CN110551023B - Method for preparing alkyl diacid monobenzyl ester - Google Patents
Method for preparing alkyl diacid monobenzyl ester Download PDFInfo
- Publication number
- CN110551023B CN110551023B CN201810541169.6A CN201810541169A CN110551023B CN 110551023 B CN110551023 B CN 110551023B CN 201810541169 A CN201810541169 A CN 201810541169A CN 110551023 B CN110551023 B CN 110551023B
- Authority
- CN
- China
- Prior art keywords
- formula
- alkyl diacid
- reaction
- represented
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
- C07C67/11—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond being mineral ester groups
-
- 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
Abstract
The invention relates to a method for preparing alkyl diacid monobenzyl ester, and belongs to the technical field of chemical industry. The method provided by the invention is characterized in that alkyl diacid is used as a raw material, and esterification reaction is carried out with benzyl bromide or benzyl chloride in a mixed system of an organic solvent and water under the action of alkali to obtain alkyl diacid monobenzyl ester. The method has the advantages of good selectivity, convenient operation, high yield and low cost, and is beneficial to implementation.
Description
Technical Field
The invention relates to a method for preparing alkyl diacid monobenzyl ester, and belongs to the technical field of chemical industry.
Background
Alkyl diacid monobenzyl esters are very important building blocks in pharmaceutical chemistry and fine chemicals, such as hexadecyl diacid monobenzyl esters are key intermediates for the preparation of insulin digluconate, and the change in length of the alkyl chain may give rise to more possibilities for derivatization of the drug, so that high selectivity and high yield synthesis of alkyl diacid monobenzyl esters are of great significance. At present, alkyl diacid monobenzyl ester is synthesized by using alkyl diacid to carry out esterification reaction, and two carboxylic acids of the alkyl diacid have the same reactivity, so that a double-esterification product is inevitably obtained in the reaction process, the operation difficulty is increased, the reaction yield is reduced by removing the double-esterification product in the reaction, the operation is complicated, the yield is not ideal, and other methods with higher yields have the problems of higher cost, difficulty in implementation and the like. Therefore, it is very necessary to develop a method for synthesizing alkyl diacid monobenzyl ester with good selectivity, convenient operation, high yield and low cost.
Disclosure of Invention
The invention aims to provide a method for preparing alkyl diacid monobenzyl ester, which has good selectivity, convenient operation, high yield and low cost. The method provided by the invention is characterized in that alkyl diacid is used as a raw material, and esterification reaction is carried out with benzyl bromide or benzyl chloride in a mixed system of an organic solvent and water under the action of alkali to obtain alkyl diacid monobenzyl ester.
Specifically, a process for producing monobenzyl alkyl diacid represented by the following formula (3), which comprises: the alkyl diacid shown in the following formula (1) and benzyl halide shown in the formula (2) are subjected to esterification reaction in a mixed system of an organic solvent and water under the action of alkali to obtain alkyl diacid monobenzyl ester shown in the formula (3),
wherein n is an integer of 14-20, and X is chlorine or bromine.
In some embodiments, n is 14, 15, 16, 17, or 18. In some embodiments, n is 14, 15, or 16. In some embodiments, n is 14 or 16.
The inventors found through researches that, for alkyl diacid shown in formula (3), the difficulty of mono-esterification increases with the increase of carbon chain, for example, when n is an integer of 2-11, the yield of mono-benzyl ester product is relatively high (50% or more, different reaction conditions and yields can be achieved) according to the method disclosed in the prior art, but after the carbon chain is increased, the yield is lower under the same relatively simple reaction conditions, and more mono-ester products are difficult to obtain. The method of the invention can obtain relatively more monoester products under simpler conditions and operation.
The organic solvent is at least one selected from ethyl acetate, isopropyl acetate, butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, chloroform, butanone and methyl isobutyl ketone. In some embodiments, the organic solvent is at least one of tetrahydrofuran, 2-methyltetrahydrofuran.
The mass ratio of the organic solvent to the alkyl diacid represented by formula (1) may be 0.5:1 to 50.0:1. In some embodiments, the mass ratio of the organic solvent to the alkyl diacid represented by formula (1) may be 1.0:1 to 40.0:1. In some embodiments, the mass ratio of the organic solvent to the alkyl diacid represented by formula (1) is preferably 2.0:1 to 30.0:1, which is advantageous for product acquisition and reaction control. In some embodiments, the mass ratio of the organic solvent to the alkyl diacid represented by formula (1) is preferably 5.0:1 to 25.0:1, which is advantageous for product acquisition and reaction control.
The base may be an organic base or an inorganic base, and is at least one selected from triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium hydroxide, and potassium hydroxide. In some embodiments, the base is at least one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, facilitating the reaction and the acquisition of the desired product.
The inventor finds that the use amount of the alkali has an important influence on the acquisition of the target product through research. The molar ratio of the base to the alkyl diacid of formula (1) may be 0.5:1 to 4:1. In some embodiments, the molar ratio of base to alkyl diacid of formula (1) is from 0.6:1 to 3.5:1, facilitating the reaction. In some embodiments, the molar ratio of base to alkyl diacid of formula (1) is from 0.6:1 to 3.0:1, facilitating reaction performance and handling.
In the above reaction, the molar ratio of the benzyl halide represented by the formula (2) to the alkyl diacid represented by the formula (1) may be 0.7:1 to 4.0:1. In some embodiments, the molar ratio of benzyl halide represented by formula (2) to alkyl diacid represented by formula (1) is preferably from 0.8:1 to 3.0:1. In some embodiments, the molar ratio of the benzyl halide represented by formula (2) to the alkyl diacid represented by formula (1) is more preferably 0.8:1 to 2.5:1, which is advantageous for product acquisition and reaction control and handling. In some embodiments, the molar ratio of the benzyl halide represented by formula (2) to the alkyl diacid represented by formula (1) is more preferably 1.0:1 to 2.0:1, which is advantageous for product acquisition and reaction control and handling.
In the above reaction, too little water is used, so that the reaction is not easy to occur and proceed, too much water can cause impurity increase, and the generation and the acquisition of target products are not facilitated. The molar ratio of water to alkyl diacid of formula (1) may be 5:1 to 800:1. In some embodiments, the molar ratio of water to alkyl diacid of formula (1) may be from 10:1 to 640:1, facilitating the reaction. In some embodiments, the molar ratio of water to alkyl diacid of formula (1) may be from 20:1 to 480:1, facilitating reaction performance and handling. In some embodiments, the molar ratio of water to alkyl diacid of formula (1) may be in the range of 50:1 to 300:1, facilitating reaction performance and handling.
In some embodiments, the benzyl halide shown in the formula (2) is benzyl bromide, the alkali is at least one of sodium carbonate and potassium carbonate, and the feeding molar ratio of the alkali to the alkyl diacid shown in the formula (1) is 0.7:1-1.1:1, so that the reaction is facilitated and the target product is obtained. In some embodiments, the alkali is at least one of sodium bicarbonate and potassium bicarbonate, and the feeding molar ratio of the alkali to the alkyl diacid shown in the formula (1) is 1.4:1-2.0:1, so that the reaction is facilitated and the target product is obtained.
In some embodiments, the benzyl halide shown in the formula (2) is benzyl chloride, the alkali is at least one of sodium carbonate and potassium carbonate, and the feeding molar ratio of the alkali to the alkyl diacid shown in the formula (1) is 1.0:1-1.4:1, so that the reaction is facilitated and the target product is obtained. In some embodiments, the alkali is at least one of sodium bicarbonate and potassium bicarbonate, and the feeding molar ratio of the alkali to the alkyl diacid shown in the formula (1) is 2.0:1-2.7:1, so that the reaction is facilitated and the target product is obtained.
In the above reaction, the reaction temperature may be 50 to 120 ℃, preferably 60 to 110 ℃, which is advantageous for the reaction.
The esterification reaction may be carried out for 18 hours to 45 hours. In some embodiments, the reaction time is 20 hours to 35 hours.
After the esterification reaction is finished, acid can be added into the mixture obtained by the reaction, the pH of the water phase is adjusted to be 1-3 by the mixed solution, then the organic layer is separated, and the solvent is removed, so that a crude product is obtained. The crude product can be subjected to extraction washing, pulping, decolorizing, and/or crystallization to obtain a product with higher purity. In some embodiments, the crude product is slurried with methylene chloride and then filtered, and the filtrate is subjected to crystallization from isopropanol to provide the mono-benzyl alkyl diacid ester product of formula (3).
The method for preparing the alkyl diacid monobenzyl ester provided by the invention is used for directly synthesizing the target compound in one step, is simple and convenient to operate, has good selectivity, has the monobenzyl ester content of the reaction product far greater than the dibenzyl ester content, has higher yield, and is beneficial to implementation.
Detailed Description
In order to better understand the technical solution of the present invention, the following non-limiting examples are further disclosed for further details of the present invention.
The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
In the invention, g: g; mL or mL: milliliters; mmol: millimoles; c: degrees celsius; h: hours; the nuclear magnetic hydrogen spectrum adopts deuterated DMSO (dimethyl sulfoxide) or deuterated chloroform.
In the present invention, in the reaction, the reaction is completed, meaning that the residual amount of the raw material is at least 10% or 5% lower than the fed amount.
In the present invention, the expression "compound represented by formula (1)" or the like, and the expression "compound (1)" or the like, are not substantially different, and refer to the same compound,
in the present invention, room temperature means a temperature of 15℃to 30 ℃.
Example 1
Sodium carbonate (424 mg,4.0 mmol) and water (14.3 g,794.4 mmol) were added to the reaction flask, and after stirring and dissolution, hexadecanedioic acid (1.43 g,5.0 mmol), 2-methyltetrahydrofuran (35.0 g) and benzyl bromide (1.37 g,8.0 mmol) were added, and the reaction system was heated to 75℃and stirred for 22 hours to stop the reaction. Hydrochloric acid is added into the system to lead the pH value of the water phase to reach 1-3, the solution is separated, and the organic layer is spin-dried to obtain solid residues. The spin-distilled residue was slurried with methylene chloride (28 g), filtered, and the filtrate was spin-dried to obtain a solid residue. The spin-distilled residue was recrystallized from isopropanol (3 g) to give 1046mg of white solid in 55.6% yield. 1H NMR (400 MHz, DMSO). Delta.11.95 (s, 1H), 7.44-7.20 (m, 5H), 5.08 (s, 2H), 2.33 (t, J=7.3 Hz, 2H), 2.17 (t, J=7.4 Hz, 2H), 1.60-1.41 (m, 4H), 1.22 (s, 20H); MS, m/z: [ M-H ]] - ＝375.2。
Example 2
To the reaction flask was added hexadecanedioic acid (1.43 g,5.0 mmol), tetrahydrofuran (18.0 g), benzyl chloride (1.01 g, 8).0 mmol), potassium carbonate (1037 mg,7.5 mmol) and water (14.3 g,794.4 mmol), the reaction system was heated to 80℃and stirred for 40h to stop the reaction. Hydrochloric acid is added into the system to lead the pH value of the water phase to reach 1-3, the solution is separated, and the organic layer is spin-dried to obtain solid residues. The spin-distilled residue was slurried with methylene chloride (28 g), filtered, and the filtrate was spin-dried to obtain a solid residue. The spin-distilled residue was recrystallized from isopropanol (3 g) to give 941mg of a white solid in 50.0% yield. 1H NMR (400 MHz, DMSO). Delta.11.95 (s, 1H), 7.44-7.20 (m, 5H), 5.08 (s, 2H), 2.33 (t, J=7.3 Hz, 2H), 2.17 (t, J=7.4 Hz, 2H), 1.60-1.41 (m, 4H), 1.22 (s, 20H); MS, m/z: [ M-H ]] - ＝375.2。
Example 3
To the reaction flask were added potassium hydrogencarbonate (901 mg,9.0 mmol) and water (15.7 g,872.2 mmol), and after stirring and dissolution, octadecanedioic acid (1.57 g,5.0 mmol), 2-methyltetrahydrofuran (15.7 g) and benzyl bromide (1.37 g,8.0 mmol) were added, and the reaction system was heated to 75℃and stirred for 30 hours to stop the reaction. Hydrochloric acid is added into the system to lead the pH value of the water phase to reach 1-3, the solution is separated, and the organic layer is spin-dried to obtain solid residues. The spin-distilled residue was slurried with methylene chloride (30 g), filtered, and the filtrate was spin-dried to obtain a solid residue. The spin-distilled residue was recrystallized from isopropanol (3 g) to give 1177mg of a white solid in 58.2% yield. 1H NMR (400 MHz, CDCl) 3 )δ11.22(s,1H),7.40-7.29(m,5H),5.11(s,2H),2.35(td,J＝7.5,2.5Hz,4H),1.63(s,4H),1.25(s,24H)；MS，m/z：[M-H] - ＝403.3。
While the methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and combinations of the methods and applications described herein can be made and applied within the spirit and scope of the invention. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention.
Claims (8)
1. A process for preparing monobenzyl alkyl diacid represented by the following formula (3), which comprises: the alkyl diacid shown in the following formula (1) and benzyl halide shown in the formula (2) are subjected to esterification reaction in a mixed system of an organic solvent and water under the action of alkali to obtain alkyl diacid monobenzyl ester shown in the formula (3),
wherein n is 14 or 16, X is chlorine or bromine, and the organic solvent is at least one selected from tetrahydrofuran and 2-methyltetrahydrofuran;
the base is at least one selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium hydroxide and potassium hydroxide.
2. The process according to claim 1, wherein the mass ratio of the organic solvent to the alkyl diacid represented by formula (1) is 1.0:1 to 40.0:1.
3. The process according to claim 1, wherein the molar ratio of the base to the alkyl diacid represented by formula (1) is from 0.6:1 to 3.5:1.
4. The process according to claim 1, wherein the molar ratio of the benzyl halide represented by formula (2) to the alkyl diacid represented by formula (1) is 0.8:1 to 3.0:1.
5. The process according to claim 1, wherein the molar ratio of water to the alkyl diacid represented by formula (1) is from 10:1 to 640:1.
6. The process of claim 1, wherein the reaction temperature is from 60 ℃ to 110 ℃.
7. The method of claim 1, wherein the reaction time is 18 hours to 45 hours.
8. The process according to claim 1, wherein, after the completion of the reaction, an acid is added to the mixture obtained by the reaction, the pH of the aqueous phase is adjusted to 1 to 3 by the mixture, and then the organic layer is separated and the solvent is removed to obtain a crude product; the crude product is beaten by methylene dichloride, then the filtration is carried out, and the obtained product after the solvent is removed from the filtrate is crystallized by isopropanol to obtain the alkyl diacid monobenzyl ester product shown in the formula (3).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810541169.6A CN110551023B (en) | 2018-05-30 | 2018-05-30 | Method for preparing alkyl diacid monobenzyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810541169.6A CN110551023B (en) | 2018-05-30 | 2018-05-30 | Method for preparing alkyl diacid monobenzyl ester |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110551023A CN110551023A (en) | 2019-12-10 |
| CN110551023B true CN110551023B (en) | 2023-08-15 |
Family
ID=68734132
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810541169.6A Active CN110551023B (en) | 2018-05-30 | 2018-05-30 | Method for preparing alkyl diacid monobenzyl ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110551023B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113075342B (en) * | 2020-01-04 | 2024-02-27 | 东莞市东阳光仿制药研发有限公司 | Method for separating and detecting related substances of insulin diglucoside side chain |
| CN113045473A (en) * | 2020-03-18 | 2021-06-29 | 广东东阳光药业有限公司 | Process for preparing long aliphatic chain diacid derivatives and their use |
| CN111333505B (en) * | 2020-03-31 | 2022-07-26 | 东莞市东阳光生物药研发有限公司 | Method for preparing long-chain fatty diacid monobenzyl ester and application thereof |
| CN111362799B (en) * | 2020-04-10 | 2021-02-26 | 天津法莫西医药科技有限公司 | Preparation method of long-chain diacid monobenzyl ester compound |
-
2018
- 2018-05-30 CN CN201810541169.6A patent/CN110551023B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| "Development and characterization of rat monoclonal antibodies for N-acylated homoserine lactones";C Xiao et al.,;《Chemical Science》;20100729;第6卷(第2期);第1011-1017页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110551023A (en) | 2019-12-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110551023B (en) | Method for preparing alkyl diacid monobenzyl ester | |
| US9701613B2 (en) | Preparation method of 1-palmitoyl-3-acetylglycerol, and preparation method of 1-palmitoyl-2-linoleoyl-3-acetylglycerol using same | |
| WO2017096772A1 (en) | Method for preparing anti-heart-failure medicine lcz696 | |
| KR101308258B1 (en) | A novel method of making Endoxifen | |
| US20150266803A1 (en) | Method for preparing monoacetyglycerols and esters thereof | |
| CN101973909B (en) | Preparation method of mildronate | |
| CN111909148A (en) | Indolizine derivative and preparation method thereof | |
| CN111533752A (en) | Preparation method of tert-butyl-7-bromo-5-oxa-2-azaspiro [3.4] octane-2-formic acid ester | |
| KR840000115B1 (en) | Process for the preparation of a carbazole derivative | |
| KR101170940B1 (en) | A process for preparing a crystalline pantoprazole sodium sesquihydrate | |
| CN111217709A (en) | Preparation method of (1-fluorocyclopropyl) methylamine hydrochloride | |
| CN114213249B (en) | Synthesis method of dolutegravir intermediate | |
| KR101699262B1 (en) | Manufacturing Method of Alpha-Arbutin | |
| CN116396330B (en) | Preparation method of cyclopropyl substituted 2H-benzopyran derivative | |
| JP2907520B2 (en) | Method for producing surfactant | |
| JP2855871B2 (en) | Method for producing thiomalic acid | |
| JP2023016443A (en) | Method for production of 1,4-diacetoxy-2-methylnaphthalene | |
| JPS6145988B2 (en) | ||
| US2782231A (en) | Preparation of malonanilic acid and substituted malonanilic acids | |
| WO2004018408A1 (en) | Synthesis and purification of nateglinide | |
| JPH0478638B2 (en) | ||
| KR100413172B1 (en) | A process for the preparation of quinolinone derivatives | |
| JP2003137835A (en) | Method for producing (r)-3-hydroxy-3-(2-phenyl)hexanoic acid | |
| JPS6127396B2 (en) | ||
| KR100516383B1 (en) | New manufacturing process of dihydrocarbostyril derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| CB02 | Change of applicant information |
Address after: 523808 No.1, Gongye North Road, Songshanhu Park, Dongguan City, Guangdong Province Applicant after: Guangdong Dongyangguang Pharmaceutical Co.,Ltd. Address before: 523808 No. 1 Industrial North Road, Songshan Industrial Park, Songshan, Guangdong, Dongguan, Hubei Applicant before: SUNSHINE LAKE PHARMA Co.,Ltd. |
|
| CB02 | Change of applicant information | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |