A preparation method of 2-biphenylpropionic acid compounds

Abstract

The present invention discloses a method for preparing a 2-biphenyl propionic acid compound. The method for preparing a 2-biphenyl propionic acid salt compound comprises the following steps: in an ether solvent, in the presence of a catalyst, a compound as shown in formula I is subjected to a coupling reaction with a 2-halogenated propionic acid salt to obtain a 2-biphenyl propionic acid salt, wherein the anion of the 2-biphenyl propionic acid salt is as shown in formula II. The preparation method of the present invention has the characteristics of short steps, easy availability of raw materials, high yield and high product purity, and is suitable for industrial production. #imgabs0#

Description

Technical Field

[0001] The invention relates to a method for preparing 2-biphenyl propionic acid compounds. Background Art

[0002] 2-Biphenylpropionic acid compound - Flurbiprofen, chemical name 2-(2-fluoro-4-biphenyl) propionic acid, is an excellent non-steroidal anti-inflammatory drug, which is characterized by low dosage, fast action, high efficacy and few side effects. The structural formula is as follows:

[0003]

[0004] About the preparation method of flurbiprofen, report a lot at home and abroad, most of reactions steps are long, raw materials are difficult to obtain, yield is low, impurities are many, cost is high, difficult for industrialized production.As patent publication number is in the Chinese patent of CN101585760A, the raw material used is difficult to obtain 2-(4-amino-3-fluorophenyl) ethyl propionate.As patent publication number is in the Chinese patent of CN108218667A, expensive phenylboron reagent and palladium reagent are used, and reactions steps are long.

[0005] The US patent publication number US3959364A discloses that 4-bromo-2-fluorobiphenyl is subjected to a Grignard reaction with magnesium chips to obtain a corresponding Grignard reagent, which is then subjected to a coupling reaction with a 2-halogenated propionate to obtain flurbiprofen. However, when the method is repeated, it is found that the method is very likely to produce a disubstituted byproduct in the coupling reaction, the structural formula of which is as follows:

[0006]

[0007] Moreover, the by-product and the product are produced simultaneously. Regardless of the feeding method and the reaction temperature, at least 30% of the side reaction is produced, resulting in a low yield of the method. The yield of the patent is less than 60%.

[0008] The Chinese patent with patent publication number CN108558651A discloses that 4-bromo-2-fluorobiphenyl is subjected to a Grignard reaction with magnesium chips to obtain a corresponding Grignard reagent, which is then subjected to a coupling reaction with ethyl 2-bromopropionate and then hydrolyzed to obtain flurbiprofen. However, when the method is repeated, it is found that the method has more side reactions in the coupling reaction, and the product only accounts for about 20% (HPLC method). Summary of the invention

[0009] The problem to be solved by the present invention is that the existing preparation methods of 2-biphenylpropionic acid compounds are relatively simple. To this end, the present invention provides a preparation method of 2-biphenylpropionic acid compounds. The preparation method of the present invention has the advantages of low cost, high yield and easy industrialization.

[0010] The present invention provides a method for preparing a 2-biphenyl propionate compound, which comprises the following steps: in an ether solvent, in the presence of a catalyst, coupling a compound as shown in formula I with a 2-halogenated propionate to obtain a 2-biphenyl propionate; the anion of the 2-biphenyl propionate is as shown in formula II,

[0011]

[0012] The catalyst is selected from any of the following options:

[0013] Scheme 1: containing cobalt inorganic salt and amine compound 1;

[0014] Scheme 2: containing cobalt organic salt 1 and amine compound 2;

[0015] Option 3: Cobalt-containing organic salt 2;

[0016] R is fluorine or hydrogen; R 1 Chlorine, iodine or bromine.

[0017] In a certain scheme of the preparation method of the 2-biphenyl propionate salt compound, some technical features are as follows, and the technical features not involved are as described in any of the above schemes (hereinafter referred to as "in a certain scheme"):

[0018] The compound as shown in formula I is selected from any of the following compounds:

[0019]

[0020] In a certain embodiment, the ether solvent is a conventional ether solvent for this type of reaction in the art, and the ether solvent may be one or more of diethyl ether, tetrahydrofuran, methyl tert-butyl ether and cyclopentyl methyl ether; preferably tetrahydrofuran.

[0021] In a certain embodiment, the amount of the ether solvent used is the conventional amount used in this type of reaction in the art. For example, the molar volume ratio of the ether solvent to the compound as shown in Formula I can be (0.5-5):1 mol / L; for example, (1-3):1 mol / L; for example, 1:1 mol / L.

[0022] In one embodiment, the cobalt-containing inorganic salt is a divalent cobalt compound or a trivalent cobalt compound.

[0023] In one embodiment, the cobalt organic salt 1 is a divalent cobalt compound or a trivalent cobalt compound.

[0024] In one embodiment, the cobalt organic salt 2 is a divalent cobalt compound or a trivalent cobalt compound.

[0025] In a certain embodiment, the cobalt-containing inorganic salt can be selected from one or more of CoCl2, CoBr2, Co(NO3)2 and CoSO4; the cobalt-containing inorganic salt is preferably selected from one or two of CoCl2 and CoSO4.

[0026] In a certain embodiment, the cobalt-containing organic salt 1 can be selected from one or more of Salen-Co, Co(OAc)2, Co(acac)2 and Co(acac)3; for example, one or more of (1R, 2R)-(-)-1,2-cyclohexanediamino-N, N'-bis(3,5-di-tert-butylsalicylicyl)cobalt(II), disalicylicaldehyde ethylenediamine cobalt, Co(OAc)2, Co(acac)2 or Co(acac)3.

[0027] In one embodiment, the cobalt-containing organic salt 2 may be Salen-Co; for example, one or both of (1R, 2R)-(-)-1,2-cyclohexanediamino-N, N'-bis(3,5-di-tert-butylsalicylicyl)cobalt(II) or disalicylicaldehyde ethylenediamine cobalt.

[0028] In one embodiment, the molar ratio of the cobalt-containing inorganic salt to the compound of formula I can be 1:(5-100), for example 1:(5-50), and for example 1:20.

[0029] In one embodiment, the molar ratio of the cobalt-containing organic salt 1 to the compound of formula I can be 1:(5-100), for example 1:(5-50), and for example 1:20.

[0030] In one embodiment, the molar ratio of the cobalt-containing organic salt 2 to the compound of formula I can be 1:(5-100), for example 1:(5-50), and for example 1:20.

[0031] In a certain embodiment, the amine compound 1 is a conventional amine compound in the art, and the amine compound 1 can be selected from one or more of triethylamine, ethylenediamine, N,N,N,N-tetramethylethylenediamine (TMEDA), N,N,N,N-tetraethylethylenediamine, propylenediamine, N,N,N,N-tetramethylpropylenediamine, N,N,N,N-tetraethylpropylenediamine, cyclohexyldiamine, N,N,N,N-tetramethylcyclohexyldiamine, N,N,N,N-tetraethylcyclohexyldiamine and urotropine, and the amine compound 1 is preferably selected from one or two of N,N,N,N-tetramethylethylenediamine (TMEDA) and urotropine (HMTA).

[0032] In a certain embodiment, the amine compound 2 is a conventional amine compound in the art, and the amine compound 2 can be selected from one or more of triethylamine, ethylenediamine, N,N,N,N-tetramethylethylenediamine (TMEDA), N,N,N,N-tetraethylethylenediamine, propylenediamine, N,N,N,N-tetramethylpropylenediamine, N,N,N,N-tetraethylpropylenediamine, cyclohexyldiamine, N,N,N,N-tetramethylcyclohexyldiamine, N,N,N,N-tetraethylcyclohexyldiamine and urotropine. The amine compound 2 is preferably selected from one or two of N,N,N,N-tetramethylethylenediamine (TMEDA) and urotropine (HMTA).

[0033] In one embodiment, the molar ratio of the amine compound 1 to the compound of formula I is 1:(5-100), for example 1:(5-50), and for example 1:20.

[0034] In one embodiment, the molar ratio of the amine compound 2 to the compound of formula I is 1:(5-100), for example 1:(5-50), and for example 1:20.

[0035] In a certain embodiment, when the catalyst is a cobalt-containing inorganic salt and an amine compound 1, the cobalt-containing inorganic salt is selected from one or both of CoCl2 and CoSO4; the amine compound 1 is selected from one or both of N,N,N,N-tetramethylethylenediamine (TMEDA) and hexamethylenetetramine (HMTA).

[0036] In a certain embodiment, when the catalyst is a cobalt-containing organic salt 1 and an amine compound 2, the cobalt-containing organic salt 1 is selected from one or two of (1R, 2R)-(-)-1,2-cyclohexanediamino-N, N'-bis(3,5-di-tert-butylsalicylicyl)cobalt(II), disalicylicaldehyde ethylenediamine cobalt, Co(OAc)2, Co(acac)2 and Co(acac)3, and the amine compound 2 is selected from one or two of N,N,N,N-tetramethylethylenediamine (TMEDA) and urotropine (HMTA).

[0037] In one embodiment, when the catalyst is a cobalt-containing organic salt 2, the cobalt-containing organic salt 2 is selected from (1R, 2R)-(-)-1,2-cyclohexanediamino-N, N'-bis(3,5-di-tert-butylsalicylicyl)cobalt(II) and disalicylicylethylenediamine cobalt.

[0038] In the present invention, the cation of the 2-halopropionate is a cation that does not affect the reaction effect; the cation is a conventional cation in the art.

[0039] In one embodiment, the 2-halopropionic acid salt is an alkali metal salt or an alkaline earth metal salt.

[0040] In one embodiment, the 2-halopropionate is 2-bromopropionate, 2-chloropropionate or 2-iodopropionate.

[0041] In a certain embodiment, when the 2-halopropionic acid salt is an alkali metal salt, the 2-halopropionic acid salt is sodium 2-halopropionate, lithium 2-halopropionate or potassium 2-halopropionate.

[0042] In a certain embodiment, when the 2-halopropionate is an alkaline earth metal salt, the 2-halopropionate is magnesium 2-halopropionate or calcium 2-halopropionate.

[0043] In a certain embodiment, the 2-halopropionic acid salt is sodium 2-bromopropionate, sodium 2-chloropropionate, sodium 2-iodopropionate, potassium 2-chloropropionate, potassium 2-bromopropionate, potassium 2-iodopropionate, magnesium 2-bromopropionate, magnesium 2-iodopropionate, magnesium 2-chloropropionate, or calcium 2-bromopropionate; for example, sodium 2-bromopropionate, sodium 2-chloropropionate, sodium 2-iodopropionate, potassium 2-bromopropionate, potassium 2-iodopropionate or magnesium 2-bromopropionate; for example, sodium 2-bromopropionate, sodium 2-chloropropionate, sodium 2-iodopropionate, potassium 2-bromopropionate, potassium 2-iodopropionate or magnesium 2-bromopropionate; for example, sodium 2-bromopropionate, potassium 2-bromopropionate or magnesium 2-bromopropionate; for example, sodium 2-bromopropionate or potassium 2-bromopropionate.

[0044] In one embodiment, the molar ratio of the anion in the 2-halopropionate to the compound as shown in Formula I in the coupling reaction is 1:(0.1-10), for example 1:(0.5-2), and for example 1:(0.8-1.2).

[0045] In one embodiment, the reaction temperature of the coupling reaction is -20 to 80°C, such as -10 to 20°C.

[0046] In a certain embodiment, the coupling reaction can be monitored by conventional monitoring methods in the art (such as HPLC or TLC), and the reaction time of the coupling reaction is 0-5h, excluding 0h; for example, 1 to 3h.

[0047] In one embodiment, in the coupling reaction, the mixture of the compound shown in Formula I and an ether solvent is preferably added dropwise to the mixture of 2-halopropionic acid salt and a catalyst.

[0048] In one embodiment, the preparation method of the 2-biphenyl propionate compound further comprises the following steps: in an ether solvent, in the presence of iodine, metallizing the compound shown in Formula III with magnesium to obtain the compound shown in Formula I.

[0049]

[0050] In the present invention, the compound shown in Formula I can be prepared by conventional reaction conditions in the art.

[0051] In a certain embodiment, the ether solvent is selected from one or more of diethyl ether, tetrahydrofuran, methyl tert-butyl ether and cyclopentyl methyl ether.

[0052] In one embodiment, the ether solvent is tetrahydrofuran.

[0053] In one embodiment, the volume molar ratio of the ether solvent to the compound represented by Formula III is (2-10):1 mol / L, for example, (3-7):1 mol / L; for example, 5:1 mol / L.

[0054] In one embodiment, the molar ratio of the compound as shown in formula III to magnesium is 1:(0.1-10), for example 1:(0.8-2), for example 1:(1-1.5), and for example 1:1.

[0055] In one embodiment, the molar ratio of the compound of formula III to iodine is 1:(0.0005-0.05), for example 1:(0.0005-0.005), and for example 1:(0.002-0.004).

[0056] In one embodiment, the reaction temperature of the metallization reaction is 20-80°C, such as 40-70°C.

[0057] In a certain scheme, the preparation method comprises the following steps: adding magnesium and iodine to an ether solvent, heating to 60°C, dripping a solution of a compound shown in formula III and an ether solvent, reacting at 55-65°C, cooling to below 10°C for standby use; mixing 2-halogenated propionate, a catalyst and an ether solvent at -5-0°C, and dripping a grout reaction solution thereto at -5-5°C, dripping for 2 hours, and keeping the temperature for reaction for 1 hour to obtain a 2-biphenylpropionate compound reaction solution.

[0058] The present invention also provides a method for preparing a 2-biphenylpropionic acid compound, which comprises the following steps:

[0059] (1) According to the aforementioned method for preparing 2-biphenyl propionate compounds, 2-biphenyl propionate compounds are obtained;

[0060] (2) subjecting the 2-biphenylpropionic acid salt compound prepared in step (1) to an acidification reaction to obtain a 2-biphenylpropionic acid compound as shown in formula V,

[0061]

[0062] In a certain scheme of the preparation method of the 2-biphenylpropionic acid compound, some technical features are as follows, and the technical features not involved are as described in any of the above schemes (hereinafter referred to as "in a certain scheme"):

[0063] The acidification reaction is a conventional acidification reaction in the art.

[0064] In a certain embodiment, the acid in the acidification reaction is a conventional acid in the art, and the acid is preferably hydrochloric acid.

[0065] In one embodiment, the hydrochloric acid is 1 mol / L hydrochloric acid.

[0066] In one embodiment, the final pH of the acidification reaction is 3-4 after acidification.

[0067] In one embodiment, the reaction temperature of the acidification reaction is a conventional reaction temperature in the art, such as room temperature.

[0068] In one embodiment, the specific operation of step (2) is: adding hydrochloric acid to the reaction solution in step (1) to adjust the pH to 3-4, stirring for 1 hour, and filtering.

[0069] In a certain embodiment, the post-treatment of the coupling reaction can be the conventional post-treatment of this type of reaction in the art, for example, it is the following steps: extracting, washing, concentrating and recrystallizing the reaction solution after the acidification reaction.

[0070] In one embodiment, the extraction agent is ethyl acetate.

[0071] In one embodiment, the volume molar ratio of ethyl acetate to the compound shown in Formula III is (1-4):1 mol / L, for example 5:3 mol / L.

[0072] In a certain embodiment, the washing liquid is a saturated NaCl solution.

[0073] In one embodiment, the volume ratio of the saturated NaCl solution to the extractant is 1:3.

[0074] In one embodiment, the concentration is carried out by distillation under reduced pressure.

[0075] In one embodiment, the soluble solvent for recrystallization may be an alcohol solvent, such as ethanol.

[0076] In one embodiment, the sparingly soluble solvent for recrystallization is water.

[0077] In one embodiment, the volume ratio of the alcohol solvent to the mass ratio of the water is 1:1.

[0078] In one embodiment, the molar volume ratio of the 2-biphenylpropionic acid compound as shown in Formula V to the alcohol solvent is (1-3):1, for example, 2:1.

[0079] In a certain embodiment, the acidification step in the step (2) comprises the following steps: adding 1N HCl solution to the reaction solution of the 2-biphenylpropionic acid compound and adjusting the pH to 3-4, stirring for 1 hour, filtering, letting the filtrate stand, separating the liquids, extracting the aqueous phase with ethyl acetate, washing the organic phase once with a saturated NaCl solution, concentrating, crystallizing with a 50% methanol / water solution, filtering, and drying to obtain the 2-biphenylpropionic acid compound shown in formula V.

[0080] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0081] The reagents and raw materials used in the present invention are commercially available.

[0082] The positive and progressive effect of the present invention is that the present invention uses 2-halogenated propionate and a Grignard reagent as shown in formula I as raw materials, and prepares 2-biphenyl propionate compounds under the catalysis of a cobalt compound and an amine compound, or a cobalt compound. The method has short steps, easy-to-obtain raw materials, well avoids the occurrence of side reactions, greatly improves the yield, increases the purity of the product, reduces the cost, has good economic benefits, and is suitable for industrial production. DETAILED DESCRIPTION

[0083] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0084] The flurbiprofen and desflurbiprofen obtained by the invention are both identified by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance hydrogen spectrum (H-NMR) for structure identification, and are simultaneously analyzed by liquid chromatography (HPLC) and reference substances for qualitative and quantitative analysis.

[0085] The conditions of HPLC in the embodiment of the present invention are as follows:

[0086] Chromatographic column: Amethyst C18-H (4.6×250mm, 5μm)

[0087] Flow rate: 1.0ml / min

[0088] Wavelength: 254nm

[0089] Column temperature: room temperature

[0090] Mobile phase A: water: acetic acid = 1000:1.5

[0091] Mobile phase B: acetonitrile

[0092] time Mobile phase A (%) Mobile phase B (%) 0 60 40 30 10 90 35 10 90 36 60 40 41 60 40

[0093] Example 1

[0094] Add 4.8g magnesium chips, 250ml THF, and catalytic amount of iodine to a 1000ml reaction bottle A, heat to 60°C, and drip a solution of 50.2g 4-bromo-2-fluorobiphenyl and 100ml THF. At the beginning of the dripping, the color of iodine disappears and the temperature rises. Complete the dripping at 55-65°C for about 1h, and then react for 1h until the raw material is less than 2% by HPLC monitoring, and cool to below 10°C for use. Add 38.5g sodium 2-bromopropionate, 200ml THF, 3.56g Co(acac)3 and 1.16g TMEDA to a 1000ml reaction bottle B, cool to -5-0°C in an ice-salt bath, drip the Grignard reaction solution in the above reaction bottle A, keep the internal temperature at -5-5°C for about 2h, and then keep warm for 1h until the reaction is unchanged by HPLC monitoring. Add about 300ml 1N HCl solution to quench the reaction and adjust the pH to 3-4, stir for 1h, filter, let the filtrate stand for 0.5h, separate the liquid, extract the lower aqueous phase twice with 300ml ethyl acetate, combine the organic layers, wash once with 100ml saturated NaCl solution, and concentrate under reduced pressure until no liquid is distilled. Add 500ml 50% methanol / water solution for crystallization, filter, and dry to obtain a white powder product flurbiprofen (45.8g, yield 93.9%, purity 99.1% (HPLC)), mp: 111.7-112.5℃. Here.

[0095] 1 H NMR (600MHz, DMSO-d6) δ (ppm): 7.67~7.21 (m, 8H, -ArH), 3.68 (q, 1H, -CH-), 1.39 (d, J = 4.8Hz, 3H, -CH3).

[0096] Example 2

[0097] Add 4.8g magnesium chips, 250ml THF, and catalytic amount of iodine to a 1000ml reaction bottle A, heat to 65°C, and drip a solution of 46.6g 4-bromobiphenyl and 100ml THF. At the beginning of the dripping, the color of iodine disappears and the temperature rises. Control the temperature at 65-70°C for about 1h to complete the dripping, and then keep the reaction for 1h until the raw material is less than 2% by HPLC monitoring, and cool to below 10°C for use. Add 38.5g sodium 2-bromopropionate, 200ml THF, 3.56g Co(acac)3 and 1.16g TMEDA to a 1000ml reaction bottle B, cool to -5-0°C in an ice-salt bath, drip the Grignard reaction solution in the above reaction bottle A, keep the internal temperature at -5-5°C for about 2h to complete the dripping, and then react for 1h until the reaction is monitored by HPLC without changes. Add about 300ml 1N HCl solution to quench the reaction and adjust the pH to 3-4, stir for 1h, filter, let the filtrate stand for 0.5h, separate the liquid, extract the lower aqueous phase twice with 300ml ethyl acetate, combine the organic layers, wash once with 100ml saturated NaCl solution, and concentrate under reduced pressure until no liquid is distilled. Add 500ml 50% methanol / water solution for crystallization, filter, and dry to obtain a white powder product desflurane flurbiprofen (41.4g, yield 91.6%, purity 99.3% (HPLC)), mp: 141.6-142.4℃. 1 H NMR (400MHz, DMSO-d6) δ (ppm): 12.35 (s, 1H, -COOH), 7.66~7.34 (m, 9H, -ArH), 3.72 (q, 1H, -CH-), 1.39 (d, J = 6.8Hz, 3H, -CH3).

[0098] Embodiments 3 to 15

[0099] Except for using different cobalt-containing compounds and different amine compounds to replace Co(acac)3 and TMEDA, the dosage ratio of each substance and the experimental operation are the same as those in Example 1 or 2. The results are shown in the following table:

[0100]

[0101]

[0102] Embodiments 16 to 17

[0103] Except that magnesium 2-bromopropionate is used instead of sodium 2-bromopropionate, the dosage ratio of each substance and the experimental operation are the same as those in Example 1 or 2. The results are shown in the following table:

[0104] Example R 2-Halopropionate Yield HPLC purity 16 F Magnesium 2-bromopropionate 90.2％ 99.1％ 17 H Magnesium 2-bromopropionate 87.6％ 98.7％

[0105] Embodiments 18 to 19

[0106] Except that other 2-halogenated propionates were used instead of sodium 2-bromopropionate, the dosage ratio of each substance and the experimental operation were the same as in Example 1. The results are shown in the following table:

[0107] Example R 2-Halopropionate Yield HPLC purity 18 F Sodium 2-chloropropionate 67.3％ 98.1％ 19 F Sodium 2-iodopropionate 73.1％ 97.4％

[0108] Embodiment 20-21

[0109] Except that other compounds as shown in formula A are used to replace benzene instead of 4-bromobiphenyl, the dosage ratio of each substance and the experimental operation are the same as in Example 2. The results are shown in the following table:

[0110] Example R <![CDATA[R 1 ]]> Yield HPLC purity 20 H chlorine 84.4％ 98.9％ 21 H iodine 89.7％ 99.3％

[0111] Comparative Examples 1 to 3

[0112] Except for using different catalysts to replace Co(acac)3 and TMEDA, the dosage ratio of each substance and the experimental operation are the same as in Example 1. The results are shown in the following table:

[0113] Comparative Example R catalyst Yield HPLC purity 1 F - 46.7％ 97.6％ 2 F <![CDATA[FeCl3]]> 62.4％ 98.1％ 3 F CuCl 48.2％ 96.4％

[0114] Comparative Example 4 (Repeating Example 1 in Patent CN108558651A)

[0115] Add 1.9g magnesium chips, 100ml THF, and catalytic amount of iodine to a 500ml reaction bottle, heat to 65°C under nitrogen protection, add about 5ml of a solution of 20g 4-bromo-2-fluorobiphenyl and 100ml THF, and stir for 30min until the color of iodine disappears and the temperature rises. Cool to 62°C and add the remaining solution, and after the drop is complete, heat to 72°C and react until the magnesium chips basically disappear. Cool to 25°C, add 11ml of ethyl 2-bromopropionate, 2ml of titanium tetrachloride and 50ml of THF in an ice-water bath, and reflux for 4h after the addition until HPLC monitors the reaction without change. Cool to room temperature and concentrate under reduced pressure to recover most of the THF. Add about 100ml of ammonium chloride solution to the residue to quench the reaction, stir for 20min, extract three times with 100ml of ethyl acetate, combine the organic layers, wash twice with 100ml water, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure until no liquid is distilled out. Add 120ml ethanol and 100ml 5% NaOH solution, and reflux for 7h. Recover ethanol under reduced pressure, wash the water layer twice with 100ml ethyl acetate, adjust the pH to less than 3 with HCl, extract twice with 100ml ethyl acetate, combine the ethyl acetate layers, wash twice with 100ml water, dry over anhydrous sodium sulfate, filter, concentrate to dryness, add 50ml petroleum ether and 1g activated carbon, heat and reflux for 20min, filter while hot, cool the filtrate to crystallize, filter and dry to obtain 6.6g of light yellow solid, with a yield of 13.5% and a purity of 94.7% (HPLC).

[0116] Comparative Example 5 (Repeat Example 1 in US3959364A)

[0117] Add 2.5g magnesium chips, 20ml THF, catalytic amount of iodine to a 1000ml reaction bottle, add a solution of 25.1g 4-bromo-2-fluorobiphenyl and 130ml THF under nitrogen protection, reflux for 60min until the raw material is less than 2% by HPLC monitoring, cool to 10°C, add a solution of 17.5g sodium 2-bromopropionate and 200ml THF, and reflux for 1h until the reaction is unchanged by HPLC monitoring. Add 150ml water under ice-water bath cooling, add 50ml 20% sulfuric acid to quench the reaction, and stir for 20min. Extract twice with 300ml ether, combine the organic layers, wash once with 200ml water, extract twice with 300ml 1N K2CO3 solution, combine the extracts, wash once with 300ml ether, adjust pH to 3 with 1N HCl, filter, and dry to obtain 21.2g of white solid, yield 43.4%, purity 98.3% (HPLC).

[0118] Comparative Example 6

[0119] Add 4.8g magnesium chips, 250ml THF, and catalytic amount of iodine to a 1000ml reaction bottle A, heat to 65℃, and drop 39.8g 2,4,6-trimethylbromobenzene and 100ml THF solution. The color of iodine disappears and the temperature rises at the beginning of the dropwise addition. Control the temperature at 65-70℃ for about 1h to complete the dropwise addition, and then keep the temperature for 1h to react until the raw material is less than 2% by HPLC monitoring, and cool to below 10℃ for standby use. Add 55.0g N,N-diethyl-6-bromohexamide, 200ml THF, 1.3g CoCl2 and 1.16g TMEDA to a 1000ml reaction bottle B, cool to -5-0℃ in an ice-salt bath, drop the Grignard reaction solution in the above reaction bottle A, keep the internal temperature at -5-5℃ for about 2h to complete the dropwise addition, and then react for 1h until there is no change in the reaction by HPLC monitoring. Add about 300 ml of 1N HCl solution to quench the reaction and adjust the pH to 3-4, stir for 1 hour, filter, let the filtrate stand for 0.5 hour, separate the liquid, extract the lower aqueous phase twice with 300 ml of ethyl acetate, combine the organic layers, wash once with 100 ml of saturated NaCl solution, and concentrate under reduced pressure until no liquid is distilled. 7.1 g (yield 12.3%, purity 97.1% (HPLC)) was obtained by column chromatography.

Claims

1. A method for preparing a 2-biphenyl propionate compound, characterized in that: The method comprises the following steps: in an ether solvent, in the presence of a catalyst, coupling a compound as shown in formula I with a 2-halogenated propionate to obtain a 2-biphenyl propionate; the anion of the 2-biphenyl propionate is a compound as shown in formula II, The catalyst is selected from any of the following options: Scheme 1: containing cobalt inorganic salt and amine compound 1; Scheme 2: containing cobalt organic salt 1 and amine compound 2; Option 3: Cobalt-containing organic salt 2; R is fluorine or hydrogen; R 1 is chlorine, iodine or bromine; The cobalt-containing inorganic salt is selected from one or both of CoCl2 and CoSO4; The amine compound 1 is selected from one or two of N,N,N,N-tetramethylethylenediamine and urotropine; The cobalt-containing organic salt 1 is selected from one or two of (1R, 2R)-(-)-1,2-cyclohexanediamino-N, N'-bis(3,5-di-tert-butyl salicyl)cobalt(II), disalicylicaldehyde ethylenediamine cobalt, Co(OAc)2, Co(acac)2 and Co(acac)3; The amine compound 2 is selected from one or two of N,N,N,N-tetramethylethylenediamine and urotropine; The cobalt-containing organic salt 2 is selected from one or two of (1R, 2R)-(-)-1,2-cyclohexanediamino-N, N'-bis(3,5-di-tert-butylsalicylicyl)cobalt (II) and disalicylicylethylenediamine cobalt.

2. The method for preparing 2-biphenyl propionate compounds according to claim 1, characterized in that: The compound as shown in formula I is selected from any of the following compounds: Or, the ether solvent is one or more of diethyl ether, tetrahydrofuran, methyl tert-butyl ether and cyclopentyl methyl ether; Or, the molar volume ratio of the ether solvent to the compound represented by formula I is (0.5-5): 1 mol / L; Or, the molar ratio of the cobalt-containing inorganic salt to the compound of formula I is 1:(5-100); Or, the molar ratio of the cobalt-containing organic salt 1 to the compound of formula I is 1:(5-100); Or, the molar ratio of the cobalt-containing organic salt 2 to the compound of formula I is 1:(5-100); Or, the molar ratio of the amine compound 1 to the compound of formula I is 1:(5-100); Or, the molar ratio of the amine compound 2 to the compound represented by formula I is 1:(5-100); Or, the 2-halopropionate is an alkali metal salt or an alkaline earth metal salt; Or, the 2-halopropionate is 2-bromopropionate, 2-chloropropionate or 2-iodopropionate; Or, in the coupling reaction, the molar ratio of the anion in the 2-halopropionate to the compound shown in Formula I is 1:(0.1-10); Or, the reaction temperature of the coupling reaction is -20 to 80°C; Or, the reaction time of the coupling reaction is 0-5h, excluding 0h; Alternatively, in the coupling reaction, a mixture of the compound shown in Formula I and an ether solvent is added dropwise to a mixture of 2-halopropionic acid salt and a catalyst.

3. The method for preparing 2-biphenyl propionate compounds according to claim 2, characterized in that: The ether solvent is tetrahydrofuran; Or, the molar volume ratio of the ether solvent to the compound represented by formula I is (1-3): 1 mol / L; Or, the molar ratio of the cobalt-containing inorganic salt to the compound of formula I is 1:(5-50); Or, the molar ratio of the cobalt-containing organic salt 1 to the compound of formula I is 1:(5-50); Or, the molar ratio of the cobalt-containing organic salt 2 to the compound of formula I is 1:(5-50); Or, the molar ratio of the amine compound 1 to the compound of formula I is 1:(5-50); Or, the molar ratio of the amine compound 2 to the compound represented by formula I is 1:(5-50); Or, in the coupling reaction, the molar ratio of the anion in the 2-halopropionate to the compound shown in Formula I is 1:(0.5-2); Or, the reaction temperature of the coupling reaction is -10 to 20°C; Or, the coupling reaction is performed by dropping a mixture of the compound shown in Formula I and an ether solvent into a mixture of 2-halopropionic acid salt and a catalyst; Or, when the 2-halopropionate is an alkali metal salt, the 2-halopropionate is sodium 2-halopropionate, lithium 2-halopropionate or potassium 2-halopropionate; Or, when the 2-halopropionate is an alkaline earth metal salt, the 2-halopropionate is magnesium 2-halopropionate or calcium 2-halopropionate.

4. The method for preparing 2-biphenyl propionate compounds according to claim 3, characterized in that: The molar volume ratio of the ether solvent to the compound represented by formula I is 1:1 mol / L; Or, the molar ratio of the cobalt-containing inorganic salt to the compound of formula I is 1:20; Or, the molar ratio of the cobalt-containing organic salt 1 to the compound of formula I is 1:20; Or, the molar ratio of the cobalt-containing organic salt 2 to the compound of formula I is 1:20; Or, the amount of the amine compound 1 to the compound of formula I is 1:20 by mole; Or, the amount of the amine compound 2 to the compound of formula I is 1:20 by mole; Or, the cobalt-containing organic salt 1 is (1R, 2R)-(-)-1,2-cyclohexanediamino-N, N'-bis(3,5-di-tert-butylsalicylicyl)cobalt(II), disalicylicaldehyde ethylenediamine cobalt, Co(OAc)2, Co(acac)2 or Co(acac)3; Or, the cobalt-containing organic salt 2 is (1R, 2R)-(-)-1,2-cyclohexanediamino-N,N'-bis(3,5-di-tert-butylsalicylicyl)cobalt(II) or disalicylicaldehyde ethylenediamine cobalt; Or, the 2-halogenated propionate is sodium 2-bromopropionate, sodium 2-chloropropionate, sodium 2-iodopropionate, potassium 2-bromopropionate, potassium 2-iodopropionate or magnesium 2-bromopropionate.

5. The method for preparing 2-biphenyl propionate compounds according to claim 1 further comprises the following steps: in an ether solvent, in the presence of iodine, metallizing the compound represented by formula III with magnesium to obtain the compound represented by formula I, 6. The method for preparing 2-biphenyl propionate compounds according to claim 5, characterized in that: In the metalation reaction, the ether solvent is selected from one or more of diethyl ether, tetrahydrofuran, methyl tert-butyl ether and cyclopentyl methyl ether; Or, in the metalation reaction, the volume molar ratio of the ether solvent to the compound represented by Formula III is (2-10): 1 mol / L; Or, the molar ratio of the compound as shown in formula III to magnesium is 1:(0.1-10); Alternatively, the reaction temperature of the metallization reaction is 20-80°C.

7. The method for preparing 2-biphenyl propionate compounds according to claim 6, characterized in that: In the metalation reaction, the ether solvent is tetrahydrofuran; Or, in the metalation reaction, the volume molar ratio of the ether solvent to the compound represented by Formula III is (3-7): 1 mol / L; Or, the molar ratio of the compound as shown in formula III to magnesium is 1:(0.8-2).

8. The method for preparing 2-biphenyl propionate compounds according to claim 7, characterized in that: In the metalation reaction, the volume molar ratio of the ether solvent to the compound represented by Formula III is 5:1 mol / L; Or, the molar ratio of the compound represented by formula III to magnesium is 1:1; Alternatively, the reaction temperature of the metallization reaction is 40-70°C.

9. The method for preparing 2-biphenylpropionic acid compounds according to claim 8, characterized in that: The preparation method comprises the following steps: adding magnesium and iodine to an ether solvent, heating to 60°C, dripping a solution of a compound shown in formula III and an ether solvent, reacting at 55-65°C, cooling to below 10°C for standby use; mixing 2-halogenated propionate, a catalyst and an ether solvent at -5-0°C, dripping a Grignard reaction solution thereto at -5-5°C, dripping for 2 hours, and keeping the temperature for reaction for 1 hour to obtain a 2-biphenylpropionate compound reaction solution.

10. A method for preparing a 2-biphenylpropionic acid compound, characterized in that: It includes the following steps: (1) A 2-biphenyl propionate compound is obtained according to the method for preparing a 2-biphenyl propionate compound according to any one of claims 1 to 9; (2) subjecting the 2-biphenylpropionic acid salt compound prepared in step (1) to an acidification reaction to obtain a 2-biphenylpropionic acid compound as shown in formula V,

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