One-pot preparation method of bepedioic acid intermediate

Abstract

The invention provides a one-pot preparation method of a bepedioic acid intermediate, which comprises the following steps: S1, taking DMSO (dimethylsulfoxide) as a reaction solvent, adding 7-bromo-2, 2-dimethyl ethyl heptanoate and p-methylbenzenesulfonyl methyl isocyanide, and carrying out addition reaction under the catalysis of alkali; s2, water is added for quenching excessive alkali, and then an organic solvent is added for extraction; s3, dropwise adding concentrated hydrochloric acid to carry out an acid hydrolysis reaction; s4, washing; s5, carrying out vacuum concentration on the organic phase, and carrying out ester hydrolysis reaction by taking an alkali metal compound as a catalyst; s6, adding water and dichloromethane for extraction, collecting a water layer, dropwise adding concentrated hydrochloric acid, crystallizing, filtering and drying to obtain a product. The target product is directly obtained through condensation, acid hydrolysis, ester hydrolysis and other basic chemical reactions through a one-pot method, the process is simple, operation is convenient, the reaction efficiency is improved, and the usage amount of solvents and reagents is reduced; and the method is energy-saving and environment-friendly, can further reduce environmental pollution, and has a good industrial application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of chemical synthesis, and particularly relates to a one-pot preparation method of a bempedoic acid intermediate. BACKGROUND

[0002] Bempedoic acid is a first-in-class daily, complementary, oral ATP citrate lyase (ACL) inhibitor, which can reduce the biosynthesis of cholesterol and reduce the level of low-density lipoprotein LDL-C by up-regulating LDL receptors.

[0003] Similar to statins, bempedoic acid also reduces high-sensitivity C-reactive protein (hsCRP), which is a key marker of inflammation associated with cardiovascular disease. Bempedoic acid has been proven to reduce the biosynthesis of cholesterol and reduce the level of LDL-C by inhibiting ACL and up-regulating LDL receptors. It can be used as a complementary treatment for statins. The drug was approved by the US Food and Drug Administration (FDA) in February 2020 and marketed as Nexletol.

[0004] The chemical name of bempedoic acid is 8-hydroxy-2,2,14,14-tetramethyl pentadecanedioic acid, and its chemical structural formula is as follows:

[0005] The synthesis route of bempedoic acid is disclosed in the compound patent (US7335799B2) and its homologous patent (WO2004067489) disclosed by the original research company, as shown in the following figure:

[0006] The route uses ethyl isobutyrate and 1,5-dibromopentane as starting materials, and condenses to obtain ethyl 7-bromo-2,2-dimethylheptanoate under the catalysis of LDA; under the condition of strong base (NaH) and catalyst (TBAI), addition is carried out with p-methylbenzenesulfonylmethyl isocyanide, and the addition product is subjected to 2-step hydrolysis to obtain 2,2,14,14-tetramethyl-8-oxopentadecanedioic acid, and finally subjected to hydrogenation reduction to obtain the target product bempedoic acid. The above-mentioned process route has a total of 5-step reactions, the process is relatively long, and the reagents such as LDA and NaH have high safety risks, and need to be carried out in anhydrous and anaerobic or ultralow temperature (-40℃) environment, which is not suitable for industrial production.

[0007] According to the above synthesis route, CN111170855A, CN111285760A, CN11349829B and other Chinese invention patents optimize and design to make the synthesis steps more suitable for industrial production. It promotes the process of domestic industrial production of bepirdac acid, but the ideas of the above inventions are limited to traditional thinking mode and quality control strategy, that is, the product of each reaction is extracted and purified separately, which undoubtedly increases the operation steps and energy consumption, and the wastewater treatment pressure is large, which is not conducive to industrial production. SUMMARY

[0008] In view of the deficiencies in the prior art, the present application provides a one-pot method for preparing a bepirdac acid intermediate, which solves the problem of separate extraction and purification of the product of each reaction in the prior art, which increases the operation steps and energy consumption, and also has the problems of large wastewater treatment pressure and is not conducive to industrial production.

[0009] According to an embodiment of the present application, a one-pot method for preparing a bepirdac acid intermediate includes the following steps: S1, DMSO is put into a reaction container as a reaction solvent, 7-bromo-2,2-dimethyl heptanoic acid ethyl ester and p-methyl phenylsulfonyl methyl isocyanide are added in a molar ratio of 1.2-2, the temperature is controlled at 15-35℃, and an addition reaction occurs under the catalysis of a base; S2, water is added to quench the excess base, then an organic solvent is added to realize the extraction and layering of the solution, then the water layer is discharged, and the organic layer at the top is left, and the feeding ratio of the base is 6-15 times the volume; S3, concentrated hydrochloric acid is added dropwise to the organic layer obtained in the above step to perform acid hydrolysis, the hydrolysis temperature is controlled at 10-40℃, and the molar ratio of concentrated hydrochloric acid is 2.0-6.0; S4, after hydrolysis, water, sodium bicarbonate solution or potassium bicarbonate solution are added for washing; S5, the washed organic phase is concentrated under reduced pressure to dryness, and an ester hydrolysis reaction is performed with DMF or DMSO as the solvent and an alkali metal compound as the catalyst; S6, water and dichloromethane are added for extraction, the water layer is collected, concentrated hydrochloric acid is slowly added for acidification, the pH is adjusted to 2-3, the crystals are completely precipitated, and the product of the bepirdac acid intermediate of the present application is obtained by filtering and drying.

[0010] Preferably, the base added in step S1 includes one of sodium hydride, sodium ethoxide, sodium methoxide and sodium tert-butoxide.

[0011] Preferably, the organic solvent in step S2 includes one of n-hexane, n-heptane, n-pentane and ethyl acetate.

[0012] Further, the washing process of step S4 is carried out in steps, first adding water to wash twice, and then adding sodium bicarbonate solution or potassium bicarbonate solution once.

[0013] Preferably, in step S5, the alkali metal compound includes one of sodium hydroxide, potassium hydroxide, and lithium hydroxide monohydrate.

[0014] Preferably, in step S5, the molar ratio of the solvent DMF or DMSO to the alkali metal compound is 1.5-6.0.

[0015] Preferably, in step S5, the temperature of the ester hydrolysis reaction is controlled to be 70-110℃.

[0016] Preferably, in step S6, the acidification temperature is controlled to be 0-20℃.

[0017] The technical principle of the present application is that 7-bromo-2,2-dimethyl heptanoic acid ethyl ester is used as a starting material to adduct with p-methyl phenylsulfonyl methyl isocyanide, the adduct is not used as an intermediate product alone and does not need to be separated and purified, and can be directly used to continue a two-step hydrolysis reaction to obtain 2,2,14,14-tetramethyl-8-oxo pentadecane diacid (i.e. the intermediate of the present application). Finally, the intermediate is reduced to efficiently prepare bepirdac.

[0018] Compared with the prior art, the present application has the following beneficial effects: The present application directly obtains the target product through one-pot method of 7-bromo-2,2-dimethyl heptanoic acid ethyl ester through condensation, acid hydrolysis, ester hydrolysis and other basic chemical reactions, the process is simple, the operation is convenient, the conditions are mild, the reaction efficiency is effectively improved, the use amount of solvents and reagents is reduced, energy is saved, the environment is protected, the environmental pollution is further reduced, the industrialized production is facilitated, and the present application has good industrialized application prospect. Specific embodiments The technical solutions in the present application are further described below in combination with examples.

[0019] Example 1: Step 1: 120 ml of DMSO, 20 g of 7-bromo-2,2-dimethyl heptanoic acid ethyl ester, and 7.36 g of p-methyl phenylsulfonyl methyl isocyanide are mixed, 46.2 g of 20% sodium ethoxide ethanol solution is added dropwise at 20-30℃, and the reaction is carried out for 2 h. Excessive sodium ethoxide is quenched by adding 120 ml of deionized water, and 60 ml of *3 n-hexane is added for extraction.

[0020] Step 2: 22.6 g of concentrated hydrochloric acid is slowly added dropwise to the organic layer at 12-18℃, and the reaction is carried out for 4 h. The organic layer is washed twice with 40 ml of *2 deionized water, and then washed once with 5% potassium bicarbonate. The organic layer is concentrated under reduced pressure to dryness, and then dissolved in 50 ml of DMF.

[0021] Step 3: Add 40g of 20% sodium hydroxide solution to the above solution, heat to 100℃, react for 2-3 hours, cool to 20℃, extract twice with 30ml of dichloromethane, and collect the aqueous phase. Cool to 0-10℃, add concentrated hydrochloric acid dropwise to adjust the pH to 2-3, crystallize for 2 hours, filter, and dry to obtain 21.04g of bepidocalic acid intermediate product, an off-white solid, with a yield of 81.46%.

[0022] Example 2: Step 1: Mix 318ml DMSO, 53g ethyl 7-bromo-2,2-dimethylheptanoate, and 19.52g p-toluenesulfonylmethylisocyanate. Add 0.3mol sodium methoxide / methanol solution dropwise at 15-25℃ and react for 4h. Add 300ml deionized water to quench excess sodium methoxide and add 150ml x 3 n-heptane for extraction.

[0023] Step 2: Slowly add 70g of concentrated hydrochloric acid to the organic layer at 12-18℃ and continue the reaction for 3 hours. Wash twice with 100ml*2 deionized water, then wash once with 5% potassium bicarbonate. Concentrate the organic layer under reduced pressure until dry, and dissolve it in 120ml of DMF.

[0024] Step 3: Add 100g of 20% sodium hydroxide solution to the above solution, heat to 90℃, react for 2-3 hours, cool to 20℃, add 75ml*2 of dichloromethane, extract twice, and collect the aqueous phase. Continue to cool the aqueous layer to 0-10℃, add concentrated hydrochloric acid dropwise to adjust the pH to 2-3, crystallize for 2 hours, filter, and dry to obtain 54.63g of bepidocalic acid intermediate product, a white solid with a yield of 84.6%.

[0025] Example 3: Step 1: Mix 300ml DMSO, 50g ethyl 7-bromo-2,2-dimethylheptanoate, and 18.41g p-methylbenzenesulfonylmethylisocyanate. Add 0.283mol sodium ethoxide ethanol solution dropwise at 20-30℃ and react for 3h. Add 300ml deionized water to quench excess sodium ethoxide, and add 150ml x 3 n-heptane for extraction.

[0026] Step 2: Slowly add 75.3g of concentrated hydrochloric acid to the organic layer at 10-20℃ and continue the reaction for 2.5h. Wash twice with 100ml*2 deionized water, then wash once with 5% sodium bicarbonate. Concentrate the organic layer under reduced pressure until dry, and dissolve it in 120ml of DMF.

[0027] Step 3: Add 140g of 20% potassium hydroxide aqueous solution to the above solution, heat to 100℃, react for 2-3h, add 100ml*2 ethyl acetate, extract twice, collect the aqueous phase, continue to cool to 0-10℃, slowly add concentrated hydrochloric acid to adjust pH to 2-3, crystallize for 2h, filter, and dry to obtain 53.72g of bepidocal acid intermediate product, off-white solid, yield 83.2%.

[0028] Example 4: Step 1: Mix 300ml DMSO, 50g ethyl 7-bromo-2,2-dimethylheptanoate, and 18.4g p-methylbenzenesulfonylmethylisocyanate. Add 0.32mol sodium ethoxide ethanol solution dropwise at 20-30℃ and react for 3h. Add 300ml deionized water to quench excess sodium ethoxide, and add 150ml x 3 n-heptane for extraction.

[0029] Step 2: Slowly add 70g of concentrated hydrochloric acid to the organic layer at 10-20℃ and continue the reaction for 3 hours. Wash twice with 100ml*2 deionized water, then wash once with 5% potassium bicarbonate. Concentrate the organic layer under reduced pressure until dry, and dissolve it in 120ml of DMF.

[0030] Step 3: Dissolve 19.8g of lithium hydroxide monohydrate in 120ml of purified water and add it to the above DMF solution. Heat to 90℃ and react for 3 hours. Cool to 20℃ and extract twice with 75ml*2 dichloromethane, collecting the aqueous phase. Continue cooling the aqueous layer to 0-10℃, add concentrated hydrochloric acid dropwise to adjust the pH to 2-3, crystallize for 2 hours, filter, and dry to obtain 56.18g of bepidocalic acid intermediate product, a white solid with a yield of 87%.

[0031] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A one-pot preparation method for a bepidocalic acid intermediate, characterized in that, Includes the following steps: S1. Add DMSO as a reaction solvent to the reaction vessel, and add ethyl 7-bromo-2,2-dimethylheptanoate and p-toluenesulfonylmethylisocyanate in a molar ratio of 1.2-2. Control the temperature at 15-35℃ and carry out an addition reaction under alkaline catalysis. S2. Add water to quench excess alkali, then add organic solvent to achieve extraction and layering of the solution. Then drain the aqueous layer, leaving the top organic layer. The alkali feed ratio is 6-15 times the volume. S3. Add concentrated hydrochloric acid dropwise to the organic layer obtained in the previous step to carry out acid hydrolysis reaction. The hydrolysis temperature is controlled at 10-40℃ and the molar ratio of concentrated hydrochloric acid is 2.0-6.

0. S4. After hydrolysis, wash with water, sodium bicarbonate solution or potassium bicarbonate solution. S5. Concentrate the washed organic phase to dryness under reduced pressure, and carry out ester hydrolysis reaction using DMF or DMSO as solvent and alkali metal compound as catalyst. S6. Add water and dichloromethane for extraction, collect the aqueous layer, slowly add concentrated hydrochloric acid for acidification, adjust the pH to 2-3, wait for the crystals to precipitate completely, filter and dry to obtain the Bepado acid intermediate product of the present invention.

2. The one-pot preparation method of a bepidocalic acid intermediate as described in claim 1, characterized in that: The alkali added in step S1 includes one of sodium hydride, sodium ethoxide, sodium methoxide, and sodium tert-butoxide.

3. The one-pot preparation method of a bepidocalic acid intermediate as described in claim 1, characterized in that: In step S2, the organic solvent includes one of n-hexane, n-heptane, n-pentane, and ethyl acetate.

4. The one-pot preparation method of a bepidocalic acid intermediate as described in claim 1, characterized in that: The washing process in step S4 is carried out in steps: first, water is added and washed twice, and then sodium bicarbonate solution or potassium bicarbonate solution is added once.

5. The one-pot preparation method of a bepidocalic acid intermediate as described in claim 1, characterized in that: In step S5, the alkali metal compound includes one of sodium hydroxide, potassium hydroxide, and lithium hydroxide monohydrate.

6. The one-pot preparation method of a bepidocalic acid intermediate as described in claim 1, characterized in that: In step S5, the molar ratio of solvent DMF or DMSO to alkali metal compound is 1.5-6.

0.

7. The one-pot preparation method of a bepidocalic acid intermediate as described in claim 1, characterized in that: In step S5, the temperature of the ester hydrolysis reaction is controlled at 70-110℃.

8. The one-pot preparation method of a bepidocalic acid intermediate as described in claim 1, characterized in that: In step S6, the acidification temperature is controlled at 0-20℃.

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