CN113121394B - Preparation method of phenoxyacetic acid derivative - Google Patents

Abstract

The invention discloses a preparation method of phenoxyacetic acid derivatives. The method adopts a one-step synthesis method. Under alkali catalysis, (E)-2,6-dimethyl-4-(3-(4-( Methylthio) phenyl)-3-oxoprop-1-ene-1-yl) phenol reacts with 2-bromoisobutyric acid to obtain. The preparation method simplifies the process route, the product is easy to separate and purify, and the operation is simple and efficient; at the same time, a large number of strong acids and brominated reagents are avoided, which is economical and environmentally friendly; in addition, the reaction efficiency is high, the reaction time is shortened, the material utilization rate is high, and the total product yield is 75% or more, and the product purity reaches more than 99%.

Description

A kind of preparation method of phenoxyacetic acid derivative

technical field

The invention relates to a preparation method of phenoxyacetic acid derivatives, in particular to a preparation method of GFT-505.

Background technique

The structure of GFT-505 is shown in I, which has the characteristic structure of phenoxyacetic acid, and is a kind of PPAR (peroxisome proliferator-activated receptor) α/δ dual agonist. In preclinical and clinical studies, GFT-505 has shown pharmacological effects such as increasing fatty acid oxidation, improving insulin sensitivity, anti-inflammation, and anti-fibrosis; in addition, it was well tolerated in clinical trials, and no serious adverse reactions occurred. GFT-505 can improve the symptoms of non-alcoholic steatohepatitis (NASH) through multiple mechanisms, and is considered to be a promising drug for the treatment of NASH.

Patent WO2004005233 discloses the synthesis method of GFT-505. In this method, 2,6-dimethylphenol and bromoisobutyrate are refluxed in potassium carbonate/acetonitrile to obtain ester intermediates, and then 10 times the equivalent of trifluoro GFT-505 was obtained after treatment with acetic acid. Wherein, the first step alkylation reaction needs to use greater than 3 times the equivalent of bromoisobutyrate, and the reaction time is long. After the reaction finishes, the phenol intermediate cannot react completely, and a large amount of by-products are generated (such as bromoisobutyl The elimination product of the ester), which greatly affects the separation of the product, requires further purification by column chromatography; the second step of the deprotection reaction requires the use of excess trifluoroacetic acid to treat the alkylated product.

Patents US20060142611, WO2018060372 and WO2018060373 have adopted similar methods to modify the alkylation conditions, but the reaction time is still too long, bromoisobutyrate needs 3 to 9 times the equivalent, and the consumption is large, which makes post-reaction treatment And the purification is more complicated; in addition, the deprotection of the carboxylate requires the use of excess trifluoroacetic acid, which increases the discharge of waste acid and poses environmental risks.

The alkylation reaction of patent WO2019186410 uses ethyl bromoisobutyrate, and hydrolyzes under alkaline conditions to obtain GFT-505. Similar to the above-mentioned route, this preparation method also has problems such as long reaction time, cumbersome post-treatment and excessive alkylating reagent.

The above-mentioned existing technologies all need to undergo two-step synthesis of bromoisobutyrate alkylation and carboxylate deprotection, the route is long, and the total yield of the two steps is low, and the material utilization rate is low.

Patent WO2019025017 uses a one-step preparation method instead. This preparation method uses 3,5-dimethyl-4-hydroxybenzaldehyde and 4-methylthioacetophenone as starting materials, and realizes One-pot preparation of GFT-505. However, there are condensation by-products of the raw materials in the reaction process, resulting in complex reaction intermediates and product components, and low yield; in addition, the preparation method is cumbersome to process and difficult to purify.

Contents of the invention

Purpose of the invention: The present invention aims to provide a preparation method of GFT-505 with simple and efficient operation, economical and environmental protection, high product yield and high purity.

Technical solution: The preparation method of the phenoxyacetic acid derivatives of the present invention, under the catalysis of the base, the (E)-2,6-dimethyl-4-(3-(4-(methylthio) dissolved in the solvent ) phenyl) -3-oxoprop-1-en-1-yl) phenol and 2-bromoisobutyric acid for insulation reaction.

In the preparation method of the present invention, (E)-2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxoprop-1-en-1-yl) Dissolve the phenol in the solvent, then add the base or the mixture of the base and the solvent, the addition form depends on the solid-liquid state of the base, and the order of addition in this step can be reversed. The mixture is then reacted with 2-bromoisobutyric acid solution to completion, and then quenched, acidified, extracted, washed, dried, concentrated and purified to obtain the product.

Preferably, the base is potassium hydroxide, sodium hydroxide, lithium hydroxide, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, magnesium tert-butoxide, triethylamine, N,N-diisopropylethylamine , 1,8-diazabicycloundec-7-ene, diethylamine or diisopropylamine.

Preferably, the base and (E)-2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxoprop-1-en-1-yl)phenol The molar ratio is 1:1-10:1.

Preferably, the solvent is toluene, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N- One or two of methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropanol, n-butanol, and water.

Preferably, the 2-bromoisobutyric acid and (E)-2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxoprop-1-ene- The molar ratio of 1-yl)phenol is 1:1-3:1; the molar ratio is further preferably 1:1-1.5:1.

Preferably, the reaction temperature of the heat preservation reaction is 20°C to 120°C.

The total yield of the phenoxyacetic acid derivatives prepared by the preparation method is more than 75%, and the purity is more than 99%.

The improvement of the present invention is: firstly, the reaction step is only one step, which simplifies the process route and avoids the use of strong acid and brominated reagent in large quantities; secondly, there are only two kinds of reaction substrates, and the reaction process is more controllable, avoiding the There are no side reactions between substances, and the products are easy to separate and purify; finally, the reaction efficiency is high, the material utilization rate is high, there are few residual phenol intermediates, few by-products, and the post-treatment operation is simple.

Beneficial effects: compared with the prior art, the preparation method of the present invention has the following significant advantages:

(1) The process operation is simple and efficient, the reaction time is shortened, and the product is easy to separate and purify; (2) The reagents used are economical and environmentally friendly; (3) The total yield of the prepared product is as high as 75%, and the purity is as high as 99%.

Description of drawings

Fig. 1 is the synthesis roadmap of GFT-505 of the present invention;

Fig. 2 is (E)-2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxoprop-1-en-1-yl)phenol of the present invention The ¹ H-NMR spectrum;

Fig. 3 is the ¹ H-NMR spectrogram of GFT-505 of the present invention;

Fig. 4 is the HPLC spectrogram of GFT-505 of the present invention.

Detailed ways

The technical solutions of the present invention will be further described below in conjunction with the embodiments.

Example 1: (E)-2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxoprop-1-en-1-yl)phenol (compound II) Preparation

Add 4-methylthioacetophenone (83g), 3,5-dimethyl-4-hydroxybenzaldehyde (75g) and ethanol (100mL) in the reaction flask, add 10M hydrogen chloride ethanol solution (100mL) therein After stirring at room temperature overnight, the temperature was lowered to 0°C and stirring was continued for 5 hours. After filtration and drying, 137 g of compound II was obtained with a yield of 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).

Embodiment 2: Preparation of GFT-505

Sodium hydroxide (20g, 0.5mol) and acetonitrile (100mL) were added into the reaction flask, and a solution of compound II (30g, 0.1mol) and acetonitrile (200mL) was added while stirring; the red reaction solution was incubated at 70°C for 1 hour. At the same temperature, acetonitrile solution (150 mL) of 2-bromoisobutyric acid (25 g, 0.15 mol) was added dropwise into the reaction solution, and the reaction progress was monitored by thin layer chromatography (TLC). After reacting for 2 hours, TLC showed that compound II was completely reacted. The reaction solution was poured into 200 mL of ice water, acidified with 6N hydrochloric acid (pH less than 3), and extracted 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 31.7g, total yield 82.5%, HPLC purity 99.37% (chromatographic column: Agilent XDB C18, 150mm×4.6mm, 5.0μm; flow rate: 1.5mL/min; mobile phase: water: acetonitrile=90:10; detector: UV 254nm). 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).

Embodiment 3: Preparation of GFT-505

In a reaction flask, compound II (3g, 10mmol) was dissolved in N,N-dimethylformamide (30mL), and 1,8-diazabicycloundec-7-ene (15.2g, 0.1 mol) and stirred at 20°C for 1 hour. Add 2-bromoisobutyric acid (5.01g, 30mmol) in N,N-dimethylformamide solution (20mL) to the reaction solution. After the addition is complete, the reaction solution is heated to 120°C for reaction, and the reaction progress is monitored by TLC . After reacting for 2 hours, TLC showed that compound II was completely reacted. The reaction solution was poured into 200 mL of ice water, acidified with 6N hydrochloric acid (pH less than 3), and extracted with ethyl acetate (50 mL×4); the organic phase was washed with saturated brine, dried and concentrated, and the residue was recrystallized from acetonitrile to obtain GFT -505 3.03g, total yield 78.9%.

Embodiment 4: Preparation of GFT-505

Potassium tert-butoxide (1.12g, 10mmol), tetrahydrofuran (10mL) and toluene (10mL) were added to the reaction flask, and a solution of compound II (3g, 10mmol) and tetrahydrofuran (20mL) was added while stirring; the reaction solution was heated at 20°C Stir for 1 hour. A tetrahydrofuran solution (10 mL) of 2-bromoisobutyric acid (1.67 g, 10 mmol) was added to the reaction liquid, reacted at 20° C. and monitored the reaction progress by TLC. After reacting for 4 hours, TLC showed that compound II was completely reacted. The reaction solution was poured into 20 mL of ice water, acidified with 6N hydrochloric acid (pH less than 3), and extracted with ethyl acetate (100 mL); the organic phase was washed with saturated brine, dried, concentrated, and the residue was recrystallized from acetonitrile to obtain GFT-505 3.08g, total yield 80.2%.

Embodiment 5: Preparation of GFT-505

With reference to the preparation method of Example 3, the amount of compound II is 3g (10mmol), and the amount of 2-bromoisobutyric acid is 5.01g (20mmol); the base is triethylamine (3.04g, 30mmol), and the solvent is ethanol. The reaction temperature was maintained at 40°C to obtain 2.96g of GFT-505 with a total yield of 77.1%.

Embodiment 6: Preparation of GFT-505

Referring to the preparation method of Example 3, the amount of compound II is 3g (10mmol), the base is cesium carbonate (26.07g, 80mmol), the solvent is 1,4-dioxane, and the reaction temperature is maintained at 80°C to obtain GFT -5053.07g, total yield 79.9%.

Embodiment 7: Preparation of GFT-505

Referring to the preparation method of Example 3, the dosage of compound II is 3g (10mmol), the base is replaced by N,N-diisopropylethylamine (3.88g, 30mmol), the solvent is replaced by water-dimethyl sulfoxide mixture Solvent (V _water : V _DMSO = 1:5), and the reaction temperature was kept at 100°C to obtain 2.92g of GFT-505 with a total yield of 76.0%.

Comparative Example 1: GFT-505 was prepared by referring to the US20060142611 method

Compound II (3.0 g) prepared by the method in Example 1 was added to acetonitrile (20 mL), potassium carbonate (2.1 g), tert-butyl 2-bromoisobutyrate (1.5 g) were added successively, and the reaction Solution was reacted at 80°C for 12 hours; filtered off inorganic salts, added potassium carbonate (2.1g) and tert-butyl 2-bromoisobutyrate (1.5g) and reacted at 80°C for 12 hours; filtered off inorganic salts again, and Potassium carbonate (2.1 g) and tert-butyl 2-bromoisobutyrate (1.5 g) were added for the third time, and reacted at 80° C. for 12 hours. The reaction solution was concentrated after filtration, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain intermediate III (2.7 g) as a yellow oil, and the yield of this step was 61.3%. The obtained intermediate was dissolved in dichloromethane (9mL), and trifluoroacetic acid (4.5mL) was added dropwise under an ice bath. The brown-red reaction solution was reacted at room temperature for 12 hours and then concentrated to dryness. After adding toluene, it was concentrated again, and the residue was purified by column chromatography. (dichloromethane:methanol=20:1), 1.81 g of GFT-505 was obtained, and the yield of this step was 76.1%.

Compared with embodiment 2, this method shortcoming is as follows:

(1) GFT-505 needs to be synthesized in two steps, and the total yield is low, only 46.8%;

(2) need to repeatedly filter out the salt that reaction generates, and operation is loaded down with trivial details;

(3) Alkali and alkylating agent need to be added three times, and each alkylation reaction time is longer, and the efficiency is lower;

(4) Use a large amount of alkylating reagents and trifluoroacetic acid, which is not environmentally friendly;

(5) Excessive reagents lead to cumbersome post-processing, and column chromatography purification is required to obtain the product.

Comparative Example 2: Preparation of GFT-505 with reference to the method of WO2019025017

3,5-Dimethyl-4-hydroxybenzaldehyde (300mg, 2mmol) was dissolved in tetrahydrofuran (6mL), sodium hydroxide (360mg, 9mmol) was added and stirred well until the yellow-green phenol sodium salt was formed. After adding n-propanol (2mL) to the suspension, the temperature was raised to 50°C; 2-bromoisobutyric acid (1002mg, 6mmol) and 4-methylthioacetophenone (332mg, 2mmol) were dissolved in 2mL of tetrahydrofuran. The mixed solution was slowly dropped into the above sodium salt suspension, and reacted at 50° C. for 2 hours. 1M sodium hydroxide solution (10 mL) was added to the reaction solution, the temperature of the reaction mixture was raised and THF was distilled off; the residue was added with 1M hydrochloric acid. The resulting mixture was extracted with methyl tert-butyl ether and washed with 1M sodium carbonate solution. Add an appropriate amount of sodium chloride to the mixed solution to ensure that the sodium salt of the final product is precipitated. The collected sodium salts were acidified again with 1M hydrochloric acid and extracted with toluene. After the extract was concentrated and crystallized, 350 mg of GFT-505 was obtained with a yield of 45.5%.

Compared with embodiment 2, this method shortcoming is as follows:

(1) There are many reaction components, resulting in more reaction intermediates, and there are self-condensation products in 4-methylthioacetophenone under alkaline conditions, resulting in a reduction in the controllability of the reaction;

(2) The operation and post-processing are extremely cumbersome, which affects the reproducibility of the reaction, and leads to a low final yield of the reaction route, which is not conducive to process scale-up;

(3) The experimental scale is small, the gram-level preparation has not been realized, and the feasibility is low.

Comparative Example 3: Preparation of GFT-505

Potassium carbonate (6.9g, 50mmol) and acetonitrile (10mL) were added to the reaction flask, compound II (3g, 10mmol) and acetonitrile (20mL) were added under stirring at 20°C; the reaction solution was incubated at 70°C for 1 hour. At the same temperature, 2-bromoisobutyric acid (2.5 g, 15 mol) in acetonitrile (15 mL) was added to the reaction liquid, and the reaction progress was monitored by thin layer chromatography (TLC). TLC showed that compound II was always present, and no product spot was formed. After reacting for 16 hours, the reaction solution was poured into 20 mL of ice water, acidified with 6N hydrochloric acid (pH less than 3), and extracted with ethyl acetate (50 mL); the organic phase was washed with saturated brine, dried, concentrated, and the residue was Purified by chromatography, compound II (2.56 g) was recovered with a recovery rate of 85.3%.

The result shows that when potassium carbonate is used as the catalyst, the target product GFT-505 cannot be obtained. Therefore, the catalyst selected by the present invention is obtained through screening research confirmation.

Comparative Example 4: Preparation of GFT-505

With reference to the preparation method of Example 2, the difference from the preparation method of Example 2 is that the compound II charging amount is 30g (0.1mol), and the sodium hydroxide charging amount is 60g (1.5mol), that is, the molar amount of sodium hydroxide and compound II The ratio was increased to 15:1 to obtain 20.4g of GFT-505 with a total yield of 53.1%.

Compared with Example 2, the results show that after increasing the molar ratio of the alkali to 15:1, due to the presence of a large amount of insoluble salts, the full contact of the reactants is hindered, and the yield of the target product is greatly reduced; in addition, increasing the ratio of the alkali After that, the amount of hydrochloric acid consumed in the subsequent neutralization increases. Therefore, the molar ratio of the base to compound II selected in the present invention is confirmed through screening studies.

Comparative Example 5: Preparation of GFT-505

Compound II (600 mg, 2 mmol) and 2-butanone (5 mL) were added to the reaction flask, and sodium hydroxide (240 mg, 6 mmol) was added in batches under stirring at room temperature; the reaction solution was incubated at 50° C. for 1 hour. At the same temperature, a solution of 2-bromoisobutyric acid (1002 mg, 6 mmol) in 2-butanone (4 mL) was added dropwise to the reaction liquid, and the reaction was continued for 2 hours after the addition was completed. 2N hydrochloric acid was added to the reaction solution to adjust the pH to acidic (pH less than 3), and extracted with ethyl acetate (5mL×3); the organic phase was washed with saturated brine, dried and concentrated, and the obtained residue was purified by column chromatography ( Dichloromethane:methanol=50:1-20:1), and 55 mg of GFT-505 was isolated with a total yield of 7.2%.

Result shows, when adopting 2-butanone as reaction solvent, target product yield is low, and therefore, the solvent that the present invention selects is confirmed to obtain through screening research.

Comparative Example 6: Preparation of GFT-505

With reference to the preparation method of Example 2, the difference from the preparation method of Example 2 is that the compound II dosage is 30g (0.1mol), and the dosage of 2-bromoisobutyric acid is 134g (0.8mol), that is, 2-bromoisobutyric acid The molar ratio of acid to compound II was raised to 8:1 to obtain 17.6 g of GFT-505 with a total yield of 45.8%.

The results compared with Example 2 show that after increasing the molar ratio of 2-bromoisobutyric acid to 8:1, the yield of the target product is greatly reduced due to the presence of a large amount of unreacted alkylating agent or its elimination by-products. Therefore, the molar ratio of 2-bromoisobutyric acid to compound II selected in the present invention is confirmed through 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 both the feeding temperature and the reaction temperature are controlled at 0° C. to obtain 16.1 g of GFT-505 with a total yield of 41.9%.

Compared with Example 2, the results show that when the reaction temperature is lowered to 0° C., the yield of the target product decreases, and the reaction temperature selected in the present invention is confirmed through screening studies.

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 was replaced with N,N-dimethylformamide, and the reaction temperature was raised to 150°C to obtain 23.3g of GFT-505 with a total yield of 60.7 %.

Compared with Example 2, the results show that when the reaction temperature is increased to 150° C., the yield of the target product decreases, and the reaction temperature selected in the present invention is obtained through screening and research confirmation.

Claims (3)

1. A preparation method of a phenoxyacetic acid compound having a structure of formula I, characterized in that, under alkali catalysis, ( E )-2,6-dimethyl-4-(3-( 4-(methylthio)phenyl)-3-oxoprop-1-en-1-yl)phenol and 2-bromoisobutyric acid carry out insulation reaction;

The base is sodium hydroxide, cesium carbonate, potassium tert-butoxide, triethylamine, N , N -diisopropylethylamine, 1,8-diazabicycloundec-7-ene; The mole of the base and ( E )-2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxoprop-1-en-1-yl)phenol The ratio is 1:1-10:1, the 2-bromoisobutyric acid and ( E )-2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3- The mol ratio of oxyprop-1-en-1-yl)phenol is 1:1-3:1; The solvent is one or two of toluene, tetrahydrofuran, 1,4-dioxane, acetonitrile, N , N -dimethylformamide, dimethyl sulfoxide, ethanol, and water; The reaction temperature of the heat preservation reaction is 20°C to 120°C. 2. preparation method according to claim 1, is characterized in that, described 2-bromoisobutyric acid and ( E )-2,6-dimethyl-4-(3-(4-(methylthio) The molar ratio of phenyl)-3-oxoprop-1-en-1-yl)phenol is 1:1-1.5:1. 3. The preparation method according to claim 1, wherein the total yield of the phenoxyacetic acid compounds is more than 75%.

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