CN113493392B - Glycine-1- 14 Process for the preparation of C - Google Patents
Glycine-1- 14 Process for the preparation of C Download PDFInfo
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- CN113493392B CN113493392B CN202110921580.8A CN202110921580A CN113493392B CN 113493392 B CN113493392 B CN 113493392B CN 202110921580 A CN202110921580 A CN 202110921580A CN 113493392 B CN113493392 B CN 113493392B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
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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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- 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
Abstract
The invention discloses glycine-1- 14 The preparation method of C comprises the following steps: (1) Under the protection of inert gas, anhydrous nitromethane and metal or metal organic reagent form nitromethane salt solution in anhydrous ether solvent, and then are reacted with 14 CO 2 The nitroacetic acid-1- 14 C, crude product; the said process 14 CO 2 Through barium carbonate- 14 Acidolysis of C; (2) Nitroacetic acid-1- 14 The crude product of C is subjected to reduction reaction with hydrogen, and after the reaction is finished, the glycine-1-percent is obtained through post-treatment 14 C. The method has short synthesis steps, mild and controllable reaction conditions, no need of harsh conditions such as high temperature, high pressure and the like, no need of using dangerous chemicals such as strong corrosiveness, extremely toxicity and the like, easy micro synthesis, low cost, 14 the utilization rate of C is high, the purity of the product obtained by final purification is high, the state is good, and the specific activity is reduced little.
Description
Technical Field
The invention relates to a method for synthesizing glycine-1 with high specific activity 14 C, in particular to a method for directly using 14 C source material barium carbonate 14 C. Synthesis of glycine-1- 14 C, also relates to 13 C source material barium carbonate 13 C. Synthesis of high-abundance glycine-1 by using cheap nitromethane and the like as raw materials 13 The method of C.
Background
Glycine is an important amino acid constituting biological proteins, and basically, various proteins, polypeptides and other biological substances composed of amino acids contain glycine; meanwhile, in the field of isotope labeling synthesis, glycine is also a raw material for synthesizing a plurality of heterocycles, amino acid modules and other important intermediates. In the case of proteins, polypeptides and other amino acids, etcIntroduction of 14 C, by 14 The introduction of C-tag glycine is a very common and efficient means. 14 C has important significance in metabolic research of proteins, polypeptides and the like and pharmacological research of medicaments of related compounds due to the characteristics of high sensitivity and easiness in tracing.
In glycine 14 Glycine-1- 14 C is a relatively common one. And for the case of 14 The labeling compound of C, especially the base compound, is essentially barium carbonate 14 C (or) 14 CO 2 ) As a means of 14 C source, thus, it can be seen that 14 C (or) 14 CO 2 ) Synthesis of Glycine-1 from Source Material 14 C has important significance.
At present, glycine-1- 14 The method of C is mainly that the source material barium carbonate- 14 C (or) 14 CO 2 ) Synthesis of acetic acid-1- 14 C, then brominating to prepare ethyl bromoacetate-1- 14 And C, synthesizing phthalimidoacetic acid ethyl ester with phthalimido potassium, and finally hydrolyzing with concentrated hydrochloric acid to obtain glycine, wherein the specific reaction route is as follows:
although each step of the method is technically mature and the reaction is relatively easy to operate, the total reaction steps are relatively long, and the reaction process is relatively complex, especially for the method 14 For the C-tag, the source material is very expensive, and the step is too long, which increases the radiation protection cost. At the same time, the reaction is used for highly toxic compounds such as bromine, and the final hydrolysis requires reflux, which is used for radioactive compounds 14 The marking of C increases environmental risks and costs.
In conclusion, a glycine-1-one which is efficient, low in cost, mild in reaction and easy to control is developed 14 The preparation method of C has important practical significance.
Disclosure of Invention
In view of the above-mentioned drawbacks, an object of the present invention is to provide a method for directly preparing barium carbonate 14 C (or) 14 CO 2 ) Is that 14 Synthesizing glycine-1- 14 C, namely directly adopting nitromethane as a substrate to prepare 14 C source material barium carbonate 14 C (or) 14 CO 2 ) Is that 14 C source, by nitromethane absorption 14 CO 2 Obtaining nitroacetic acid-1- 14 C, then reducing to obtain glycine-1- 14 C。
Glycine-1- 14 The preparation method of C comprises the following steps:
(1) Under the protection of inert gas, anhydrous nitromethane and metal or metal organic reagent form nitromethane salt solution in anhydrous ether solvent, and then are reacted with 14 CO 2 The nitroacetic acid-1- 14 C, crude product;
the said process 14 CO 2 Through barium carbonate- 14 Acidolysis of C;
(2) Nitroacetic acid-1- 14 The crude product of C is subjected to reduction reaction with hydrogen, and after the reaction is finished, the glycine-1-percent is obtained through post-treatment 14 C。
The specific synthetic route of the invention is as follows:
the method has short synthesis steps, mild and controllable reaction conditions, no need of harsh conditions such as high temperature, high pressure and the like, no need of using dangerous chemicals such as strong corrosiveness, extremely toxicity and the like, easy micro synthesis, low cost, 14 the utilization rate of C is high, the purity of the product obtained by final purification is high, the state is good, and the specific activity is reduced little.
Preferably, in step (1), the metal is lithium, magnesium or sodium;
the metal organic reagent is LDA or n-butyllithium.
Preferably, in the step (1), the anhydrous ether solvent is absolute anhydrous diethyl ether or absolute anhydrous THF.
Preferably, in the step (1), the barium carbonate 14 C. The molar ratio of the anhydrous nitromethane to the metal or metal organic reagent is 1:1 to 1.2:1 to 20.
Preferably, in step (1), the acid used for acidolysis is concentrated sulfuric acid.
Preferably, in step (1), the post-treatment process is as follows: after the reaction is finished, dilute hydrochloric acid is added for extraction and deactivation, the pH value is regulated to be between 0 and 3 to be acidic, sediment is removed by filtration, and the solvent is dried by spin to obtain nitroacetic acid-1- 14 C crude product.
Preferably, in the step (2), the solvent used for the reduction reaction is a mixed solution of water and acetic acid or a methanolic hydrochloric acid solution.
Preferably, in the step (2), the temperature of the reduction reaction is room temperature for 2 to 24 hours.
Preferably, the post-treatment process is as follows: after the reaction is finished, filtering to remove the palladium-carbon catalyst, and spin-drying the solvent in vacuum to obtain glycine-1- 14 Crude C acetate; dissolving the crude product in absolute ethyl alcohol, regulating pH value to be 4.5-7.5 by using triethylamine alcohol solution, then standing for 2-48 hours at low temperature, and separating out glycine-1- 14 Filtering the C solid at low temperature to obtain glycine-1- 14 C, pure product.
Further, glycine-1-like compounds of the present invention 14 The preparation method of C comprises the following specific steps:
(1) Absolute anhydrous nitromethane (1-20 equivalent barium carbonate- 14 C) Dissolving in 0-50 times of absolute anhydrous ether (or absolute anhydrous ether such as THF) to obtain mixed solution, adding 1.2 equivalent (equivalent to barium carbonate- 14 C) The treated metallic lithium (or magnesium, or sodium, or LDA, or n-butyllithium, etc.) forms nitromethane salt solution, and then the barium carbonate is acidolyzed with concentrated sulfuric acid under vacuum or nitrogen 14 C formation 14 CO 2 Fully reacting with the nitromethane salt solution for 0.5 to 24 hoursAfter the completion of the reaction, dilute hydrochloric acid is added for extraction and deactivation, the pH value is adjusted to be between 0 and 3, the acid is developed, the sediment is removed by filtration, and the solvent is dried by spin to obtain nitroacetic acid-1- 14 C crude product.
(2) The nitroacetic acid-1- 14 The crude product C is dissolved in a mixed solution of water and acetic acid (volume ratio of water: acetic acid=1:0.01-100) or a methanol hydrochloric acid solution (1-5 drops of concentrated hydrochloric acid are added dropwise into methanol), then 0.01-1 times of palladium-carbon catalyst is added for reaction for 2-24 hours at room temperature under hydrogen atmosphere. After the reaction is finished, filtering to remove the palladium-carbon catalyst, and spin-drying the solvent in vacuum to obtain glycine-1- 14 Crude C acetate. Dissolving the crude product in absolute ethyl alcohol, regulating pH value to be 4.5-7.5 by using triethylamine alcohol solution, then standing for 2-48 hours at low temperature, and separating out glycine-1- 14 Filtering the C solid at low temperature to obtain glycine-1- 14 C, pure product.
Compared with the traditional method, the method has the advantages of simple and easily controlled reaction process, easy operation, short steps, convenient product purification, high yield and low cost.
The invention has the advantages that:
1. all reactions are carried out at room temperature or low temperature, the reaction conditions are mild and easy to control, dangerous chemicals such as drastic drugs and the like are not used, and radiation pollution caused by dissipation of radioactive substances due to uncontrollable factors in the reaction process can be avoided;
2. the method has the advantages of short steps, higher total yield, greatly reduced synthesis cost, and obviously reduced radioactive waste generated by not using separation means such as column chromatography and the like, and reduced disposal cost of the radioactive waste, which is characterized in that 14 The C isotope labeling synthesis has great advantages.
3. The invention avoids synthesizing low boiling point intermediates such as acetic acid, the only intermediate nitroacetic acid is of high boiling point, and is relatively easy to separate from solvent, the product is not screwed off when the solvent is dried, and the glycine-1- 14 Synthesis yield of C. The final product is reduced by palladium-carbon hydrogenation, and the obtained substrate is relatively easy to purify.
Detailed Description
Example 1
200mg of barium carbonate was charged into a 25mL single-necked flask equipped with a dropping funnel (about 15mL of concentrated sulfuric acid was previously added to the dropping funnel) 14 C (specific activity 50-60 mCi/mmol), the dropping funnel is connected to a 25mL two-port bottle (about 10mg of the surface-treated lithium particles are put in advance) by a catheter, a high-tightness valve is arranged in the middle of the catheter, and the other port of the two-port bottle is sealed by a reverse-port plug, so that the air tightness of the whole device is detected. The whole device is vacuumized by an oil pump, under the condition that a conduit valve is kept closed, 5mL of absolute anhydrous tetrahydrofuran and 300mg of absolute anhydrous nitromethane are sequentially injected from a needle head into a two-medium bottle reverse-mouth bottle under the protection of nitrogen, and then bubbles are generated, if no bubbles are generated, the temperature can be properly raised. After stirring reaction is maintained for 2 hours, a valve of a guide pipe is opened, concentrated sulfuric acid in a dropping funnel is slowly dropped into a single-mouth bottle to generate 14 CO 2 Gas until the solid in the single-mouth bottle is dissolved, then freezing the two-mouth bottle by liquid nitrogen, and then cooling all 14 CO 2 After the gas was transferred into the two-port flask, the valve of the conduit was closed, and then the reaction was allowed to warm to room temperature overnight. After the reaction is finished, dilute hydrochloric acid is added for extraction and deactivation reaction, the pH value of the solution is regulated to be about 1-3, and then the solvent is dried in a vacuum manner, so that a crude product is obtained.
The crude product produced above was dissolved in acetic acid, and then a small amount of water was added dropwise, 50mg of palladium on carbon (5%) was added, and stirred at room temperature under a hydrogen atmosphere overnight. After the reaction is finished, filtering to remove the catalyst, and then spin-drying the solution in vacuum to obtain glycine-1- 14 About 110mg of crude C. Glycine-1- 14 Regulating pH to about 6.0 with triethylamine methanol solution in anhydrous methanol, standing overnight at-10deg.C, separating out solid, filtering, and drying to obtain white flaky solid about 30mg, and total yield (in barium carbonate- 14 C) about 39% by HPLC analysis of purity>98% liquid flash analysis showed a specific activity of about 58.2mCi/mmol.
Example 2
To a 50mL single-necked flask equipped with a dropping funnel (about 30mL of concentrated sulfuric acid was previously added to the dropping funnel), 400mg of barium carbonate was added 14 C (ratio)The activity is 50-60 mCi/mmol), the dropping funnel is connected into a 25mL two-port bottle by a conduit, a high-tightness valve is arranged in the middle of the conduit, the other port of the two-port bottle is sealed by a reverse port plug, and the air tightness of the whole device is detected. The whole device is vacuumized by an oil pump, under the condition that a conduit valve is kept closed, 10mL of absolute ethyl ether and 600mg of absolute nitromethane are sequentially injected from a needle head into a two-medium bottle reverse mouth bottle under the protection of nitrogen, then the temperature is reduced to-78 ℃, and then 2.5mL of LDA (2 mol/L THF solution) is added. Removing low temperature after LDA is added, heating to room temperature, maintaining room temperature, stirring and reacting for 2 hours, opening a conduit valve, slowly dripping concentrated sulfuric acid in a dropping funnel into a single-mouth bottle to generate 14 CO 2 Gas until the solid in the single-mouth bottle is dissolved, then freezing the two-mouth bottle by liquid nitrogen, and then cooling all 14 CO 2 After the gas was transferred into the two-port flask, the valve of the conduit was closed, and then the reaction was allowed to warm to room temperature overnight. After the reaction is finished, dilute hydrochloric acid is added for extraction and deactivation reaction, the pH value of the solution is regulated to be about 1-3, and then the solvent is dried in a vacuum manner, so that a crude product is obtained.
The crude product produced above was dissolved in methanol, then 1 drop of concentrated hydrochloric acid was added dropwise, 50mg of palladium on carbon (5%) was added, and stirred at room temperature under a hydrogen atmosphere overnight. After the reaction is finished, filtering to remove the catalyst, and then spin-drying the solution in vacuum to obtain glycine-1- 14 About 180mg of crude C. Glycine-1- 14 Regulating pH to about 6.0 with triethylamine methanol solution in anhydrous methanol, standing overnight at-10deg.C, separating out solid, filtering, and drying to obtain white flaky solid about 50mg, with total yield (in barium carbonate- 14 C) about 32% by HPLC analysis purity>98% liquid flash analysis gave a specific activity of about 58.8mCi/mmol.
Claims (8)
1. Glycine-1- 14 The preparation method of C is characterized by comprising the following steps:
(1) Through barium carbonate- 14 Acidolysis of C to give 14 CO 2 The method comprises the steps of carrying out a first treatment on the surface of the Under the protection of inert gas, anhydrous nitromethane and metal or metal organic reagent form nitromethane salt solution in anhydrous ether solvent, and then react with the nitromethane salt solution 14 CO 2 The nitroacetic acid-1- 14 C, crude product;
(2) Nitroacetic acid-1- 14 The crude product of C is subjected to reduction reaction with hydrogen, and after the reaction is finished, the glycine-1-percent is obtained through post-treatment 14 C；
In the step (1), the metal is lithium;
the metal organic reagent is LDA.
2. Glycine-1-ene as described in claim 1 14 The preparation method of C is characterized in that in the step (1), the anhydrous ether solvent is absolute anhydrous diethyl ether or absolute anhydrous THF.
3. Glycine-1-ene as described in claim 1 14 The process for producing C, characterized in that in the step (1), the barium carbonate 14 C. The molar ratio of the anhydrous nitromethane to the metal or metal organic reagent is 1: 1-1.2: 1-20.
4. Glycine-1-ene as described in claim 1 14 The preparation method of C is characterized in that in the step (1), the acid used for acidolysis is concentrated sulfuric acid.
5. Glycine-1-ene as described in claim 1 14 The preparation method of C is characterized in that in the step (1), the post-treatment process is as follows: after the reaction is finished, dilute hydrochloric acid is added for extraction and deactivation, the pH value is regulated to be 0-3, the acidity is developed, sediment is removed by filtration, and the solvent is dried by spin to obtain nitroacetic acid-1- 14 C crude product.
6. Glycine-1-ene as described in claim 1 14 The preparation method of C is characterized in that in the step (2), the solvent used in the reduction reaction is a mixed solution of water and acetic acid or a methanol hydrochloric acid solution.
7. Glycine-1-ene as described in claim 1 14 The preparation method of the C is characterized in that in the step (2), the temperature of the reduction reaction is room temperature, and the time is 2-24 hours.
8. Glycine-1-ene as described in claim 1 14 The preparation method of C is characterized in that the post-treatment process is as follows: after the reaction is finished, filtering to remove the palladium-carbon catalyst, and spin-drying the solvent in vacuum to obtain glycine-1- 14 Crude C acetate; dissolving the crude product in absolute ethyl alcohol, regulating the pH value to be 4.5-7.5 by using a triethylamine ethanol solution, and then standing for 2-48 hours at a low temperature to separate out glycine-1- 14 Filtering the C solid at low temperature to obtain glycine-1- 14 C, pure product.
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Citations (4)
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| JP2012246255A (en) * | 2011-05-27 | 2012-12-13 | Natl Inst Of Radiological Sciences | Method for producing 11c-labeled amino acid analogue, and nuclear medical image diagnostic agent |
| JP2016222590A (en) * | 2015-05-29 | 2016-12-28 | 国立大学法人東京海洋大学 | Manufacturing method of isotope-labeled compound of aliphatic acid, isotope-labeled compound of aliphatic acid obtained by the method and diagnostic agent |
| CN108341839A (en) * | 2018-01-10 | 2018-07-31 | 浙江大学 | A kind of insecticide chlorpyrifos and its synthetic method of the label of radioactive isotope carbon -14 |
| CN113024565A (en) * | 2021-03-31 | 2021-06-25 | 上海启甄环境科技有限公司 | Radioactive isotope carbon-14 labeled ibrutinib and synthesis method thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1976796A2 (en) * | 2005-12-21 | 2008-10-08 | GE Healthcare Limited | Miniaturized liquid surface reactions using nanomolar amounts of concentrated ý11c¨carbon dioxide in a stationary gas-phase |
| WO2008011033A2 (en) * | 2006-07-11 | 2008-01-24 | Spectra Gases, Inc. | Synthesis of isotopically labeled alpha-keto acids and esters |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2012246255A (en) * | 2011-05-27 | 2012-12-13 | Natl Inst Of Radiological Sciences | Method for producing 11c-labeled amino acid analogue, and nuclear medical image diagnostic agent |
| JP2016222590A (en) * | 2015-05-29 | 2016-12-28 | 国立大学法人東京海洋大学 | Manufacturing method of isotope-labeled compound of aliphatic acid, isotope-labeled compound of aliphatic acid obtained by the method and diagnostic agent |
| CN108341839A (en) * | 2018-01-10 | 2018-07-31 | 浙江大学 | A kind of insecticide chlorpyrifos and its synthetic method of the label of radioactive isotope carbon -14 |
| CN113024565A (en) * | 2021-03-31 | 2021-06-25 | 上海启甄环境科技有限公司 | Radioactive isotope carbon-14 labeled ibrutinib and synthesis method thereof |
Non-Patent Citations (1)
| Title |
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