Process for the preparation of fenofibrate and its impurities

Abstract

The present application relates to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of fenofibrate and impurities thereof. The present application carries out Friedel-Crafts acylation reaction on 4-chlorobenzoyl chloride, anisole, Lewis acid and benzene solvent, then carries out demethylation reaction, and then separates and purifies to obtain compound II, impurity compound IV and impurity compound V; the compound II (or impurity compound IV), 2-bromoisobutyric acid isopropyl ester, an alkaline reagent and an alcohol solvent are mixed to carry out etherification reaction, and then separated and purified to obtain fenofibrate (or impurity compound VI). The preparation method provided by the present application has high yield and high purity of fenofibrate, can realize identification of impurities in the preparation process of fenofibrate, and provides a convenient condition for quality control of bulk drug. Moreover, the raw materials and solvents used are widely sourced, low in cost and small in danger, the preparation method is high in safety factor, simple in operation, and suitable for large-scale industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of fenofibrate and impurities thereof. BACKGROUND

[0002] Fenofibrate, the chemical name of which is 2-methyl-2-(4-(4-chlorobenzoyl) phenoxy) isopropyl propionate, the trade name of which is TRICOR, and the structural formula of which is shown as formula I, belongs to the class of fibrates, and can be used for treating hyperlipidemia in adult diet control therapy which is not ideal, can reduce the levels of high cholesterol, high triglycerides (fatty acids), low protein lipoprotein (LDL) and very low density lipoprotein (VLDL) in blood, and at the same time, can increase the level of high-density lipoprotein, thereby reducing the level of aspergillus and reducing the risk of onset of diseases related to heart disease.

[0003]

[0004] The safety of a drug depends not only on the toxicology of the active pharmaceutical ingredient (or bulk drug), but also on the toxicology formed in various chemical synthesis, formulation processes or product degradation processes. Therefore, the identification, quantification and control of impurities in the bulk drug are important parts of the development of the bulk drug to obtain market approval.

[0005] At present, the synthesis of fenofibrate mainly has route 1 and route 2.

[0006]

[0007] In Route 1, the preparation of compound (II) is as follows: European patent EP1903024A1 discloses that 4-chlorobenzoyl chloride reacts with phenol in the presence of AlCl3 as catalyst and o-dichlorobenzene as solvent to prepare compound (II); Chinese patent CN106278842A discloses that 4-chlorobenzoyl chloride reacts with anisole in the presence of AlCl3-IL-SiO2@y-Fe2O3 as catalyst and chlorinated solvent, then demethylation in acetic acid using HBr to obtain compound (II); Chinese patent CN110668928A discloses that 4-chlorobenzoyl chloride reacts with anisole in the presence of AlCl3 as catalyst and chlorobenzene as solvent at 125-130℃ to prepare compound (II), then purifies in chlorobenzene; Jina Kim et al. (Jina, Kim, Jungwook, et al. Synthesis and biological evaluation of novel 4-hydroxytamoxifen analogs as estrogen-related receptor gamma inverse agonists [J]. European Journal of Medicinal Chemistry, 2016, 120, 338-352.) reports that 4-chlorobenzoyl chloride reacts with anisole in the presence of AlCl3 as catalyst and chlorinated solvent (dichloromethane), then demethylation in the presence of toluene and AlCl3 catalyst to prepare compound (II). The preparation of compound (III) is as follows: patent WO 2005 / 046575A2 discloses that compound (II) reacts with CHCl3 and acetone in the presence of NaOH, then purifies using toluene as solvent to prepare compound (III).

[0008] In route 1 and route 2, the preparation method of fenofibrate is as follows: US4739101A discloses that compound (II) is reacted with isopropyl 2-bromoisobutyrate in the presence of solvent-free and excess K2CO3 to prepare fenofibrate; US6897333B2 discloses that 4-chloro-4'-hydroxybenzophenone is etherified with isopropyl 2-bromoisobutyrate in the presence of potassium bicarbonate as a base and isopropyl alcohol as a solvent at 82-84℃ to prepare fenofibrate; Indian patent 1851 / MUM / 2006 discloses that compound (II) is reacted with isopropyl 2-bromoisobutyrate in the presence of tetrabutylammonium bromide and potassium carbonate in isopropyl alcohol to prepare fenofibrate; US2010 / 0185008A1 discloses a method for preparing fenofibrate by reacting fenofibrate acid with sulfuryl chloride and isopropyl alcohol; US20100185008 discloses a method for producing fenofibrate from fenofibrate acid, wherein fenofibrate acid is reacted with a chlorinating agent to prepare fenofibrate acid chloride in situ, and then the fenofibrate acid chloride is reacted with isopropyl alcohol without isolation of the acid chloride to synthesize fenofibrate from fenofibrate acid. However, the above preparation methods do not realize the qualitative identification of the impurities in the intermediate and fenofibrate. SUMMARY

[0009] Therefore, the present application aims to provide a preparation method of fenofibrate and its impurities, which realizes the qualitative identification of the impurities in the intermediate and fenofibrate, and provides a convenient condition for the quality control of the bulk drug.

[0010] In order to achieve the above-mentioned application purposes, the present application provides the following technical solutions:

[0011] The present application provides a preparation method of fenofibrate and its impurities, which comprises the following steps:

[0012] (1) mixing 4-chlorobenzoyl chloride, anisole, Lewis acid and a benzene solvent to perform Friedel-Crafts acylation reaction, then performing demethylation reaction and first separation and purification to obtain compound II, impurity compound IV and impurity compound V, respectively;

[0013] (2) mixing compound II, isopropyl 2-bromoisobutyrate, an alkaline reagent and an alcohol solvent to perform first etherification reaction and then second separation and purification to obtain fenofibrate;

[0014] (3) mixing impurity compound IV, isopropyl 2-bromoisobutyrate, an alkaline reagent and an alcohol solvent to perform second etherification reaction and then third separation and purification to obtain impurity compound VI;

[0015]

[0016] Step (2) and step (3) have no time sequence.

[0017] Preferably, the benzene solvents include one or more of toluene, xylene and chlorobenzene.

[0018] Preferably, the molar ratio of the 4-chlorobenzoyl chloride, the anisole and the Lewis acid is 1:1.2-1.4:2-2.2.

[0019] The Lewis acid includes one or more of AICI3, FeCI3and ZnCI2.

[0020] Preferably, the temperature of the Friedel-Crafts acylation reaction is -20 to -10°C, and the time is 3-4h.

[0021] Preferably, the temperature of the demethylation reaction is 80-90°C, and the time is 4-5h.

[0022] The demethylation reagent used in the demethylation reaction includes one or more of AICI3, BBr3and BCI3.

[0023] Preferably, the first separation and purification includes:

[0024] (a) mixing the demethylation reaction liquid obtained from the demethylation reaction with water, and then separating the solid and liquid to obtain a first liquid component and a first solid component, respectively;

[0025] (b) sequentially washing the first solid component with water, an alkaline solution and drying to obtain compound II;

[0026] (c) separating the phases of the first liquid component, dissolving the obtained organic phase in ethyl acetate-n-heptane mixed solvent, and then performing first cooling crystallization and solid-liquid separation to obtain a second liquid component and a second solid component, respectively;

[0027] (d) washing and drying the second solid component to obtain impurity compound IV;

[0028] (e) dissolving the second liquid component in ethyl acetate-cyclohexane mixed solvent after concentration, and then performing second cooling crystallization and solid-liquid separation, washing and drying the obtained third solid component to obtain impurity compound V;

[0029] Step (b) and step (c) have no time sequence;

[0030] Step (d) and step (e) have no time sequence.

[0031] Preferably, the molar ratio of the compound II, isopropyl 2-bromoisobutyrate and the basic reagent is 1:1.8-2.2:1.5-1.8.

[0032] The basic reagent includes one or more of potassium carbonate, potassium bicarbonate and sodium hydroxide.

[0033] Preferably, the temperature of the first etherification reaction and the second etherification reaction is independently 95-120℃, and the time is independently 6-25h.

[0034] Preferably, the second separation and purification includes: solid-liquid separation of the first etherification reaction liquid obtained from the first etherification reaction, hot mixing of the obtained solid crude product with an alcohol solvent and activated carbon, solid-liquid separation after activated carbon adsorption decolorization, cooling crystallization of the obtained liquid component, drying of the obtained crystal after alcohol washing, to obtain fenofibrate; the alcohol solvent and the alcohol used for alcohol washing independently include one or more of isopropyl alcohol, n-propanol and isobutyl alcohol; the temperature of the hot mixing is 60-75℃; the starting temperature of the cooling crystallization is 60-75℃, the final temperature is 0-5℃, and the cooling rate is 0.1-0.3℃ / min.

[0035] Preferably, the third separation and purification includes: solid-liquid separation of the second etherification reaction liquid obtained from the second etherification reaction after mixing with water, and drying of the obtained solid component after water washing, to obtain the impurity compound VI.

[0036] The preparation method provided by the present application has high yield and high purity of fenofibrate; meanwhile, the qualitative identification of impurities in the preparation process of fenofibrate can be realized, which provides a convenient condition for the quality control of the bulk drug. Moreover, the raw materials and solvents used in the preparation method provided by the present application have wide sources, low cost and small danger, the preparation method has high safety factor, is simple to operate, and is suitable for large-scale industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0037] Figure 1 Mass spectrum of the compound II prepared in Example 1;

[0038] Figure 2 Hydrogen spectrum of the compound II prepared in Example 1;

[0039] Figure 3 Carbon spectrum of the compound II prepared in Example 1;

[0040] Figure 4 Infrared spectrum of the compound II prepared in Example 1;

[0041] Figure 5 HPLC spectrum of the compound II prepared in Example 1;

[0042] Figure 6HPLC profile of compound II prepared for Example 2;

[0043] Figure 7 HPLC profile of compound II prepared for Example 3;

[0044] Figure 8 HPLC profile of compound II prepared for Example 4;

[0045] Figure 9 HPLC profile of crude Fenofibrate prepared for Example 5;

[0046] Figure 10 HPLC profile of crude Fenofibrate prepared for Example 6;

[0047] Figure 11 HPLC profile of crude Fenofibrate prepared for Example 7;

[0048] Figure 12 HPLC profile of pure Fenofibrate prepared for Example 8;

[0049] Figure 13 Mass spectrum of impurity compound IV prepared for Example 9;

[0050] Figure 14 Hydrogen spectrum of impurity compound IV prepared for Example 9;

[0051] Figure 15 Carbon spectrum of impurity compound IV prepared for Example 9;

[0052] Figure 16 Infrared spectrum of impurity compound IV prepared for Example 9;

[0053] Figure 17 Mass spectrum of impurity compound V prepared for Example 10;

[0054] Figure 18 Hydrogen spectrum of impurity compound V prepared for Example 10;

[0055] Figure 19 Carbon spectrum of impurity compound V prepared for Example 10;

[0056] Figure 20 Infrared spectrum of impurity compound V prepared for Example 10;

[0057] Figure 21 Mass spectrum of impurity compound VI prepared for Example 11;

[0058] Figure 22 Hydrogen spectrum of impurity compound VI prepared for Example 11;

[0059] Figure 23 Carbon spectrum of impurity compound VI prepared in Example 11;

[0060] Figure 24 Infrared spectrum of fenofibrate pure product prepared in Example 12;

[0061] Figure 25 HPLC spectrum of fenofibrate pure product prepared in Example 13.

[0062] Figure 26 HPLC spectrum of fenofibrate pure product prepared in Example 13. DETAILED DESCRIPTION

[0063] The present application provides a preparation method of fenofibrate and its impurities, comprising the following steps:

[0064] (1) mixing 4-chlorobenzoyl chloride, anisole, Lewis acid and benzene solvent to perform Friedel-Crafts acylation reaction, then performing demethylation reaction and first separation and purification, to obtain compound II, impurity compound IV and impurity compound V, respectively;

[0065] (2) mixing compound II, isopropyl 2-bromoisobutyrate, alkaline reagent and alcohol solvent to perform first etherification reaction and second separation and purification, to obtain fenofibrate;

[0066] (3) mixing impurity compound IV, isopropyl 2-bromoisobutyrate, alkaline reagent and alcohol solvent to perform second etherification reaction and third separation and purification, to obtain impurity compound VI;

[0067]

[0068] Steps (2) and (3) have no time sequence.

[0069] In the present application, the synthesis route of the fenofibrate is as follows:

[0070]

[0071] Unless otherwise specified, the raw materials used in the present application are all commercially available.

[0072] In the present application, 4-chlorobenzoyl chloride, anisole, Lewis acid and benzene solvent are mixed to perform Friedel-Crafts acylation reaction, then performing demethylation reaction and first separation and purification, to obtain compound II, impurity compound IV and impurity compound V, respectively.

[0073] In the present application, the Lewis acid preferably comprises one or more of AlCl3, FeCl3and ZnCl2, more preferably AlCl3, FeCl3or ZnCl2. In the present application, the molar ratio of the 4-chlorobenzoyl chloride, the anisole and the Lewis acid is preferably 1:1.2-1.4:2-2.2, more preferably 1:1.25-1.35:2.05-2.15, and further preferably 1:1.3:2.1.

[0074] In the present application, the benzene solvent preferably comprises one or more of toluene, xylene and chlorobenzene, more preferably toluene, xylene or chlorobenzene. In the present application, the ratio of the mass of the 4-chlorobenzoyl chloride to the volume of the benzene solvent is preferably 1 kg:8L-10L, more preferably 1 kg:8-9L.

[0075] In the present application, the temperature of the Friedel-Crafts acylation reaction is preferably -20--10℃, more preferably -15℃; the time of the Friedel-Crafts acylation reaction is preferably 3-4h, more preferably 3.5h.

[0076] In the present application, the demethylation reaction preferably comprises mixing the Friedel-Crafts acylation reaction liquid obtained with a demethylation reagent to perform the demethylation reaction. In the present application, the demethylation reagent preferably comprises one or more of AlCl3, BBr3and BCl3, more preferably AlCl3, BBr3or BCl3. In the present application, the temperature of the demethylation reaction is preferably 80-90℃, more preferably 85℃; the time of the demethylation reaction is preferably 4-5h, more preferably 4.5h.

[0077] In the present application, the first separation and purification preferably comprises: (a) mixing the demethylation reaction liquid obtained from the demethylation reaction with water, and then performing solid-liquid separation to obtain a first liquid component and a first solid component; (b) sequentially performing water washing, alkaline solution washing and drying on the first solid component to obtain compound II; (c) performing phase separation on the first liquid component, dissolving the obtained organic phase in ethyl acetate-n-heptane mixed solvent, performing first cooling crystallization, and then performing solid-liquid separation to obtain a second liquid component and a second solid component; (d) performing washing and drying on the second solid component to obtain impurity compound IV; (e) concentrating the second liquid component, dissolving the second liquid component in ethyl acetate-cyclohexane mixed solvent, performing second cooling crystallization, and then performing solid-liquid separation, and performing washing and drying on the obtained third solid component to obtain impurity compound V; steps (b) and (c) have no time sequence; steps (d) and (e) have no time sequence.

[0078] The demethylation reaction liquid obtained by the demethylation reaction is mixed with water, and then solid-liquid separation is performed to obtain a first liquid component and a first solid component. The first solid component is sequentially subjected to water washing, alkaline solution washing, and drying to obtain compound II. The mass of the water used for mixing is not particularly limited in the present application, and the water is added to the solid until the addition no longer increases. In the present application, the solid-liquid separation is preferably filtration. In the present application, the purpose of the water washing is to remove acid. In the present application, the alkaline solution preferably includes one or more of NaHCO3 solution, NaOH solution, and NaCO3 solution, and the mass concentration of the alkaline solution is preferably 5-10%, more preferably 5-8%. In the present application, the drying temperature is preferably 70-75°C, more preferably 72-73°C; and the time for drying is not particularly limited in the present application, and the drying is performed until the weight is constant.

[0079] After obtaining the first liquid component, the first liquid component is subjected to phase separation, and the obtained organic phase is concentrated, then dissolved in an ethyl acetate-n-hexane mixed solvent, subjected to first cooling crystallization, and then subjected to solid-liquid separation to obtain a second liquid component and a second solid component. The second solid component is washed and dried to obtain impurity compound IV. In the present application, the concentration is preferably rotary evaporation. The conditions for the concentration are not particularly limited in the present application, and the concentration is performed until no solvent flows out. In the present application, the volume ratio of ethyl acetate to n-hexane in the ethyl acetate-n-hexane mixed solvent is preferably 1:4-6, more preferably 1:4-5; and the volume ratio of the second liquid component to the ethyl acetate-n-hexane mixed solvent is preferably 1:8-10, more preferably 1:9-10. In the present application, the temperature for the first dissolution is preferably 50-60°C, more preferably 55°C. In the present application, the first cooling crystallization is preferably natural cooling from the temperature for the first dissolution to room temperature. In the present application, the solid-liquid separation is preferably filtration. In the present application, the washing solvent is preferably the ethyl acetate-n-hexane mixed solvent. In the present application, the drying temperature is preferably 70-75°C, more preferably 72-73°C; and the time for drying is not particularly limited in the present application, and the drying is performed until the weight is constant.

[0080] After obtaining the second liquid component, the present application concentrates the second liquid component, then dissolves the second liquid component in ethyl acetate-cyclohexane mixed solvent, then separates the solid and liquid after the second cooling crystallization, then washes and dries the third solid component to obtain the impurity compound V. In the present application, the concentration is preferably rotary evaporation. The present application does not have special limitations on the conditions of the concentration, and the concentration is performed until no solvent flows out. In the present application, the volume ratio of ethyl acetate and cyclohexane in the ethyl acetate-cyclohexane mixed solvent is preferably 1:1-2, and more preferably 1:1-1.5. In the present application, the temperature of the second dissolution is preferably 45-55°C, and more preferably 50°C. In the present application, the second cooling crystallization is preferably natural cooling from the temperature of the second dissolution to room temperature. In the present application, the solid-liquid separation is preferably filtration. In the present application, the washing solvent is preferably the ethyl acetate-cyclohexane mixed solvent. In the present application, the drying temperature is preferably 70-75°C, and more preferably 72-73°C. The present application does not have special limitations on the drying time, and the drying is performed until the weight is constant.

[0081] After obtaining the compound II, the present application mixes the compound II, isopropyl 2-bromoisobutyrate, a basic reagent, and an alcoholic solvent, then performs the first etherification reaction, and then separates and purifies the second to obtain fenofibrate.

[0082] In the present application, the molar ratio of the compound II, isopropyl 2-bromoisobutyrate, and the basic reagent is preferably 1:1.8-2.2:1.5-1.8, more preferably 1:1.85-2.15:1.55-1.75, and further preferably 1:1.9-2.1:1.6-1.7. In the present application, the basic reagent preferably includes one or more of potassium carbonate, potassium bicarbonate, and sodium hydroxide, and more preferably potassium carbonate, potassium bicarbonate, or sodium hydroxide.

[0083] In the present application, the alcoholic solvent preferably includes one or more of n-propanol, isobutyl alcohol, and n-butyl alcohol, and more preferably n-propanol, isobutyl alcohol, or n-butyl alcohol. In the present application, the mass of the compound II to the volume of the alcoholic solvent is preferably 1 kg:5-8 L, and more preferably 1 kg:5-6 L.

[0084] In the present application, the temperature of the first etherification reaction is preferably 95-120°C, and the time is preferably 6-25h. In the present application, when n-propanol is used as the solvent, the temperature of the first etherification reaction is preferably 95-102°C, more preferably 100°C, and the time of the first etherification reaction is preferably 18-25h, more preferably 20h; when isobutanol is used as the solvent, the temperature of the first etherification reaction is preferably 108-110°C, more preferably 109°C, and the time of the first etherification reaction is preferably 10-15h, more preferably 12h; when n-butanol is used as the solvent, the temperature of the first etherification reaction is preferably 115-120°C, more preferably 118°C, and the time of the first etherification reaction is preferably 6-10h, more preferably 8h.

[0085] In the present application, the second separation and purification preferably comprises: solid-liquid separation of the first etherification reaction liquid obtained from the first etherification, hot mixing of the obtained solid crude product with an alcohol solvent and activated carbon, solid-liquid separation after activated carbon adsorption decolorization, cooling crystallization of the obtained liquid component, drying of the obtained crystal after alcohol washing, to obtain fenofibrate. In the present application, the alcohol solvent and the alcohol used for washing are independently preferably one or more of isopropyl alcohol, n-propanol, isobutanol, more preferably isopropyl alcohol, n-propanol or isobutanol. In the present application, the temperature of the hot mixing is preferably 60-75°C, more preferably 65-70°C. In the present application, the mass ratio of the solid crude product (dry weight) to activated carbon is preferably 1:0.01-0.1, more preferably 1:0.01-0.02. In the present application, the temperature of the activated carbon adsorption decolorization is preferably 60-75°C, more preferably 65-70°C; and the time of the activated carbon adsorption decolorization is preferably 15-30min, more preferably 20-25min. In the present application, the starting temperature of the cooling crystallization is preferably 60-75°C, more preferably 65-70°C; the final temperature of the cooling crystallization is preferably 0-5°C, more preferably 2-3°C; and the cooling rate of the cooling crystallization is preferably 0.1-0.3°C / min, more preferably 0.1-0.2°C / min. In the present application, the temperature of the drying is preferably 50-55°C, more preferably 50°C; and the time of the drying is not particularly limited in the present application, and the drying can be performed until the weight is constant.

[0086] After obtaining the impurity compound IV, the impurity compound IV, isopropyl 2-bromoisobutyrate, an alkaline reagent and an alcohol solvent are mixed to perform a second etherification reaction, followed by a third separation and purification to obtain the impurity compound VI.

[0087] In the present application, the conditions of the second etherification reaction (i.e. the preparation conditions of the second etherification reaction solution) are only different from the conditions of the first etherification reaction (i.e. the preparation conditions of the first etherification reaction solution) in that the compound II is replaced by the impurity compound IV, and the conditions of the second etherification reaction are not described here again.

[0088] In the present application, the third separation and purification preferably comprises: mixing the second etherification reaction solution obtained from the second etherification reaction with water, then performing solid-liquid separation, washing the obtained solid component with water, and then drying to obtain the impurity compound VI. The present application does not have special limitations on the quality of the water used for mixing, and the water is added to the solid material until the addition no longer increases. In the present application, the solid-liquid separation is preferably filtration. The present application does not have special limitations on the water washing, and the water washing is performed until neutral. In the present application, the temperature of the drying is preferably 50-55°C, and more preferably 50°C. The present application does not have special limitations on the time of the drying, and the drying is performed until the constant weight.

[0089] The technical solutions in the present application will be described clearly and completely below in combination with the embodiments in the present application. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative labor fall within the protection scope of the present application.

[0090] Embodiment 1

[0091] Into a round-bottom flask, 800 mL of toluene, 74 g of anisole and 100 g of 4-chlorobenzoyl chloride were added, and the flask was cooled to -20 to -10°C. Then, 152 g of aluminum chloride was added to the flask, and stirred at -20 to -10°C. The temperature was heated to 80 to 90°C, and reacted for 3 h. After adding water and mixing, a first liquid component and a first solid component were obtained by filtration. The first solid component was washed with water until neutral, and then washed with a 5% NaHCO3 aqueous solution. Then, the first solid component was dried at 75°C until the constant weight to obtain compound II (123.6 g, yield 93%).

[0092] The mass spectrum of compound II is shown in Figure 1 , the hydrogen spectrum is shown in Figure 2 , the carbon spectrum is shown in Figure 3 , the infrared spectrum is shown in Figure 4 , and it can be known from Figures 1 to 4 that compound II is successfully prepared.

[0093] The HPLC spectrum of compound II is shown in Figure 5 and Table 1:

[0094] Table 1: Peak information of the HPLC spectrum of compound II

[0095] Peak No. Retention Time Area Height Area % 1 9.457 11916147 538395 99.563 2 18.635 17851 465 0.149 3 30.303 34397 649 0.287 Total 11968394 539509 100.000

[0096] From Figure 5 As shown in Table 1, the purity of compound II is 99.56%, and the mass percentage of impurity compound IV and impurity compound V in the product is 0.15% and 0.29%, respectively.

[0097] Example 2

[0098] A round-bottom flask was charged with 8 L of toluene, 740 g of anisole, and 1000 g of 4-chlorobenzoyl chloride, and cooled to -20 to -10 °C. 1520 g of aluminum chloride was added to the flask, and stirred at -20 to -10 °C, heated to 80 to 90 °C for 4 h, and filtered after mixing with water, to obtain a first liquid component and a first solid component. The first solid component was washed with water to neutral, and then washed with a 5% NaHCO3 aqueous solution, and then dried at 75 °C to constant weight to obtain compound II (1.23 kg, yield 92.5%).

[0099] The HPLC spectrum of compound II is shown in Figure 6 and Table 2:

[0100] Table 2 HPLC spectrum peak information of compound II

[0101] Peak No. Retention Time Area Height Area % 1 9.447 11932566 536505 99.732 2 18.654 6491 195 0.054 3 30.300 25562 516 0.214 Total 11964619 537216 100.000

[0102] From Figure 6 As shown in Table 2, the purity of compound II is 99.73%, and the mass percentage of impurity compound IV and impurity compound V is 0.05% and 0.21%, respectively.

[0103] Example 3

[0104] A round-bottom flask was charged with 800 mL of toluene, 80.3 g of anisole, and 100 g of 4-chlorobenzoyl chloride, and cooled to -20 to -10 °C. 160 g of aluminum chloride was added to the flask, and stirred at -20 to -10 °C, heated to 80 to 90 °C for 5 h, and filtered after mixing with water, to obtain a first liquid component and a first solid component. The first solid component was washed with water to neutral, and then washed with a 5% NaHCO3 aqueous solution, and then dried at 75 °C to constant weight, to obtain compound II (117 g, yield 88%).

[0105] The HPLC spectrum of compound II is shown in Figure 7 and Table 3:

[0106] Table 3 HPLC spectrum peak information of compound II

[0107] Peak No. Retention Time Area Height Area % 1 5.489 4111 342 0.033 2 9.215 12287499 629969 99.196 3 23.864 24672 594 0.199 4 29.632 70805 1376 0.572 Total 12387087 632282 100.000

[0108] By Figure 7 As shown in Table 3, the purity of compound II is 99.2%, and the mass percentage of impurity compound IV and impurity compound V in the product is 0.2% and 0.57%, respectively.

[0109] Example 4

[0110] Into a round bottom flask, 800 mL of toluene, 86.5 g of anisole and 100 g of 4-chlorobenzoyl chloride were added, and the flask was cooled to -20 to -10°C. Then, 167.6 g of aluminum chloride was added into the flask, and stirred at -20 to -10°C. The temperature was heated to 80 to 90°C, and reacted for 5 h. After mixing with water, the first liquid component and the first solid component were obtained by filtration. The first solid component was washed with water to neutral, and then washed with 5% NaHCO3 aqueous solution. Then, the first solid component was dried at 75°C until the weight was constant, and compound II (106.35 g, yield 80%) was obtained.

[0111] The HPLC spectrum of compound II is shown in Figure 8 and Table 4:

[0112] Table 4: Peak information of HPLC spectrum of compound II

[0113] Peak No. Retention Time Area Height Area % 1 2.153 837 121 0.007 2 5.499 3128 239 0.025 3 9.229 12489875 568921 99.442 4 23.616 24894 591 0.198 5 29.438 41176 804 0.328 Total 12559911 570675 100.00

[0114] By Figure 8 As shown in Table 4, the purity of compound II is 99.44%, and the mass percentage of impurity compound IV and impurity compound V in the product is 0.2% and 0.33%, respectively.

[0115] Example 5

[0116] 100 mL of n-propanol, 20 g of compound II prepared in Example 2, 17.8 g of K2CO3 and 32.4 g of isopropyl 2-bromoisobutyrate were mixed uniformly, and heated to 95 to 102°C for 24 h. After mixing with water, the solid component was filtered, and washed with water. Then, the solid component was dried at 50°C until the weight was constant, and non-fibrate crude product (27.8 g, yield 89.63%) was obtained.

[0117] The HPLC spectrum of non-fibrate crude product is shown in Figure 9 and Table 5:

[0118] Table 5: Peak information of HPLC spectrum of non-fibrate crude product

[0119] Peak No. Retention Time Area Height Area % 1 3.089 9805 1907 0.062 2 9.743 15753762 1367711 99.878 3 13.806 9482 670 0.060 Total 15778049 1370288 100.000

[0120] By Figure 9 As shown in Table 5, the purity of non-fibrate crude product is 99.88%. As shown in Table 5, the purity of non-fibrate crude product is 99.88%.

[0121] Example 6

[0122] To 100 mL of isobutanol, 20 g of compound II prepared in Example 2, 21.35 g of K2CO3 and 39.6 g of isopropyl 2-bromoisobutyrate were heated to 108-110 °C for 10 h, mixed with water, filtered, and the solid component obtained was washed with water and dried at 50 °C to constant weight to obtain crude fenofibrate (27.3 g, yield 88.01 %).

[0123] The HPLC profile of crude fenofibrate is shown in Figure 10 and Table 6:

[0124] Table 6: Peak information of HPLC profile of crude fenofibrate

[0125] Peak No. Retention Time Area Height Area % 1 5.947 1314 190 0.008 2 6.575 4807 609 0.030 3 9.81 16194202 1427754 99.817 4 13.366 23510 1638 0.145 Total 16223832 1430192 100.000

[0126] From Figure 10 and Table 6, it is known that the purity of crude fenofibrate is 99.82 %.

[0127] Example 7

[0128] To 100 mL of n-butanol, 20 g of compound II prepared in Example 2, 17.8 g of K2CO3 and 36 g of isopropyl 2-bromoisobutyrate were heated to 115-120 °C for 7 h, mixed with water, filtered, and the solid component obtained was washed with water and dried at 50 °C to constant weight to obtain crude fenofibrate (26.2 g, yield 84.47 %).

[0129] The HPLC profile of crude fenofibrate is shown in Figure 11 and Table 7:

[0130] Table 7: Peak information of HPLC profile of crude fenofibrate

[0131] Peak No. Retention Time Area Height Area % 1 3.559 1057 162 0.010 2 9.482 10613018 955775 98.747 3 12.719 115157 8135 1.071 4 13.359 18489 1242 0.172 Total 10747721 965314 100.000

[0132] From Figure 11 and Table 7, it is known that the purity of crude fenofibrate is 98.75 %.

[0133] Example 8

[0134] To 120 mL of isopropyl alcohol, 20 g of crude fenofibrate prepared in Example 7 were heated to 70 °C, decolored with activated carbon and filtered, the filtrate was cooled to 0-5 °C at a rate of 0.1 °C / min, filtered, and the solid component obtained was washed with isopropyl alcohol and dried at 50 °C to constant weight to obtain pure fenofibrate (18.1 g, yield 90.5 %).

[0135] The HPLC profile of pure fenofibrate is shown in Figure 12 and Table 8:

[0136] Table 8 HPLC spectrum peak information of fenofibrate pure product

[0137] Peak No. Retention Time Area Height Area % 1 7.356 1184 132 0.008 2 9.353 14944058 1369154 99.949 3 13.148 6479 362 0.043 Total 14951720 1369648 100.000

[0138] From Figure 12 and Table 8, the purity of the fenofibrate pure product is 99.95%.

[0139] Example 9

[0140] The toluene layer of the first liquid component obtained in Example 2 is 8 L, and is concentrated to 1 L by rotary evaporation at 50°C. 10 L of ethyl acetate-n-hexane mixed solvent (ethyl acetate:n-hexane volume ratio = 1:4) is added to the concentrated solution of impurity compound IV, and the mixture is stirred to dissolve at 50-60°C. The mixture is naturally cooled to room temperature, filtered, and the second liquid component and the second solid component are obtained. The second solid component is washed with ethyl acetate-n-hexane mixed solvent (ethyl acetate:n-hexane volume ratio = 1:4), and dried to constant weight at 50°C to obtain impurity compound IV (0.5 g, purity 99.36%).

[0141] The LC-MS identification of impurity compound IV is shown in Figure 13 The M / Z peak of impurity compound IV is 232.9.

[0142] The hydrogen spectrum of impurity compound IV is shown in Figure 14 The carbon spectrum is shown in Figure 15 The infrared spectrum is shown in Figure 16 It can be seen from Figures 13 to 16 that impurity compound IV is successfully prepared.

[0143] Example 10

[0144] The second liquid component obtained in Example 9 is concentrated to 500 mL by rotary evaporation at 50°C, and 5 L of ethyl acetate-cyclohexane mixed solvent (ethyl acetate:cyclohexane volume ratio = 1:1) is added to the mixture, which is stirred to dissolve at 50-60°C. The mixture is then naturally cooled to room temperature, filtered, and the obtained solid component is washed with ethyl acetate-cyclohexane mixed solvent (ethyl acetate:cyclohexane volume ratio = 1:1), and dried to constant weight at 40°C to obtain impurity compound V (1.8 g, purity 99.84%).

[0145] The LC-MS identification of impurity compound V is shown in Figure 17 It can be seen from Figure 17 that the M / Z peak of impurity compound V is 231.0.

[0146] The hydrogen spectrum of impurity compound V is shown in Figure 18 The carbon spectrum is shown in Figure 19The infrared spectrum is shown in Figure 1. Figure 20 The infrared spectrum is shown in Figure 1. Figures 17 to 20 It can be seen that the impurity compound V is successfully prepared.

[0147] Example 11

[0148] In a round bottom flask, 100 mL of n-propanol, 20 g of the impurity compound IV prepared in Example 9, 17.8 g of K2CO3 and 39.6 g of isopropyl 2-bromoisobutyrate were added, and the reaction liquid was heated to 95-102°C for 25 h. The n-propanol was removed by distillation, water was added for mixing, and the solid component obtained was washed with water and dried at 50°C until the weight was constant, to obtain 25 g of the impurity compound VI (yield 80.6%, purity 99.9%).

[0149] The mass spectrum of the impurity compound VI is shown in Figure 1. Figure 21 The hydrogen spectrum is shown in Figure 1. Figure 22 The carbon spectrum is shown in Figure 1. Figure 23 The infrared spectrum is shown in Figure 1. Figure 24 The infrared spectrum is shown in Figure 1. Figures 21 to 24 It can be seen that the impurity compound VI is successfully prepared.

[0150] Example 12

[0151] In a round bottom flask, 100 mL of n-propanol, 20 g of the impurity compound IV prepared in Example 9, 17.8 g of K2CO3 and 39.6 g of isopropyl 2-bromoisobutyrate were added, and the reaction liquid was heated to 95-102°C for 25 h. The n-propanol was removed by distillation, water was added for mixing, and the solid component obtained was washed with water and dried at 50°C until the weight was constant, to obtain 25 g of the impurity compound VI (yield 80.6%, purity 99.9%).

[0152] The HPLC spectrum of the pure fenofibrate is shown in Figure 1. Figure 25 and Table 9:

[0153] Table 9: Peak information of the HPLC spectrum of the pure fenofibrate

[0154] Peak No. Retention Time Area Height Area % 1 7.352 1067 122 0.007 2 9.348 14938405 1371786 99.971 3 13.134 3273 166 0.022 Total 14962745 1372074 100.000

[0155] The HPLC spectrum of the pure fenofibrate is shown in Figure 1. Figure 25 and Table 9: The purity of the pure fenofibrate is 99.97%.

[0156] Example 13

[0157] To a round bottom flask was added 100 mL of n-propanol, 20 g of compound II prepared in example 2, 17.8 g of K2CO3 and 39.6 g of 2-bromo isobutyl isopropyl ester, heated to 95-102 °C for 25 h, after completion of the reaction, the reaction mass was cooled to 70-80 °C, toluene was added and the undissolved salts were filtered, then the toluene was distilled completely under vacuum at below 60 °C, then it was taken in 150 mL of isopropanol, heated to 70 °C to dissolve the solid, cooled to 0-5 °C at a rate of 0.1 °C / min to crystallize, filtered, the crystals obtained were washed with isopropanol, dried at 50 °C to constant weight to obtain pure fenofibrate (25.8 g, yield 83.18 %).

[0158] The HPLC profile of pure fenofibrate is shown in Figure 26 and table 10:

[0159] Table 10: Peak information of HPLC profile of pure fenofibrate

[0160] Peak No. Retention Time Area Height Area % 1 3.036 1071 224 0.007 2 9.297 14843694 1357210 99.993 Total 14844765 1357435 100.000

[0161] From Figure 26 and table 10, it is evident that the purity of pure fenofibrate is 99.99 %.

[0162] The above description is only preferred embodiments of the present application, it should be noted that for those skilled in the art, without departing from the principles of the present application, can make a number of improvements and refinements, these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A process for the preparation of fenofibrate and its impurities, characterized in that, The method comprises the following steps: (1) mixing 4-chlorobenzoyl chloride, anisole, a Lewis acid and a benzene solvent to perform a Friedel-Crafts acylation reaction, then performing a demethylation reaction and first separation and purification to obtain compound II; The molar ratio of the 4-chlorobenzoyl chloride, the anisole and the Lewis acid is 1:1.2:2; The benzene solvent is toluene; The Lewis acid is AlCl3; The demethylation reagent used in the demethylation reaction is AlCl3; The temperature of the Friedel-Crafts acylation reaction is -20 to -10℃; The temperature of the demethylation reaction is 80 to 90℃, and the time is 3h or 4h; The first separation and purification comprises: (a) mixing the demethylation reaction liquid obtained by the demethylation reaction with water, and then performing solid-liquid separation to obtain a first liquid component and a first solid component; (b) sequentially performing water washing, alkaline solution washing and drying on the first solid component to obtain compound II; (2) mixing the compound II, isopropyl 2-bromoisobutyrate, an alkaline reagent and an alcohol solvent to perform a first etherification reaction, and then performing second separation and purification to obtain fenofibrate; the alkaline reagent comprises one or more of potassium carbonate and potassium bicarbonate; When n-propanol is used as the solvent, the temperature of the first etherification reaction is 95 to 102℃, and the time is 20 to 24h; When isobutanol is used as the solvent, the temperature of the first etherification reaction is 108 to 110℃, and the time is 10 to 15h; The second separation and purification comprises: performing solid-liquid separation on the first etherification reaction liquid obtained by the first etherification reaction, mixing the obtained solid crude product with an alcohol solvent and activated carbon, performing activated carbon adsorption decolorization and then performing solid-liquid separation, performing cooling crystallization on the obtained liquid component, performing alcohol washing on the obtained crystals and then performing drying to obtain fenofibrate; the alcohol solvent and the alcohol washing alcohol independently comprise one or more of isopropyl alcohol, n-propanol and isobutanol; the temperature of the hot mixing is 60 to 75℃; the starting temperature of the cooling crystallization is 60 to 75℃, the final temperature is 0 to 5℃, and the cooling rate is 0.1 to 0.3℃ / min; 2. The production method according to claim 1, characterized by, The molar ratio of the compound II, isopropyl 2-bromoisobutyrate and the alkaline reagent is 1:1.8 to 2.2:1.5 to 1.8.

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