Synthetic method of bempedoic acid and intermediate thereof

A synthesis method and intermediate technology, which are applied in the field of chemical synthesis of raw materials, can solve the problems of difficult purification of final products, high cost of scaled production, and many side reactions in double alkylation reactions.

Inactive Publication Date: 2020-12-22
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Although these two methods have greatly simplified the synthetic route of bempedelic acid, there are still certain defects in these routes for scale-up production: the ester group of ethyl 6-bromo-2,2-dimethylhexanoate has certain Reactivity, acylation reaction with diethyl 1,3-acetone dicarboxylate is easy to occur, and there are many side reactions in double alkylation reaction; the total yield of alkylation and alkaline hydrolysis reaction is relatively low, and the cost of enlarged production is relatively low High; the crystallization performance of the intermediate obtained by alkylation is poor, it is not easy to purify and separate, and some viscous by-products cannot be removed from the system in time, which makes it difficult to purify the final product; the carbonyl reduction reaction requires the use of a large equivalent of sodium borohydride. Disposal has certain risks and there are many three wastes, and it is still necessary to continue to study the low-cost and high-efficiency green synthesis route of bempedelic acid

Method used

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  • Synthetic method of bempedoic acid and intermediate thereof
  • Synthetic method of bempedoic acid and intermediate thereof
  • Synthetic method of bempedoic acid and intermediate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070]

[0071] Add compound 1a (11.52g, 100mmol) and 57mL tetrahydrofuran into a three-necked flask, stir to dissolve and cool down to an internal temperature of about -70~-65°C, slowly add n-butyllithium solution (1M, 105mL, 105mmol) dropwise, and add After the completion, keep stirring for 0.5 hours, then add dropwise the THF solution of 2a (21.59g, 100mmol, dissolved in 57mL THF), stir evenly and then naturally heat up to 20-30°C for 2-3 hours. Dilute hydrochloric acid (5%, 115mL) was added at the end of the reaction, ethyl acetate (115mL) was added to extract three times, the combined organic phase was washed twice with saturated brine, dried, filtered, concentrated, and distilled under reduced pressure to obtain compound 3a (19.64g, 78.6 %). MS(ESI)m / z=250.1[M+H] +

[0072] In Example 1, tetrahydrofuran can be replaced by N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile or 2-methyltetrahydrofuran; n-butyllithium can be replaced by LDA,...

Embodiment 2

[0075]

[0076] Add compound 1b (15.72g, 100mmol) and 78mL tetrahydrofuran into a three-neck flask, stir to dissolve and cool down to an internal temperature of about -70~-65°C, slowly drop in LDA solution (1M, 105mL, 105mmol), keep warm after the addition is complete Stir for 0.5 hour, then drop into the THF solution of 2a (21.59g, 100mmol, dissolved in 77mL THF), stir well, then naturally heat up to 20-30°C and react for 2-3 hours. Dilute hydrochloric acid (5%, 156mL) was added at the end of the reaction, ethyl acetate (156mL) was added to extract 3 times, the combined organic phase was washed 2 times with saturated brine, dried, filtered, concentrated, and distilled under reduced pressure to obtain compound 3b (23.00g, 78.7 %). MS(ESI)m / z=292.0[M+H] +

[0077] In Example 2, tetrahydrofuran can be replaced by N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile or 2-methyltetrahydrofuran; LDA can be replaced by n-butyllithium, tert-butyl Sodi...

Embodiment 3

[0080]

[0081] Add compound 1c (15.52g, 100mmol) and 77mL tetrahydrofuran into a three-neck flask, stir to dissolve and cool at low temperature to an internal temperature of about -15~-10°C, slowly add LiHMDS (1M toluene solution, 105mL), keep stirring for 0.5 hours after the addition is complete , and then drop into the tetrahydrofuran solution of 2a (21.59g, 100mmol, dissolved in 77mL tetrahydrofuran), stir evenly and then naturally heat up to 0-5°C to react for 2-3 hours. After the reaction, dilute hydrochloric acid (5%, 155 mL) was added, ethyl acetate (154 mL) was added to extract 3 times, the combined organic phases were washed with saturated brine twice, dried, filtered, concentrated, and distilled under reduced pressure to obtain compound 3c (23.02 g, 79.3 %).

[0082] MS(ESI)m / z=290.0[M+H] +

[0083] In Example 3, tetrahydrofuran can be replaced by N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetonitrile or 2-methyltetrahydrofuran; LiHMDS ...

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PUM

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Abstract

The invention discloses new intermediate compounds 6 and 7 of bempedoic acid, and also discloses a synthetic method of bempedoic acid. The method shortens the route steps, improves the yield, lowers the process cost, improves the structure of the bempedoic acid intermediate, enhances the crystallinity of the intermediate compounds, and is beneficial to enhancing the purity of the final product, and suitable for enlarged production. The structural formulas of the compound 6 and the compound 7 are shown in the specification, wherein -N(R2)2 represents N,N-dimethylamino, cyclohexylamino, morpholinyl or amino; and M is an inorganic base or organic alkali, and comprises sodium, potassium, calcium, cyclohexanediamine or morpholine.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a chemical synthesis method of a raw material drug of a novel oral lipid-lowering drug bempedelic acid. Background technique [0002] Bempedoic acid (code name ETC-1002) is a non-statin, LDL-C lowering once-daily oral drug developed by Esperion Therapeutic Company of the United States. In February 2020, the U.S. Food and Drug Administration (FDA) approved the use of bempedelic acid in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD). Additional lowering of LDL-C in ASCVD patients or high-risk groups, especially those who are statin intolerant, provides an important new complementary and less expensive and more convenient oral drug option. [0003] The chemical name of bempedic acid is: 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid. The structural formula is as follows: [0004] [000...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C233/05C07D295/185C07C303/30C07C309/73C07C235/74C07C253/30C07C255/22C07C51/06C07C59/347C07C231/06C07C51/02C07C59/105
CPCC07C231/12C07D295/185C07C303/30C07C253/30C07C51/06C07C231/06C07C51/02C07C233/05C07C309/73C07C235/74C07C255/22C07C59/347C07C59/105
Inventor 郑旭春张一平吴怡华
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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