CN114105768B - Preparation by exchange method 18 O-marking method for ethyl formate - Google Patents
Preparation by exchange method 18 O-marking method for ethyl formate Download PDFInfo
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- CN114105768B CN114105768B CN202111512650.0A CN202111512650A CN114105768B CN 114105768 B CN114105768 B CN 114105768B CN 202111512650 A CN202111512650 A CN 202111512650A CN 114105768 B CN114105768 B CN 114105768B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The invention relates to a method for preparing by using an exchange method 18 A method of O marking ethyl formate comprising the steps of: (1) Adding ethyl formate and H into a hydrothermal reaction kettle 2 18 O and catalyst, heating to react, filtering the obtained product to remove the catalyst, and distilling and separating to obtain 18 O marks crude ethyl formate and H 2 18 O; (2) The obtained product is then processed 18 O marks the crude product of ethyl formate to replace ethyl formate and repeats the step (1) for a plurality of times, thus obtaining the high abundance of the target product 18 O marks ethyl formate. Compared with the prior art, the method provided by the invention only needs one-step reaction, the utilization rate of the isotope atoms can reach more than 94%, a complex reaction system is not needed, and dilution of the isotope abundance can be effectively avoided.
Description
Technical Field
The invention belongs to 18 The technical field of O-marked ethyl formate synthesis, relates to a method for preparing by using an exchange method 18 O-labelling ethyl formate.
Background
Oxygen element in nature is composed of 16 O、 17 O and O 18 Three isotopes of O are present in a ratio of 500:0.2:1, natural abundance was 99.76atom%, 0.04atom% and 0.20atom%, respectively. 18 O、 17 O and O 16 The separation and enrichment method of O mainly comprises distillation method, thermal diffusion method, electrolytic method, etc., and at present, H with isotope abundance more than 97atom% is mainly obtained by enrichment of water distillation method 2 18 O. By H 2 18 O is used as raw material to prepare a series of 18 The preparation method of the O-labeled compound mainly comprises a chemical exchange method and a chemical synthesis method.
The preparation method of the carboxylic ester compound mainly comprises the following steps: (1) dehydrating and esterifying carboxylic acid and alcohol; (2) carboxylate and halogen action; (3) carboxylate and sulfate, sulfonate action; (4) reacting anhydride with alcohol and phenol; (5) reacting acyl chloride with alcohol and phenol; (6) transesterification of carboxylic esters with alcohols and phenols; (7) alcoholysis reaction of nitrile.
Because of limited isotope raw materials and precursor species, 18 the synthesis method of the O-marked carboxylic ester compound mainly adopts carboxylic acid and alcohol to dehydrate and esterify under the action of acid catalyst, and adopts isotope-marked precursor as the raw material 18 O-labelling carboxylic acids, however, this method suffers from two problems: (1) The long synthesis step results in low isotope atom utilization rate; (2) Complicated process conditions lead to 18 The abundance of the O isotope is easy to dilute.
Disclosure of Invention
The invention aims to provide a method for preparing by utilizing an exchange method 18 O-marking ethyl formate method for solving the problems of the prior art 18 The O-marked ethyl formate has the problems of low utilization rate of isotope atoms, easy dilution of isotope abundance and the like in the synthesis process. The method only needs one-step reaction, the utilization ratio of the isotope atoms can reach more than 94%, a complex reaction system is not needed, and dilution of the isotope abundance can be effectively avoided.
The aim of the invention can be achieved by the following technical scheme:
preparation by exchange method 18 A method of O marking ethyl formate comprising the steps of:
(1) Adding ethyl formate and H into a hydrothermal reaction kettle 2 18 O and catalyst, heating to react, filtering the obtained product to remove the catalyst,and distilled and separated to obtain 18 O marks crude ethyl formate and H 2 18 O；
(2) The obtained product is then processed 18 O marks the crude product of ethyl formate to replace ethyl formate and repeats the step (1) for a plurality of times, thus obtaining the high abundance of the target product 18 O marks ethyl formate.
Further, in the step (1), ethyl formate and H 2 18 The molar ratio of O is 1: (1-10), preferably 1:2-10.
Further, in the step (1), 0.1 to 0.3g, preferably 0.2g of the catalyst is added to 0.5mol of ethyl formate.
Further, in the step (1), the catalyst is a monoatomically dispersed metal catalyst. Further, in the step (1), the catalyst is at least one of a monoatomically dispersed palladium catalyst, a monoatomically dispersed copper catalyst, and a monoatomically dispersed iron catalyst.
Furthermore, in the step (1), before the reaction, the hydrothermal reaction kettle is replaced by inert gas. Further, in the step (1), the inert gas used is nitrogen.
Further, in the step (1), the heating reaction is carried out at a temperature of 20 to 100 ℃, preferably 50 to 90 ℃, for a time of 1 to 10 hours, preferably 5 to 8 hours.
Further, in the step (2), 18 o marks the crude product of ethyl formate to replace ethyl formate and repeats the step (1) for 2 to 6 times. In addition, equimolar amounts are generally substituted here.
Further, the high abundance 18 The isotopic abundance of the O-labelled ethyl formate is greater than 97atom%.
The isotope exchange reaction is a reversible chemical process of two isotope exchanges of the same element, and the raw material of the isotope exchange reaction of oxygen in the organic compound is mainly H 2 18 O, no net chemical change occurs in these reactions, only isotopically labeled exchange occurs. Conventional acid or base catalyzed H 2 18 The mechanism of the transesterification reaction of O is through hydrolytic cleavage of the acyl-oxygen bond, whereas the monoatomically dispersed metal catalyst used in the present invention has isolated metalActive sites, therefore, can be accomplished by formation of a four covalent intermediate or by direct bimolecular transition state substitution 16 O- 18 Exchange reaction of O, thus exhibiting higher selectivity 16 O- 18 The catalytic activity of O exchange, thus the technology has the advantages of higher isotope utilization rate and higher product isotope abundance.
Compared with the prior art, the invention has the following advantages:
(1) The number of the reactions is reduced from 2 steps to 1 step, and the isotope exchange reaction is carried out from the atomic layer, thereby greatly improving 18 The utilization rate of O isotope atoms reduces the preparation cost of the product;
(2) The reaction process does not need to use a complex acid-base catalytic system, and the risk of diluting the isotope abundance is reduced.
Detailed Description
The present invention will be described in detail with reference to specific examples. The present embodiment is implemented on the premise of the technical scheme of the present invention, and a detailed implementation manner and a specific operation process are given, but the protection scope of the present invention is not limited to the following examples.
In the following examples, the method described in the preparation references CN109589978B of the monoatomically dispersed metal catalysts such as the monoatomically dispersed palladium catalyst, the monoatomically dispersed iron catalyst, the monoatomically dispersed copper catalyst, and the like: (1) Adding 1g of hydroxylated fullerene into 20mL of anhydrous n-hexane, dropwise adding 0.5mL of 2.5M n-butyllithium diethyl ether solution under nitrogen, stirring while dropwise adding, maintaining the system temperature at-78 ℃, stirring and refluxing for reaction for 6h at 60 ℃ under nitrogen atmosphere after dropwise adding, filtering, and washing and drying a filter cake by using the anhydrous n-hexane to obtain an intermediate product; (2) The intermediate product obtained was combined with 124mg of CuCl (FeCl) 2 、PdCl 2 ) Dispersing in 20mL anhydrous n-hexane under nitrogen atmosphere, stirring and refluxing at 60 ℃ for 6h to obtain a mixture of a monoatomic dispersed copper (iron, palladium) catalyst and lithium chloride; (3) And (3) fully dissolving the mixture obtained in the step (2) with water, filtering, and drying a filter cake at 100 ℃ to obtain the target product of the monoatomic dispersed copper (iron and palladium) catalyst.
The remainder, unless specifically stated, is indicative of a conventional commercially available feedstock product or conventional processing technique in the art.
Example 1:
exchange method preparation 18 A method of O-tagging ethyl formate comprising the steps of:
(1) 37.04g (0.5 mol) of ethyl formate and 2eq (20 g) of H with the abundance of 97.1atom% are added into a hydrothermal reaction kettle 2 18 O and 0.2g of monoatomic dispersion palladium catalyst, replacing with high-purity nitrogen, and stirring and reacting for 8 hours at 50 ℃;
(2) After the reaction, the catalyst is removed by filtration and distilled for separation 18 O-tagged ethyl formate and H 2 18 O, distilled H 2 18 O can be recycled;
(3) Separated by distillation 18 O-labeled Ethyl formate was substituted for the ethyl formate in step (1), and steps (1) and (2) were repeated 2 times to give 37g of ethyl formate- 18 O 2 The isotope abundance is 97.1atom%, and the isotope atom utilization rate is 94.8%.
Example 2
In comparison with example 1, the same is largely true except that the catalyst added is a monoatomically dispersed copper catalyst.
Example 3
In comparison with example 1, the same is largely true except that the catalyst added is a monoatomically dispersed iron catalyst.
Comparative example 1:
compared with the example 1, the method is the same as the most part except that the monoatomic dispersion palladium catalyst is replaced by p-toluenesulfonic acid catalyst commonly used in the field, high-purity nitrogen is replaced, and the reaction is stirred for 8 hours at 50 ℃; repeating the exchange for 3 times to obtain 22g of ethyl formate- 18 O has an isotopic abundance of 92.4atom% and an isotopic atom utilization of 55.0%.
Comparative example 2:
compared with example 1, the method is largely the same except that the monoatomically dispersed palladium catalyst is replaced by a potassium carbonate catalyst commonly used in the art, high-purity nitrogenReplacing, and stirring and reacting for 8 hours at 50 ℃; after 3 times of repeated exchange, 17g of ethyl formate was obtained 18 O has an isotopic abundance of 93.6atom% and an isotopic atom utilization of 43.1%.
It can be seen that, compared with comparative examples 1 and 2, the products obtained in example 1 are different from each other, specifically, the single-atom dispersed metal catalyst used in example 1 has isolated metal active sites, all oxygen atoms in the molecular structure of the compound can be marked, and the product is a diatomic marked product, and has high isotope abundance and isotope atom utilization rate; in comparative examples 1 and 2, the acid and base catalysis mechanisms are different from the metal catalysis mechanisms, and the acid and base catalysis is hydrolysis and fission through acyl-oxygen bonds, and only one oxygen-18 atom can be marked in the hydrolysis and fission process, so that a single-atom marked product is obtained, and meanwhile, the whole isotope abundance and the atom utilization rate are low.
Example 4:
compared with example 1, the method is largely the same except that H is regulated 2 18 The amount of O added was 1eq.
Example 5:
compared with example 1, the method is largely the same except that H is regulated 2 18 The amount of O added was 10eq.
Example 6:
the procedure was the same as in example 1, except that the reaction temperature was controlled at 20℃for 10 hours.
Example 7
The procedure was the same as in example 1, except that the reaction temperature was controlled to 100℃for 1 hour.
The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. It will be apparent to those skilled in the art that various modifications can be readily made to these embodiments and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the present disclosure, should make improvements and modifications without departing from the scope of the present invention.
Claims (4)
1. Preparation by exchange method 18 A method for O-marking ethyl formate comprising the steps of:
(1) Adding ethyl formate and H into a hydrothermal reaction kettle 2 18 O and catalyst, heating to react, filtering the obtained product to remove the catalyst, and distilling and separating to obtain 18 O marks crude ethyl formate and H 2 18 O；
(2) The obtained product is then processed 18 O marks the crude product of ethyl formate to replace ethyl formate and repeats the step (1) for a plurality of times, thus obtaining the high abundance of the target product 18 O marks ethyl formate;
in the step (1), ethyl formate, H 2 18 The molar ratio of O is 1: (1-10);
in the step (1), 0.1-0.3 g of catalyst is added corresponding to 0.5mol of ethyl formate;
in the step (1), the catalyst is at least one of a monoatomic dispersed palladium catalyst, a monoatomic dispersed copper catalyst and a monoatomic dispersed iron catalyst;
in the step (1), before the reaction, the hydrothermal reaction kettle is replaced by inert gas;
in the step (1), the temperature of the heating reaction is 20-100 ℃ and the time is 1-10 h.
2. A process according to claim 1 18 The method for marking ethyl formate by O is characterized in that in the step (1), the inert gas is nitrogen.
3. A process according to claim 1 18 A method for marking ethyl formate by O is characterized in that in the step (2), 18 o marks the crude product of ethyl formate to replace ethyl formate and repeats the step (1) for 2-6 times.
4. According to claimA process for preparing by the exchange method as claimed in claim 1 18 A method for O-labelling ethyl formate, characterized in that the high abundance 18 The isotopic abundance of the O-labelled ethyl formate is greater than 97atom%.
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| CN103641733A (en) * | 2013-11-27 | 2014-03-19 | 上海化工研究院 | Preparation method of 18O-dimethylformamide |
| CN105693496B (en) * | 2016-03-18 | 2019-01-18 | 上海化工研究院有限公司 | A kind of stable isotope13The synthetic method of C or D label P-hydroxybenzoic acid |
| CN106542982A (en) * | 2016-10-31 | 2017-03-29 | 上海化工研究院 | A kind of preparation method of the deuterium-labeled acetone of stable isotope |
| CN107935850B (en) * | 2017-12-04 | 2020-12-29 | 上海化工研究院有限公司 | Synthesis method of stable isotope 18O-labeled nipagin ester |
| CN109589978B (en) * | 2018-11-29 | 2021-06-11 | 江南大学 | Preparation method of metal monatomic catalyst |
| CN111423456A (en) * | 2020-04-03 | 2020-07-17 | 南京昊绿生物科技有限公司 | Synthesis process of rifaximin-D6 |
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