Process for the preparation of a phenopicolinic acid intermediate and the intermediate thereof

Abstract

The application discloses a preparation method of a phenopicolinic acid intermediate and the intermediate. The preparation method comprises the following steps: under the action of an alkali, compound 2 is reacted with 1,3-propanedione dicarboxylic acid diethyl ester in a solvent to obtain compound 3 as shown in the figure. The intermediate involved in the preparation method is protected by triphenylmethyl, can be purified through recrystallization, has high yield, the reagent used is safe, the operation is simple, the production cost is low, the yield and purity of the obtained product are high, and the method is beneficial to industrial mass production.

Description

TECHNICAL FIELD

[0001] The present application relates to a preparation method of a bempedoic acid intermediate and the intermediate thereof. BACKGROUND

[0002] Bempedoic acid is a new small molecule compound developed by Esperion Therapeutic Company in the United States for the treatment of dyslipidemia and the reduction of other cardiovascular disease risks. The advantage of bempedoic acid over the statins widely used in the clinic is that it has better tolerance, and can be used in combination with statins for the treatment of LDL-C that cannot be controlled by existing methods. Bempedoic acid is the first non-statin oral cholesterol-lowering drug approved by FDA in the past 20 years, and its structural formula is as follows:

[0003]

[0004] The synthesis method of bempedoic acid reported in WO2004067489 is shown in Scheme 1:

[0005]

[0006] The second step of the process uses p-tolylsulfonylmethyl isocyanate, which is toxic and has poor atom economy, and uses the hazardous chemical sodium hydride. Sodium hydride can spontaneously ignite in moist air, and when heated or in contact with moisture or acids, it releases heat and hydrogen gas, causing combustion and explosion, which is not conducive to industrial production operation. The third step of hydrolysis will produce potential genotoxic impurity A (p-tolylsulfonyl derivative), which is not conducive to the quality control of the drug substance. In addition, the purification of intermediate compound 3 also needs to use column chromatography. The yield of each reaction is low, and the reaction conditions are harsh, so this route is not suitable for industrial mass production.

[0007] The synthesis method reported in CN111170855A is shown in Scheme 2:

[0008]

[0009] This route uses isobutyrate as the starting material, which is subjected to alkylation with 1,4-dihalogenated alkane to obtain compound 1; compound 1 is then subjected to condensation with acetonedicarboxylic acid diester to obtain compound 2; then compound 2 is subjected to alkaline hydrolysis in an ethanol system and acidification to obtain compound 3; finally, sodium borohydride reduction is performed to obtain bempedoic acid. The second step of condensation reaction in this route has selectivity and multiple substitution problems, resulting in low reaction yield. Therefore, this route has problems such as low total yield and harsh reaction conditions.

[0010] The synthesis method reported in CN111825546A is shown in Scheme 3:

[0011]

[0012] WO2020141419 reported 4 synthetic methods, the second method also used toxic reagent p-methylbenzenesulfonylmethyl isocyanate, the fourth method was similar to CN111170855A. The first and third synthetic methods are shown in Scheme 4 and Scheme 5, respectively:

[0013]

[0014]

[0015] Both Route 4 and Route 5 need to use 6-bromo-2,2-dimethylhexanoate, which needs to be purified by rectification.

[0016] Therefore, how to develop a preparation process of phenytoin which is simple and safe in operation, low in production cost, and high in yield and quality is a technical problem to be solved by the present application. SUMMARY

[0017] The technical problem to be solved by the present application is that the preparation method of the phenytoin intermediate in the prior art has defects such as the need for toxic and explosive hazardous reagents, long route, low yield, and unsuitability for industrial mass production, and a preparation method of a phenytoin intermediate and the intermediate thereof are proposed. The intermediate involved in the preparation method of the present application is protected by triphenylmethyl, can be purified by recrystallization, has high yield, uses safe reagents, is simple and safe to operate, low in production cost, high in product yield and purity, and is conducive to industrial mass production.

[0018] The present application solves the above technical problems through the following technical solutions.

[0019] The present application provides a preparation method of compound 3, which comprises the following steps: reacting compound 2 with 1,3-propanedione diethyl ester in a solvent under the action of a base to obtain compound 3 as shown below.

[0020]

[0021] In the preparation method of compound 3, the method and conditions of the reaction can be conventional in the art, and the preferred method and conditions are as follows:

[0022] The solvent is an alcohol solvent, preferably one or more of methanol, ethanol and isopropanol, for example, anhydrous ethanol. The volume molar ratio of the solvent to compound 2 is 2.0-6.0 L / mol, for example, 4.63 L / mol.

[0023] The base is a carbonate of an alkali metal, preferably one or more of cesium carbonate, potassium carbonate and sodium carbonate. The molar ratio of the base to 1,3-acetonedicarboxylic acid diethyl ester is 2.0 to 5.0, for example, 3.58.

[0024] The molar ratio of compound 2 to 1,3-acetonedicarboxylic acid diethyl ester is 1.8 to 2.5, for example, 2.25.

[0025] Preferably, the reaction is carried out in the presence of an iodide. The iodide is preferably an iodide of an alkali metal, for example, sodium iodide and / or potassium iodide. The amount of the iodide used can be a conventional amount used in the art for such a reaction, preferably the molar ratio of the iodide to compound is 0.9 to 1.2, for example, 1.0.

[0026] The reaction temperature of the reaction is 50 to 80°C, for example, 60 to 70°C.

[0027] The progress of the reaction can be monitored by a conventional monitoring method in the art (for example, TLC, HPLC or NMR), and the reaction is generally terminated when the content of 1,3-acetonedicarboxylic acid diethyl ester no longer changes. The reaction time of the reaction is 12 to 15 hours.

[0028] The reaction can further include a post-treatment. The method of the post-treatment is a conventional post-treatment method for such a reaction, and preferably includes the following steps: cooling to room temperature, filtration, washing the filter cake with an alcoholic solvent, concentrating the filtrate, adding acetone and n-hexane in a volume ratio of 1:4 to dissolve the solid at 50 to 60°C, cooling to -10°C, filtering to obtain compound 3.

[0029] The method of preparing compound 3 can further include the following steps: reacting compound 1 with 1,4-dibromobutane in a solvent in the presence of a base to obtain compound 2 as shown below.

[0030]

[0031] In the method of preparing compound 2, the method and conditions of the reaction can be conventional in the art, and preferably the following method and conditions:

[0032] The solvent is an ethereal solvent, preferably tetrahydrofuran and / or diethyl ether, for example, anhydrous tetrahydrofuran. The volume molar ratio of the solvent to compound 1 is 2.0 to 4.0 L / mol, for example, 3.25 L / mol.

[0033] The base is lithium diisopropylamide. The molar ratio of the base to compound 1 is 1.0 to 1.5, for example, 1.20.

[0034] The temperature for adding the base is -10 to 0°C.

[0035] The molar ratio of the 1,4-dibromobutane to the compound 1 is 1.0 to 1.5, for example, 1.20.

[0036] The progress of the reaction can be detected by using conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), and the reaction is generally terminated when the content of the compound 1 is no longer changed. The reaction time is 2 to 5 hours.

[0037] The reaction can further include a post-treatment. The method for the post-treatment is a conventional post-treatment method for such reactions, and preferably includes the following steps: quenching the reaction, separating the liquid, washing the organic phase with saturated brine, concentrating, and adding n-hexane to crystallize the compound 2.

[0038] The method for preparing the compound 3 can further include the following step: performing a condensation reaction of triphenylmethanol and isobutyric acid in a solvent under the action of a condensing agent to obtain the compound 1 as shown below.

[0039]

[0040] In the method for preparing the compound 1, the method and conditions for the reaction can be conventional methods and conditions for performing such reactions in the art, and preferably the following methods and conditions:

[0041] The solvent is a halogenated hydrocarbon solvent, and preferably dichloromethane. The volume-molar ratio of the solvent to triphenylmethanol is 2.0 to 4.0 L / mol, for example, 2.7 L / mol.

[0042] The condensing agent is DIC. The molar ratio of the condensing agent to triphenylmethanol is 1.0 to 1.5, for example, 1.2.

[0043] The temperature for adding the condensing agent is 0 to 10°C.

[0044] The molar ratio of the isobutyric acid to triphenylmethanol is 1.0 to 1.5, for example, 1.1.

[0045] The reaction temperature is room temperature.

[0046] The progress of the reaction can be detected by using conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), and the reaction is generally terminated when the content of the compound 1 is no longer changed. The reaction time is 2 to 5 hours.

[0047] The reaction can further comprise a post-treatment. The post-treatment can be performed by using a conventional post-treatment method for such a reaction, and preferably comprises the following steps: filtration, washing the filtrate with saturated aqueous sodium bicarbonate solution and water in sequence, drying, and concentrating to obtain compound 1.

[0048] The present application also provides a preparation method of compound 4, which comprises the following step: performing a hydrolysis reaction on compound 3 in a solvent under the action of a base to obtain compound 4, as shown in the following formula:

[0049]

[0050] The preparation method of compound 3 in the hydrolysis reaction is as described above.

[0051] In the hydrolysis reaction, the solvent can be a conventional solvent for such a reaction in the art, and preferably a mixed solvent of an alcohol solvent and water. The alcohol solvent is preferably one or more of methanol, ethanol and isopropanol. In the mixed solvent, the volume ratio of the alcohol solvent to water is preferably 1.0-3.0, for example, 2.0. The amount of the solvent can be a conventional amount for such a hydrolysis reaction in the art, and preferably has a volume / mole ratio of 6.0-10.0 L / mol to compound 3, for example, 8.82 L / mol.

[0052] In the hydrolysis reaction, the base can be a conventional base for such a hydrolysis reaction in the art, and preferably a hydroxide of an alkali metal, and more preferably sodium hydroxide and / or potassium hydroxide. The amount of the base can be a conventional amount for such a hydrolysis reaction in the art, and preferably has a mole ratio of 4.0-6.0, for example, 5.0, to compound 3.

[0053] The reaction temperature of the hydrolysis reaction can be a conventional temperature for such a hydrolysis reaction in the art, and preferably heating to reflux in the solvent.

[0054] The progress of the hydrolysis reaction can be detected by using a conventional monitoring method in the art (such as TLC, HPLC or NMR), and generally the reaction endpoint is when the content of compound 3 no longer changes. The reaction time is 1-5 hours.

[0055] The reaction can further comprise a post-treatment. The post-treatment can be performed by using a conventional post-treatment method for such a reaction, and preferably comprises the following steps: removing triphenylmethanol, adjusting the pH of the aqueous phase to 1-2, filtration, dissolving the obtained filter cake with an ether solvent, washing with water, liquid separation, concentrating the organic phase, and recrystallizing with methyl tert-butyl ether and n-hexane in a volume ratio of 1:6.

[0056] Alternatively, the present application provides a preparation method of compound 4, which comprises the following steps:

[0057] (1) the compound 1 can be obtained by condensation reaction of triphenylmethanol and isobutyric acid in a solvent under the action of a condensing agent as shown below;

[0058] (2) the compound 2 can be obtained by reaction of the compound 1 with 1,4-dibromobutane in a solvent under the action of a base as shown below;

[0059] (3) the compound 3 can be obtained by reaction of the compound 2 with 1,3-propanedione diethyl ester in a solvent under the action of a base as shown below;

[0060] (4) the compound 4 can be obtained by hydrolysis reaction of the compound 3 in a solvent under the action of a base as shown below;

[0061]

[0062] The present application provides a phenopicolinic acid intermediate, which has the following structure:

[0063]

[0064] In the present application, the room temperature is -10-35℃, preferably 10-30℃.

[0065] In the present application, the DIC is 1,3-diisopropylcarbodiimide.

[0066] On the basis of not violating the common sense of the art, the above-mentioned preferred conditions can be combined arbitrarily, that is, to obtain each preferred example of the present application.

[0067] The reagents and raw materials used in the present application are commercially available.

[0068] The positive progress effect of the present application is that the obtained intermediate can be purified by recrystallization by adopting triphenylmethyl protection, and the yield is high; the reagents used in the preparation method are safe, the operation is simple, the production cost is low, the yield and purity of the obtained product are high, and it is beneficial to industrialized mass production. DETAILED DESCRIPTION

[0069] Example 1: preparation of compound 1

[0070] Into a three-necked flask was placed 26.0 g (0.1 mol) of triphenylmethanol, 9.68 g (0.11 mol) of isobutyric acid, 270 ml of dichloromethane, and then stirring was started. The temperature was lowered to 0-10 °C, and 13.7 g (0.12 mol) of DIC (1,3-diisopropylcarbodiimide) was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 5-8 hours. TLC showed that the reaction was complete. The solid was filtered off, and the organic phase was washed with 100 ml of saturated aqueous sodium bicarbonate solution and 100 ml of water. The organic phase was concentrated and dried to obtain 31.5 g of triphenylmethyl isobutyrate in the form of a crystalline solid, with a yield of 95.4% and an ESI-MS (m / Z): 331.26 [M+H] + .

[0071] Example 2: Preparation of compound 2

[0072] Into a three-necked flask was placed 26.4 g (0.08 mol) of triphenylmethyl isobutyrate, 20.65 g (0.096 mol) of 1,4-dibromobutane, and 260 ml of tetrahydrofuran. Stirring was started, and the temperature was lowered to -10-0 °C. 48 ml of lithium diisopropylamide (2N, 0.096 mol) was added dropwise while maintaining the temperature at -10-0 °C. After the addition was completed, the mixture was stirred for 2-5 hours. TLC showed that the reaction was complete. 100 ml of water was added to quench the reaction. The pH was adjusted to 6-7 using 2N hydrochloric acid. The organic phase was washed with 50 ml*2 of saturated aqueous sodium chloride solution. The organic phase was concentrated and then 20 ml of n-hexane was added. The mixture was stirred rapidly to obtain 26.4 g of 2,2-dimethyl-6-bromohexanoic acid triphenylmethyl ester in the form of a crystalline solid, with a yield of 70.9%, a HPLC purity of 98.2%, and an ESI-MS (m / Z): 487.23 [M+Na] + ;1H NMR (CDCl3, 400 MHz) δH 7.29 (d, 3H), 7.28 (d, 6H), 7.27 (dd, 6H), 3.53 (t, 2H), 1.83 (m, 2H), 1.64 (t, 2H), 1.30 (m, 2H), 1.28 (s, 6H).

[0073] Example 3: Preparation of compound 3

[0074] Into a three necked flask was placed 25 g (0.054 mol) of 2,2-dimethyl-6- bromohexanoic acid triphenylmethyl ester, followed by the addition of 250 ml of absolute ethanol, 4.8 g (0.024 mol) of diethyl 1,3-propanedioate, 28 g (0.086 mol) of cesium carbonate, 9.0 g (0.054 mol) of potassium iodide. The reaction mixture was heated to 60-70 °C and maintained for 12-15 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and 20 ml of n-hexane was added. The mixture was further concentrated and 20 ml of n-hexane was added. The distillate was transferred to a single necked flask and 30 ml of acetone and 120 ml of n-hexane were added. The mixture was heated to 50 °C and dissolved. The mixture was cooled to -10 °C and stirred for 2 hours. The product, 7,9-diethyl 14,2-di(triphenylmethyl) 2,14-dimethyl-8-oxapentadecane-2,7,9,14-tetraoate, was obtained in 19.4 g (0.020 mol) yield, 83% purity by HPLC and ESI-MS (m / Z): 971.6 [M+H]. + ; 1 HNMR (CDC13, 400 MHz) δH7.29 (d, 6H), 7.28 (d, 12H), 7.27 (dd, 12H), 4.21 (t, 4H), 3.10 (t, 2H), 1.92 (m, 4H), 1.63 (t, 4H), 1.29 (t, 6H), 1.27 (s, 12H), 1.24-1.26 (m, 8H).

[0075] Example 4: Preparation of compound 3

[0076] Into a three necked flask was placed 125 g (0.27 mol) of 2,2-dimethyl-6- bromohexanoic acid triphenylmethyl ester, followed by the addition of 1200 ml of absolute ethanol, 24 g (0.12 mol) of diethyl 1,3-propanedioate, 140 g (0.43 mol) of cesium carbonate, 40.0 g (0.27 mol) of potassium iodide. The reaction mixture was heated to 60-70 °C and maintained for 12-15 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated and 80 ml of n-hexane was added. The mixture was further concentrated and 80 ml of n-hexane was added. The distillate was transferred to a single necked flask and 150 ml of acetone and 600 ml of n-hexane were added. The mixture was heated to 50 °C and dissolved. The mixture was cooled to -10 °C and stirred for 2 hours. The product, 7,9-diethyl 14,2-di(triphenylmethyl) 2,14-dimethyl-8-oxapentadecane-2,7,9,14-tetraoate, was obtained in 19.4 g (0.11 mol) yield, 85% purity by HPLC and ESI-MS (m / Z): 971.6 [M+H]. + .

[0077] Example 5 Preparation of compound 4

[0078] Dissolve 7,9-diethyl 14,2-di(trityl) 2,14-dimethyl-8-oxopentadecane-2,7,9,14- tetraoate 16.5 g (0.017 mol) in 50 ml water, 100 ml ethanol, add sodium hydroxide 3.4 g (0.085 mol) and heat to reflux. After 3 hours, TLC to determine completion of the reaction. Extract with 50 ml*3 n-hexane to recover the trityl alcohol. Adjust the pH of the aqueous phase to 1-2 with 36% concentrated hydrochloric acid, control the temperature at 0-10 °C, stir for 30 minutes, filter, dissolve the filter cake with 30 ml methyl tert-butyl ether, wash with 20 ml purified water, separate the layers, and then concentrate the organic phase to dryness. Recrystallize with methyl tert-butyl ether:n-hexane = 1:6 (V:V) to obtain 8-keto-2,2,14,14-tetramethyl pentadecanedioic acid as a white solid. Yield 5 g (0.014 mol), 82.3% yield. Recover trityl alcohol from the n-hexane phase, 6.5 g. HPLC purity 99.6% (200 nm), ESI-MS (m / Z): 343.25 [M+H] + .

Claims

1. A method for preparing compound 4, comprising the steps of, (1) reacting compound 2 with diethyl 1,3-propanedione dicarboxylate in a solvent in the presence of a base to obtain compound 3, cooling the reaction solution to room temperature, filtering, washing the filter cake with an alcohol solvent, concentrating the filtrate, adding acetone and n-hexane in a volume ratio of 1:4 to dissolve the solid at 50-60°C, cooling to -10°C, filtering the precipitated solid to obtain compound 3; ; (2) hydrolyzing compound 3 obtained in step (1) in a solvent in the presence of a base to obtain compound 4; 。 2. The production method according to claim 1, wherein in step (1), one of the following conditions is satisfied: the solvent is an alcohol solvent; the volume / mole ratio of the solvent to compound 2 is 2.0-6.0 L / mol; the base is an alkali metal carbonate; the mole ratio of the base to diethyl 1,3-propanedione dicarboxylate is 2.0-5.0; the mole ratio of compound 2 to diethyl 1,3-propanedione dicarboxylate is 1.8-2.5; the reaction is carried out in the presence of an iodide; the reaction temperature is 50-80°C.

3. The production method according to claim 2, wherein in step (1), one of the following conditions is satisfied: the solvent is one or more of methanol, ethanol and isopropanol; the base is one or more of cesium carbonate, potassium carbonate and sodium carbonate; the iodide is an alkali metal iodide; the reaction temperature is 60-70°C.

4. The production method according to claim 1, wherein in step (2), one of the following conditions is satisfied: the solvent is a mixed solvent of an alcohol solvent and water; the volume / mole ratio of the solvent to compound 3 is 6.0-10.0 L / mol; the base is an alkali metal hydroxide; the mole ratio of the base to compound 3 is 4.0-6.0; the reaction temperature of the hydrolysis reaction is heating to reflux in the solvent.

5. The production method according to claim 4, wherein in step (2), one of the following conditions is satisfied: the alcohol solvent is one or more of methanol, ethanol and isopropanol; in the mixed solvent, the volume ratio of the alcohol solvent to water is 1.0-3.0; the base is sodium hydroxide / potassium hydroxide.

6. A process for the preparation of compound 4 characterized in that, comprising the steps of, (1) condensing triphenylmethanol and isobutyric acid in a solvent in the presence of a condensing agent to obtain compound 1; (2) reacting compound 1 with 1,4-dibromobutane in a solvent in the presence of a base to obtain compound 2; (3) reacting compound 2 with diethyl 1,3-propanedione dicarboxylate in a solvent in the presence of a base to obtain compound 3, cooling the reaction solution to room temperature, filtering, washing the filter cake with an alcohol solvent, concentrating the filtrate, adding acetone and n-hexane in a volume ratio of 1:4 to dissolve the solid at 50-60°C, cooling to -10°C, filtering the precipitated solid to obtain compound 3; (4) hydrolyzing compound 3 in a solvent in the presence of a base to obtain compound 4; the reaction scheme is as follows: 。

Images