A preparation method of (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid

Abstract

The object of the present invention is to provide a method for preparing (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid by asymmetric catalytic synthesis of (R,R)-BenzP* / iron salt, which has the advantages of mild reaction conditions, simple operation, high yield and optical purity, and suitability for industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a method for preparing a non-steroidal anti-inflammatory drug (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl) propionic acid. Background Art

[0002] Flurbiprofen, with the chemical name (±)-2-(2-fluoro-[1,1'-biphenyl]-4-yl) propionic acid, is a racemic compound and a derivative of aromatic propionic acid. It is a non-steroidal anti-inflammatory analgesic with a wide range of clinical applications. (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl) propionic acid is the S-isomer of flurbiprofen, also known as S-flurbiprofen or Aifluprofen. Among them, S-flurbiprofen has anti-inflammatory and analgesic effects, while R-flurbiprofen has no anti-inflammatory and analgesic effects. The S-flurbiprofen patch was approved for marketing by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) in 2015 for use in local joint osteoarthritis. It is not currently available in China. The chemical structures of flurbiprofen (FP), S-flurbiprofen (SFP), and R-flurbiprofen (RFP) are as follows:

[0003]

[0004] At present, there are mainly two methods for preparing (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid:

[0005] (1) Physical chiral resolution method: chiral amine and flurbiprofen are used to form salts, and the solubility difference of the salts is used for crystallization and purification to obtain (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl) propionic acid. For example, CN117430475A uses glucosylamine as a chiral amine resolution agent with a yield of about 30%; another example is CN112321424A uses S-(-)-phenylethylamine as a chiral amine resolution agent with a yield of 66.0%; CN1326922A uses (+)-dehydroabietinamine or chiral deoxyglucitolamine as a chiral amine resolution agent with a yield of 66.8%. The method of physical chiral amine resolution requires multiple recrystallizations, which is complicated to operate, has low resolution efficiency, low material utilization, and causes waste of resources. This method has high material and environmental costs.

[0006] (2) Chemical method to construct chiral center:

[0007] Patent CN108026014B reports a method for directly obtaining (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl) propionic acid by chiral synthesis using a nickel catalyst and an optically active bisoxazoline ligand, wherein a magnesium bromide Grignard reagent is prepared by 4-bromo-2-fluorobiphenyl, and then reacted with zinc bromide to prepare an organic zinc reagent, and a catalytic amount of a nickel compound and a catalytic amount of an optically active bisoxazoline ligand are added to react with 2-bromopropionate to obtain S-flurbiprofen ester, and finally optically active aflurbiprofen is obtained by hydrolysis. This method requires the preparation of a Grignard reagent first, and then the Grignard reagent is converted into a zinc reagent before a coupling reaction is performed, which is complicated to operate and increases uncontrollable factors.

[0008] The literature (J.Am.Chem.Soc., 2010.132, 1264.) reported an asymmetric Kumada reaction using a nickel catalyst and an optically active bisoxazoline ligand using α-haloketone as the starting material. The literature (J.Am.Chem.Soc., 2014.136, 17662.) and patent CN103755566 reported an asymmetric Kumada reaction using a cobalt catalyst and an optically active bisoxazoline ligand. These reactions were carried out at -60 to -40°C and -80°C respectively, which were harsh conditions and not suitable for industrial production. The literature (J.Am.Chem.Soc., 2015.137, 7128.) reported the asymmetric Kumada reaction using an iron catalyst and an optically active bisoxazoline ligand for the first time, but there was no report on its application in the synthesis of aifurofen.

[0009] In summary, although there are some methods reported for the asymmetric synthesis of (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid, there are still some problems, such as cumbersome operation, high cost, harsh reaction conditions, etc. Therefore, it is very necessary to develop a method for synthesizing (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid with mild reaction conditions and low cost. Summary of the invention

[0010] The purpose of the present invention is to provide a method for preparing (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid by asymmetric catalytic synthesis of (R,R)-BenzP* / iron salt, which has the advantages of mild reaction conditions, simple operation, high yield and optical purity, and suitability for industrial production.

[0011] In order to achieve the above objectives, this law adopts the following technical solutions:

[0012] The method uses (R,R)-BenzP* / iron salt as a catalyst, reacts racemic 2-halogenated propionate with (2-fluoro-[1,1'-biphenyl]-4-yl)magnesium bromide to synthesize (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate, then dissolves (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate in an organic solvent, stirs and reacts in the presence of an acid or a base, and obtains high-purity (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid through post-treatment. The (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid product obtained by the method has high optical purity (ee≥99%).

[0013] The synthesis method of asymmetric synthesis of (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid of the present invention is shown in Formula 2.

[0014]

[0015] The method for asymmetric synthesis of (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid of the present invention comprises the following steps:

[0016] Step (1): Preparation method of (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl) propionate (4)

[0017] In an inert atmosphere, in an organic solvent, under the catalysis of (R,R)-BenzP* / iron salt shown in structure 2, the racemic 2-halogenated propionate shown in structure 3 is reacted with (2-fluoro-[1,1'-biphenyl]-4-yl)magnesium bromide shown in structure 1. The reaction is quenched, extracted, concentrated under reduced pressure, and purified to obtain (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate (shown in structure 4).

[0018] Step (2): Preparation method of (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propanoic acid (5)

[0019] The (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl) propionic acid ester (shown in structure 4) obtained in step (1) is dissolved in an organic solvent, stirred for reaction in the presence of an acid or a base, and subjected to post-treatment and purification to obtain high-purity (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl) propionic acid.

[0020] It should be noted that in the above steps (1) to (2), among the compounds of the above structural formulas 1 to 5,

[0021] The halogen atom X is Cl, Br and I,

[0022] The substituent R1 is methyl, ethyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, heptyl, phenyl, benzyl, preferably tert-butyl.

[0023] Preferably, in step (1), the organic solvent is tetrahydrofuran, diethyl ether, toluene and xylene, preferably tetrahydrofuran.

[0024] The preparation method described in Formula 2, wherein the amount of the chiral phosphine ligand (R,R)-BenzP* catalyst used in step (1) is 3.0 to 6.0 mol%, preferably 5.0 mol%;

[0025] In the preparation method described in Formula 2, the amount of the iron salt catalyst used in step (1) is 1.5 to 6.0 mol%, preferably 4.0 mol%.

[0026] In the preparation method described in Formula 2, the molar equivalent ratio of the chiral phosphine ligand (R,R)-BenzP* and the iron salt used in step (1) is 2:1 to 1:1, preferably 5:4.

[0027] In the preparation method described in Formula 2, the chiral phosphine ligand (R,R)-BenzP* used in step (1) is (1R,1'R)-1,1'-(1,2-phenylene)bis[1-(1,1-dimethylethyl)-1-methylphosphine].

[0028] In the preparation method described in Formula 2, the iron salt used in step (1) is one of ferric chloride, ferric bromide, ferric acetylacetonate, and ferric trifluoromethanesulfonate, preferably ferric acetylacetonate.

[0029] In the preparation method described in Formula 2, the reaction temperature in step (1) is -40°C to 20°C, preferably -5°C to 5°C.

[0030] In the preparation method described in Formula 2, the molar equivalent ratio of racemic 2-halopropionate to (2-fluoro-[1,1'-biphenyl]-4-yl)magnesium bromide in step (1) is 1:1 to 1:4, preferably 1:1.5; and the coupling reaction time is 10 min to 2 h, preferably 30 min.

[0031] In the preparation method described in Formula 2, the acid used in step (2) includes one of sulfuric acid, hydrochloric acid, trifluoroacetic acid, and methanesulfonic acid, and the base includes one of sodium hydroxide, potassium hydroxide, and lithium hydroxide. It is preferred to use acidic conditions, and trifluoroacetic acid is more preferred.

[0032] In the preparation method described in Formula 2, the reaction temperature in step (2) is 0°C to 50°C, preferably 20°C to 30°C; and the reaction time is 2 to 24 hours, preferably 3 to 5 hours.

[0033] The beneficial effects of the present invention are:

[0034] 1) The present invention uses (R,R)-BenzP* / iron salt as a catalyst system for the asymmetric cross-coupling reaction in step (1). Compared with the traditional cross-coupling reaction using only iron salt as a catalyst, the catalyst system of the present invention significantly improves the optical purity of the propionate product.

[0035] 2) The asymmetric cross-coupling reaction in step (1) of the present invention is carried out in a temperature range of -5°C to 5°C. Compared with the low temperature conditions of -40°C or even -80°C required for the traditional cross-coupling reaction, the reaction conditions of the present invention are milder, the reaction control is simpler, and it is more in line with the actual needs of industrial production.

[0036] 3) Compared with the traditional Negishi asymmetric coupling reaction, the asymmetric cross-coupling reaction in step 1) of the present invention does not need to further react the Grignard reagent with the zinc halide to prepare the zinc reagent, but directly uses the Grignard reagent to couple under the catalysis of iron salt. This design not only simplifies the reaction steps, but also reduces the operational complexity and uncontrollable factors caused by multi-step feeding, and effectively reduces the production cost, showing higher economy and operational convenience. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 HPLC detection spectrum of crude (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)ethyl propionate obtained in Example 1

[0038] Figure 2 HPLC detection spectrum of (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid tert-butyl ester product obtained in Example 2

[0039] Figure 3 This is the isomer detection spectrum of the (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid tert-butyl ester product obtained in Example 2

[0040] Figure 4 HPLC detection spectrum of (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid product obtained in Example 3

[0041] Figure 5 This is the isomer detection spectrum of the (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid product obtained in Example 2 DETAILED DESCRIPTION

[0042] Example 1

[0043] Synthesis of Ethyl (S)-2-(2-Fluoro-[1,1'-biphenyl]-4-yl) Propionate

[0044] Under nitrogen protection, temperature controlled at 0℃, add (2-fluoro-[1,1'-biphenyl]-4-yl)magnesium bromide tetrahydrofuran solution (100ml, concentration: 1.1M) dropwise to 2-bromopropionic acid ethyl ester (13.80g, 76.25mmol), (R,R)-BenzP* (1.54g, 5.45mmol) and acetylacetonate iron (1.92g, 5.45mmol) tetrahydrofuran (110mL) solution, and the addition is completed in about 1h. After the addition is completed, continue to keep the temperature at 0±5℃ and stir the reaction for 30min. Filter to obtain a clear reaction solution, add dilute hydrochloric acid (3M) solution to the reaction solution, adjust the pH to 2-4, and stand for 10-20min to separate the liquid to obtain the organic layer. The organic layer was concentrated to dryness under reduced pressure at 40-45°C to obtain crude ethyl ester with a conversion rate of 89.3% and an ee value of 57.6%. The product was a yellow oily viscous substance and was not further purified.

[0045] Example 2

[0046] Synthesis of tert-butyl (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl) propionate

[0047] Under nitrogen protection, temperature controlled at 0℃, add (2-fluoro-[1,1'-biphenyl]-4-yl) magnesium bromide tetrahydrofuran solution (182ml, concentration: 1.0M) dropwise to tert-butyl 2-bromopropionate (25.43g, 0.12mol), (R,R)-BenzP* (2.56g, 9.08mmol) and ferric acetylacetonate (2.56g, 7.26mmol) tetrahydrofuran (160mL) solution, and the addition is completed in about 1h. After the addition is completed, continue to keep the temperature at 0±5℃ and stir the reaction for 30min. Filter to obtain a clear reaction solution, add dilute hydrochloric acid (3M) solution to the reaction solution, adjust the pH to 2-4, and stand for 10-20min to separate the liquids to obtain the organic layer. The organic layer is concentrated to dryness under reduced pressure at 40-45℃ to obtain 49.0g of crude tert-butyl ester as a light yellow solid. The obtained crude tert-butyl ester was recrystallized with a mixed solvent of ethanol (150 mL) and water (50 mL) to obtain 44.1 g of tert-butyl ester as an off-white solid. The product purity was 98.8% and the ee value was 91.9%.

[0048] Example 3

[0049] Synthesis of (S)-2-(2-Fluoro-[1,1'-biphenyl]-4-yl)propionic acid

[0050] The tert-butyl ester (40.0 g, 0.13 mol) prepared in Example 2 was dissolved in dichloromethane (120 mL), cooled to 0 ° C, and trifluoroacetic acid (45.6 g, 0.40 mol) was slowly added dropwise thereto. The addition was completed in about 1 h. The reaction solution was slowly raised to 20 ° C to 30 ° C, and stirring was continued for 3 h. The reaction was completed. The reaction solution was controlled to 30 to 40 ° C and concentrated to dryness under reduced pressure to obtain 33.2 g of off-white solid powder. Ethyl acetate (33 mL) was added thereto, heated to 40-60 ° C, stirred and dissolved, filtered while hot, and n-heptane (264 mL) was added to the filtrate. A large amount of product was precipitated, cooled to 0 to 10 ° C, stirred for 1 to 2 h, filtered, and washed with n-heptane (33 mL) to obtain a solid. The obtained solid was dried under reduced pressure at 40-50° C. to obtain 27.3 g of (S)-2-(2-fluoro-[1,1′-biphenyl]-4-yl)propanoic acid. The product purity was 99.87% and the ee value was 99.40%.

Claims

1. A method for asymmetric catalytic synthesis of (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid, characterized in that: The following steps are involved: Step (1): Asymmetric catalytic synthesis of (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl) propionate In an inert gas, an organic solvent is used to react racemic 2-halogenated propionate with (2-fluoro-[1,1'-biphenyl]-4-yl)magnesium bromide under the catalysis of (R,R)-BenzP* / iron salt to prepare (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionate. The reaction formula is as follows: Wherein, X is a halogen atom selected from Cl, Br and I; Step (2): Hydrolysis of propionate to synthesize (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl)propionic acid The (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl) propionic acid ester obtained in step (1) is dissolved in an organic solvent and stirred for reaction in the presence of an acid or a base to prepare high-purity (S)-2-(2-fluoro-[1,1'-biphenyl]-4-yl) propionic acid. The specific reaction formula is as follows: Among them, the substituent R1 is methyl, ethyl, isopropyl, tert-butyl, cyclopentyl, cyclohexyl, heptyl, phenyl, or benzyl.

2. The preparation method according to claim 1, characterized in that: The organic solvent described in step (1) is selected from tetrahydrofuran, ether, toluene or xylene.

3. The preparation method according to any one of claims 1 or 2, characterized in that: The amount of the chiral phosphine ligand (R, R)-BenzP* catalyst used in step (1) is 3.0-6.0 mol%, and the amount of the iron salt catalyst is 1.5-6.0 mol%.

4. The preparation method according to claim 3, characterized in that: The molar equivalent ratio of the chiral phosphine ligand (R,R)-BenzP* / iron salt described in step (1) is 2:1 to 1:

1.

5. The preparation method according to claim 3, characterized in that: The (R,R)-BenzP* in step (1) is (1R,1'R)-1,1'-(1,2-phenylene)bis[1-(1,1-dimethylethyl)-1-methylphosphine].

6. The preparation method according to claim 3, characterized in that: The iron salt in step (1) is one of ferric chloride, ferric bromide, ferric acetylacetonate and ferric trifluoromethanesulfonate.

7. The preparation method according to claim 3, characterized in that: The reaction temperature in step (1) is -40°C to 20°C.

8. The preparation method according to claim 3, characterized in that: In the coupling reaction of step (1), the molar equivalent ratio of racemic 2-halopropionate to (2-fluoro-[1,1'-biphenyl]-4-yl)magnesium bromide is 1:1 to 1:4, and the coupling reaction time is 10 minutes to 2 hours.

9. The preparation method according to claim 3, characterized in that: The acid described in step (2) includes one of sulfuric acid, hydrochloric acid, trifluoroacetic acid, and methanesulfonic acid, and the base includes one of sodium hydroxide, potassium hydroxide, and lithium hydroxide.

10. The preparation method according to claim 3, characterized in that: The temperature of the hydrolysis reaction in step (2) is 0°C to 50°C, and the reaction time is 2 to 24 hours.

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