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CN-121991020-A - Bei Pei polyacid intermediate and preparation method thereof, and preparation method of Bei Pei polyacid

CN121991020ACN 121991020 ACN121991020 ACN 121991020ACN-121991020-A

Abstract

The invention provides intermediate compounds c and d of Bei Pei polyacid, a preparation method thereof and a preparation method of Bei Pei polyacid, wherein the preparation method has the advantages of economic raw materials, simplicity and easiness in obtaining, simple operation, high selectivity and high efficiency, the yield of Bei Pei polyacid prepared by adopting the intermediate is improved, tosmic reagents with great toxicity are avoided, the cryogenic reaction is avoided, the energy consumption can be reduced, and the environment-friendly chemistry and the industrial large-scale production are facilitated.

Inventors

  • HU MENG
  • LV LIANGFEI
  • MI FUYUAN
  • WANG ZHIQIAO
  • LI WEILONG
  • LIU PAN

Assignees

  • 安礼特（上海）医药科技有限公司

Dates

Publication Date
20260508
Application Date
20241107

Claims (10)

  1. 1. An intermediate compound, characterized in that said compound is a compound c and a compound d of the formula: Wherein, the X is a leaving group selected from halogen, OMs and OTs; R 1 and R 2 are each independently selected from H, C 1 -C 6 alkyl, or R 1 and R 2 are linked to form a 4-6 membered cyclic acetal; R 3 is selected from COR 4 or CN; R 4 is selected from H, C 1 -C 6 alkyl and NR 5 R 6 ; R 5 and R 6 are each independently selected from H, C 1 -C 6 alkyl, or R 5 and R 6 are linked to form a 4-6 membered nitrogen containing heterocycle.
  2. 2. A process for the preparation of an intermediate compound according to claim 1, wherein said intermediate compound is compound d, comprising the steps of: (i) The caprolactone is subjected to self-condensation and hydrolysis decarboxylation to obtain a compound a; (ii) The compound a is subjected to substitution reaction to obtain a compound b; (iii) Protecting the compound b by using R 1 and R 2 to obtain a compound c, and carrying out coupling reaction on the compound c and a compound SM2 to obtain a compound d; Wherein X, R 1 、R 2 and R 3 are as defined in claim 1.
  3. 3. The method of claim 2, wherein step (i) comprises one or more of the following features: The self-condensation of caprolactone is carried out in the presence of a base catalyst or an acid catalyst; the base catalyst is selected from one or more of sodium ethoxide, sodium methoxide, sodium tert-butoxide and potassium tert-butoxide; the acid catalyst is selected from lewis acids; the hydrolytic decarboxylation is performed in the presence of a first acidic reagent or a first basic reagent; The first acidic reagent is selected from one of hydrochloric acid, hydrobromic acid, hydrofluoric acid and sulfuric acid; The first alkaline reagent is selected from sodium hydroxide or sodium carbonate, and/or The molar volume ratio of the caprolactone to the alkali catalyst is 1:0.5-1:10.
  4. 4. The method according to claim 3, wherein in the step (i), the self-condensation of caprolactone is performed in a first organic solvent containing a base catalyst, and the reaction is performed for 10 to 30 hours at a temperature of 60 to 80 ℃; the hydrolysis decarboxylation comprises the steps of further adding hydrochloric acid, and reacting for 1-10 hours at the temperature of 55-65 ℃ to obtain the compound a; wherein the first organic solvent is selected from one or more of ethanol, methanol, phenethyl alcohol and benzyl alcohol; the molar volume ratio of the base catalyst in the first organic solvent is 1:10-1:90.
  5. 5. The method of claim 2, wherein step (ii) comprises reacting compound a with a nucleophile to provide compound b; Wherein the nucleophilic reagent is selected from one or more of hydrobromic acid, methanesulfonyl chloride, hydroiodic acid, hydrochloric acid and p-toluenesulfonyl chloride; the molar ratio of the compound a to the nucleophile is 1:1-1:10.
  6. 6. The process according to claim 5, wherein step (ii) comprises reacting the compound a with hydrobromic acid at 70 ℃ to 110 ℃ for 10 hours to 30 hours to obtain the compound b; wherein the molar ratio of the compound a to hydrobromic acid is 1:1-1:10; Or, the step (ii) comprises the steps of reacting the compound a with methanesulfonyl chloride in a second organic solvent at room temperature for 1-10 h to obtain the compound b; The second organic solvent is triethylamine and/or dichloromethane, the molar ratio of the compound a to the methanesulfonyl chloride is 1:1-1:5, and the mass percentage of the compound a in the second organic solvent is 1:5-1:50.
  7. 7. The method of claim 2, wherein step (iii) comprises reacting compound b with an alcoholic solvent in the presence of a second acidic reagent to give compound c, and further reacting compound c with SM2 in the presence of a second basic reagent to give compound d; the alcohol solvent is selected from one or more of methanol, ethanol, ethylene glycol and propylene glycol; the mass volume ratio of the compound b to the alcohol solvent is 1:1-1:10; The second acidic solvent is selected from one or more of p-toluenesulfonic acid, benzenesulfonic acid and toluenesulfonic acid; The SM2 is selected from one or more of ethyl isobutyrate, methyl isobutyrate, isobutyramide, N-dimethyl isobutyramide, N, 2-trimethyl propionamide, isobutyronitrile, isobutyramide and 2-methyl-1-morpholinopropan-1-one; The second alkaline reagent is selected from one or more of lithium diisopropylamide, sodium bis (trimethylsilyl) amide and lithium bis (trimethylsilyl) amide.
  8. 8. The preparation method of the catalyst according to claim 7, wherein the step (iii) comprises dissolving the compound b and ethylene glycol in a third organic solvent in the presence of p-toluenesulfonic acid, and reacting at 100-120 ℃ for 1-20 h to obtain the compound C, mixing the compound C and the compound SM2 in tetrahydrofuran solvent, adding lithium diisopropylamide, reacting at-30-0 ℃ for 10-2 h, and continuously adding sodium hydroxide to react to obtain the compound d; the third organic solvent is selected from benzene, toluene, xylene and ethylbenzene.
  9. 9. The preparation method of Bei Pei polyacid is characterized by comprising the following steps: (v) Hydrolyzing the compound d to obtain a compound e; (vi) Reducing the compound e to obtain Bei Pei polyacid; Wherein, the R 1 and R 2 are each independently selected from H and C 1 -C 6 alkyl, or said R 1 and R 2 are linked to form a 4-6 membered cyclic acetal; R 3 is selected from-COR 4 or-CN; R 4 is selected from H, C 1 -C 6 alkyl and-NR 5 R 6 ; R 5 and R 6 are each independently selected from H, C 1 -C 6 alkyl, or R 5 and R 6 are linked to form a 4-6 membered nitrogen containing heterocycle.
  10. 10. The method of claim 9, wherein the hydrolysis of step (v) comprises: In the presence of a third alkaline reagent, reacting the compound d at 90-120 ℃ for 1-10 hours to obtain a compound e; the reduction reaction of step (vi) comprises adding a third acidic reagent to the compound e to give Bei Pei polyacid; Wherein the third alkaline reagent is selected from sodium hydroxide or potassium hydroxide; The third acidic reagent is selected from hydrogen chloride or sulfuric acid.

Description

Bei Pei polyacid intermediate and preparation method thereof, and preparation method of Bei Pei polyacid Technical Field The invention belongs to the field of organic synthesis, and particularly relates to Bei Pei polyacid intermediate, a preparation method thereof and a preparation method of Bei Pei polyacid. Background Bei Pei polyacid (Bempedoic acid, trade name Nexletol, nilemdo) is an adenosine triphosphate-citrate hydrolase (ACL) inhibitor, developed by us Esperion, approved by the FDA for marketing in month 2 of 2020, the first oral, once daily, non-statin hypolipidemic agent approved for use in the treatment of adult heterozygous familial hypercholesterolemia (HeFH) patients, or in atherosclerosis cardiovascular disease (ASCVD) patients in need of further reduction of low density lipoprotein cholesterol (LDL-C) levels, was the first oral, once daily, non-statin hypolipidemic agent approved for use in the last 20 years. Bei Pei the chemical name of the polyacid is 8-hydroxy-2,2,14,14-tetramethyl pentadecanedioic acid, the molecular weight is 344.49, the molecular formula is C 19H36O5, and the structural formula is as follows: Patent WO2004067489 reports a synthetic route of Bei Pei polyacid, which uses ethyl isobutyrate and 1, 5-dibromopentane as raw materials, 7-bromo-2, 2-dimethylheptanoic acid ethyl ester is obtained by low-temperature condensation of lithium diisopropylamide, then the 7-bromo-2, 2-dimethylheptanoic acid ethyl ester and p-toluenesulfonyl methyl isonitrile (Tosmic) are subjected to strong alkaline condition, tetrabutylammonium iodide is used as a catalyst to prepare Tosmic adduct, and then Bei Pei polyacid is obtained by hydrolysis and reduction. The specific synthetic route is as follows: In the Bei Pei polyacid synthesis route, tosmic in the step 2 has high toxicity and poor atom economy, p-toluenesulfonyl derivative and other genotoxic impurities are generated after hydrolysis in the step 3, the quality control is not facilitated, and a large amount of sodium borohydride is used for reduction in the step 5, so that the conversion rate is not high easily, and a high-viscosity oily matter is obtained. Patent CN111285760B reports another synthetic route of Bei Pei polyacid, in the route, 5-bromo-n-butanol and Tosmic are catalyzed by NaH to prepare Tosmic adduct by tetrabutylammonium iodide, the adduct is hydrolyzed and brominated to obtain intermediate 5-keto-1, 9-dibromononane, 3-bromo-2, 2-dimethyl methyl propionate and bisboronic acid pinacol ester are catalyzed by palladium to prepare boric acid intermediate, then intermediate 5-keto-1, 9-dibromononane and boric acid intermediate are coupled by palladium catalysis, and finally the intermediate is hydrolyzed and reduced by sodium borohydride to obtain Bei Pei polyacid. The specific synthetic route is as follows: the 3-bromo-2, 2-dimethyl methyl propionate as a starting material in the Bei Pei polyacid route is not easily available in the market, and a palladium catalyst is needed in the route, so that the route has low yield, high cost and difficult raw material acquisition. Patent CN111170855B reports another synthetic route of Bei Pei polyacid, which uses ethyl isobutyrate and 1, 4-dibromobutane as raw materials, and uses Lithium Diisopropylamide (LDA) to obtain ethyl 6-bromo-2, 2-dimethylhexanoate by low-temperature condensation, then uses potassium iodide as catalyst with diethyl 1, 3-acetonedicarboxylate under the condition of potassium carbonate to obtain alpha-alkylated product, and then uses hydrolysis, decarboxylation and reduction to obtain Bei Pei polyacid. The specific synthetic route is as follows: the starting materials of the above route are low in cost and simple in steps, but the first and second steps of the route are reacted Problems of polysubstituted and poor selectivity result in low overall yields and many impurities that are difficult to control. Patent WO2020141419 reports a further synthetic route to Bei Pei polyacids which, although readily available, avoids the use of Tosmic, has long reaction steps and poor selectivity, results in a large number of by-products and low yields, and makes the quality of Bei Pei polyacids difficult to control. The specific synthetic route is as follows: In summary, in the above route for preparing Bei Pei polyacid, there are problems of expensive price of key raw material Tosmic, long reaction step, poor selectivity, difficult impurity control and the like, so that Bei Pei polyacid has high production cost, many impurities and is difficult to realize large-scale industrial production. Therefore, a synthetic process of Bei Pei polyacid which is simple, convenient, economical, efficient, safe and easy to realize industrial production is required to be developed. Disclosure of Invention The invention aims to provide a Bei Pei polyacid intermediate compound which is economical, efficient and suitable for industrial production and a preparation method thereof. Another object