CN113121394B - Preparation method of phenoxyacetic acid derivative - Google Patents
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Abstract
The invention discloses a preparation method of phenoxyacetic acid derivatives, which adopts a one-step synthesis method and is obtained by reacting (E) -2, 6-dimethyl-4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) phenol with 2-bromoisobutyric acid under the catalysis of alkali. The preparation method simplifies the process route, the product is easy to separate and purify, and the operation is simple and efficient; simultaneously, a large amount of strong acid and bromization reagent is avoided, and the method is economical and environment-friendly; in addition, the reaction efficiency is high, the reaction time is shortened, the material utilization rate is high, the total yield of the product is over 75 percent, and the product purity is over 99 percent.
Description
Technical Field
The invention relates to a preparation method of phenoxyacetic acid derivatives, in particular to a preparation method of GFT-505.
Background
The structure of GFT-505 is shown in I, it has characteristic structure of phenoxyacetic acid, it is PPAR (peroxisome proliferator-activated receptor) alpha/delta double agonist. In preclinical and clinical studies, GFT-505 shows effects of increasing fatty acid oxidation, improving insulin sensitivity, anti-inflammatory, anti-fibrosis, etc.; in addition, the tolerance of the traditional Chinese medicine preparation is good in clinical test, and no serious adverse reaction occurs. GFT-505 can improve symptoms of nonalcoholic steatohepatitis (NASH) by various mechanisms and is considered to be a very potential NASH therapeutic drug.
Patent WO2004005233 discloses a synthesis method of GFT-505, which comprises refluxing 2, 6-dimethylphenol and bromoisobutyrate in potassium carbonate/acetonitrile to obtain an ester intermediate, and treating with 10-fold equivalent of trifluoroacetic acid to obtain GFT-505. The first step of alkylation reaction needs bromoisobutyrate with the equivalent weight more than 3 times, the reaction time is long, after the reaction is finished, the phenol intermediate cannot be completely reacted, and a large amount of byproducts are generated (such as elimination products of the bromoisobutyrate), so that the separation of the products is greatly influenced, and the further purification by column chromatography is needed; the second deprotection step requires the use of an excess of trifluoroacetic acid to treat the alkylated product.
Patents US20060142611, WO2018060372 and WO2018060373 adopt similar methods to change alkylation conditions, but still have overlong reaction time, 3 to 9 times of equivalent of bromoisobutyrate, large consumption amount, and more complicated post-reaction treatment and purification; in addition, excessive trifluoroacetic acid is needed for deprotection of carboxylic ester, so that waste acid discharge is increased, and environmental protection hidden trouble exists.
Patent WO2019186410 uses ethyl bromoisobutyrate for alkylation reaction and obtains GFT-505 by hydrolysis under alkaline conditions. Similar to the above route, the preparation method also has problems of long reaction time, cumbersome post-treatment, excessive alkylating reagent, and the like.
The prior art needs to be synthesized by two steps of bromo-isobutyrate alkylation and carboxylic ester deprotection, the route is long, the total yield of the two steps is low, and the material utilization rate is low.
In patent WO2019025017, a one-pot preparation method is adopted instead, and 3, 5-dimethyl-4-hydroxybenzaldehyde and 4-methylthioacetophenone are used as starting materials, and the addition sequence of alkali and the raw materials is controlled, so that the one-pot preparation of GFT-505 is realized. However, the reaction process has a byproduct of self-condensation of raw materials, so that reaction intermediates and products have complex components and low yield; in addition, the preparation method has complex post-treatment and high purification difficulty.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to provide a preparation method of GFT-505, which is simple and efficient to operate, economic and environment-friendly and has high total product yield and purity.
The technical scheme is as follows: the preparation method of the phenoxyacetic acid derivative comprises the step of carrying out heat preservation reaction on (E) -2, 6-dimethyl-4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) phenol and 2-bromoisobutyric acid dissolved in a solvent under the catalysis of alkali.
The preparation method of the invention firstly dissolves (E) -2, 6-dimethyl-4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) phenol in a solvent, then adds a base or a mixture of the base and the solvent, and the adding mode depends on the solid-liquid state of the base, and the adding sequence of the steps can be inverted. The mixture reacts with 2-bromoisobutyric acid solution till the end, and then the product is obtained through the steps of quenching, acidification, extraction, washing, drying, concentration and purification.
Preferably, the base is potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, magnesium tert-butoxide, triethylamine, N-diisopropylethylamine, 1, 8-diazabicycloundecen-7-ene, diethylamine or diisopropylamine.
Preferably, the molar ratio of the base to (E) -2, 6-dimethyl-4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) phenol is 1 to 10.
Preferably, the solvent is one or two of toluene, tetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, N-propanol, isopropanol, N-butanol and water.
Preferably, the molar ratio of 2-bromoisobutyric acid to (E) -2, 6-dimethyl-4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) phenol is 1 to 1; the molar ratio is further preferably 1.
Preferably, the reaction temperature of the incubation reaction is 20 ℃ to 120 ℃.
The total yield of the phenoxyacetic acid derivative prepared by the preparation method is more than 75%, and the purity is more than 99%.
The improvement of the invention is that: firstly, the reaction step is only one step, so that the process route is simplified, and a large amount of strong acid and a large amount of bromization reagent are avoided; secondly, the reaction substrates are only two, the reaction process is more controllable, side reaction between the reaction substrates is avoided, and the product is easy to separate and purify; and finally, the reaction efficiency is high, the material utilization rate is high, the residual of the phenol intermediate is less, the byproducts are less, and the post-treatment operation is simple and convenient.
Has the beneficial effects that: compared with the prior art, the preparation method has the following remarkable advantages:
(1) The process operation is simple, convenient and efficient, the reaction time is shortened, and the product is easy to separate and purify; (2) the reagent is economical and environment-friendly; (3) The total yield of the prepared product is up to more than 75%, and the purity is up to more than 99%.
Drawings
FIG. 1 is a schematic diagram of the synthetic route for GFT-505 of the present invention;
FIG. 2 shows the preparation of (E) -2, 6-dimethyl-4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) phenol according to the present invention 1 H-NMR spectrum;
FIG. 3 shows a GFT-505 of the present invention 1 H-NMR spectrum;
FIG. 4 is an HPLC chromatogram of GFT-505 of the present invention.
Detailed Description
The technical solution of the present invention is further illustrated by the following examples.
Example 1: (E) Preparation of (E) -2, 6-dimethyl-4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) phenol (Compound II)
4-methylthioacetophenone (83 g), 3, 5-dimethyl-4-hydroxybenzaldehyde (75 g) and ethanol (100 mL) were charged in a reaction flask, to which 10M ethanol solution of hydrogen chloride (100 mL) was added, and after stirring overnight at room temperature, the mixture was cooled to 0 ℃ and stirred for 5 hours. After filtration and drying, 137g of compound II was obtained, yield 92%. 1 H-NMR(300MHz,CDCl 3 )δ7.99(d,J＝8.5Hz,1H),7.76(d,J＝15.6Hz,1H),7.41(d,J＝15.6Hz,1H),7.37-7.30(m,4H),5.23(s,1H),2.57(s,3H),2.32(s,6H)。
Example 2: preparation of GFT-505
Sodium hydroxide (20g, 0.5mol) and acetonitrile (100 mL) were added to a reaction flask, and a solution of compound II (30g, 0.1mol) and acetonitrile (200 mL) was added thereto while stirring; the red reaction solution was incubated at 70 ℃ for 1 hour. At the same temperature, 2-bromoisobutyric acid (25g, 0.15mol) in acetonitrile was dropped into the reaction solutionSolution (150 mL) and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). After 2 hours of reaction, TLC showed compound II to react completely. Pouring the reaction solution into 200mL of ice water, and sequentially acidifying with 6N hydrochloric acid (the pH is less than 3) and extracting with ethyl acetate (500 mL); the organic phase was washed with saturated brine, dried, concentrated, and the residue was recrystallized from acetonitrile to obtain GFT-505.7 g, a total yield of 82.5% and an HPLC purity of 99.37% (column: agilent XDB C18, 150 mm. Times.4.6 mm,5.0 μm; flow rate: 1.5mL/min; mobile phase: water: acetonitrile = 90; detector: UV 254 nm). 1 H-NMR(300MHz,DMSO)δ12.90(brs,1H),8.09(d,J＝8.5Hz,2H),7.81(d,J＝15.6Hz,1H),7.62(d,J＝15.6Hz,1H),7.56(s,2H),7.40(d,J＝8.5Hz,2H),2.56(s,3H),2.23(s,6H),1.40(s,6H)。
Example 3: preparation of GFT-505
In a reaction flask, compound II (3 g, 10mmol) was dissolved in N, N-dimethylformamide (30 mL), and 1, 8-diazabicycloundecen-7-ene (15.2 g, 0.1mol) was added thereto and stirred at 20 ℃ for 1 hour. To the reaction solution was added a solution of 2-bromoisobutyric acid (5.01g, 30mmol) in N, N-dimethylformamide (20 mL), and after the addition was completed, the reaction solution was warmed to 120 ℃ for reaction, and the progress of the reaction was monitored by TLC. After 2 hours of reaction, TLC showed compound II to react completely. Pouring the reaction solution into 200mL of ice water, and sequentially acidifying with 6N hydrochloric acid (the pH is less than 3) and extracting with ethyl acetate (50 mL multiplied by 4); the organic phase is washed by saturated saline solution, dried and concentrated, and the residue acetonitrile is recrystallized to obtain GFT-505.03g with the total yield of 78.9 percent.
Example 4: preparation of GFT-505
Potassium tert-butoxide (1.12g, 10mmol), tetrahydrofuran (10 mL) and toluene (10 mL) were added to a reaction flask, and a solution of compound II (3g, 10mmol) and tetrahydrofuran (20 mL) was added while stirring; the reaction mixture was stirred at 20 ℃ for 1 hour. To the reaction solution was added a tetrahydrofuran solution (10 mL) of 2-bromoisobutyric acid (1.67g, 10 mmol), reacted at 20 ℃ and the progress of the reaction was monitored by TLC. After 4 hours of reaction, TLC showed compound II to react completely. Pouring the reaction solution into 20mL of ice water, and sequentially acidifying with 6N hydrochloric acid (the pH is less than 3) and extracting with ethyl acetate (100 mL); the organic phase was washed with saturated brine, dried, concentrated, and the residue acetonitrile was recrystallized to obtain GFT-505.08g, with a total yield of 80.2%.
Example 5: preparation of GFT-505
Referring to the preparation method of example 3, the charge amount of compound II was 3g (10 mmol), and the charge amount of 2-bromoisobutyric acid was 5.01g (20 mmol); the base is triethylamine (3.04g, 30mmol), the solvent is ethanol, the reaction temperature is kept at 40 ℃, and GFT-505.96g is obtained, the total yield is 77.1%.
Example 6: preparation of GFT-505
Referring to the preparation method of example 3, the charge amount of compound II was 3g (10 mmol), the base was cesium carbonate (26.07g, 80mmol), the solvent was 1, 4-dioxane, and the reaction temperature was maintained at 80 ℃ to obtain GFT-5053.07g, with a total yield of 79.9%.
Example 7: preparation of GFT-505
Referring to the preparation method of example 3, the charge amount of compound II was 3g (10 mmol), the base was replaced with N, N-diisopropylethylamine (3.88g, 30mmol), and the solvent was replaced with water-dimethylsulfoxide mixed solvent (V) Water (W) ：V DMSO = 1.
Comparative example 1: reference US20060142611 method for preparing GFT-505
Compound II (3.0 g) prepared according to the method in reference example 1 was added to acetonitrile (20 mL), potassium carbonate (2.1 g) and tert-butyl 2-bromoisobutyrate (1.5 g) were sequentially added, and the reaction solution was reacted at 80 ℃ for 12 hours; filtering inorganic salt, adding potassium carbonate (2.1 g) and tert-butyl 2-bromoisobutyrate (1.5 g), and reacting at 80 ℃ for 12 hours; the inorganic salt was again filtered off, and potassium carbonate (2.1 g) and tert-butyl 2-bromoisobutyrate (1.5 g) were added a third time to react at 80 ℃ for 12 hours. The reaction was filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate =10: 1) to give intermediate III (2.7 g) as a yellow oil in 61.3% yield. The obtained intermediate was dissolved in dichloromethane (9 mL), trifluoroacetic acid (4.5 mL) was added dropwise under ice bath, and the red-brown reaction solution was warmed for 12 hours and then concentrated to dryness, toluene was added and then concentrated again, and the residue was purified by column chromatography (dichloromethane: methanol =20 1) to obtain GFT-505.81g, which was a yield of 76.1%.
The disadvantages of this process compared to example 2 are as follows:
(1) Needs two steps to synthesize GFT-505, has low total yield which is only 46.8%;
(2) The salt generated by the reaction needs to be filtered repeatedly, so that the operation is complicated;
(3) Three times of alkali and alkylating reagent are needed, and each alkylation reaction time is long and the efficiency is low;
(4) A large amount of alkylating reagents and trifluoroacetic acid are used, so that the method is not environment-friendly;
(5) Excessive reagent causes complicated post-treatment, and column chromatography purification is needed to obtain the product.
Comparative example 2: reference WO2019025017 method for preparing GFT-505
3, 5-dimethyl-4-hydroxybenzaldehyde (300mg, 2mmol) was dissolved in tetrahydrofuran (6 mL), and after adding sodium hydroxide (360mg, 9mmol), the mixture was stirred well until a greenish yellow phenolic sodium salt was formed. Adding n-propanol (2 mL) into the suspension, and heating to 50 ℃; 2-Bromobutyric acid (1002mg, 6mmol) and 4-methylthioacetophenone (332mg, 2mmol) were dissolved in 2mL of tetrahydrofuran, and the mixed solution was slowly dropped into the above sodium salt suspension, followed by reaction at 50 ℃ for 2 hours. Adding 1M sodium hydroxide solution (10 mL) into the reaction solution, heating the reaction mixed solution, and evaporating tetrahydrofuran; 1M hydrochloric acid was added to the residue. The resulting mixture was extracted with methyl tert-butyl ether and washed with 1M sodium carbonate solution. And adding a proper amount of sodium chloride into the mixed solution to ensure that the sodium salt of the final product is separated out. The collected sodium salts were acidified again with 1M hydrochloric acid and extracted with toluene. After the extract liquid is concentrated and crystallized, GFT-505 mg is obtained, and the yield is 45.5%.
The disadvantages of this process compared to example 2 are as follows:
(1) The reaction components are more, so that more reaction intermediates are generated, and the 4-methylthioacetophenone has a self-condensation product under the alkaline condition, so that the reaction controllability is reduced;
(2) The operation and post-treatment are very complicated, the reaction reproducibility is influenced, the final yield of the reaction route is low, and the process amplification is not facilitated;
(3) The experimental scale is small, gram-grade preparation is not realized, and the feasibility is low.
Comparative example 3: preparation of GFT-505
Potassium carbonate (6.9g, 50mmol) and acetonitrile (10 mL) are added into a reaction bottle, and compound II (3g, 10mmol) and acetonitrile (20 mL) are added under stirring at 20 ℃; the reaction solution was incubated at 70 ℃ for 1 hour. At the same temperature, an acetonitrile solution (15 mL) of 2-bromoisobutyric acid (2.5 g, 15mol) was added to the reaction liquid, and the progress of the reaction was monitored by Thin Layer Chromatography (TLC). TLC showed compound II was always present and no product spot was formed. After the reaction is carried out for 16 hours, pouring the reaction liquid into 20mL of ice water, and sequentially acidifying with 6N hydrochloric acid (the pH is less than 3) and extracting with ethyl acetate (50 mL); the organic phase was washed with saturated brine, dried, concentrated, and the residue was purified by column chromatography to recover compound II (2.56 g) with a recovery rate of 85.3%.
The result shows that when potassium carbonate is used as a catalyst, the target product GFT-505 cannot be obtained, and therefore, the catalyst selected by the invention is obtained through screening research and confirmation.
Comparative example 4: preparation of GFT-505
Referring to the preparation method of example 2, the difference from the preparation method of example 2 is that the charging amount of compound II is 30g (0.1 mol) and the charging amount of sodium hydroxide is 60g (1.5 mol), that is, the molar ratio of sodium hydroxide to compound II is increased to 15.
The comparison result with the example 2 shows that after the molar ratio of the alkali is increased to 15; in addition, increasing the proportion of base increases the amount of hydrochloric acid consumed for subsequent neutralization. Therefore, the molar ratio of the base selected for use in the present invention to the compound II was confirmed by screening studies.
Comparative example 5: preparation of GFT-505
Compound II (600mg, 2mmol) and 2-butanone (5 mL) were added to a reaction flask, and sodium hydroxide (240mg, 6mmol) was added portionwise with stirring at room temperature; the reaction was incubated at 50 ℃ for 1 hour. At the same temperature, a solution (4 mL) of 2-bromoisobutyric acid (1002mg, 6mmol) in 2-butanone was added dropwise to the reaction mixture, and the reaction was continued for 2 hours after completion of the addition. Adding 2N hydrochloric acid into the reaction solution, adjusting the pH to acidity (the pH is less than 3), and extracting with ethyl acetate (5 mL multiplied by 3); the organic phase was washed with saturated brine, dried and concentrated, and the resulting residue was purified by column chromatography (dichloromethane: methanol = 50.
The result shows that when the 2-butanone is adopted as the reaction solvent, the yield of the target product is low, and therefore, the solvent selected by the invention is obtained by screening research and confirmation.
Comparative example 6: preparation of GFT-505
Referring to the production method of example 2, the difference from the production method of example 2 is that the feed amount of compound II was 30g (0.1 mol) and the feed amount of 2-bromoisobutyric acid was 134g (0.8 mol), that is, the molar ratio of 2-bromoisobutyric acid to compound II was increased to 8.
Comparison with example 2 shows that increasing the molar ratio of 2-bromoisobutyric acid to 8: after 1, the yield of the desired product is greatly reduced due to the presence of large amounts of unreacted alkylating agent or its elimination by-products. Therefore, the molar ratio of 2-bromoisobutyric acid to compound II selected for use in the present invention was confirmed by screening studies.
Comparative example 7: preparation of GFT-505
Referring to the preparation method of example 2, the difference from the preparation method of example 2 is that the feeding temperature and the reaction temperature are controlled at 0 ℃ to obtain GFT-505.1g with an overall yield of 41.9%.
The comparison result with the example 2 shows that the yield of the target product is reduced after the reaction temperature is reduced to 0 ℃, and the reaction temperature selected by the invention is obtained through screening research and confirmation.
Comparative example 8: preparation of GFT-505
Referring to the preparation method of example 2, the difference from the preparation method of example 2 is that the solvent is changed to N, N-dimethylformamide, and the reaction temperature is raised to 150 ℃ to obtain GFT-505.3g with an overall yield of 60.7%.
The comparison result with the example 2 shows that the yield of the target product is reduced after the reaction temperature is increased to 150 ℃, and the reaction temperature selected by the invention is confirmed by screening research.
Claims (3)
1. A preparation method of phenoxyacetic acid compounds with a structure shown in formula I is characterized in that (I) is dissolved in a solvent under the catalysis of alkaliE) -2, 6-dimethyl-4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) phenol and 2-bromoisobutyric acid are reacted under incubation;
the alkali is sodium hydroxide, cesium carbonate, potassium tert-butoxide, triethylamine,N,N-diisopropylethylamine, 1, 8-diazabicycloundec-7-ene;
said base and (A)E) -2, 6-dimethyl-4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) phenol in a molar ratio of 1 to 1, the 2-bromoisobutyric acid to (b) (1E) -2, 6-dimethyl-4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) phenol in a molar ratio of 1;
the solvent is toluene, tetrahydrofuran, 1, 4-dioxane, acetonitrile,N,N-one or two of dimethylformamide, dimethylsulfoxide, ethanol, water;
the reaction temperature of the heat preservation reaction is 20 ℃ to 120 ℃.
2. The method according to claim 1, wherein the 2-bromoisobutyric acid is reacted with (A) or (B)E) -2, 6-dimethyl-4- (3- (4- (methylthio) phenyl) -3-oxoprop-1-en-1-yl) phenol in a molar ratio of 1 to 1.5.
3. The method according to claim 1, wherein the total yield of the phenoxyacetic acid compound is 75% or more.
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| CN1071416A (en) * | 1991-09-27 | 1993-04-28 | 伊莱利利公司 | N-alkyl-3-phenyl-3-(2-alkylthiophe-noxy) propylamine |
| CN1668565A (en) * | 2002-07-08 | 2005-09-14 | 基恩菲特公司 | Substituted 1,3-diphenylprop-2-en-1-one derivatives and preparation and uses thereof |
| CN101522192A (en) * | 2006-07-24 | 2009-09-02 | 基恩菲特 | Substituted imidazolone derivatives, preparation and uses |
| WO2019025017A1 (en) * | 2017-08-04 | 2019-02-07 | Advitech Advisory And Technologies Sa | Process for the preparation of elafibranor and novel synthesis intermediates |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2857361B1 (en) * | 2003-07-08 | 2005-09-09 | Genfit S A | PREPARATION OF 1,3-DIPHENYPROP-2-¼n-1-one DERIVATIVES |
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| CN1071416A (en) * | 1991-09-27 | 1993-04-28 | 伊莱利利公司 | N-alkyl-3-phenyl-3-(2-alkylthiophe-noxy) propylamine |
| CN1668565A (en) * | 2002-07-08 | 2005-09-14 | 基恩菲特公司 | Substituted 1,3-diphenylprop-2-en-1-one derivatives and preparation and uses thereof |
| CN101522192A (en) * | 2006-07-24 | 2009-09-02 | 基恩菲特 | Substituted imidazolone derivatives, preparation and uses |
| WO2019025017A1 (en) * | 2017-08-04 | 2019-02-07 | Advitech Advisory And Technologies Sa | Process for the preparation of elafibranor and novel synthesis intermediates |
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| 苯氧乙酸类化合物的合成及其降脂活性;吴洁等;《中国药科大学学报》;20021231;第33卷(第6期);478-482 * |
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