CN114105768A - Preparation by exchange method18Method for marking ethyl formate by using O - Google Patents
Preparation by exchange method18Method for marking ethyl formate by using O Download PDFInfo
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- CN114105768A CN114105768A CN202111512650.0A CN202111512650A CN114105768A CN 114105768 A CN114105768 A CN 114105768A CN 202111512650 A CN202111512650 A CN 202111512650A CN 114105768 A CN114105768 A CN 114105768A
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- ethyl formate
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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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Abstract
The invention relates to a preparation method by using an exchange method18A method for O-labeling ethyl formate, comprising the steps of: (1) adding ethyl formate and H into a hydrothermal reaction kettle2 18Heating O and catalyst to react, filtering the obtained product to remove the catalyst, and distilling and separating to obtain18O-labeling of crude Ethyl formate and H2 18O; (2) subjecting the obtained product to18The ethyl formate is replaced by the crude ethyl formate marked by O and the step (1) is repeated for a plurality of times to obtain the target product with high abundance18And O marks ethyl formate. Compared with the prior art, the method only needs one-step reaction, the utilization rate of the isotope atoms can reach more than 94 percent, a complex reaction system is not needed, and the dilution of the isotope abundance can be effectively avoided.
Description
Technical Field
The invention belongs to18The technical field of synthesis of O-marked ethyl formate, and relates to a method for preparing ethyl formate by using an exchange method18And O, a method for marking ethyl formate.
Background
Oxygen element in nature is composed of16O、17O and18the ratio of the three isotopes of O is 500:0.2:1, and the natural abundance is 99.76 atom%, 0.04 atom% and 0.20 atom% respectively.18O、17O and16the separation and enrichment method of O mainly comprises a distillation method, a thermal diffusion method, an electrolysis method and the like, and H with the isotopic abundance of more than 97atom percent is mainly obtained by enrichment through a water distillation method at present2 18And O. With H2 18O is used as raw material, and a series of products can be prepared18The 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: dehydrating and esterifying carboxylic acid and alcohol; carboxylate and halogen; ③ carboxylate, sulfate and sulfonate; anhydride reacts with alcohol and phenol; reacting acyl chloride with alcohol and phenol; ester exchange reaction between carboxylic ester and alcohol or phenol; alcoholysis reaction of nitrile.
Because of the limited variety of isotope starting materials and precursors,18the synthesis method of the O-labeled carboxylic ester compound mainly adopts carboxylic acid and alcohol to dehydrate and esterify under the action of an acid catalyst, and the adopted isotope-labeled precursor is18O-labeled carboxylic acids, but this method has two problems: (1) long synthesis steps lead toThe utilization rate of isotope atoms is not high; (2) complicated process conditions lead to18The abundance of the O isotope is easy to dilute.
Disclosure of Invention
The invention aims to provide a method for preparing the compound by using an exchange method18The method for marking ethyl formate by using O solves the existing problems18The problems of low utilization rate of isotope atoms, easy dilution of isotope abundance and the like in the O-labeled ethyl formate synthesis process. The method only needs one-step reaction, the utilization rate of isotope atoms can reach more than 94 percent, a complex reaction system is not needed, and the dilution of isotope abundance can be effectively avoided.
The purpose of the invention can be realized by the following technical scheme:
preparation by exchange method18A method for O-labeling ethyl formate, comprising the steps of:
(1) adding ethyl formate and H into a hydrothermal reaction kettle2 18Heating O and catalyst to react, filtering the obtained product to remove the catalyst, and distilling and separating to obtain18O-labeling of crude Ethyl formate and H2 18O；
(2) Subjecting the obtained product to18The ethyl formate is replaced by the crude ethyl formate marked by O and the step (1) is repeated for a plurality of times to obtain the target product with high abundance18And O marks ethyl formate.
Further, in the step (1), ethyl formate and H2 18The 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 a catalyst is added to 0.5mol of ethyl formate.
Further, in the step (1), the catalyst is a monoatomic dispersion metal catalyst. Further, in the step (1), the catalyst is at least one of a monoatomic dispersion palladium catalyst, a monoatomic dispersion copper catalyst, and a monoatomic dispersion iron catalyst.
Further, 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 temperature is 20-100 ℃, preferably 50-90 ℃, and the time is 1-10 hours, preferably 5-8 hours.
Further, in the step (2),18and (3) marking the ethyl formate crude product by O to replace ethyl formate, and repeating the step (1) for 2-6 times. In addition, here, generally equimolar amounts are substituted.
Further, the high abundance18The isotopic abundance of the O-labeled ethyl formate is more than 97 atom%.
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 H2 18O, no net chemical change occurs in these reactions, only isotopic label exchange occurs. Conventional acid or base catalysis H2 18The mechanism of the ester exchange reaction of O and the ester exchange reaction is through the hydrolytic fission of acyl-oxygen bond, while the monoatomic dispersed metal catalyst used in the invention has isolated metal active sites, so that the reaction can be completed through forming a tetra-covalent intermediate or through direct bimolecular transition state replacement16O-18Exchange reaction of O, thus exhibiting higher selectivity16O-18The 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 reaction is reduced from 2 steps to 1 step, and the exchange reaction of isotopes is carried out from the atom level, thereby greatly improving18The utilization rate of O isotope atoms reduces the preparation cost of the product;
(2) and a complex acid-base catalysis system is not needed in the reaction process, so that the risk of isotope abundance dilution 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 solution of the present invention, and a detailed implementation manner and a specific operation process are given, but the scope of the present invention is not limited to the following embodiments.
In the following examples, the method described in reference CN109589978B for the preparation of monoatomic dispersion metal catalysts such as monoatomic dispersion palladium catalyst, monoatomic dispersion iron catalyst, and monoatomic dispersion copper catalyst: (1) adding 1g of hydroxylated fullerene into 20mL of anhydrous n-hexane, dropwise adding 0.5mL of 2.5M n-butyllithium ethyl ether solution into the mixture under nitrogen while stirring, maintaining the temperature of the system at-78 ℃ in the dropwise adding process, stirring the mixture at 60 ℃ under nitrogen atmosphere for reflux reaction for 6 hours after the dropwise adding is finished, filtering the mixture again, and washing and drying a filter cake through the anhydrous n-hexane to obtain an intermediate product; (2) the resulting intermediate product was mixed with 124mg of CuCl (FeCl)2、PdCl2) Dispersing in 20mL of anhydrous n-hexane under nitrogen atmosphere, stirring and refluxing at 60 ℃ for 6h to obtain a mixture of a monoatomic dispersed copper (iron and palladium) catalyst and lithium chloride; (3) and (3) fully dissolving the mixture obtained in the step (2) by using water, filtering, and drying a filter cake at 100 ℃ to obtain the target product, namely the monoatomic copper (iron or palladium) dispersed catalyst.
Otherwise, unless otherwise specified, all the conventional commercial raw material products or conventional processing techniques are used in the art.
Example 1:
exchange method preparation18A method of O-labeling ethyl formate comprising the steps of:
(1) 37.04g (0.5mol) of ethyl formate and 2eq (20g) of H having an abundance of 97.1 atom% were put into a hydrothermal reaction vessel2 18O and 0.2g of monoatomic dispersion palladium catalyst, replacing with high-purity nitrogen, and stirring at 50 ℃ for reacting for 8 hours;
(2) after the reaction, the catalyst was removed by filtration and separated by distillation18O-labelling of Ethyl formate and H2 18O, H distilled off2 18The O can be recycled;
(3) separated by distillation18O-labeled ethyl formate was substituted for ethyl formate in step (1), and steps (1) and (2) were repeated 2 times to obtain 37g of ethyl formate-18O2The isotopic abundance ratio is 97.1 atom%, and the isotopic atom utilization ratio is 94.8%.
Example 2
Compared to example 1, most of the same except that the catalyst added was a monoatomic dispersion copper catalyst.
Example 3
Compared to example 1, most of them are the same except that the catalyst added is a monoatomic dispersion iron catalyst.
Comparative example 1:
compared with the embodiment 1, most of the catalyst is the same, except that the monatomic dispersed palladium catalyst is replaced by a p-toluenesulfonic acid catalyst commonly used in the field, high-purity nitrogen is replaced, and the reaction is stirred at 50 ℃ for 8 hours; after repeating the exchange 3 times, 22g of ethyl formate-18O, with an isotopic abundance of 92.4 atom% and an isotopic atom utilization of 55.0%.
Comparative example 2:
compared with the embodiment 1, most of the catalyst is the same, except that the monatomic dispersed palladium catalyst is replaced by potassium carbonate catalyst which is commonly used in the field, high-purity nitrogen is replaced, and the reaction is stirred for 8 hours at 50 ℃; after repeating the exchange 3 times, 17g of ethyl formate-18O, with an isotopic abundance of 93.6 atom%, and an isotopic atom utilization rate of 43.1%.
It can be seen that, compared with comparative examples 1 and 2, the products obtained by the two methods are different, specifically, the monoatomic metal catalyst used in example 1 has isolated metal active sites, all oxygen atoms in the molecular structure of the compound can be labeled, and the product is a diatomic labeled product, and the isotopic abundance and the isotopic atom utilization rate are high; in the comparative examples 1 and 2, different catalysts are adopted, the acid and base catalysis mechanisms are different from the metal catalysis mechanism, the acid and base catalysis is hydrolysis fission through an acyl-oxygen bond, only one oxygen-18 atom can be marked in the hydrolysis fission process, so that a product marked by a single atom is obtained, and meanwhile, the integral isotopic abundance and the atom utilization rate are low.
Example 4:
compared with example 1, most of them are the same except that H is adjusted2 18The amount of O added was 1 eq.
Example 5:
compared with example 1, most of them are the same except that H is adjusted2 18The amount of O added was 10 eq.
Example 6:
compared with example 1, the reaction was almost the same except that the reaction temperature was controlled at 20 ℃ for 10 hours.
Example 7
Compared with example 1, the reaction was almost the same except that the reaction temperature was controlled at 100 ℃ for 1 hour.
The embodiments described above are described to facilitate an understanding and use of the invention by those skilled in the art. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, 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 embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (10)
1. Preparation by exchange method18The method for marking ethyl formate is characterized by comprising the following steps:
(1) adding ethyl formate and H into a hydrothermal reaction kettle2 18Heating O and catalyst to react, filtering the obtained product to remove the catalyst, and distilling and separating to obtain18O-labeling of crude Ethyl formate and H2 18O；
(2) Subjecting the obtained product to18The ethyl formate is replaced by the crude ethyl formate marked by O and the step (1) is repeated for a plurality of times to obtain the target product with high abundance18And O marks ethyl formate.
2. The preparation of claim 1 by exchange18The method for marking ethyl formate by O is characterized in that in the step (1), ethyl formate and H2 18The molar ratio of O is 1: (1-10).
3. The preparation of claim 1 by exchange18The method for marking ethyl formate by O is characterized in that in the step (1), 0.1-0.3 g of catalyst is added corresponding to 0.5mol of ethyl formate.
4. The preparation of claim 1 by exchange18The method for marking ethyl formate by O is characterized in that in the step (1), the catalyst is a monoatomic dispersion metal catalyst.
5. A process according to claim 1 or 4, which is prepared by the exchange method18The method for O-labeling ethyl formate is characterized in that in the step (1), the catalyst is at least one of a monoatomic dispersion palladium catalyst, a monoatomic dispersion copper catalyst and a monoatomic dispersion iron catalyst.
6. The preparation of claim 1 by exchange18The method for marking ethyl formate by O is characterized in that in the step (1), before reaction, the hydrothermal reaction kettle is replaced by inert gas.
7. A process according to claim 6, wherein the preparation is carried out by the exchange method18The method for marking ethyl formate by O is characterized in that in the step (1), the inert gas is nitrogen.
8. The preparation of claim 1 by exchange18The method for marking ethyl formate by O is characterized in that in the step (1), the heating reaction temperature is 20-100 ℃, and the time is 1-10 hours.
9. The preparation of claim 1 by exchange18The method for marking ethyl formate by O is characterized in that in the step (2),18and (3) marking the ethyl formate crude product by O to replace ethyl formate, and repeating the step (1) for 2-6 times.
10. The preparation of claim 1 by exchange18Method for O-labelling ethyl formate, characterised in that said high abundance is18The isotopic abundance of the O-labeled ethyl formate is more than 97 atom%.
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Citations (6)
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| CN103641733A (en) * | 2013-11-27 | 2014-03-19 | 上海化工研究院 | Preparation method of 18O-dimethylformamide |
| CN105693496A (en) * | 2016-03-18 | 2016-06-22 | 上海化工研究院 | Synthesis method of p-hydroxybenzoic acid marked with stable isotope 13C or D |
| 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 |
| CN107935850A (en) * | 2017-12-04 | 2018-04-20 | 上海化工研究院有限公司 | A kind of synthetic method of the nipagin esters of stable isotope 18O marks |
| CN109589978A (en) * | 2018-11-29 | 2019-04-09 | 江南大学 | A kind of preparation method of the monatomic catalyst of metal |
| 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 |
-
2021
- 2021-12-11 CN CN202111512650.0A patent/CN114105768B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103641733A (en) * | 2013-11-27 | 2014-03-19 | 上海化工研究院 | Preparation method of 18O-dimethylformamide |
| CN105693496A (en) * | 2016-03-18 | 2016-06-22 | 上海化工研究院 | Synthesis method of p-hydroxybenzoic acid marked with stable isotope 13C or D |
| 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 |
| CN107935850A (en) * | 2017-12-04 | 2018-04-20 | 上海化工研究院有限公司 | A kind of synthetic method of the nipagin esters of stable isotope 18O marks |
| CN109589978A (en) * | 2018-11-29 | 2019-04-09 | 江南大学 | A kind of preparation method of the monatomic catalyst of metal |
| 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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