CN111170855B - Compound and method for synthesizing 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid by using same - Google Patents
Compound and method for synthesizing 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid by using same Download PDFInfo
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Abstract
The invention belongs to the field of chemical synthesis, and relates to a compound, which has the following structural formula:
R 1 ，R 2 ，R 3 each independently is C1-C6 alkyl, alkenyl or cycloalkyl. The method for synthesizing 8-hydroxy-2,2,14,14-tetramethyl pentadecanedioic acid by using the compound has the advantages of short reaction step, simplified operation and greatly reduced production cost. (3) Avoids using toxic and dangerous raw materials and is safer.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and relates to a compound and a method for synthesizing 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid by using the compound.
Background
8-hydroxy-2,2,14,14-tetramethylpentadecanedioic Acid (Bempedoic Acid), also known as ETC-1002, has the following structural formula:
bempedoic Acid was developed by Imperion Therapeutic Inc., is a novel ATP Citrate Lyase (ACL) inhibitor, can lower cholesterol biosynthesis by up-regulating LDL receptors and lower LDL-C levels, and can be used for treating dyslipidemia and reducing the risk of other cardiovascular diseases. Compared with the statins widely used clinically at present, the Bempedoic Acid has the advantages of better tolerance and can be used for treating LDL-C which cannot be inhibited by the existing method when being used together with the statins.
WO2004067489 reports the synthetic route for Bempedoic Acid as follows:
the method takes ethyl isobutyrate and 1,5-dibromopentane as initial raw materials, and obtains 7-bromo-2,2-dimethylheptanoic acid ethyl ester (compound 1) by lithium diisopropylamide condensation at low temperature; under the strong alkaline condition, the compound 1 and p-methyl benzenesulfonyl methyl isocyan are catalyzed by tetrabutyl ammonium iodide to prepare a adduct of the p-methyl benzenesulfonyl methyl isocyan (a compound 2); hydrolyzing the compound 2 under an acidic condition to obtain 8-oxo-2,2,14,14-tetramethyl pentadecanedioic acid diethyl ester (compound 3); the compound 3 is subjected to alkaline hydrolysis in an ethanol system and then is acidified to obtain 8-oxo-2,2,14,14-tetramethylpentadecanedioic acid (compound 4); and reducing the compound 4 in methanol by using sodium borohydride, and finally acidifying by using hydrochloric Acid to obtain a target product Bempedoic Acid. The p-methyl benzenesulfonyl methyl isocyanic acid used in the second step of the process has high toxicity and poor atom economy, and uses sodium hydride which is a dangerous material, so that the process is not beneficial to industrial production operation. Potential genotoxic impurities (p-toluenesulfonyl derivatives) are generated after the third step of hydrolysis, which is not beneficial to the quality control of the raw material medicaments. It is also necessary to purify compound 3 by column chromatography. In a word, the synthesis method has low efficiency, large loss and high potential risk, and is not suitable for industrial production.
CN109721486a reports a synthetic method for preparing Bempedoic Acid from compound 4. The method comprises the steps of converting a compound 4 into a corresponding dicarboxylic acid salt, and then carrying out operations of reduction by using sodium borohydride, acid precipitation, organic solvent extraction, organic solvent evaporation, and the like to obtain the Bempedioi acid. The method requires that all the organic solvent is evaporated to dryness to obtain the product, the operation cannot be realized in industrial production, and the product obtained by the method is not subjected to any crystallization or recrystallization, so that the product quality is difficult to ensure.
Therefore, it is necessary to provide a method for preparing 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid, which is suitable for industrial production.
Disclosure of Invention
The invention designs a brand-new path for synthesizing the Bempedoic Acid, has short steps and mild conditions, and the used reagents and operation are beneficial to industrial production.
An object of the present invention is to provide a compound i having the following structural formula:
R 1 ，R 2 ，R 3 each independently is C1-C6 alkyl, alkenyl or cycloalkyl, R 1 ，R 2 ，R 3 May represent the same substituent.
The second purpose of the invention is to provide the application of the compound, which is used for synthesizing 8-hydroxy-2,2,14,14-tetramethyl pentadecanedioic Acid (Bempedoic Acid).
The direct synthetic route is as follows:
R 1 ，R 2 ，R 3 each independently is C1-C6 alkyl, alkenyl or cycloalkyl.
The compound I reacts to generate 8-keto-2,2,14,14-tetramethylpentadecanedioic acid under the alkaline condition, and then the 8-keto-2,2,14,14-tetramethylpentadecanedioic acid is reduced to generate 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid.
The compound I is synthesized from 6-halogen-2,2-dimethyl hexanoate and acetone dicarboxylic acid diester.
The synthetic route is as follows:
R 1 ，R 2 ，R 3 each independently is C1-C6 alkyl, alkenyl and cycloalkyl, and X is Cl, br or I.
6-halo-2,2-dimethylhexanoate can be synthesized by the following route:
R 1 is C1-C6 alkyl, alkenyl and cycloalkyl substituents, X 1 And X 2 Each independently Cl, br or I. X 1 And X 2 When different, X is X 1 And X 2 Of lower activity, i.e. when X is 1 And X 2 Respectively Cl, br or Cl, when I, X is Cl; when X is present 1 And X 2 When the compounds are Br and I respectively, X is Br; when X is present 1 And X 2 When the same Cl, br and I are used, X is the corresponding Cl, br and I.
The invention also provides a complete synthetic route of 8-hydroxy-2,2,14,14-tetramethyl pentadecanedioic acid, which comprises the following steps:
R 1 ，R 2 ，R 3 each independently of the other is C1-C6 alkyl, alkenyl or cycloalkyl, X 1 And X 2 Each independently Cl, br or I. X 1 And X 2 When different, X is X 1 And X 2 Of lower activity, i.e. when X is 1 And X 2 Respectively Cl, br or Cl, when I, X is Cl; when X is present 1 And X 2 When the compounds are Br and I respectively, X is Br; when X is present 1 And X 2 When the same Cl, br and I are used, X is the corresponding Cl, br and I.
The specific operation steps are as follows:
s-1. Mixing isobutyrate with 1,4-dihalobutane;
s-2, adding alkali into the solution obtained in the step S-1, and reacting to obtain 6-halogen-2,2-dimethyl hexanoate; the base is lithium diisopropylamide or sodium bis (trimethylsilyl) amide;
s-3, adding 6-halogen-2,2-dimethyl hexanoate into a solvent;
s-4, adding dialkyl acetone dicarboxylate, alkali and potassium iodide into the solution obtained in the step S-3, heating a reaction system, and controlling the temperature to be 30-80 ℃ for reaction;
s-5, filtering the reaction liquid obtained in the step S-4, adding water and alkali into the mother liquid, heating to 60-100 ℃ for reaction, and adjusting acid to obtain 8-keto-2,2,14,14-tetramethylpentadecanedioic acid; or filtering the reaction liquid obtained in the S-4 step, adding acid into the mother liquid, heating to 60-100 ℃ for reaction, and obtaining 8-keto-2,2,14,14-tetramethylpentadecanedioic acid.
S-6, adding 8-keto-2,2,14,14-tetramethylpentadecanedioic acid into a solvent, adding alkali and a reducing agent to react to obtain 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid.
The more detailed operation steps are as follows:
(1) Isobutyrate was mixed with 1,4-dihalobutane in a solvent. The solvent herein means tetrahydrofuran, methyl t-butyl ether, toluene or n-heptane, preferably tetrahydrofuran; the volume ratio of solvent to substrate is 1 to 50 volumes, preferably 5 to 10 volumes. The Neat reaction can also be carried out without any solvent. The molar ratio of isobutyrate to 1,4-dihalobutane was 1:1-5, preferably 1:1.1-2;
(2) To the above solution was added a base. The base here means lithium diisopropylamide or sodium bis (trimethylsilyl) amide, preferably lithium diisopropylamide; the temperature is controlled at-70-30 ℃, preferably 0-10 ℃, and the molar ratio of isobutyrate to base is 1:1.02-1.1, preferably 1:1.05;
(3) Stirring for 1 hour;
(4) A terminating reagent is added to the reaction solution. The terminating reagent here means water, saturated ammonium chloride or dilute hydrochloric acid, preferably water; the amount added is 0.2-10 volumes, preferably 0.2-0.3 volumes; controlling the temperature to be lower than 20 ℃, preferably lower than 10 ℃;
(5) 3N hydrochloric acid was added dropwise to pH =6-7. Controlling the temperature to be lower than 20 ℃;
(6) Separating out an organic phase, washing the organic phase with saturated saline water, concentrating, and performing vacuum rectification to obtain 6-halogen-2,2-dimethyl hexanoate;
(7) 6-halo-2,2-dimethylhexanoate was added to the solvent. The solvent refers to one or a mixture of several of methanol, ethanol, N-propanol, isopropanol, N-butanol, isobutanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetone, butanone, methyl isobutyl ketone, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone; the volume ratio of solvent to substrate is 5-50 volumes, preferably 5-10 volumes;
(8) Acetone dicarboxylic acid diester was added. The molar ratio of 6-halo-2,2-dimethylhexanoate to acetone dicarboxylic acid diester is 1:0.2-0.8, preferably 1:0.42-0.6;
(9) A base is added. The base is one or more of lithium diisopropylamide, sodium hydride, sodium bis (trimethylsilyl) amide, sodium amide, potassium carbonate, cesium carbonate, sodium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium ethoxide, diisopropylethylamine and triethylamine, and potassium carbonate is preferred; the molar ratio is 1:2-5 preferably 1:2.5;
(10) Potassium iodide was added. The molar ratio is 1:0.1-2, preferably 1:1;
(11) The reaction system was heated. Controlling the temperature to be 30-80 ℃ for reaction, preferably 60-70 ℃;
(12) The reaction system is filtered and water, base or acid is added to the mother liquor. The alkali here refers to sodium hydroxide, potassium hydroxide, lithium hydroxide, in a ratio of 1:5-10, preferably 1:9; here, the acid refers to hydrochloric acid, sulfuric acid, in a ratio of 1:5-20, preferably 1:10, in this case, the acid adjusting operation (15) is not performed.
(13) Heating to 60-100 deg.C, preferably 80-90 deg.C;
(14) After the reaction is finished, concentrating the reaction system, adding water for dissolving, adding a solvent for mixing, and separating out a water phase, wherein the solvent is methyl tert-butyl ether and ethyl acetate; other water immiscible solvents such as toluene, isopropyl acetate, methylene chloride, and the like may also be used.
(15) Adjusting the pH of the aqueous phase to =1-2 with an acid, wherein the acid is hydrochloric acid, sulfuric acid, and the temperature is in the range of 0-30 ℃, preferably 0-10 ℃;
(16) Filter and dissolve the filter cake in the solvent and wash the organic phase with water. The solvents herein are methyl tert-butyl ether, ethyl acetate;
(17) Concentrating the organic phase after liquid separation, and recrystallizing in a solvent to obtain 8-keto-2,2,14,14-tetramethylpentadecanedioic acid, wherein the solvent refers to one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, methyl tert-butyl ether, n-heptane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, butanone, 1,4-dioxane, toluene, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, dichloromethane and water. The volume ratio of solvent to substrate is 1 to 50 volumes, preferably 5 to 10 volumes. The filter cake obtained in step (16) can also be directly recrystallized in a solvent.
(18) 8-keto-2,2,14,14-tetramethylpentadecanedioic acid was added to the solvent. The solvent refers to water, methanol and ethanol; the volume ratio of solvent to substrate is 5-50 volumes, preferably 5-10 volumes;
(19) Adding a base, wherein the base refers to sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine and diisopropylethylamine, and the molar ratio of the substrate to the base is 1:2-3, preferably 1:2.5;
(20) Adding a reducing agent, wherein the reducing agent comprises sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride and other common reducing agents. The molar ratio of the substrate to the reducing agent is 1:0.9-1.1, preferably 1:1.02;
(21) Adjusting the pH =1-2 using an acid, where acid refers to dilute hydrochloric acid, dilute sulfuric acid, at a temperature in the range of 0-30 ℃, preferably 0-10 ℃;
(22) Extracting the crude product with a solvent extraction system, wherein the solvent is methyl tert-butyl ether, ethyl acetate, isopropyl acetate;
(23) Concentrating the organic phase, adding a solvent to crystallize and filtering to obtain 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid, wherein the solvent refers to one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, methyl tert-butyl ether, n-heptane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, butanone, 1,4-dioxane, toluene, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, dichloromethane and water. Dichloromethane is preferred.
Compared with the prior art, the invention has the following beneficial effects:
(1) A novel process for the preparation of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid is provided.
(2) The reaction steps are short, the operation is simplified, and the production cost is greatly reduced. The p-methyl benzenesulfonyl methyl isocyano is avoided, the atom economy is better, and the production process is greener.
(3) Avoids using toxic and dangerous raw materials and is safer.
(4) Avoids generating potential genotoxic impurities such as p-toluenesulfonic acid derivatives and the like, and is more beneficial to the control of the quality of the raw material medicaments of the final product.
(5) The final product is purified by adopting a crystallization mode, so that impurities are effectively removed, and the purity of the product is improved.
Detailed Description
The invention is further illustrated by the following examples; it should be noted that a person skilled in the art may make several improvements and optimizations without departing from the inventive concept, and these improvements and optimizations should also be considered within the scope of protection of the present invention.
The test materials and reagents referred to in the following are commercially available unless otherwise specified.
First step of
Example 1
Adding 300g (2.58 mol) ethyl isobutyrate, 724.9g (3.36mol, 1.3eq) 1,4-dibromobutane into 1500ml tetrahydrofuran, starting stirring, cooling to-10-0 ℃, controlling the temperature to-10 ℃, dropwise adding 1.36L lithium diisopropylamide (2N, 2.71mol, 1.05eq.) at the temperature of-10 ℃, after dropwise adding, GC shows that the conversion rate is 76.14%, adding 100ml water for quenching reaction, adjusting the pH value by using 3N HCl =6-7 (980 ml), separating liquid, washing an organic phase by using 600ml sodium chloride saturated with 2, concentrating, rectifying, collecting the vacuum degree 180Pa, collecting the distillate fraction at 82-87 ℃ to obtain 423.7g ethyl 2, 2-dimethyl-6-bromohexanoate, and obtaining the yield: 65.3 percent.
Other examples are described below, differing from example 1 as shown in the following table:
second and third step
Example 24
Adding 60g (239 mmol) of 2,2-dimethyl-6-bromoethyl hexanoate into 300ml of ethanol, adding 26.6g (131 mmol) of 1,3-acetonedicarboxylic acid diethyl ester, 49.5g (359 mmol) of potassium carbonate and 39.7g (239 mmol) of potassium iodide sequentially under stirring, heating to 65-70 ℃, keeping the temperature for 20 hours, cooling the system to room temperature, filtering, leaching a filter cake with 50ml of ethanol, adding 43g (1075 mmol) of sodium hydroxide into a mother solution, heating to reflux, keeping the reflux for 4 hours, concentrating the system after the NMR tracing reaction is finished, adding water to dissolve 400ml of water, extracting with 200ml of methyl tert-butyl ether after dissolution, adjusting the pH of an aqueous phase to be between =1 and 2 by using 36% concentrated hydrochloric acid, controlling the temperature of the system to be between 0 and 10 ℃, stirring for 15 minutes, filtering, dissolving the filter cake with 300ml of methyl tert-butyl ether, washing with 200ml of methyl tert-butyl ether, concentrating an upper layer of purified organic phase after the separation, and then using methyl: n-heptane =1:5 (V: V) is recrystallized to obtain a white solid, namely 8-keto-2,2,14,14-tetramethylpentadecanedioic acid, and the yield of the two steps is 57.2 percent.
Example 25
Adding 30g (119 mmol) of 2,2-dimethyl-6-bromoethyl hexanoate into 200ml of tetrahydrofuran, sequentially adding 12.08g (59.7 mmol) of 1,3-acetone dicarboxylic acid diethyl ester, 19g (137.5 mmol) of potassium carbonate and 2g (12.0 mmol) of potassium iodide while stirring, heating to reflux, keeping the temperature for 100 hours, cooling the system to room temperature, filtering, leaching the filter cake with 20ml of tetrahydrofuran, concentrating the mother liquor, adding 90ml of ethanol, 120ml of purified water and 21.3g (535 mmol) of sodium hydroxide, heating to reflux, keeping reflux for 4 hours, concentrating the system after the completion of NMR tracking reaction, adding 80ml of water for dissolving, extracting with 100ml of methyl tert-butyl ether after dissolution, regulating the pH of the water phase to be 1-2 by using 36% concentrated hydrochloric acid, controlling the system temperature to be 0-10 ℃ in the whole process, stirring for 15 minutes, filtering, recrystallizing the filter cake by using 80ml of n-heptane to obtain a light yellow solid, namely 8-keto-2,2,14,14-tetramethyl diacid, and the yield of fifteen (61.5.5.5).
Example 26
Adding 10g (39.8 mmol) of 2,2-dimethyl-6-bromoethyl hexanoate into 50ml of tetrahydrofuran, adding 4.03g (19.9 mmol) of 1,3-acetone diethyl dicarboxylate, 6.88g (49.8 mmol) of potassium carbonate, 6.61g (39.8 mmol) of potassium iodide and 5ml of DMF in sequence under stirring, heating to reflux, keeping the temperature for 22 hours, cooling the system to room temperature, filtering, leaching a filter cake with 10ml of tetrahydrofuran, concentrating a filtered mother liquor, adding 50ml of ethanol, 50ml of purified water and 7.2g (180 mmol) of sodium hydroxide under stirring, heating to reflux, keeping the reflux for 4 hours after the completion of NMR tracking reaction, concentrating the system to dryness, adding 50ml of water for dissolving, extracting with 40ml of methyl tert-butyl ether after dissolution, separating, adjusting the pH =1-2 of a lower aqueous phase with 36% of concentrated hydrochloric acid under stirring, controlling the temperature of the system to 0-10 ℃ after the completion of the whole process, adjusting the temperature, 15 minutes, filtering, washing the filter cake with 50ml of methyl tert-butyl ether, separating, dissolving an upper phase, purifying an organic tert-butyl ether phase, and purifying the organic tert-butyl ether: n-heptane =1:5 (V: V) recrystallization to obtain a white solid, namely 8-keto-2,2,14,14-tetramethylpentadecanedioic acid. The yield of the two steps is 55.2%.
Example 27
Adding 10g (39.8 mmol) of 2,2-dimethyl-6-bromoethyl hexanoate into 50ml of tetrahydrofuran, sequentially adding 0.81g (4.0 mmol) of 1,3-acetone dicarboxylic acid diethyl ester, 6.88g (49.8 mmol) of potassium carbonate, 6.61g (39.8 mmol) of potassium iodide and 5ml of DMF under stirring, heating to reflux, preserving heat for 22 hours, cooling the system to room temperature, filtering, leaching a filter cake with 10ml of tetrahydrofuran, concentrating a filtered mother liquor, adding 50ml of ethanol, 50ml of purified water and 7.2g (180 mmol) of sodium hydroxide under stirring, heating to reflux after adding, keeping reflux for 4 hours, concentrating the system to dryness after NMR tracking reaction is finished, adding 50ml of water for dissolving, extracting with 40ml of methyl tert-butyl ether, separating, adjusting the pH =1-2 of a lower-layer aqueous phase by using 36% of concentrated hydrochloric acid under stirring, controlling the temperature of the system to be 0-10 ℃ in the whole process, adjusting the temperature for 15 minutes, filtering, washing by using 40ml of methyl tert-butyl ether, separating a filtered cake, and purifying a white concentrated organic phase, and separating a dried ketone phase, and obtaining a white solid, and separating a 3763-378-tetramethyl ketone phase. The yield of the two steps is 8.1%.
Example 28
Adding 10g (39.8 mmol) of 2,2-dimethyl-6-bromoethyl hexanoate into 50ml of tetrahydrofuran, sequentially adding 8.04g (39.8 mmol) of 1,3-acetone dicarboxylic acid diethyl ester, 6.88g (49.8 mmol) of potassium carbonate, 6.61g (39.8 mmol) of potassium iodide and 5ml of DMF under stirring, heating to reflux, keeping the temperature for 22 hours, cooling the system to room temperature, filtering, leaching a filter cake with 10ml of tetrahydrofuran, concentrating a filtered mother liquor, adding 50ml of ethanol, 50ml of purified water and 7.2g (180 mmol) of sodium hydroxide under stirring, heating to reflux, keeping the reflux for 4 hours after the temperature preservation is finished, concentrating the system to dryness after NMR tracking reaction is finished, adding 50ml of water for dissolving, extracting with 40ml of methyl tert-butyl ether, separating, adjusting the pH =1-2 of a lower-layer water phase by using 36% of acid under stirring, controlling the temperature of the system to be 0-10 ℃ in the whole process, adjusting the temperature, stirring, filtering for 15 minutes, washing the filtered cake with 40ml of methyl tert-butyl ether, separating, purifying a white concentrated organic phase, and separating a concentrated acetone phase, and obtaining a white concentrated acetone-3763-ethyl lactate-ethyl acetate phase, purifying solid. The yield of the two steps is 5.2%.
Example 29
Adding 10g (42.2 mmol) of 2,2-dimethyl-6-bromomethyl hexanoate into 50ml of tetrahydrofuran, adding 4.27g (21.1 mmol) of 1,3-acetone diethyl dicarboxylate, 7.29g (52.8 mmol) of potassium carbonate, 7.01g (42.2 mmol) of potassium iodide and 5ml of DMF in sequence under stirring, heating to reflux, keeping the temperature for 22 hours, cooling the system to room temperature, filtering, leaching a filter cake with 10ml of tetrahydrofuran, concentrating a filtered mother liquor, adding 50ml of ethanol, 50ml of purified water and 7.2g (180 mmol) of sodium hydroxide under stirring, heating to reflux, keeping the reflux for 4 hours after the NMR tracing reaction is completed, concentrating the system to dryness, adding 50ml of water for dissolving, extracting with 40ml of methyl tert-butyl ether after dissolution, separating, adjusting the pH of a lower aqueous phase with 36% of hydrochloric acid to 1-2 under stirring, controlling the temperature of the system to 0-10 ℃ after the whole process is completed, adjusting the temperature, stirring for 15 minutes, filtering, washing the filter cake with 20ml of methyl tert-butyl ether, separating, dissolving an upper phase, purifying an organic tert-butyl ether phase, and purifying the organic tert-butyl ether: n-heptane =1:5 (V: V) recrystallization to obtain a white solid, namely 8-keto-2,2,14,14-tetramethyl pentadecane diacid. The yield of the two steps is 52.8%.
Example 30
Adding 10g (48.4 mmol) of 2,2-dimethyl-6-chlorohexanoic acid ethyl ester into 50ml of tetrahydrofuran, adding 4.89g (24.2 mmol) of 1,3-acetone dicarboxylic acid diethyl ester, 8.36g (60.5 mmol) of potassium carbonate, 8.03g (48.4 mmol) of potassium iodide and 5ml of DMF in sequence under stirring, heating to reflux, keeping the temperature for 22 hours, cooling the system to room temperature, filtering, leaching a filter cake with 10ml of tetrahydrofuran, concentrating a filtered mother liquor, adding 50ml of ethanol, 50ml of purified water and 7.2g (180 mmol) of sodium hydroxide under stirring, heating to reflux after adding, keeping the reflux for 4 hours, concentrating the system to dryness after NMR tracing reaction is completed, adding 50ml of water for dissolving, extracting with 40ml of methyl tert-butyl ether after dissolving, separating, adjusting the pH =1-2 of a lower-layer aqueous phase by using 36% of concentrated hydrochloric acid under stirring, controlling the temperature of the system to be 0-10 ℃ after the whole process is finished, adjusting the temperature for 15 minutes, filtering, washing the filter cake with 50ml of methyl tert-butyl ether, separating, purifying an upper layer by using 20ml of organic tert-butyl ether, and concentrating a concentrated solution: n-heptane =1:5 (V: V) recrystallization to obtain a white solid, namely 8-keto-2,2,14,14-tetramethylpentadecanedioic acid. The yield of the two steps is 45.5%.
Example 31
Adding 10g (39.8 mmol) of 2,2-dimethyl-6-bromoethyl hexanoate into 50ml of tetrahydrofuran, adding 3.47g (19.9 mmol) of 1,3-dimethyl acetonedicarboxylate, 6.88g (49.8 mmol) of potassium carbonate, 6.61g (39.8 mmol) of potassium iodide and 5ml of DMF in sequence under stirring, heating to reflux, keeping the temperature for 22 hours, cooling the system to room temperature, filtering, leaching the filter cake with 10ml of tetrahydrofuran, concentrating the filtered mother liquor, adding 50ml of ethanol, 50ml of purified water and 7.2g (180 mmol) of sodium hydroxide under stirring, heating to reflux, keeping the reflux for 4 hours after the NMR tracing reaction is completed, concentrating the system to dryness, adding 50ml of water for dissolving, extracting with 40ml of methyl tert-butyl ether after dissolution, separating, adjusting the lower aqueous phase with 36% of hydrochloric acid under stirring to pH =1-2, controlling the temperature of the system to 0-10 ℃ after the whole process is completed, adjusting the temperature, stirring for 15 minutes, filtering, washing the filter cake with 20ml of methyl tert-butyl ether, separating, purifying the filtered organic phase by using 20ml of concentrated tert-butyl ether: n-heptane =1:5 (V: V) to obtain a white solid, namely 8-keto-2,2,14,14-tetramethylpentadecanedioic acid. The yield of the two steps is 54.6%.
The fourth step
Synthesis of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid from Compound II
Example 32
To 340ml of water were added 42.5g of 8-keto-2,2,14,14-tetramethylpentadecanedioic acid (124 mmol), 12.4g of sodium hydroxide (310 mmol), the solution was stirred at 20 to 30 ℃, 4.7g of sodium borohydride (124 mmol) was added, after the follow-up reaction was completed, pH =1-2 was adjusted with 120ml of 4N HCl, 210ml of MTBE was added, the liquid was separated, the aqueous phase was extracted once with 120ml of MTBE, the organic phases were combined, and washed once with 210ml of water. Concentrating the organic phase, adding 425ml of n-heptane, heating to 50-60 ℃, keeping the temperature for 0.5 hour, cooling to 15-25 ℃, stirring overnight, and performing suction filtration to obtain 40.90g of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid, wherein the yield is as follows: 95.67 percent.
Example 33
To 100ml of water were added 10g of 8-keto-2,2,14,14-tetramethylpentadecanedioic acid (29.2 mmol) and 3.06g of lithium hydroxide (73 mmol), the solution was stirred at 20 to 30 ℃ and dissolved, 1.11g of sodium borohydride (29.2 mmol) was added, and after the completion of the tracking reaction, pH =1-2 was adjusted with 120ml of 4N HCl, 210ml of MTBE was added, liquid separation was performed, the aqueous phase was extracted once with 120ml of MTBE, and the organic phases were combined and washed once with 210ml of water. Concentrating the organic phase, adding 425ml of n-heptane, heating to 50-60 ℃, keeping the temperature for 0.5 hour, cooling to 15-25 ℃, stirring overnight, and performing suction filtration to obtain 9.58g of 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid, wherein the yield is as follows: 95.22 percent.
Claims (15)
1. A method of synthesizing 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid, comprising the steps of:
(1) Reacting 6-halogen-2,2-dimethyl hexanoate with acetone dicarboxylic acid diester in a solvent in the presence of potassium carbonate and potassium iodide to obtain a compound I, wherein the reaction equation is as follows:
wherein R1 is C 1 -C 6 Alkyl, propenyl or cis-3-hexenyl, R2, R3 are each independently C 1 -C 6 Alkyl, X is Cl or Br,
(2) Carrying out hydrolysis reaction on the compound I obtained in the step (1) under alkaline conditions, and converting a hydrolysate into a compound II in an acidic environment, wherein the reaction equation is as follows:
wherein R1 is C 1 -C 6 Alkyl, propenyl or cis-3-hexenyl, R2, R3 are each independently C 1 -C 6 Alkyl, X is Cl or Br,
compound II is purified by crystallization/recrystallization,
(3) Reducing the purified compound II to obtain 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid, wherein the reaction equation is as follows:
2. the method of claim 1, wherein step (1) has one or more characteristics selected from the group consisting of:
the solvent is selected from one or more of methanol, ethanol, N-propanol, isopropanol, N-butanol, isobutanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetone, butanone, methyl isobutyl ketone, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone, and/or mixed solvent of methanol, ethanol, N-propanol, isopropanol, N-butanol, isobutanol, tert-butanol, tetrahydrofuran, acetone, methyl-N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone, and/or
The reaction temperature is 65-70 ℃.
3. The process of claim 1, wherein the molar ratio of 6-halo-2,2-dimethylhexanoate to acetone dicarboxylic acid diester in step (1) is 1:0.2-0.8.
4. The method of claim 1, wherein the reaction temperature in step (2) is 60-100 ℃.
5. The method according to claim 1, wherein the acid in step (2) is selected from hydrochloric acid or sulfuric acid.
6. The method according to claim 1, wherein the reduction in step (3) is carried out under alkaline conditions using a reducing agent.
7. The process according to claim 6, wherein the base used is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine and diisopropylethylamine.
8. The process according to claim 6, wherein the reducing agent is selected from sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.
9. The method according to claim 1, wherein the crystallization/recrystallization of compound II comprises the steps of:
adding the compound II into a solvent, heating to 50-80 ℃, cooling to 15-25 ℃ after the solid is dissolved, stirring and filtering to obtain a purified compound II,
wherein the solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, methyl tert-butyl ether, n-heptane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, butanone, 1,4-dioxane, toluene, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, dichloromethane and water.
10. The method of claim 1 further comprising crystallizing/recrystallizing 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid, wherein crystallizing/recrystallizing 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid comprises the steps of:
concentrating the organic phase obtained by treating the reaction liquid in the step (3), adding a solvent, heating to 50-80 ℃, cooling to 15-25 ℃ after dissolving the solid, stirring and filtering to obtain 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid crystals,
wherein the solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, methyl tert-butyl ether, n-heptane, acetone, tetrahydrofuran, 2-methyltetrahydrofuran, butanone, 1,4-dioxane, toluene, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, dichloromethane and water.
11. A process for the preparation of compound I, characterized in that the process comprises step (1): reacting 6-halogen-2,2-dimethyl hexanoate with acetone dicarboxylic acid diester in a solvent in the presence of potassium carbonate and potassium iodide to obtain the compound I, wherein the reaction equation is as follows:
and X is Cl or Br.
12. The method of claim 11, wherein step (1) has one or more characteristics selected from the group consisting of:
the solvent is selected from one or more of methanol, ethanol, N-propanol, isopropanol, N-butanol, isobutanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, acetone, butanone, methyl isobutyl ketone, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone, and/or mixed solvent of methanol, ethanol, N-propanol, isopropanol, N-butanol, isobutanol, tert-butanol, tetrahydrofuran, acetone, methyl-N-dimethylacetamide, dimethyl sulfoxide, acetonitrile and 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone, and/or
The reaction temperature is 65-70 ℃.
13. The method of claim 11, wherein the molar ratio of 6-halo-2,2-dimethylhexanoate to acetonedicarboxylic acid diester in step (1) is 1:0.2-0.8.
14. The method of claim 11, wherein the 6-halo-2,2-dimethylhexanoate is prepared by a method comprising the steps of:
(1-i) reacting isobutyrate with 1,4-dihalobutane under basic conditions to obtain 6-halo-2,2-dimethylhexanoate, wherein the reaction equation is as follows:
15. The method according to claim 14, wherein the base used in step (1-i) is selected from lithium diisopropylamide and sodium bis (trimethylsilyl) amide.
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