CN116589341A - Preparation method of antihyperlipidemic drug intermediate - Google Patents
Preparation method of antihyperlipidemic drug intermediate Download PDFInfo
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- CN116589341A CN116589341A CN202310402064.3A CN202310402064A CN116589341A CN 116589341 A CN116589341 A CN 116589341A CN 202310402064 A CN202310402064 A CN 202310402064A CN 116589341 A CN116589341 A CN 116589341A
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- 239000003524 antilipemic agent Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims abstract description 87
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 78
- 238000006243 chemical reaction Methods 0.000 claims abstract description 71
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 70
- 239000012074 organic phase Substances 0.000 claims abstract description 50
- 239000008367 deionised water Substances 0.000 claims abstract description 37
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 37
- 239000000243 solution Substances 0.000 claims abstract description 36
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims abstract description 35
- 239000002798 polar solvent Substances 0.000 claims abstract description 34
- SNKVTFNYCZVRJL-UHFFFAOYSA-N C(C)(CCCCCCl)(C(=O)OCC)C Chemical compound C(C)(CCCCCCl)(C(=O)OCC)C SNKVTFNYCZVRJL-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003513 alkali Substances 0.000 claims abstract description 24
- 239000003880 polar aprotic solvent Substances 0.000 claims abstract description 21
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000007788 liquid Substances 0.000 claims abstract description 19
- IAYSDKUKIIYRRA-UHFFFAOYSA-N 1-(isocyanatomethylsulfonyl)-4-methylbenzene Chemical compound CC1=CC=C(S(=O)(=O)CN=C=O)C=C1 IAYSDKUKIIYRRA-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000007864 aqueous solution Substances 0.000 claims abstract description 13
- 238000001914 filtration Methods 0.000 claims abstract description 13
- ZHUVNVRTGUOCNN-UHFFFAOYSA-N 2,2,14,14-tetramethylpentadecan-8-one Chemical compound CC(C)(C)CCCCCC(=O)CCCCCC(C)(C)C ZHUVNVRTGUOCNN-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 10
- 239000012065 filter cake Substances 0.000 claims abstract description 10
- 230000003472 neutralizing effect Effects 0.000 claims abstract description 7
- 238000002425 crystallisation Methods 0.000 claims abstract description 4
- 230000008025 crystallization Effects 0.000 claims abstract description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 4
- 238000010791 quenching Methods 0.000 claims abstract description 4
- 230000000171 quenching effect Effects 0.000 claims abstract description 4
- 239000000376 reactant Substances 0.000 claims description 70
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 52
- 238000003756 stirring Methods 0.000 claims description 37
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 238000012544 monitoring process Methods 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- 239000012071 phase Substances 0.000 claims description 8
- 239000002002 slurry Substances 0.000 claims description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- -1 alkali metal hydrogencarbonate Chemical class 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 150000001733 carboxylic acid esters Chemical class 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 3
- 150000004679 hydroxides Chemical class 0.000 claims description 3
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 claims description 3
- NHVXRVOYVVPVDU-UHFFFAOYSA-N 2,2,14,14-tetramethyl-8-oxopentadecanedioic acid Chemical compound OC(=O)C(C)(C)CCCCCC(=O)CCCCCC(C)(C)C(O)=O NHVXRVOYVVPVDU-UHFFFAOYSA-N 0.000 abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 8
- 229940011051 isopropyl acetate Drugs 0.000 description 8
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- HYHMLYSLQUKXKP-UHFFFAOYSA-N bempedoic acid Chemical compound OC(=O)C(C)(C)CCCCCC(O)CCCCCC(C)(C)C(O)=O HYHMLYSLQUKXKP-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- UNOVUOFLAAXPMB-UHFFFAOYSA-N C(C)OC(C(CCCCCI)(C)C)=O Chemical compound C(C)OC(C(CCCCCI)(C)C)=O UNOVUOFLAAXPMB-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000000853 LDL receptors Human genes 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 102000004317 Lyases Human genes 0.000 description 1
- 108090000856 Lyases Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229940126239 Nexletol Drugs 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229950002974 bempedoic acid Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- SYRIIFZUZOIRNU-UHFFFAOYSA-N ethyl 7-bromo-2,2-dimethylheptanoate Chemical compound CCOC(=O)C(C)(C)CCCCCBr SYRIIFZUZOIRNU-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 231100000483 muscle toxicity Toxicity 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application discloses a preparation method of an antihyperlipidemic drug intermediate, which comprises the steps of a, reacting 2, 2-dimethyl-7-chloroheptanoic acid ethyl ester and p-methylbenzenesulfonyl methyl isocyanate in a polar aprotic solvent containing sodium ethoxide, quenching a reaction solution by deionized water, and extracting and separating a liquid by a water-insoluble polar solvent to obtain an organic phase which is an intermediate I; b, after acidolysis of the intermediate I, neutralizing the reaction solution by using alkali, separating the solution, and concentrating the organic phase until the organic phase is dried to obtain an intermediate II; c, dissolving the intermediate II in ethanol, hydrolyzing the intermediate II by using an alkaline aqueous solution, acidifying the reaction solution, extracting and separating liquid, concentrating an organic phase, adding n-heptane for crystallization, and filtering to obtain a filter cake which is the anti-hyperlipoic acid drug intermediate 8-oxo-2,2,14,14-tetramethyl pentadecane diacid. The application can reduce the difficulty of preparing the anti-hyperlipoic acid drug intermediate 8-oxo-2,2,14,14-tetramethyl pentadecanedioic acid and improve the preparation efficiency.
Description
Technical Field
The application relates to the technical field of medicines, in particular to a preparation method of an antihyperlipidemic drug intermediate.
Background
Bempedoic acid (code ETC-1002) is a long chain carboxylic acid compound, which was approved by 21 th day of the United states FDA for marketing, under the trade name Nexletol, under the name of Esperion, inc. in the United states, 2 nd month in 2020. Bevacizidine, an oral small molecule adenosine triphosphate-citrate lyase (ACL) inhibitor, reduces cholesterol biosynthesis by upregulating LDL receptors and reduces LDL-C levels, and is useful in the treatment of dyslipidemia and in reducing the risk of other cardiovascular diseases. Compared with the statin drugs widely applied clinically at present, the bevacizidine can avoid muscle toxicity related to the statin drugs, has better tolerance, and can be used for treating LDL-C which cannot be controlled by the prior method when being combined with the statin drugs.
8-oxo-2,2,14,14-tetramethyl pentadecane diacid is an important intermediate for the synthesis of bevacizidine acid. Patent WO200467489 discloses a process for the synthesis of 8-oxo-2,2,14,14-tetramethylpentadecanedioic acid, but uses sodium hydride with a high safety risk during the synthesis of intermediate (intermediate I), and in addition, uses column chromatography purification with low economic and time efficiency during the synthesis of intermediate I, which is not suitable for mass production. Patent WO2020257573A1 successfully avoids column chromatography purification and adopts n-heptane to extract the intermediate I, but the specific process of the step is that 2, 2-dimethyl-7-chloroheptanoic acid ethyl ester is converted into 7-iodine-2, 2-dimethylheptanoic acid ethyl ester and then reacted with methylbenzenesulfonyl methyl isocyanate to synthesize the intermediate I, and the process is complex. In addition, in the synthesis of intermediate I, 5 to 10% of mono-hydrolysis byproducts are produced, which can be finally converted into 8-oxo-2,2,14,14-tetramethylpentadecanedioic acid, which cannot be collected by column chromatography and n-heptane extraction, resulting in waste of part of the raw materials.
Therefore, the application provides a preparation method of an antihyperlipidemic drug intermediate.
Disclosure of Invention
The application aims to overcome the defects in the prior art and provide a preparation method of an antihyperlipidemic drug intermediate, which can reduce the difficulty in preparing the antihyperlipidemic drug intermediate 8-oxo-2,2,14,14-tetramethyl pentadecane diacid and improve the preparation efficiency.
In order to solve the technical problems, the application adopts the following technical scheme:
the application provides a preparation method of an antihyperlipidemic drug intermediate, which comprises the following steps:
a, reacting 2, 2-dimethyl-7-chloroheptanoic acid ethyl ester and p-toluenesulfonyl methyl isocyanide in a polar aprotic solvent containing sodium ethoxide, then quenching the reaction solution by deionized water, and extracting and separating the solution by a polar solvent insoluble in water, wherein the obtained organic phase is an intermediate I;
b, after acidolysis of the intermediate I, neutralizing the reaction solution by using alkali, separating the solution, and concentrating the organic phase until the organic phase is dried to obtain an intermediate II;
c, dissolving the intermediate II in ethanol, hydrolyzing the intermediate II by using an alkaline aqueous solution, acidifying the reaction solution, extracting and separating liquid, concentrating an organic phase, adding n-heptane for crystallization, and filtering to obtain a filter cake which is the anti-hyperlipoic acid drug intermediate 8-oxo-2,2,14,14-tetramethyl pentadecane diacid.
Further, step a includes:
s11, after mixing 2, 2-dimethyl-7-chloroheptanoic acid ethyl ester and a polar aprotic solvent, adding p-toluenesulfonyl methyl isocyanate into a reactant, and stirring until a solid is completely dissolved;
s12, cooling the reactant to below 20 ℃, adding sodium ethoxide, continuously cooling to 0-10 ℃, stirring for reaction, and monitoring the completion of the reaction by HPLC;
s13, after controlling the temperature of the reactant below 20 ℃, adding deionized water while stirring, extracting the reactant by using a polar solvent which is insoluble in water, standing and separating the liquid, wherein the obtained organic phase is an intermediate I;
preferably, after controlling the temperature of the reactant to be 0-10 ℃, deionized water is added while stirring, the reactant is extracted by a polar solvent which is insoluble in water, and the obtained organic phase is an intermediate I after standing and liquid separation.
Further, in step a:
in the S11, the volume mass ratio of the polar aprotic solvent to the ethyl 2, 2-dimethyl-7-chloroheptanoate is 4-15 mL/g;
preferably, the volume mass ratio of the polar aprotic solvent to the ethyl 2, 2-dimethyl-7-chloroheptanoate is 5-8 mL/g;
further, in the step S11, the molar equivalent ratio of the p-toluenesulfonyl methyl isocyanate to the ethyl 2, 2-dimethyl-7-chloroheptanoate is 0.5-0.7;
further, the molar equivalent ratio of sodium ethoxide in S12 to p-toluenesulfonyl methyl isocyanate in S11 is 2.0-2.5;
preferably, the molar equivalent ratio of the sodium ethoxide in the S12 to the p-toluenesulfonyl methyl isocyanate in the S11 is 2.0-2.3;
further, the molar equivalent ratio of sodium ethoxide in S12 to ethyl 2, 2-dimethyl-7-chloroheptanoate in S11 is 1.0-1.5;
preferably, the molar equivalent ratio of the sodium ethoxide in the S12 to the ethyl 2, 2-dimethyl-7-chloroheptanoate in the S11 is 1.1-1.3;
further, the volume ratio of deionized water in the step S13 to the polar aprotic solvent in the step S11 is 0.5-2;
further, the volume ratio of the polar solvent insoluble in water in S13 to the polar aprotic solvent in S11 is 1-2;
in the step S12, the stirring reaction time is 6 hours or longer.
Further, step b includes:
s21, washing the intermediate I by deionized water, standing for layering, and reserving an organic phase;
s22, cooling the organic phase to below 10 ℃, adding hydrochloric acid, stirring at 10-30 ℃ for reaction, and monitoring the completion of the reaction by HPLC;
s23, neutralizing the reaction liquid by using alkali, separating to remove the water phase, washing, drying the organic phase, concentrating the organic phase to be dry, adding n-heptane to pulp, filtering to obtain slurry, and concentrating the slurry to be dry to obtain an intermediate II.
Further, in S21, the volume ratio of deionized water to intermediate I is 1;
further, the molar ratio of the hydrochloric acid in the S22 to the intermediate I in the S21 is 1-5;
further, in the step S22, the duration of the stirring reaction is 15 hours or more;
further, the molar ratio of the alkali in S23 to the hydrochloric acid in S22 is 0.7-1.1;
further, the volume ratio of the n-heptane in S23 to the deionized water in S21 is 3-4.
Further, in S22, the hydrochloric acid concentration is greater than 4M;
preferably, in the step S22, the hydrochloric acid concentration is 4 to 12M;
preferably, in the step S22, the hydrochloric acid concentration is 8 to 12M;
further, in S23, the alkali is selected from one or more of alkali metal bicarbonate, alkali metal carbonate, and alkali metal hydroxide.
Further, step c includes:
s31, after the intermediate II is dissolved in ethanol, adding an alkaline water solution, heating the reactant to 45-85 ℃, stirring for reaction, and monitoring the reaction by HPLC;
preferably, after dissolving intermediate II in ethanol, S31 is added with an aqueous base and the reaction is heated to 65-80 degrees celsius.
In the step S31, the volume ratio of the ethanol to the alkaline water solution is 0.5-2.5;
preferably, in the step S31, the volume ratio of the ethanol to the aqueous alkali solution is 0.8 to 1.3;
s32, concentrating the reactant to remove ethanol, adding deionized water, controlling the temperature of the reactant below 20 ℃, and adjusting the pH value of the reactant to 1-2 by utilizing hydrochloric acid;
s33, extracting a reactant by using a water-insoluble polar solvent, separating a liquid to remove a water phase, washing, drying an organic phase, concentrating the organic phase to remove 80% of the water-insoluble polar solvent, then raising the temperature of the reactant to 45-55 ℃, and dropwise adding n-heptane;
further, in the step S33, the volume ratio of the n-heptane to the residual water-insoluble polar solvent is 1-5;
preferably, the volume ratio of n-heptane to the remaining water-insoluble polar solvent is 2 to 3;
s34, maintaining the temperature of the reactant at-10-30 ℃, stirring for reaction, and filtering the reactant after the reaction is monitored by HPLC, wherein the obtained filter cake is an antihyperlipidemic drug intermediate 8-oxo-2,2,14,14-tetramethyl pentadecane diacid;
preferably, S34 maintains the temperature of the reactants at 0 to 10 degrees celsius.
In the step S31, the stirring reaction time is more than or equal to 6 hours;
further, in the step S34, the stirring reaction time is 5-10 hours;
in the step S31, the volume weight ratio of the ethanol to the intermediate II is 1-10 mL/g;
preferably, in the step S31, the volume weight ratio of the ethanol to the intermediate II is 4-6 mL/g;
further, in S31, the volume ratio of the ethanol to the aqueous alkali solution is 1;
further, the volume ratio of the ethanol in the S31 to the deionized water in the S32 is 0.5-2.5;
preferably, the volume ratio of the ethanol in the S31 to the deionized water in the S32 is 0.8-1.3;
further, the volume ratio of the polar solvent which is insoluble in water in the S33 to the ethanol in the S31 is 1-2;
further, the volume ratio of the n-heptane in S33 to the ethanol in S31 is 0.2-1.
Further, in the step S32, the concentration of hydrochloric acid is 2-12M;
further, in the step S31, the concentration of the aqueous alkali solution is 15-25wt%;
further, in S31, the aqueous alkali solution is one or more selected from aqueous solutions of hydroxides of alkali metals;
preferably, in S31, the aqueous alkali solution is one or more selected from an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide, and an aqueous solution of lithium hydroxide.
Further, the polar aprotic solvent is selected from one or more of dimethylacetamide (DMAc), dimethylformamide (DMF) and azomethylpyrrolidone (NMP);
further, the water-insoluble polar solvent is selected from one or more of liquid chlorinated hydrocarbon of C1-C8, carboxylic ester and ether;
preferably, the water-insoluble polar solvent is selected from one or more of dichloromethane, isopropyl acetate, methyl tertiary butyl ether and ethyl acetate;
preferably, the polar solvent insoluble in water in S33 is methyl tert-butyl ether or ethyl acetate;
preferably, the water-insoluble polar solvent in S13 and S21 is isopropyl acetate or methylene chloride.
The application has the beneficial effects that:
the method for preparing the antihyperlipidemic drug intermediate 8-oxo-2,2,14,14-tetramethyl pentadecane diacid has the advantages of easily available raw materials, simple process operation, high yield, no special production equipment in the reaction, and higher economic benefit.
Drawings
FIG. 1 shows the NMR spectrum of 8-oxo-2,2,14,14-tetramethylpentadecane diacid according to the present application;
FIG. 2 shows the HPLC profile of 8-oxo-2,2,14,14-tetramethylpentadecanedioic acid of the present application.
Detailed Description
The application is further described below. The following examples are only for more clearly illustrating the technical aspects of the present application, and are not intended to limit the scope of the present application.
In the description of the present application, it should be understood that the terms "center", "longitudinal", "lateral", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", etc. indicate orientations or positional relationships based on the orientations or positional relationships shown in the drawings, are merely for convenience in describing the present application and simplifying the description, and do not indicate or imply that the devices or elements referred to must have a specific orientation, be configured and operated in a specific orientation, and thus should not be construed as limiting the present application. Furthermore, the terms "first," "second," and the like, are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defining "a first", "a second", etc. may explicitly or implicitly include one or more such feature. In the description of the present application, unless otherwise indicated, the meaning of "a plurality" is two or more.
In the description of the present application, it should be noted that, unless explicitly specified and limited otherwise, the terms "mounted," "connected," and "connected" are to be construed broadly, and may be either fixedly connected, detachably connected, or integrally connected, for example; can be mechanically or electrically connected; can be directly connected or indirectly connected through an intermediate medium, and can be communication between two elements. The specific meaning of the above terms in the present application can be understood by those of ordinary skill in the art in a specific case.
The application provides a preparation method of an antihyperlipidemic drug intermediate, wherein one synthetic route is as follows:
specifically, the preparation method of the antihyperlipidemic drug intermediate comprises the steps a, b and c.
Step a after reacting ethyl 2, 2-dimethyl-7-chloroheptanoate and p-toluenesulfonylmethyl isocyanide in a polar aprotic solvent containing sodium ethoxide, quenching the reaction solution with deionized water and extracting the separated liquid with a polar solvent insoluble in water, the organic phase obtained being intermediate I.
Specifically, the step a includes S11 to S13:
s11, after the ethyl 2, 2-dimethyl-7-chloroheptanoate and the polar aprotic solvent are mixed, p-toluenesulfonyl methyl isocyanate is added to the reactant and stirred until the solid is completely dissolved.
In the step S11, the volume mass ratio of the polar aprotic solvent to the ethyl 2, 2-dimethyl-7-chloroheptanoate is 4-15 mL/g; the molar equivalent ratio of the p-toluenesulfonyl methyl isocyanate to the ethyl 2, 2-dimethyl-7-chloroheptanoate is 0.5-0.7.
In a preferred embodiment, in step S11, the volume to mass ratio of the polar aprotic solvent to the ethyl 2, 2-dimethyl-7-chloroheptanoate is from 5 to 8mL/g.
S12, cooling the reactant to below 20 ℃, adding sodium ethoxide, continuously cooling to 0-10 ℃, stirring the reaction, and monitoring the reaction completion by HPLC.
In addition, the molar equivalent ratio of sodium ethoxide in the step S12 to the p-toluenesulfonyl methyl isocyanate in the step S11 is 2.0-2.5; the molar equivalent ratio of sodium ethoxide in the step S12 to the ethyl 2, 2-dimethyl-7-chloroheptanoate in the step S11 is 1.0-1.5; in step S12, the reaction is stirred for 6 hours or longer.
In a preferred embodiment, the molar equivalent ratio of sodium ethoxide in step S12 to p-toluenesulfonyl methyl isocyanate in S11 is 2.0 to 2.3.
In a preferred embodiment, the molar equivalent ratio of sodium ethoxide in step S12 to ethyl 2, 2-dimethyl-7-chloroheptanoate in S11 is from 1.1 to 1.3.
S13, after controlling the temperature of the reactant below 20 ℃, adding deionized water while stirring, extracting the reactant by using a polar solvent which is insoluble in water, standing and separating the liquid, and obtaining an organic phase which is an intermediate I.
In a preferred embodiment, after controlling the temperature of the reactant to be 0-10 ℃, deionized water is added while stirring, the reactant is extracted by a polar solvent which is insoluble in water, and the obtained organic phase is an intermediate I after standing and separating.
In addition, the volume ratio of deionized water to polar aprotic solvent in the step S13 to the step S11 is 0.5-2; the volume ratio of the polar solvent insoluble in water in the step S13 to the polar aprotic solvent in the step S11 is 1 to 2.
And b, after acidolysis of the intermediate I, neutralizing the reaction solution by using alkali, separating the solution, and concentrating the organic phase to be dry to obtain an intermediate II.
Specifically, the step b includes S21 to S23:
s21, washing the intermediate I by deionized water, standing for layering, and reserving an organic phase.
In addition, in step S21, the volume ratio of deionized water to intermediate I is 1. S22, cooling the organic phase to below 10 ℃, adding hydrochloric acid, stirring the mixture at the temperature of 10-30 ℃ for reaction, and monitoring the completion of the reaction by HPLC.
In addition, the molar ratio of the hydrochloric acid in the step S22 to the intermediate I in the step S21 is 1-5; in the step S22, the duration of the stirring reaction is more than or equal to 15 hours; in step S22, the hydrochloric acid concentration is greater than 4M.
In a preferred embodiment, in step S22, the hydrochloric acid concentration is 4 to 12M.
In a preferred embodiment, in step S22, the hydrochloric acid concentration is 8 to 12M.
S23, neutralizing the reaction liquid by using alkali, separating to remove the water phase, washing, drying the organic phase, concentrating the organic phase to be dry, adding n-heptane to pulp, filtering to obtain slurry, and concentrating the slurry to be dry to obtain an intermediate II.
In addition, the molar ratio of the alkali in the step S23 to the hydrochloric acid in the step S22 is 0.7-1.1; the volume ratio of the n-heptane in the step S23 to the deionized water in the step S21 is 3-4; in step S23, the base is selected from one or more of alkali metal hydrogencarbonate, alkali metal carbonate and alkali metal hydroxide.
Step c, dissolving the intermediate II in ethanol, hydrolyzing the intermediate II by using an alkaline aqueous solution, acidifying the reaction solution, extracting and separating liquid, concentrating an organic phase, adding n-heptane for crystallization, and filtering to obtain a filter cake which is the antihyperlipidemic drug intermediate 8-oxo-2,2,14,14-tetramethyl pentadecanedioic acid.
Specifically, step c includes S31 to S34:
s31, after the intermediate II is dissolved in ethanol, an alkaline water solution is added, the temperature of the reactant is raised to 45-85 ℃, the reaction is stirred and monitored by HPLC, and the reaction is finished.
In a preferred embodiment, after dissolving intermediate II in ethanol, S31 is added with aqueous base and the reaction is heated to 65-80 degrees celsius, stirred and the reaction is stirred and monitored by HPLC for the end of the reaction.
In step S31, the volume ratio of the ethanol to the aqueous alkali solution is 0.5 to 2.5; the stirring reaction time is longer than or equal to 6 hours; the volume weight ratio of the ethanol to the intermediate II is 1-10 mL/g; the volume ratio of the ethanol to the alkaline water solution is 1; the concentration of the alkaline water solution is 15-25wt%; the aqueous alkali solution is selected from one or more of aqueous solutions of hydroxides of alkali metals.
In addition, the polar aprotic solvent is selected from one or more of dimethylacetamide (DMAc), dimethylformamide (DMF) and azomethylpyrrolidone (NMP); the water-insoluble polar solvent is selected from one or more of liquid chlorinated hydrocarbon of C1-C8, carboxylic ester and ether.
In a preferred embodiment, in step S31, the volume ratio of ethanol to aqueous alkali is 0.8 to 1.3.
In a preferred embodiment, in the step S31, the volume weight ratio of the ethanol to the intermediate II is 4-6 mL/g;
in a preferred embodiment, in step S31, the aqueous alkali solution is one or more selected from the group consisting of aqueous sodium hydroxide, aqueous potassium hydroxide, and aqueous lithium hydroxide.
In a preferred embodiment, in step S31, the water-insoluble polar solvent is dichloromethane, isopropyl acetate, methyl tert-butyl ether or ethyl acetate;
in a preferred embodiment, the water-insoluble polar solvent in step S13 and step S21 is isopropyl acetate or methylene chloride.
S32, concentrating the reactant to remove ethanol, adding deionized water, controlling the temperature of the reactant below 20 ℃, and adjusting the pH value of the reactant to 1-2 by utilizing hydrochloric acid.
In addition, the volume ratio of the ethanol in the step S31 to the deionized water in the step S32 is 0.5-2.5; in step S32, the concentration of hydrochloric acid is 2-12M.
In a preferred embodiment, the volume ratio of the ethanol in the step S31 to the deionized water in the step S32 is 0.8-1.3.
S33, extracting the reactant by using a water-insoluble polar solvent, separating to remove the water phase, washing, drying the organic phase, concentrating the organic phase to remove 80% of the water-insoluble polar solvent, then raising the temperature of the reactant to 45-55 ℃, and dropwise adding n-heptane.
In step S33, the volume ratio of n-heptane to the remaining water-insoluble polar solvent is 1 to 5; the volume ratio of the polar solvent which is insoluble in water in the step S33 to the ethanol in the step S31 is 1-2; the volume ratio of the n-heptane to the ethanol in the step S33 is 0.2-1.
In a preferred embodiment, in step S33, the volume ratio of n-heptane to the remaining water-insoluble polar solvent is 2 to 3.
In a preferred embodiment, in step S33, the water-insoluble polar solvent is methyl tert-butyl ether or ethyl acetate.
S34, maintaining the temperature of the reactant at-10-30 ℃, stirring for reaction, and filtering the reactant after the reaction is monitored by HPLC, wherein the obtained filter cake is 8-oxo-2,2,14,14-tetramethyl pentadecane diacid.
In a preferred embodiment, S34 keeps the temperature of the reactant at 0-10 ℃, the reactant is stirred for reaction, after the reaction is monitored by HPLC, the reactant is filtered, and the obtained filter cake is anti-hyperester drug intermediate 8-oxo-2,2,14,14-tetramethyl pentadecane diacid.
In step S34, the stirring reaction time is 5 to 10 hours.
Example 1
a preparation of intermediate I
S11, 200g of ethyl 2, 2-dimethyl-7-chloroheptanoate and 1200mL of N, N-dimethylacetamide were added to a reaction flask, and after stirring and mixing, 106g of p-toluenesulfonylmethisocyanide was added to the reaction flask, and stirred until the solid was completely dissolved.
S12, using an ice salt bath outside the reaction bottle, cooling the reaction bottle to minus 10 ℃ to control the temperature of reactants in the reaction bottle to be below 20 ℃, then adding 80g of sodium ethoxide into the reaction bottle, continuously controlling the temperature of the reactants to be between 0 and 10 ℃, stirring and reacting for 6 hours, and monitoring the completion of the reaction by HPLC.
S3, controlling the temperature of the reactant below 20 ℃, pouring the reaction mixture into 1200mL of deionized water under stirring, extracting the reactant with 1200mL of dichloromethane, standing for liquid separation, extracting the aqueous phase with 1200mL of dichloromethane again, and combining the organic phases to obtain an intermediate I.
b preparation of intermediate II
S21 the dichloromethane solution of intermediate I was washed with 1200mL deionized water, allowed to stand for separation, leaving the organic phase.
S22, after the organic phase is cooled to below 10 ℃, 250g of 12M hydrochloric acid is added, the temperature of the reactant is controlled between 10 and 30 ℃, the reaction is stirred for 15 hours, and the reaction is monitored by HPLC.
After the reaction product was neutralized by adding 700g of 5% sodium hydrogencarbonate to S23, the aqueous phase was separated and removed, the organic phase was washed with 1L of deionized water, dried over 200g of anhydrous sodium sulfate and filtered to remove sodium sulfate, and after concentrating the filtrate under reduced pressure to dryness, it was slurried with 4L of n-heptane for 1h and filtered to remove insoluble matters, and the slurry was concentrated to dryness to obtain intermediate II.
c preparation of antihyperlipidemic drug intermediate
S31, after the intermediate II is dissolved in 1L of ethanol, 1L of 20wt% sodium hydroxide aqueous solution is added, the temperature of the reactant is raised to 65-75 ℃, the reaction is stirred for 6h, and the reaction is monitored by HPLC.
S32, concentrating the reactant under reduced pressure to remove ethanol, adding 1L of deionized water to dilute the reactant, controlling the temperature of the reactant below 20 ℃, and adjusting the pH value of the reactant to be 1-2 by using 12M hydrochloric acid.
S33, extracting the reactant twice by using methyl tertiary butyl ether, separating liquid to remove water phase, wherein the extraction dosage is 1L each time, combining organic phases, washing the organic phases by using 1L of 10wt% sodium chloride water, drying 200g of anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating filtrate under reduced pressure to remove 80% of methyl tertiary butyl ether, heating a reactor to 50-55 ℃, controlling the temperature of the reactant to 45-55 ℃, and dropwise adding 1L of n-heptane.
S34, cooling the reactant to 0 ℃ in 5 hours, continuously stirring and reacting for 5 hours, filtering the reactant, washing a filter cake with 320mL of n-heptane containing 25wt% of ethyl acetate, and drying in a vacuum environment at 40-50 ℃ to obtain 117.5g of off-white solid, wherein the HPLC purity is 96.5%, and the total yield is 75.6%.
117.5g of white solid obtained by high performance liquid chromatography and nuclear magnetic resonance analysis is determined to be the anti-hyperlipoic acid drug intermediate 8-oxo-2,2,14,14-tetramethyl pentadecane diacid, and reference is made to fig. 1 and 2.
In practical application, the off-white solid obtained in the embodiment can be applied to synthesis of the antihyperlipidemic drug bevacizidine.
Example 2
a preparation of intermediate I
S11, 200g of ethyl 2, 2-dimethyl-7-chloroheptanoate and 1200mL of N, N-dimethylacetamide were added to a reaction flask, and after stirring and mixing, 106g of p-toluenesulfonylmethisocyanide was added to the reaction flask, and stirred until the solid was completely dissolved.
S12, using an ice salt bath outside the reaction bottle, cooling the reaction bottle to minus 10 ℃ to control the temperature of reactants in the reaction bottle to be below 20 ℃, then adding 80g of sodium ethoxide into the reaction bottle, continuously controlling the temperature of the reactants to be between 0 and 10 ℃, stirring and reacting for 6 hours, and monitoring the completion of the reaction by HPLC.
S3, after controlling the temperature of the reactant below 20 ℃, pouring the reaction mixture into 1200mL of deionized water under stirring, extracting the reactant by using 1200mL of isopropyl acetate, standing for liquid separation, extracting the aqueous phase by using 600mL of isopropyl acetate again, and combining the organic phases to obtain an intermediate I.
b preparation of intermediate II
S21, washing the isopropyl acetate solution of the intermediate I by 1000mL of deionized water, standing for delamination, and reserving an organic phase.
S22, after the organic phase is cooled to below 10 ℃, 250g of 12M hydrochloric acid is added, the temperature of the reactant is controlled between 10 and 30 ℃, the reaction is stirred for 7 hours, and the reaction is monitored by HPLC.
After the reaction product was neutralized by adding 740g of 5wt% sodium hydrogencarbonate to S23, the aqueous phase was separated and removed, the organic phase was washed with 1L of deionized water, dried over 200g of anhydrous sodium sulfate and filtered to remove sodium sulfate, and after concentrating the filtrate under reduced pressure to dryness, it was slurried with 3L of n-heptane for 1 hour and filtered to remove insoluble matters, and the slurry was concentrated to dryness to obtain intermediate II.
c preparation of antihyperlipidemic drug intermediate
S31, dissolving the intermediate II in 1L of ethanol, adding 1L of 18wt% sodium hydroxide aqueous solution, heating the reactant to 65-75 ℃, stirring for reaction for 6h, and monitoring the end of the reaction by HPLC.
S32, concentrating the reactant under reduced pressure to remove ethanol, adding 1L of deionized water to dilute the reactant, cooling to 5 ℃ in an external ice-water bath of the reactor, controlling the temperature of the reactant to be below 20 ℃, and adjusting the pH value of the reactant to be 1-2 by using 6M hydrochloric acid.
S33, extracting a reactant twice by using methyl tertiary butyl ether, separating liquid to remove water phase, wherein the extraction dosage is 1L each time, combining organic phases, washing the organic phases by using 1L of 10wt% sodium chloride aqueous solution, drying by 200g of anhydrous sodium sulfate, filtering to remove sodium sulfate, concentrating filtrate under reduced pressure to remove 80% of methyl tertiary butyl ether, heating a reactor to 50-55 ℃, controlling the temperature of the reactant to 45-55 ℃, and dropwise adding 1L of n-heptane.
After the completion of the dropwise addition of S34 n-heptane, the reaction mixture was cooled to 0℃for 15 hours and stirred for 8 hours, after the completion of the HPLC monitoring reaction, the reaction mixture was filtered, and the filter cake was washed with 320mL of n-heptane containing 25wt% ethyl acetate and dried in a vacuum atmosphere at 40 to 50℃to give 111.0g of an off-white solid with an HPLC purity of 95.9% and a total yield of 71.5%.
In practical application, the off-white solid obtained in the embodiment can be applied to synthesis of the antihyperlipidemic drug bevacizidine.
The preparation method of the antihyperlipidemic drug intermediate 8-oxo-2,2,14,14-tetramethyl pentadecanedioic acid adopts 2, 2-dimethyl-7-chloroheptanoic acid ethyl ester to replace 7-bromo-2, 2-dimethyl heptanoic acid ethyl ester or 7-iodo-2, 2-dimethyl heptanoic acid ethyl ester in the existing method to react with p-toluenesulfonyl methyl isocyanate; the sodium ethoxide is used for replacing sodium tert-amyl alcohol, so that the cost of raw materials can be greatly reduced, the difficulty of obtaining raw materials is reduced, the application range of the process is improved, and simultaneously, the intermediate I and the mono-hydrolysis byproducts are extracted by using dichloromethane or isopropyl acetate, so that the utilization rate of the raw materials and the total yield of synthesis can be improved; in addition, the application directly uses the extract of the intermediate I for acidolysis reaction and directly uses the crude product of the intermediate II for saponification, thereby greatly simplifying the process flow.
The foregoing is merely a preferred embodiment of the present application, and it should be noted that modifications and variations could be made by those skilled in the art without departing from the technical principles of the present application, and such modifications and variations should also be regarded as being within the scope of the application.
Claims (10)
1. The preparation method of the antihyperlipidemic drug intermediate is characterized by comprising the following steps:
a, reacting 2, 2-dimethyl-7-chloroheptanoic acid ethyl ester and p-toluenesulfonyl methyl isocyanide in a polar aprotic solvent containing sodium ethoxide, then quenching the reaction solution by deionized water, and extracting and separating the solution by a polar solvent insoluble in water, wherein the obtained organic phase is an intermediate I;
b, after acidolysis of the intermediate I, neutralizing the reaction solution by using alkali, separating the solution, and concentrating the organic phase until the organic phase is dried to obtain an intermediate II;
c, dissolving the intermediate II in ethanol, hydrolyzing the intermediate II by using an alkaline aqueous solution, acidifying the reaction solution, extracting and separating liquid, concentrating an organic phase, adding n-heptane for crystallization, and filtering to obtain a filter cake which is the anti-hyperlipoic acid drug intermediate 8-oxo-2,2,14,14-tetramethyl pentadecane diacid.
2. The method for preparing an antihyperlipidemic drug intermediate according to claim 1, wherein step a comprises:
s11, after mixing 2, 2-dimethyl-7-chloroheptanoic acid ethyl ester and a polar aprotic solvent, adding p-toluenesulfonyl methyl isocyanate into a reactant, and stirring until a solid is completely dissolved;
s12, cooling the reactant to below 20 ℃, adding sodium ethoxide, continuously cooling to 0-10 ℃, stirring for reaction, and monitoring the completion of the reaction by HPLC;
s13, after controlling the temperature of the reactant below 20 ℃, adding deionized water while stirring, extracting the reactant by using a polar solvent which is insoluble in water, standing and separating the liquid, and obtaining an organic phase which is an intermediate I.
3. The process for the preparation of an antihyperlipidemic drug intermediate as claimed in claim 2, wherein in step a:
in the S11, the volume mass ratio of the polar aprotic solvent to the ethyl 2, 2-dimethyl-7-chloroheptanoate is 4-15 mL/g;
and/or in the S11, the molar equivalent ratio of the p-toluenesulfonyl methyl isocyanate to the ethyl 2, 2-dimethyl-7-chloroheptanoate is 0.5-0.7;
and/or the molar equivalent ratio of sodium ethoxide in S12 to p-toluenesulfonyl methyl isocyanate in S11 is 2.0-2.5;
and/or the molar equivalent ratio of sodium ethoxide in S12 to ethyl 2, 2-dimethyl-7-chloroheptanoate in S11 is 1.0-1.5;
and/or the volume ratio of deionized water in the S13 to the polar aprotic solvent in the S11 is 0.5-2;
and/or the volume ratio of the polar solvent insoluble in water in the S13 to the polar aprotic solvent in the S11 is 1-2;
and/or, in the step S12, stirring and reacting for more than or equal to 6 hours.
4. The process for preparing an antihyperlipidemic drug intermediate as claimed in claim 1 wherein step b comprises:
s21, washing the intermediate I by deionized water, standing for layering, and reserving an organic phase;
s22, cooling the organic phase to below 10 ℃, adding hydrochloric acid, stirring at 10-30 ℃ for reaction, and monitoring the completion of the reaction by HPLC;
s23, neutralizing the reaction liquid by using alkali, separating to remove the water phase, washing, drying the organic phase, concentrating the organic phase to be dry, adding n-heptane to pulp, filtering to obtain slurry, and concentrating the slurry to be dry to obtain an intermediate II.
5. The process for preparing an antihyperlipidemic drug intermediate according to claim 4, wherein,
in the step S21, the volume ratio of deionized water to the intermediate I is 1;
and/or the molar ratio of the hydrochloric acid in the S22 to the intermediate I in the S21 is 1-5;
and/or, in the step S22, the duration of the stirring reaction is greater than or equal to 15 hours;
and/or the molar ratio of the alkali in S23 to the hydrochloric acid in S22 is 0.7-1.1
And/or the volume ratio of the n-heptane in the S23 to the deionized water in the S21 is 3-4.
6. The method for preparing an antihyperlipidemic drug intermediate according to claim 4, wherein in S22, the concentration of hydrochloric acid is greater than 4M;
in S23, the alkali is selected from one or more of alkali metal hydrogencarbonate, alkali metal carbonate and alkali metal hydroxide.
7. The method for preparing an antihyperlipidemic drug intermediate according to claim 1, wherein step c comprises:
s31, after the intermediate II is dissolved in ethanol, adding an alkaline water solution, heating the reactant to 45-85 ℃, stirring for reaction, and monitoring the reaction by HPLC;
s32, concentrating the reactant to remove ethanol, adding deionized water, controlling the temperature of the reactant below 20 ℃, and adjusting the pH value of the reactant to 1-2 by utilizing hydrochloric acid;
s33, extracting a reactant by using a water-insoluble polar solvent, separating a liquid to remove a water phase, washing, drying an organic phase, concentrating the organic phase to remove 80% of the water-insoluble polar solvent, then raising the temperature of the reactant to 45-55 ℃, and dropwise adding n-heptane;
s34, maintaining the temperature of the reactant at-10-30 ℃, stirring for reaction, and filtering the reactant after the reaction is monitored by HPLC, wherein the obtained filter cake is the antihyperlipidemic drug intermediate 8-oxo-2,2,14,14-tetramethyl pentadecane diacid.
8. The process for preparing an antihyperlipidemic drug intermediate according to claim 7, wherein,
in the step S31, the stirring reaction time is longer than or equal to 6 hours;
and/or in the step S34, stirring and reacting for 5-10 hours;
and/or in the S31, the volume weight ratio of the ethanol to the intermediate II is 1-10 mL/g;
and/or, in S31, the volume ratio of ethanol to aqueous alkali is 1;
and/or the volume ratio of the ethanol in the S31 to the deionized water in the S32 is 0.5-2.5;
and/or the volume ratio of the polar solvent which is insoluble in water in the S33 to the ethanol in the S31 is 1-2;
and/or the volume ratio of the n-heptane in the S33 to the ethanol in the S31 is 0.2-1.
9. The process for preparing an antihyperlipidemic drug intermediate according to claim 7, wherein,
in the step S32, the concentration of hydrochloric acid is 2-12M;
and/or, in the step S31, the concentration of the aqueous alkali solution is 15-25wt%;
and/or, in S31, the aqueous alkali solution is selected from one or more of aqueous solutions of hydroxides of alkali metals.
10. The process for preparing an antihyperlipidemic drug intermediate according to any one of claims 1 to 5 and 7 to 8,
the polar aprotic solvent is selected from one or more of dimethylacetamide, dimethylformamide and azomethylpyrrolidone;
and/or the polar solvent which is insoluble in water is selected from one or more of liquid chlorinated hydrocarbon of C1-C8, carboxylic ester and ether.
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| US20070155704A1 (en) * | 2003-12-24 | 2007-07-05 | Esperion Therapeutics, Inc. | Ketone compounds and compositions for cholesterol management and related uses |
| CN112521282A (en) * | 2020-12-02 | 2021-03-19 | 苏州汉德创宏生化科技有限公司 | Bepaidic acid intermediate and synthesis method thereof |
| US20210139405A1 (en) * | 2019-06-21 | 2021-05-13 | Esperion Therapeutics, Inc. | Methods of making bempedoic acid and compositions of the same |
| WO2022149161A1 (en) * | 2021-01-05 | 2022-07-14 | Dr. Reddy's Laboratories Limited | Process for preparation of bempedoic acid and its intermediates |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070155704A1 (en) * | 2003-12-24 | 2007-07-05 | Esperion Therapeutics, Inc. | Ketone compounds and compositions for cholesterol management and related uses |
| US20210139405A1 (en) * | 2019-06-21 | 2021-05-13 | Esperion Therapeutics, Inc. | Methods of making bempedoic acid and compositions of the same |
| CN112521282A (en) * | 2020-12-02 | 2021-03-19 | 苏州汉德创宏生化科技有限公司 | Bepaidic acid intermediate and synthesis method thereof |
| WO2022149161A1 (en) * | 2021-01-05 | 2022-07-14 | Dr. Reddy's Laboratories Limited | Process for preparation of bempedoic acid and its intermediates |
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