CN112047840A - Synthesis method of 7-bromo-2, 2-dimethylheptanoic acid ethyl ester and product obtained by synthesis - Google Patents
Synthesis method of 7-bromo-2, 2-dimethylheptanoic acid ethyl ester and product obtained by synthesis Download PDFInfo
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- SYRIIFZUZOIRNU-UHFFFAOYSA-N ethyl 7-bromo-2,2-dimethylheptanoate Chemical compound CCOC(=O)C(C)(C)CCCCCBr SYRIIFZUZOIRNU-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 238000001308 synthesis method Methods 0.000 title claims abstract description 18
- 230000015572 biosynthetic process Effects 0.000 title abstract description 6
- 238000003786 synthesis reaction Methods 0.000 title abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 60
- WDAXFOBOLVPGLV-UHFFFAOYSA-N ethyl isobutyrate Chemical compound CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 claims abstract description 54
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000012312 sodium hydride Substances 0.000 claims abstract description 33
- 229910000104 sodium hydride Inorganic materials 0.000 claims abstract description 33
- IBODDUNKEPPBKW-UHFFFAOYSA-N 1,5-dibromopentane Chemical compound BrCCCCCBr IBODDUNKEPPBKW-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000002904 solvent Substances 0.000 claims abstract description 20
- 239000002994 raw material Substances 0.000 claims abstract description 6
- VGGNVBNNVSIGKG-UHFFFAOYSA-N n,n,2-trimethylaziridine-1-carboxamide Chemical group CC1CN1C(=O)N(C)C VGGNVBNNVSIGKG-UHFFFAOYSA-N 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 239000012295 chemical reaction liquid Substances 0.000 claims description 22
- 238000010791 quenching Methods 0.000 claims description 22
- TVQGDYNRXLTQAP-UHFFFAOYSA-N heptanoic acid ethyl ester Natural products CCCCCCC(=O)OCC TVQGDYNRXLTQAP-UHFFFAOYSA-N 0.000 claims description 21
- 239000012043 crude product Substances 0.000 claims description 19
- 238000005406 washing Methods 0.000 claims description 19
- 230000000171 quenching effect Effects 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 abstract description 10
- 238000009776 industrial production Methods 0.000 abstract description 10
- 229910052744 lithium Inorganic materials 0.000 abstract description 10
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 6
- 239000003638 chemical reducing agent Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 239000003513 alkali Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000012074 organic phase Substances 0.000 description 28
- 239000008213 purified water Substances 0.000 description 23
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 16
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 238000010438 heat treatment Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 238000000926 separation method Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 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 description 5
- 208000032928 Dyslipidaemia Diseases 0.000 description 5
- 208000017170 Lipid metabolism disease Diseases 0.000 description 5
- LDURYVDWYUCWGK-UHFFFAOYSA-N diethyl 2,2,14,14-tetramethyl-8-oxopentadecanedioate Chemical compound CCOC(=O)C(C)(C)CCCCCC(=O)CCCCCC(C)(C)C(=O)OCC LDURYVDWYUCWGK-UHFFFAOYSA-N 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- LZJHACNNMBYMSO-UHFFFAOYSA-N 1,1-dimethyl-3-propylurea Chemical compound CCCNC(=O)N(C)C LZJHACNNMBYMSO-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 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
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229950002974 bempedoic acid Drugs 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 239000002274 desiccant Substances 0.000 description 2
- 150000002085 enols Chemical class 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- -1 small molecule compound Chemical class 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003350 kerosene Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Images
Classifications
-
- 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
Abstract
The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of 7-bromo-2, 2-dimethylheptanoic acid ethyl ester and a product obtained by synthesis. The synthesis method comprises the following steps: ethyl isobutyrate, 1, 5-dibromopentane and sodium hydride are used as initial raw materials and react for 20-25h at the temperature of 5-85 ℃ in the presence of a solvent to obtain 7-bromo-2, 2-dimethylheptanoic acid ethyl ester; wherein the molar ratio of ethyl isobutyrate to 1, 5-dibromopentane to sodium hydride is 1: (1-1.2): (1-1.2); the solvent is N, N-dimethyl propylene urea. The method effectively avoids the situation that a lithium reagent with strong reaction activity and difficult control is used as a reducing agent and is replaced by a strong alkali substance sodium hydride, so that the method is simple to operate and easy for industrial production, and effectively solves the problems of high use risk and high cost of the lithium reagent and difficulty in industrial production in the prior art.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of 7-bromo-2, 2-dimethylheptanoic acid ethyl ester and a product obtained by synthesis.
Background
Dyslipidemia is commonly called hyperlipidemia, which is the most main factor causing atherosclerosis, and has obvious correlation with the morbidity and mortality of cardiovascular and cerebrovascular diseases, and the mortality accounts for more than 50 percent of the total mortality of human beings. At present, the dyslipidemia of people over 18 years old in China reaches 2 hundred million, only 39 percent of people receive lipid-lowering treatment, and the standard reaching rate of low-density lipoprotein cholesterol (LDL-C) is 25.8 percent. Therefore, the chronic cardiovascular disease of dyslipidemia seriously harms human health, and the current treatment situation is not optimistic. Therefore, effective prevention and treatment of dyslipidemia is an important and difficult point of modern medicine.
8-hydroxy-2, 2,14, 14-tetramethylpentadecanedioic acid (Bempedoic acid), developed by Esperion Therapeutic, USA, is a novel small molecule compound for treating dyslipidemia and reducing the risk of other cardiovascular diseases. Bempedoic acid is a white crystalline solid, and its synthetic route is as follows: ethyl isobutyrate and 1, 5-dibromopentane are used as initial raw materials and condensed by Lithium Diisopropylamide (LDA) at low temperature to obtain ethyl 7-bromo-2, 2-dimethylheptanoate (1); under the strong alkaline condition, the compound 1 is used as an alkylating reagent and is catalyzed by tetrabutylammonium iodide (TBAI) to prepare an adduct (2) of p-methyl benzenesulfonyl methyl isonitrile with p-methyl benzenesulfonyl methyl isonitrile (TosMIC); hydrolyzing the compound 2 under an acidic condition to obtain 8-oxo-2, 2,14, 14-tetramethyl pentadecanedioic acid diethyl ester (3); the compound 3 is firstly alkalized and hydrolyzed in an ethanol system and then acidified to obtain 8-oxo-2, 2,14, 14-tetramethyl pentadecanedioic acid (4); compound 4 in methanol over NaBH4Reducing, and finally acidifying with HCl to obtain a target product, i.e. the benpedoic acid.
Therefore, 7-bromo-2, 2-dimethyl ethyl heptanoate is an important intermediate for preparing benmedioic acid, and at present, ethyl isobutyrate and 1, 5-dibromopentane are mainly used as raw materials for synthesizing the 7-bromo-2, 2-dimethyl ethyl heptanoate, and the 7-bromo-2, 2-dimethyl ethyl heptanoate is obtained by condensation of Lithium Diisopropylamide (LDA) or lithium bis (trimethyl) -silicon-based amide (LiNMDS) under the protection of low-temperature nitrogen. However, when lithium reagents such as Lithium Diisopropylamide (LDA) or lithium bis (trimethyl) -silylamido (LiNMDDS) are used as reducing agents, the lithium reagents are expensive and have strong reactivity, and if the reaction conditions are not strictly controlled, various impurities are generated and byproducts are more.
Therefore, the development of a novel synthesis method of 7-bromo-2, 2-dimethylheptanoic acid ethyl ester to solve the problems of high risk, high cost and difficulty in industrial production in the prior art is a technical problem to be solved in the field.
Disclosure of Invention
The invention aims to provide a synthetic method of 7-bromo-2, 2-dimethylheptanoic acid ethyl ester, which is simple to operate and easy for industrial production;
the second purpose of the invention is to provide the 7-bromo-2, 2-dimethylheptanoic acid ethyl ester, which has high purity and can meet the industrial production requirement.
The invention provides a synthesis method of 7-bromo-2, 2-dimethylheptanoic acid ethyl ester, which comprises the following steps:
ethyl isobutyrate, 1, 5-dibromopentane and sodium hydride are used as initial raw materials and react for 20-25h at the temperature of 5-85 ℃ in the presence of a solvent to obtain 7-bromo-2, 2-dimethylheptanoic acid ethyl ester;
wherein the molar ratio of ethyl isobutyrate to 1, 5-dibromopentane to sodium hydride is 1: (1-1.2): (1-1.2);
the solvent is N, N-dimethyl propylene urea.
In the invention, only one hydrogen atom is arranged on the alpha-carbon of the ethyl isobutyrate, and because the acidity is weak, the active hydrogen is lost under the action of sodium hydride and strong alkali to generate enol negative ions, and the enol negative ions and the 1, 5-dibromopentane alpha-carbon positive ions are subjected to condensation reaction to obtain the 7-bromo-2, 2-dimethylheptanoic acid ethyl ester. In this reaction, the molar ratio of ethyl isobutyrate, 1, 5-dibromopentane and sodium hydride is 1: (1-1.2): (1-1.2), and the solvent is used in an amount to ensure that the reactants are completely dissolved. The method effectively avoids lithium reagents which have strong reactivity and are difficult to control, such as Lithium Diisopropylamide (LDA) or bis (trimethyl) -silicon amino Lithium (LiNMDS), and the like as reducing agents, and sodium hydride which is a strong base substance is used for replacing the reducing agents, so that the method is simple to operate, is easy for industrial production, and effectively solves the problems that in the prior art, the lithium reagents are high in using risk and high in cost and are difficult to industrially produce.
Further, the method specifically comprises the following steps:
s1, mixing ethyl isobutyrate, 1, 5-dibromopentane, sodium hydride and a solvent at the temperature of 5-15 ℃ and uniformly stirring;
s2, stirring the mixed system at 5-85 ℃ to react for 20-25h to obtain reaction liquid;
s3, sequentially quenching, extracting, washing and drying the reaction liquid to obtain a crude product of the 7-bromo-2, 2-dimethylheptanoic acid ethyl ester;
s4, carrying out reduced pressure distillation on the 7-bromo-2, 2-dimethyl ethyl heptanoate crude product to obtain the 7-bromo-2, 2-dimethyl ethyl heptanoate.
Further, step S1 includes: mixing ethyl isobutyrate, 1, 5-dibromopentane and a solvent, controlling the temperature of a mixed system to be 5-15 ℃, and slowly adding sodium hydride into the mixed system in multiple batches under the protection of nitrogen.
In step S1, ethyl isobutyrate and 1, 5-dibromopentane are first dissolved in a solvent, and sodium hydride is a strong alkali substance, so as to avoid violent reaction caused by adding a large amount of sodium hydride, which is difficult to control, the temperature of the mixed system is controlled to be 5-15 ℃, and sodium hydride is slowly added into the mixed system in multiple batches under the protection of nitrogen, in this step, with the addition of sodium hydride, hydrogen atoms on the α -carbon of ethyl isobutyrate are continuously lost, and the condensation reaction of ethyl isobutyrate and 1, 5-dibromopentane is also continuously carried out, so that the reaction is mild and stable, and the industrial production is easy.
Further, step S1 specifically includes: mixing 1, 5-dibromopentane with a solvent, controlling the temperature of the mixed system to be 5-15 ℃, slowly adding sodium hydride into the mixed system in multiple batches under the protection of nitrogen, finally dropwise adding ethyl isobutyrate into the mixed system, and controlling the dropwise adding time to be 5-20 min.
In step S1 of the present invention, 1, 5-dibromopentane may be dissolved in a solvent, and since the sodium hydride actually used mostly includes minerals such as kerosene and the like, including 60% sodium hydride, and as the sodium hydride is added, a large amount of bubbles are generated due to the dissolution of the minerals, and the presence of the bubbles may affect the reaction, and in addition, the sodium hydride may also react with the moisture in the mixed system, at this time, the temperature of the mixed system should be controlled to 5-15 ℃, the sodium hydride is slowly added to the mixed system in multiple batches under the protection of nitrogen, and finally ethyl isobutyrate is added dropwise to the mixed system, and the dropping time is controlled to 5-20min, and the dropping of ethyl isobutyrate to the mixed system is also intended to avoid the violent reaction and to prevent the generation of byproducts.
Further, step S2 specifically includes: the mixed system is firstly stirred and reacted for 20-30min at the temperature of 5-15 ℃, then stirred and reacted for 0.3-0.8h at the temperature of 40-50 ℃, and finally stirred and reacted for 20-24h at the temperature of 70-85 ℃ to obtain reaction liquid.
In order to prevent violent reaction and influence on product purity, the reaction is carried out in multiple steps, firstly, the mixed system is stirred and reacted for 20-30min at the temperature of 5-15 ℃, then stirred and reacted for 0.3-0.8h at the temperature of 40-50 ℃, finally stirred and reacted for 20-24h at the temperature of 70-85 ℃, and reaction liquid is obtained after the reaction is finished.
Further, in step S3, in the quenching, after cooling the reaction solution to 5to 15 ℃, a quencher at 0to 10 ℃ is added;
the volume ratio of the quenching agent to the solvent is (0.8-1.2): 1;
the quenching agent is one or a mixture of two of saturated ammonium chloride and water mixed in any proportion.
After the reaction is finished, quenching is firstly needed to stop the reaction, when the quenching is carried out, the reaction liquid is firstly needed to be cooled to 5-15 ℃, then a quenching agent with the temperature of 0-10 ℃ is added into the system, the using amount of the quenching agent is 0.8-1.2 times of the volume of the solvent, the quenching agent can use any one or two of saturated ammonium chloride or water, and the water as the quenching agent has the advantages of good quenching effect and low price.
Further, during extraction, mixing the quenched reaction liquid with an extracting agent, standing for separation, and collecting an organic phase;
the volume ratio of the extracting agent to the solvent is (1-3): 1;
the extractant is a mixture of one or more of ethyl acetate or isopropyl ether mixed in any proportion.
After quenching, the 7-bromo-2, 2-dimethylheptanoic acid ethyl ester is extracted by extraction, during extraction, the quenched reaction liquid is directly and fully mixed with an extracting agent, and the mixture is kept stand and separated to obtain an organic phase containing a product, so that the extracting agent can be used for multiple times to improve the extraction efficiency. The extractant is any one or a mixture of more of ethyl acetate or isopropyl ether mixed in any proportion.
Further, in step S3, in the washing, the organic phase is washed with water and saturated sodium chloride in sequence;
during drying, a drying agent is added into the washed organic phase, and a crude product of the 7-bromo-2, 2-dimethylheptanoic acid ethyl ester is obtained through separation;
the drying agent is one or a mixture of two of anhydrous magnesium sulfate and anhydrous sodium sulfate mixed according to any proportion.
And after extraction is finished, fully washing with water, then washing with saturated sodium chloride, finally adding anhydrous magnesium sulfate or anhydrous sodium sulfate into the washed organic phase for drying, and separating to obtain a filtrate.
Further, in step S4, during the reduced pressure distillation, the crude product of ethyl 7-bromo-2, 2-dimethylheptanoate is placed under a vacuum degree of 05-1.5 Torr, and the fraction with the distillation range of 100 ℃ and 120 ℃ is collected, thus obtaining ethyl 7-bromo-2, 2-dimethylheptanoate.
For further purifying the product, the crude product of the 7-bromo-2, 2-dimethyl ethyl heptanoate is placed under the vacuum degree of 05-1.5 Torr, and the fraction with the distillation range of 100 ℃ and 120 ℃ is collected, thus obtaining the 7-bromo-2, 2-dimethyl ethyl heptanoate.
The 7-bromo-2, 2-dimethylheptanoic acid ethyl ester is synthesized by the synthesis method.
Compared with the prior art, the synthesis method of the 7-bromo-2, 2-dimethylheptanoic acid ethyl ester has the following technical effects:
1. according to the synthesis method, sodium hydride is used for replacing a lithium reagent, so that the danger of reaction is reduced, and the operation steps are simplified;
2. according to the synthetic method, water is used as a quenching agent and a washing agent, so that the cost input amount of a solvent and raw materials is reduced, and the environmental pollution is reduced;
3. the synthesis method of the invention has the advantages of high yield and purity of the obtained product, lower cost compared with the prior art and easy industrial production.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the embodiments or the prior art descriptions will be briefly introduced below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 is a nuclear magnetic spectrum of ethyl 7-bromo-2, 2-dimethylheptanoate prepared according to example 1 of the present invention;
FIG. 2 is a nuclear magnetic spectrum of ethyl 7-bromo-2, 2-dimethylheptanoate prepared in example 4 of the present invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments, and it should be understood that the described embodiments are some, but not all, embodiments of the present invention. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
In the description of the present invention, it is to be understood that the terms "center", "longitudinal", "lateral", "length", "width", "thickness", "upper", "lower", "front", "rear", "left", "right", "vertical", "horizontal", "top", "bottom", "inner", "outer", "clockwise", "counterclockwise", and the like, indicate orientations and positional relationships based on those shown in the drawings, and are used only for convenience of description and simplicity of description, and do not indicate or imply that the device or element being referred to must have a particular orientation, be constructed and operated in a particular orientation, and thus, should not be considered as limiting the present invention.
Furthermore, the terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, features defined as "first", "second", may explicitly or implicitly include one or more of the described features. In the description of the present invention, "a plurality" means two or more unless specifically defined otherwise. Furthermore, the terms "mounted," "connected," and "connected" are to be construed broadly and may include, for example, a fixed connection, a removable connection, or an integral connection; can be mechanically or electrically connected; they may be connected directly or indirectly through intervening media, or they may be interconnected between two elements. The specific meaning of the above terms in the present invention can be understood in specific cases to those skilled in the art.
Example 1
S11, taking 116g of ethyl isobutyrate, 229g of 1, 5-dibromopentane and 500mL of N, N-dimethylpropylurea, adding the mixture into a 1.5L reaction bottle, controlling the temperature of the mixed system to be 5 ℃, and slowly adding 40g of 60% sodium hydride into the reaction bottle in three batches under the protection of nitrogen;
s12, stirring at 5 ℃ for 20min, heating to 50 ℃ for reaction for 0.3h, and heating to 70 ℃ for reaction for 20h to obtain a reaction solution.
S13, after the reaction is finished, cooling the reaction liquid to 5 ℃, and adding 400mL of purified water with the temperature of 0 ℃ into the reaction liquid to quench the reaction; then extracting with ethyl acetate for 3 times, wherein the usage amount of the ethyl acetate is 300mL each time, and combining organic phases; finally, washing the organic phase by using purified water and saturated sodium chloride in sequence, wherein the organic phase is washed twice by using purified water, 200mL of the purified water is used each time, 300mL of the saturated sodium chloride is used, after washing, anhydrous magnesium sulfate is added into the washed organic phase for drying, and a crude product of the 7-bromo-2, 2-dimethylheptanoic acid ethyl ester is obtained by separation;
s14, placing the crude product of the 7-bromo-2, 2-dimethyl ethyl heptanoate in a vacuum degree of 0.5 Torr, and collecting the fraction with the fraction temperature of 100 ℃ and 120 ℃ to obtain the colorless oily 7-bromo-2, 2-dimethyl ethyl heptanoate.
Example 2
S21, adding 116g of ethyl isobutyrate, 274.8g of 1, 5-dibromopentane and 500mL of N, N-dimethylpropylurea into a 1.5L reaction bottle, controlling the temperature of a mixed system to be 15 ℃, and slowly adding 48g of 60% sodium hydride into the reaction bottle in three batches under the protection of nitrogen;
s22, stirring the mixture for 30min at 15 ℃, heating the mixture to 40 ℃ for reaction for 0.8h, and heating the mixture to 85 ℃ for reaction for 24h to obtain a reaction solution.
S23, after the reaction is finished, cooling the reaction liquid to 15 ℃, and adding 400mL of saturated ammonium chloride with the temperature of 10 ℃ into the reaction liquid to quench the reaction; then extracting with ethyl acetate for 3 times, wherein the usage amount of the ethyl acetate is 300mL each time, and combining organic phases; finally, washing the organic phase by using purified water and saturated sodium chloride in sequence, wherein the organic phase is washed twice by using purified water, 200mL of the purified water is used each time, 300mL of the saturated sodium chloride is used, after washing, anhydrous sodium sulfate is added into the washed organic phase for drying, and a crude product of the 7-bromo-2, 2-dimethylheptanoic acid ethyl ester is obtained by separation;
s24, placing the crude product of the 7-bromo-2, 2-dimethyl ethyl heptanoate in a vacuum degree of 1.5 Torr, and collecting the fraction with the fraction temperature of 100 ℃ and 120 ℃ to obtain the colorless oily 7-bromo-2, 2-dimethyl ethyl heptanoate.
Example 3
S31, taking 116g of ethyl isobutyrate, 251.9g of 1, 5-dibromopentane and 500mL of N, N-dimethylpropylurea, adding the mixture into a 1.5L reaction bottle, controlling the temperature of the mixed system to be 10 ℃, and slowly adding 44g of 60% sodium hydride into the reaction bottle in three batches under the protection of nitrogen;
s32, stirring at 10 ℃ for 25min, heating to 50 ℃ for reaction for 0.3h, and heating to 75 ℃ for reaction for 24h to obtain a reaction solution.
S33, after the reaction is finished, cooling the reaction liquid to 10 ℃, adding 400mL of a mixture of 0 ℃ purified water and saturated ammonium chloride into the reaction liquid, and quenching the reaction; then extracting with ethyl acetate for 3 times, wherein the usage amount of ethyl acetate is 300mL each time, and combining organic phases; finally, washing the organic phase by using purified water and saturated sodium chloride in sequence, wherein the organic phase is washed twice by using purified water, 200mL of the purified water is used each time, 300mL of the saturated sodium chloride is used, after washing, anhydrous magnesium sulfate is added into the washed organic phase for drying, and a crude product of the 7-bromo-2, 2-dimethylheptanoic acid ethyl ester is obtained by separation;
s34, placing the crude product of the 7-bromo-2, 2-dimethyl ethyl heptanoate in a vacuum degree of 1.0 Torr, and collecting the fraction with the fraction temperature of 100 ℃ and 120 ℃ to obtain the colorless oily 7-bromo-2, 2-dimethyl ethyl heptanoate.
Example 4
S41, 229g of 1, 5-dibromopentane and 500mL of N, N-dimethylpropylurea are taken and added into a 1.5L reaction bottle, the temperature of a mixed system is controlled to be 10 ℃, 40g of 60% sodium hydride is slowly added into the reaction bottle in three batches under the protection of nitrogen, and finally 116g of ethyl isobutyrate is dropwise added into the reaction bottle, and the dropwise adding time is controlled to be 10 min;
s42, stirring at 10 ℃ for 20min, heating to 40 ℃ for reaction for 0.5h, and heating to 70 ℃ for reaction for 24h to obtain a reaction solution.
S43, after the reaction is finished, cooling the reaction liquid to 10 ℃, and adding 400mL of purified water with the temperature of 0 ℃ into the reaction liquid to quench the reaction; then extracting with ethyl acetate, wherein the using amount of the ethyl acetate is 300mL each time, and combining organic phases; finally, washing the organic phase by using purified water and saturated sodium chloride in sequence, wherein the organic phase is washed twice by using purified water, 200mL of the purified water is used each time, 300mL of the saturated sodium chloride is used, after washing, anhydrous sodium sulfate is added into the washed organic phase for drying, and a crude product of the 7-bromo-2, 2-dimethyl heptanoic acid ethyl ester is obtained by separation;
s44, placing the crude product of the 7-bromo-2, 2-dimethyl ethyl heptanoate in a vacuum degree of 1.0 Torr, and collecting the fraction with the fraction temperature of 100 ℃ and 120 ℃ to obtain the colorless oily 7-bromo-2, 2-dimethyl ethyl heptanoate.
Example 5
S51, adding 270g of 1, 5-dibromopentane and 500mL of dimethyl sulfoxide into a 1.5L reaction bottle, controlling the temperature of a mixed system to be 5 ℃, slowly adding 45g of 60% sodium hydride into the reaction bottle in three batches under the protection of nitrogen, and finally dropwise adding 116g of ethyl isobutyrate into the reaction bottle for 20 min;
s52, stirring at 5 ℃ for 20min, heating to 50 ℃ for reaction for 0.3h, and heating to 75 ℃ for reaction for 24h to obtain a reaction solution.
S53, after the reaction is finished, cooling the reaction liquid to 5 ℃, and adding 400mL of purified water with the temperature of 8 ℃ into the reaction liquid to quench the reaction; then extracting with isopropyl ether for 4 times, wherein the dosage of isopropyl ether used each time is 200mL, and combining organic phases; finally, washing the organic phase by using purified water and saturated sodium chloride in sequence, wherein the purified water is used for washing twice, 300mL of the purified water is used each time, 300mL of the saturated sodium chloride is used, after washing, anhydrous sodium sulfate is added into the washed organic phase for drying, and a crude product of the 7-bromo-2, 2-dimethyl heptanoic acid ethyl ester is obtained through separation;
s54, placing the crude product of the 7-bromo-2, 2-dimethyl ethyl heptanoate in a vacuum degree of 1.0 Torr, and collecting the fraction with the fraction temperature of 100 ℃ and 120 ℃ to obtain the colorless oily 7-bromo-2, 2-dimethyl ethyl heptanoate.
Example 6
S61, adding 255g of 1, 5-dibromopentane and 500mL of dimethyl sulfoxide into a 1.5L reaction bottle, controlling the temperature of a mixed system to be 15 ℃, slowly adding 45g of 60% sodium hydride into the reaction bottle in three batches under the protection of nitrogen, finally dropwise adding 116g of ethyl isobutyrate into the reaction bottle, and controlling the dropping time to be 10 min;
s62, stirring at 15 ℃ for 20min, heating to 40 ℃ for reaction for 0.5h, and heating to 75 ℃ for reaction for 24h to obtain a reaction solution.
S63, after the reaction is finished, cooling the reaction liquid to 15 ℃, and adding 400mL of 10 ℃ purified water into the reaction liquid to quench the reaction; then extracting with ethyl acetate for 3 times, wherein the usage amount of the ethyl acetate is 300mL each time, and combining organic phases; finally, washing the organic phase by using purified water and saturated sodium chloride in sequence, wherein the organic phase is washed by using purified water for three times, 200mL of the purified water is used each time, 300mL of the saturated sodium chloride is used, after washing, anhydrous sodium sulfate is added into the washed organic phase for drying, and a crude product of the 7-bromo-2, 2-dimethylheptanoic acid ethyl ester is obtained by separation;
s64, placing the crude product of the 7-bromo-2, 2-dimethyl ethyl heptanoate in a vacuum degree of 1.0 Torr, and collecting the fraction with the fraction temperature of 100 ℃ and 120 ℃ to obtain the colorless oily 7-bromo-2, 2-dimethyl ethyl heptanoate.
Using nuclear magnetic spectrum (600MHz, CDC)l3) And mass spectrum to confirm the structure of the 7-bromo-2, 2-dimethylheptanoic acid ethyl ester prepared in example 1 and example 4, wherein FIG. 1 and FIG. 2 are corresponding nuclear magnetic spectra respectively.
As can be seen from fig. 1, the different chemical shift values correspond to hydrogen atoms at different positions, wherein 4.07 (q, 2H, J ═ 7.2 HZ); 3.34(t, 2H, J ═ 6.8 Hz); 1.82(m, 2H); 1.49-1.35 (m, 4H); 1.22(t, 3H, J ═ 7.2 Hz); 1.20-1.18(m, 2H); 1.11(s, 6H).
Known from the mass spectrum, (M + H)+265.27，266.27(M+Na)+287.27，289.17。
To further examine and compare the yield and purity of the ethyl 7-bromo-2, 2-dimethylheptanoate prepared in examples 1 to 6, the ethyl 7-bromo-2, 2-dimethylheptanoate prepared in examples 1 to 6 was subjected to gas chromatography detection, respectively. Table 1 shows the reactant ratios of examples 1-6, and Table 2 shows the yields and purities of the products of examples 1-6.
Table 1 examples 1-6 reactant ratios
| Chinese medicinal compositionEthyl acetate (g) | 1, 5-Dibromopentane (g) | Sodium hydride (g) | |
| Example 1 | 116 | 229 | 40 |
| Example 2 | 116 | 274.8 | 48 |
| Example 3 | 116 | 251.9 | 44 |
| Example 4 | 116 | 229 | 40 |
| Example 5 | 116 | 270 | 45 |
| Example 6 | 116 | 255 | 45 |
Table 2 examples 1-6 product yields and purities
| The actual amount received (g) | Total yield (%) | Purity (%) | |
| Example 1 | 133.9 | 50.5 | 93.5 |
| Example 2 | 125.6 | 47.3 | 84.3 |
| Example 3 | 119.8 | 45.2 | 88.3 |
| Example 4 | 130.5 | 49.2 | 92.6 |
| Example 5 | 123.0 | 46.4 | 83.2 |
| Example 6 | 121.5 | 45.8 | 87.9 |
As can be seen from tables 1 and 2, the purity of the 7-bromo-2, 2-dimethylheptanoic acid ethyl ester prepared by the synthesis method of the present invention is high, both of which are 83% or more, and the total yield is 45% or more, wherein example 1 is the best example, the product yield is 50.5%, and the purity is 93.5%. Therefore, the method can meet the requirement of industrial production no matter the purity or the yield of the product, effectively avoids the use of a lithium reagent, and has the advantages of simple operation, low preparation cost and easy industrial production.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and such modifications and substitutions do not depart from the spirit and scope of the present invention as defined by the appended claims.
Claims (7)
1. A synthetic method of 7-bromo-2, 2-dimethylheptanoic acid ethyl ester is characterized by comprising the following steps:
ethyl isobutyrate, 1, 5-dibromopentane and sodium hydride are used as initial raw materials and react for 20-25h at the temperature of 5-85 ℃ in the presence of a solvent to obtain 7-bromo-2, 2-dimethylheptanoic acid ethyl ester;
wherein the molar ratio of ethyl isobutyrate to 1, 5-dibromopentane to sodium hydride is 1: (1-1.2): (1-1.2);
the solvent is N, N-dimethyl propylene urea.
2. The synthesis method according to claim 1, characterized by comprising in particular the following steps:
s1, mixing ethyl isobutyrate, 1, 5-dibromopentane, sodium hydride and a solvent at the temperature of 5-15 ℃ and uniformly stirring;
s2, stirring the mixed system at 5-85 ℃ to react for 20-25h to obtain reaction liquid;
s3, sequentially quenching, extracting, washing and drying the reaction liquid to obtain a crude product of the 7-bromo-2, 2-dimethylheptanoic acid ethyl ester;
s4, carrying out reduced pressure distillation on the 7-bromo-2, 2-dimethyl ethyl heptanoate crude product to obtain the 7-bromo-2, 2-dimethyl ethyl heptanoate.
3. The synthesis method according to claim 2, wherein step S1 includes: mixing ethyl isobutyrate, 1, 5-dibromopentane and a solvent, controlling the temperature of a mixed system to be 5-15 ℃, and slowly adding sodium hydride into the mixed system in multiple batches under the protection of nitrogen.
4. The synthesis method according to claim 2, wherein step S1 specifically includes: mixing 1, 5-dibromopentane with a solvent, controlling the temperature of a mixed system to be 5-15 ℃, slowly adding sodium hydride into the mixed system in multiple batches under the protection of nitrogen, finally dropwise adding ethyl isobutyrate into the mixed system, and controlling the dropwise adding time to be 5-20 min.
5. The synthesis method according to any one of claims 3 or 4, wherein step S2 specifically comprises: the mixed system is firstly stirred and reacted for 20-30min at the temperature of 5-15 ℃, then stirred and reacted for 0.3-0.8h at the temperature of 40-50 ℃, and finally stirred and reacted for 20-24h at the temperature of 70-85 ℃ to obtain reaction liquid.
6. The synthesis method according to claim 5, wherein in the step S3, in the quenching, after the reaction solution is cooled to 5-15 ℃, a quencher at 0-10 ℃ is added;
the volume ratio of the quenching agent to the solvent is (0.8-1.2): 1;
the quenching agent is one or a mixture of two of saturated ammonium chloride and water mixed in any proportion.
7. Ethyl 7-bromo-2, 2-dimethylheptanoate synthesized by the synthesis method of any one of claims 1 to 6.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040198814A1 (en) * | 2000-10-11 | 2004-10-07 | Dasseux Jean-Louis Henri | Ketone compounds and compositions for cholesterol management and related uses |
| CN101534643A (en) * | 2006-09-15 | 2009-09-16 | 安佐制药股份有限公司 | Hindered ester-based biodegradable linkers for oligonucleotide delivery |
| US20170073286A1 (en) * | 2003-01-23 | 2017-03-16 | Esperion Therapeutics, Inc. | Cycloalkyl-hydroxyl compounds and compositions for cholesterol management and related uses |
| CN111448182A (en) * | 2017-10-02 | 2020-07-24 | 阿里萨制药有限公司 | Aztreonam derivative and application thereof |
-
2020
- 2020-08-31 CN CN202010894967.4A patent/CN112047840A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040198814A1 (en) * | 2000-10-11 | 2004-10-07 | Dasseux Jean-Louis Henri | Ketone compounds and compositions for cholesterol management and related uses |
| US20170073286A1 (en) * | 2003-01-23 | 2017-03-16 | Esperion Therapeutics, Inc. | Cycloalkyl-hydroxyl compounds and compositions for cholesterol management and related uses |
| CN101534643A (en) * | 2006-09-15 | 2009-09-16 | 安佐制药股份有限公司 | Hindered ester-based biodegradable linkers for oligonucleotide delivery |
| CN111448182A (en) * | 2017-10-02 | 2020-07-24 | 阿里萨制药有限公司 | Aztreonam derivative and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 胡炳成等: "2,3-二甲基-4-甲氧甲酰-2-环己烯醇的合成", 《应用化学》 * |
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