07 | 2016-03-30 | 法尔玛赞公司 | A novel process for the preparation of febuxostat |
| CN106478500A (en) * | 2015-09-02 | 2017-03-08 | 广东东阳光药业有限公司 | Carboxylic acid-substituted（Miscellaneous）Aromatic ring analog derivative and its production and use |
Non-Patent Citations (3)
| Title |
|---|
| 2-( 3-氰基-4-异丁氧基苯基) -4-甲基-5-噻唑甲酸的合成;冯明声等;《中国新药杂志》;20091231;第18卷(第11期);第1066-1069页 * |
| Facile One-Pot Transformation of Phenols into o-Cyanophenols;Yuhta Nakai等;《Eur. J. Org. Chem.》;20140811;第6077-6083页 * |
| 冯明声等.2-( 3-氰基-4-异丁氧基苯基) -4-甲基-5-噻唑甲酸的合成.《中国新药杂志》.2009,第18卷(第11期),第1066-1069页. * |
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