Preparation method of bepiridic acid

Abstract

The invention discloses a preparation method of bepiridic acid, and belongs to the technical field of organic synthesis. The method comprises the following steps: by taking acetone and 4-chlorobutanol as raw materials, generating 1, 9-dichloro-5-carbonyl nonane under the action of a palladium catalyst, nickel bromide, TMEDA and alkali; the preparation method comprises the following steps: carrying out carbonyl protection on 1, 9-dichloro-5-carbonyl nonane, carrying out a reaction on the 1, 9-dichloro-5-carbonyl nonane and 2-methylpropionitrile by using a lithium reagent, and carrying out nitrile group hydrolysis and deprotection to generate 8-carbonyl-2, 2, 14, 14-tetramethyl pentadecanedioic acid; and reducing the 2, 8-carbonyl-2, 2, 14, 14-tetramethyl pentadecanedioic acid to generate a target product, i.e., the bepidioic acid. The route is overall reasonable and is carried out in five steps, 1, 9-dichloro-5-carbonyl nonane is generated through key acetone and 4-chlorobutanol under the combined action of the palladium catalyst and the nickel catalyst, the reaction yield is high, and a concise, effective and brand-new route is provided for preparation of bepiridic acid.

Description

Technical Field

[0001] The invention relates to a method for preparing bepedic acid, and belongs to the technical field of organic synthesis. Background Art

[0002] Bepedic acid (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a new lipid-lowering drug with a new mechanism of action. It targets cholesterol synthesis by inhibiting ATP citrate lyase, helping to reduce the risk of cardiovascular disease in patients. Bepedic acid was approved by the U.S. Food and Drug Administration (FDA) in February 2020 for adults with heterozygous familial hypercholesterolemia or ASCVD.

[0003] There are relatively many methods for synthesizing bepedic acid, and representative routes include: [CN109721486A; CN113233975A; CN111170855A] using 8-carbonyl-2,2,14,14-tetramethylpentadecanedioic acid as a raw material, and obtaining the product bepedic acid through a reduction reaction. The chemical reaction equation is as follows:

[0004]

[0005] Patent [CN113735701A] uses 3-carbonyl glutaric acid dimethyl ester or 3-carbonyl glutaronitrile to react with 6-halogenated-2,2-dimethyl n-hexanenitrile to generate 8-carbonyl-2,2,14,14-tetramethylpentadecanedioic acid after multiple steps of reaction. The chemical reaction equation is as follows:

[0006]

[0007] Patent [CN116120163A] uses 5-bromo-1-pentene, 1,6-dibromohexane and ethyl 2-methylpropionate as raw materials to prepare bepedic acid through multi-step reactions. The chemical reaction equation is as follows:

[0008]

[0009] Patent [CN114907204A] uses 1,5-valerolactone as the starting material, generates 1,7-dioxa[5.5]undecane under the action of sodium ethoxide, and obtains 1,9-dibromo-5-carbonylnonane through bromination reaction. After carbonyl protection, 1,9-dibromo-5-carbonylnonane reacts with 3,3-dimethyloxacyclobutane-2-one through Grignard reaction. The product is deprotected and reduced to obtain the target compound bepedic acid. The chemical reaction equation is as follows:

[0010]

[0011] In view of the defects of the above-mentioned technical routes, it is necessary to conduct in-depth research on the synthesis route of bepedic acid to provide a better, easy-to-obtain raw material, simple, safe, stable and economical process route to meet the growing market demand. Summary of the invention

[0012] In order to overcome the above technical defects, the present invention provides a method for preparing bepedic acid. Acetone and 4-chlorobutanol are used as raw materials, and 1,9-dichloro-5-carbonylnonane is generated under the action of palladium catalyst, nickel bromide, TMEDA and base; after the carbonyl protection of 1,9-dichloro-5-carbonylnonane, a lithium reagent is used to react with 2-methylpropionitrile, and then the nitrile group is hydrolyzed and deprotected to generate 8-carbonyl-2,2,14,14-tetramethylpentadecanedioic acid; 8-carbonyl-2,2,14,14-tetramethylpentadecanedioic acid is reduced to generate the target product bepedic acid. The route of the present invention is reasonable as a whole, and is carried out in five steps, which provides a simple and effective new route for the preparation of bepedic acid.

[0013] The preparation method of bepedic acid described in the present invention is represented by the following reaction equation:

[0014] The steps include:

[0015] A. Acetone, 4-chlorobutanol, palladium carbon catalyst (5% Pd), nickel bromide, TMEDA and potassium tert-butoxide are mixed in an organic solvent and reacted under elevated temperature to generate 1,9-dichloro-5-carbonylnonane;

[0016] B. Mix 1,9-dichloro-5-carbonylnonane, ethylene glycol, p-toluenesulfonic acid and pyridine in toluene and react under elevated temperature to obtain ethylene glycol-protected 1,9-dichloro-5-carbonylnonane;

[0017] C. Mix 2-methylpropionitrile and tetrahydrofuran, add n-butyl lithium at low temperature, then add ethylene glycol to protect 1,9-dichloro-5-carbonylnonane, and then acid hydrolyze to obtain 8-carbonyl-2,2,14,14-tetramethylpentadecanedinitrile;

[0018] D. Mixing 8-carbonyl-2,2,14,14-tetramethylpentadecanedionitrile and trimethylsilyl chloride in alcohol and reacting them under elevated temperature to generate 8-carbonyl-2,2,14,14-tetramethylpentadecanedioate;

[0019] E. 8-Carbonyl-2,2,14,14-tetramethylpentadecanedioate is reduced in the presence of sodium borohydride and then hydrolyzed to produce bepedic acid.

[0020] Furthermore, in the above step A, the organic solvent is toluene, xylene or chlorobenzene.

[0021] Furthermore, in the above step A, the molar ratio of acetone, 4-chlorobutanol, palladium-carbon catalyst, nickel bromide, TMEDA and base is 1:2.4-2.8:0.002-0.005:0.02-0.05:0.02-0.05:1-1.2.

[0022] Furthermore, in the above step B, the molar ratio of 1,9-dichloro-5-carbonylnonane, ethylene glycol, p-toluenesulfonic acid and pyridine is 1:1.05-1.1:0.02-0.04:0.01-0.02.

[0023] Furthermore, in the above step C, the molar ratio of the ethylene glycol-protected-1,9-dichloro-5-carbonylnonane, 2-methylpropionitrile and n-butyl lithium is 1:2-2.1:2.1-2.3.

[0024] Furthermore, in the above step D, the alcohol is selected from methanol or ethanol.

[0025] Furthermore, in the above step D, the molar ratio of the 8-carbonyl-2,2,14,14-tetramethylpentadecanedinitrile to trimethylchlorosilane is 1:4-4.2.

[0026] Furthermore, in the above step E, the molar ratio of the 8-carbonyl-2,2,14,14-tetramethylpentadecanedioate to sodium borohydride is 1:1-2.

[0027] Furthermore, in the above step E, the reduction reaction is carried out in methanol.

[0028] Compared with the synthesis method reported in the literature, the present invention has the following beneficial effects:

[0029] 1. Acetone and 4-chlorobutanol are used to generate 1,9-dichloro-5-carbonylnonane under the action of palladium catalyst and nickel catalyst. The reaction yield is high, the operation is simple, and the route is novel.

[0030] 2. Using trimethylsilyl chloride and alcohol to directly convert the nitrile group into an ester is a novel and feasible route that avoids the use of large amounts of acid or base to hydrolyze the nitrile group at high temperature.

[0031] 3. The raw materials of this process are easily available in the market, the process is simple, safe and stable, and is suitable for industrial scale expansion. Specific embodiments

[0032] The present invention will be further described below by specific examples. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0033] Example 1

[0034] Under nitrogen protection, 5.8 g (0.1 mol) of acetone, 28.2 g (0.26 mol) of 4-chlorobutanol, 0.64 g (5% palladium carbon catalyst), 0.66 g (0.003 mol) of nickel bromide, 0.35 g (0.003 mol) of TMEDA and 1.2 g (0.011 mol) of potassium tert-butoxide were mixed in 200 mL of toluene, heated to 60-65 ° C, reacted for 5 hours, cooled to room temperature, filtered, and the filtrate was washed twice with 60 mL of water. The organic layer was concentrated and distilled under reduced pressure to obtain 1,9-dichloro-5-carbonylnonane, 19.4 g, with a yield of 81% and a GC of 99.0%.

[0035] Example 2

[0036] 23.9 g (0.1 mol) of 1,9-dichloro-5-carbonylnonane, 6.6 g (0.106 mol) of ethylene glycol, 0.57 g (0.003 mol) of p-toluenesulfonic acid and 0.12 g (0.0015 mol) of pyridine were mixed in 360 mL of toluene, reacted for 5 hours under reflux, cooled to room temperature, and the reaction solution was washed twice with 90 mL of water. The organic layer was concentrated and distilled under reduced pressure to obtain ethylene glycol-protected 1,9-dichloro-5-carbonylnonane, 25.5 g, with a yield of 90% and a GC of 98.6%.

[0037] Example 3

[0038] Under nitrogen protection, 14.2 g (0.205 mol) of 2-methylpropionitrile and 90 mL of tetrahydrofuran were mixed, the temperature was controlled below -20 ° C, and 1.6 M n-butyl lithium solution 134.5 mL was slowly added dropwise. After the addition was completed, ethylene glycol was added to protect 1,9-dichloro-5-carbonylnonane 28.3 g (0.1 mol) and reacted for 6 hours. The reaction system was controlled below 10 ° C, and 50% trifluoroacetic acid aqueous solution was added for hydrolysis. The pH was controlled to be <1, and then the temperature of the reaction system was raised to 80 ° C for 6 hours. The reaction was cooled to room temperature and the layers were separated. The organic layer was washed with a saturated sodium bicarbonate aqueous solution, and the organic layer was concentrated and distilled under reduced pressure to obtain 8-carbonyl-2,2,14,14-tetramethylpentadecanedinitrile, 22.2 g, with a yield of 73%, and GC98.3%.

[0039] Example 4

[0040] Under nitrogen protection, 15.2 g (0.05 mol) of 8-carbonyl-2,2,14,14-tetramethylpentadecanedinitrile and 22.3 g (0.21 mol) of trimethylsilyl chloride were mixed in 100 mL of ethanol, heated to 60-65 ° C, reacted for 6 hours, cooled to room temperature, added with saturated sodium carbonate aqueous solution, adjusted to pH = 8-9, added with 80 mL of dichloromethane and extracted twice, the organic layer was concentrated, purified by column chromatography, ethyl acetate / n-hexane (v / v = 1 / 11), and 8-carbonyl-2,2,14,14-tetramethylpentadecanediethyl ester was obtained, 13.5 g, yield 73%, HPLC 98.2%. 1 HNMR (400MHz, CDCl 3 ):4.13(t,4H),2.40(t,4H),1.46-1.57(m,8H),1.12-1.36(m,8H),1.26(t,6H),1.16(s,12H).

[0041] Example 5

[0042] Under nitrogen protection, 18.5 g (0.05 mol) of 8-carbonyl-2,2,14,14-tetramethylpentadecanedioate was mixed with 160 mL of methanol, the temperature was controlled to be less than 0°C, 2.3 g (0.06 mol) of sodium borohydride was slowly added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, 2 M aqueous sodium hydroxide solution was added to adjust the pH to 11-12, and then the temperature was raised to 40-45°C for 8 hours, and the mixture was cooled to room temperature, 1 M hydrochloric acid was added to adjust the pH to 2-3, and the mixture was extracted three times with 80 mL of dichloromethane, concentrated, and slurried with methyl tert-butyl ether and heptane (1 / 5) to obtain 14.3 g of white solid bepedic acid with a yield of 83% and an HPLC yield of 99.7%. 1 HNMR (400MHz, CDCl 3 ):7.44(s,3H),3.59(s,1H),1.02-1.64(m,20H),1.20(s,12H).

[0043] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing bepedic acid, characterized in that: The steps include: A. Acetone, 4-chlorobutanol, palladium-carbon catalyst, nickel bromide, TMEDA and potassium tert-butoxide are mixed in an organic solvent and reacted under elevated temperature to generate 1,9-dichloro-5-carbonylnonane; B. Mix 1,9-dichloro-5-carbonylnonane, ethylene glycol, p-toluenesulfonic acid and pyridine in toluene and react under elevated temperature to obtain ethylene glycol-protected 1,9-dichloro-5-carbonylnonane; C. Mix 2-methylpropionitrile and tetrahydrofuran, add n-butyl lithium at low temperature, then add ethylene glycol to protect 1,9-dichloro-5-carbonylnonane, and then acid hydrolyze to obtain 8-carbonyl-2,2,14,14-tetramethylpentadecanedinitrile; D. Mixing 8-carbonyl-2,2,14,14-tetramethylpentadecanedionitrile and trimethylsilyl chloride in alcohol and reacting them under elevated temperature to generate 8-carbonyl-2,2,14,14-tetramethylpentadecanedioate; E. 8-Carbonyl-2,2,14,14-tetramethylpentadecanedioate is reduced in the presence of sodium borohydride and then hydrolyzed to produce bepedic acid.

2. The method for preparing bepedic acid according to claim 1, characterized in that: In step A, the organic solvent is toluene, xylene or chlorobenzene.

3. The method for preparing bepedic acid according to claim 1, characterized in that: In step A, the molar ratio of acetone, 4-chlorobutanol, palladium-carbon catalyst, nickel bromide, TMEDA and base is 1:2.4-2.8:0.002-0.005:0.02-0.05:0.02-0.05:1-1.

2.

4. The method for preparing bepedic acid according to claim 1, characterized in that: In step B, the molar ratio of 1,9-dichloro-5-carbonylnonane, ethylene glycol, p-toluenesulfonic acid and pyridine is 1:1.05-1.1:0.02-0.04:0.01-0.

02.

5. The method for preparing bepedic acid according to claim 1, characterized in that: In step C, the molar ratio of the ethylene glycol-protected 1,9-dichloro-5-carbonylnonane, 2-methylpropionitrile and n-butyl lithium is 1:2-2.1:2.1-2.

3.

6. The method for preparing bepedic acid according to claim 1, characterized in that: In step D, the alcohol is selected from methanol or ethanol.

7. The method for preparing bepedic acid according to claim 1, characterized in that: In step E, the molar ratio of 8-carbonyl-2,2,14,14-tetramethylpentadecanedioate to sodium borohydride is 1:1-2.

8. The method for preparing bepedic acid according to claim 1, characterized in that: In step E, the reduction reaction is carried out in methanol.

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