CN111423410A - Stable isotope13Method for synthesizing C-labeled 1, 4-dithio-2, 5-diol - Google Patents
Stable isotope13Method for synthesizing C-labeled 1, 4-dithio-2, 5-diol Download PDFInfo
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- CN111423410A CN111423410A CN202010392890.0A CN202010392890A CN111423410A CN 111423410 A CN111423410 A CN 111423410A CN 202010392890 A CN202010392890 A CN 202010392890A CN 111423410 A CN111423410 A CN 111423410A
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- C07B2200/05—Isotopically modified compounds, e.g. labelled
Abstract
Stable isotope13A method for synthesizing C-labeled 1, 4-dithio-2, 5-diol, to13Reacting C-labeled chloroethanol serving as raw material with an oxidant to obtain an intermediate13C marking chloroacetaldehyde solution, and then adding the obtained intermediate13C-labeled chloroacetaldehyde solution reacts with sodium hydrosulfide to obtain13C marks 1, 4-dithio-2, 5-diol. The invention not only provides a method for synthesizing 1, 4-dithio-2, 5-diol with mild reaction conditions, simple reaction device, convenient process control and convenient product purification, but also provides stable isotope13The synthesis of C-labelled 1, 4-dithio-2, 5-diols provides a convenient method, which is equally applicable to radioisotopes14C-labeled 1, 4-dithio-2, 5-diol.
Description
Technical Field
The invention relates to a method for synthesizing 1, 4-dithio-2, 5-diol by isotope labeling, in particular to a method for synthesizing 1, 4-dithio-2, 5-diol by isotope labelingStable isotope13A method for synthesizing C-marked 1, 4-dithio-2, 5-diol.
Background
1, 4-dithio-2, 5-diol is an important organic chemical raw material and intermediate, and has wide markets in the industries of medicine, spice, organic synthesis and the like, and particularly has great development prospects in spice compounds. At present, the method for producing 1, 4-dithio-2, 5-diol in China is few, the reaction for synthesizing the 1, 4-dithio-2, 5-diol generally has the phenomenon of single fixed initial raw material, and the condition leads to isotope labeling for synthesizing the 1, 4-dithio-2, 5-diol-13C4And 1, 4-dithio-2, 5-diol-14C4The cost is high and even difficult to realize, which is very disadvantageous for the synthesis of corresponding isotope-labeled compounds required for the intensive pharmacological, environmental and metabolic studies of 1, 4-dithio-2, 5-diol and derivatives thereof.
The existing method for synthesizing 1, 4-dithio-2, 5-diol mainly comprises the following steps: for example, ZongqiangWang (chem.commun.,2014,50,7004 — 7006) adopts chloroacetaldehyde to be dripped into sodium hydrosulfide aqueous solution for reaction to obtain a mercaptoacetaldehyde intermediate, the reaction operation is simple, the product yield can reach 75.3%, mercaptoacetaldehyde needs further synthesis to obtain 1, 4-dithio-2, 5-diol, and the process operation is complex and the byproducts are increased in the process of converting mercaptoacetaldehyde into 1, 4-dithio-2, 5-diol. For example, in a paper published in the journal of the national war 2003, the Sun Bao, the Limenglan and the like in the journal of university of Beijing Industrial and commercial, "the synthesis of 1, 4-dithiane perfume compounds and the application thereof in food" mention a wide application prospect of 1, 4-disulfide-2, 5-diol, and mention that 1, 4-disulfide-2, 5-diol is obtained by dripping chloroacetaldehyde into sodium hydrosulfide aqueous solution for reaction, but no detailed reaction data exists, and the reaction takes chloroacetaldehyde as a raw material and is not suitable for laboratory and industrial synthesis of isotopically labeled compounds.
Disclosure of Invention
The technical problem to be solved by the invention is to overcome the defects in the prior art and provide a stable reaction device which has the advantages of cheap and easily available reaction raw materials, mild reaction conditions, simple reaction device, convenient operation and convenient product purificationQualitative isotope13The isotope labeled synthetic products and various stable isotope labeled intermediates obtained by the C-labeled 1, 4-dithio-2, 5-diol synthetic method are not reported in documents, and the isotope abundance cannot be diluted in the synthetic process, so that the production cost is effectively reduced.
The technical scheme adopted by the invention for solving the technical problems is as follows: stable isotope13The method for synthesizing the C-labeled 1, 4-dithio-2, 5-diol comprises the following steps:
(1) adding into a dry single-neck flask13C-labeled chloroethanol is used as a raw material, dichloromethane is added, an oxidant is added at the temperature of minus 10 ℃, the natural temperature rise reaction is carried out after the addition is finished, after the reaction is completed, diatomite is added into obtained reaction liquid, the reaction liquid is stirred and filtered, filter cakes are washed by the dichloromethane, washing liquid and filtrate are combined, isovolumetric diethyl ether is added into the obtained solution, a saturated sodium bicarbonate solution is added into an ice water bath to adjust the pH value to be 7-8, the filtration is carried out, the filter cakes are washed by the diethyl ether, the washing liquid and the filtrate are combined, the obtained solution is dried in a spinning mode at the temperature of 10 ℃, crude products are obtained, the diethyl ether is added, the crude products are pulped and filtered, the filtrate is directly subjected to silica gel column chromatography, the diethyl ether is used for passing13C, marking chloroacetaldehyde solution;
(2) adding sodium hydrosulfide into a dry single-neck flask, adding water for dissolving, and dropwise adding the intermediate obtained in the step (1) at the temperature of minus 10 DEG C13Marking chloroacetaldehyde solution with C, generating solid in the dropping process, stopping dropping when the pH value of the reaction solution is 8-9, and filtering to obtain an intermediate 2;
(3) adding sodium hydrosulfide into a dry single-neck flask, adding water for dissolving, and dropwise adding the intermediate obtained in the step (1) at the temperature of minus 10 DEG C13Marking chloroacetaldehyde solution with C, generating solid in the dropping process, stopping dropping when the pH value of the reaction solution is 8-9, and filtering to obtain an intermediate 3;
(4) mixing the intermediate 2 obtained in the step (2) and the intermediate 3 obtained in the step (3), adding methanol to pulp at-10 ℃, filtering, washing a filter cake with glacial methanol, filtering, and drying the obtained filter cake to obtain the product13C marks 1, 4-dithio-2, 5-diol.
Preferably, in step (1), the13Feeding mol ratio of the C-marked chloroethanol, the dichloromethane and the oxidant is 1: 18-22: 0.8-1.2.
Preferably, in step (1), the oxidizing agent is at least one of dess-martin oxidizing agent, pyridinium chlorochromate, sulfur trioxide pyridine or 9-BBN.
Preferably, in the step (1), the amount of the diatomaceous earth added is 1/3 to 2/3 parts by weight of the reaction solution.
Preferably, in the step (2), the sodium hydrosulfide accounts for 70% by mass and is dihydrate.
Preferably, in the step (3), the sodium hydrosulfide accounts for 70% by mass and is dihydrate.
Stable isotopes of the invention13Method for synthesizing C-labeled 1, 4-dithio-2, 5-diol applied to radioactive isotope14C-labeled 1, 4-dithio-2, 5-diol.
The reaction process of the invention is as follows:
note: is a stable isotope13C or radioactive isotopes14C。
Compared with the prior art, the invention has the following beneficial effects: the complex or difficultly obtained labeled compound is avoided being used as the starting material, and the labeled acetic acid which is easily obtained on the market is directly used as the starting material, so that the synthesis cost is greatly reduced; synthesized13The purity of the C-marked 1, 4-dithio-2, 5-diol is more than or equal to 98 percent, and the abundance of the marked points is more than or equal to 99 percent; not only fills the domestic blank, but also can be applied to radioactive isotopes14C, synthesizing 1, 4-dithio-2, 5-diol labeled by C; but also helps to meet the huge demands of domestic and international markets; the process has mild reaction conditions, can realize the maximized obtaining of the high-purity 1, 4-dithio-2, 5-diol, is directly synthesized by chloroacetaldehyde in one step, greatly shortens the reaction time, saves time and labor, effectively reduces the production cost, and is suitable for industrial production.
Detailed Description
The present invention will be further described with reference to the following examples.
The chemical reagents used in the examples of the present invention, unless otherwise specified, are commercially available in a conventional manner.
Example 1
The embodiment comprises the following steps:
(1) 1g (12.1mmo L,1.0eq) of commercially available stable isotope labeled [1,2-13C2]Adding 15ml of dichloromethane into chloroethanol serving as a raw material, adding 6g of dess-martin oxidant at-10 ℃, naturally heating to react for 20min after the addition is finished, after the reaction is carried out for 3h, adding kieselguhr with the mass equivalent to 1/3 of the reaction liquid into the obtained reaction liquid, stirring for 5min, filtering, washing a filter cake with dichloromethane, combining a washing liquid with a filtrate, adding equal volume of diethyl ether into the obtained solution, adding a saturated sodium bicarbonate solution into an ice water bath at 0 ℃ to adjust the pH value to 7 (an organic phase or an organic phase is used for measuring the water phase), filtering, washing the filter cake with diethyl ether, combining a washing liquid with the filtrate, carrying out spin-drying on the obtained solution at 10 ℃ to obtain 3.5g of crude product, adding 7m L of diethyl ether to carry out pulping and column chromatography, filtering, directly applying silica gel to the filtrate, passing through a column with diethyl ether, collecting 150m L of chromatographic solution, adding 1.0g of water, carrying out spin-drying at 10 ℃ to obtain 2.6g of crude product13C about 0.9g of chloroacetaldehyde;
(2) adding 1g of 70% sodium hydrosulfide hydrate into a dry 25m L single-neck flask, dissolving with 1.3m L water, and dropwise adding the intermediate obtained in the step (1) at-10 DEG C13Labeling chloroacetaldehyde solution with C, generating solid in the dropping process, stopping dropping when the pH value of the reaction solution is 8 when the pH value is added to 2.6g, and filtering to obtain 139mg of intermediate 2 (which is not dried);
(3) 1.9g of hydrated 70% sodium hydrosulfide was added to a dry 25m L single-neck flask, dissolved in water with the addition of 2.4m L, and the intermediate obtained in step (1) was added dropwise at-10 deg.C13Labeling chloroacetaldehyde solution with C, generating solid in the dropping process, stopping dropping when the pH value of the reaction solution is 8 when the pH value is 4.4g, and filtering to obtain 230mg of intermediate 3 (which is not dried);
(4) mixing the intermediate 2 obtained in the step (2) and the intermediate 3 obtained in the step (3),adding 1.5m L methanol, pulping at-10 deg.C, filtering, washing the filter cake with glacial methanol, filtering, and drying the filter cake to obtain 310mg13C-labeled 1, 4-dithio-2, 5-diol, yield 17%, chemical purity 98%, isotopic abundance 99 Atom%13C。
Example 2
The embodiment comprises the following steps:
(1) in a dry 50m L one-neck flask was placed 2.7g (32.7mmol,1.0eq) of a commercially available stable isotope-labeled [1,2-13C2]Adding 40ml of dichloromethane into chloroethanol serving as a raw material, adding 16g (1.2eq) of dess-martin oxidant at-10 ℃, naturally heating to react for 20min after adding the dichloromethane, after reacting for 3h, adding kieselguhr with the mass equivalent to 1/3 of reaction liquid into the obtained reaction liquid, stirring for 5min, filtering, washing a filter cake with dichloromethane, combining washing liquid with the filtrate, adding aether with the same volume into the obtained solution, adding saturated sodium bicarbonate solution into an ice water bath at 0 ℃ to adjust the pH value to be 7 (organic phase or organic phase water phase), filtering, washing the filter cake with diethyl ether, combining the washing liquid and the filtrate, spin-drying the obtained solution at 10 ℃ to obtain 9.5g of crude product, adding 20m L of diethyl ether to pulp the crude product, filtering, directly performing silica gel column chromatography on the filtrate, passing through the diethyl ether column, collecting 300m L of chromatographic solution, adding 2.0g of water, spin-drying at 10 ℃ to obtain 7.0g of crude product containing white solid, washing with water, filtering to obtain 18.86g of intermediate labeled chloroacetaldehyde solution13C about 2.5g of chloroacetaldehyde;
(2) adding 3g of 70% sodium hydrosulfide hydrate into a dry 25m L single-neck flask, dissolving with 3.5m L of water, and dropwise adding the intermediate obtained in the step (1) at-10 DEG C13Marking chloroacetaldehyde solution with C, generating solid in the dropping process, stopping dropping when the pH value of the reaction solution is 8 when the pH value is 7.0g, and filtering to obtain 375mg of intermediate 2 (which is not dried);
(3) 5g of 70% sodium hydrosulfide hydrate was added to a dry 25m L single-neck flask, dissolved in 6.5m L water, and the intermediate obtained in step (1) was added dropwise at-10 deg.C13Labeling chloroacetaldehyde solution with C, generating solid in the dropping process, stopping dropping when the pH value of the reaction solution is 8 when the pH value is 11.86g, and filtering to obtain 620mg of intermediate 3 (which is not dried);
(4) subjecting the product obtained in the step (2)Mixing the intermediate 2 and the intermediate 3 obtained in step (3), adding 4m L methanol at-10 deg.C, pulping, filtering, washing the filter cake with glacial methanol, filtering, and drying the filter cake to obtain 870mg13C-labeled 1, 4-dithio-2, 5-diol, yield 18%, chemical purity 98%, isotopic abundance 99 Atom%13C。
Example 3
The embodiment comprises the following steps:
(1) in a dry 50m L one-neck flask was placed 5.4g (65.5mmol,1.0eq) of a commercially available stable isotope-labeled [1,2-14C2]Adding 70ml of dichloromethane into chloroethanol serving as a raw material, adding 32g (1.2eq) of dess-martin oxidant at-10 ℃, naturally heating to react for 20min after adding, adding kieselguhr with the mass equivalent to 1/3 of the reaction liquid into the obtained reaction liquid after reacting for 3h, stirring for 5min, filtering, washing a filter cake with dichloromethane, combining washing liquid with the filtrate, adding aether with the same volume into the obtained solution, adding a saturated sodium bicarbonate solution into an ice water bath at 0 ℃ to adjust the pH value to be 7 (measuring the water phase of an organic phase or the organic phase), filtering, washing the filter cake with the aether, combining the washing liquid and the filtrate, spin-drying the obtained solution at 10 ℃ to obtain 20g of crude product, adding 30m L of aether into the obtained solution for pulping, filtering, directly coating the filtrate on silica gel, passing through an aether column, collecting 500m L of chromatographic liquid, adding 4.0g of water, spin-drying at 10 ℃ to obtain 15g of crude product containing white solid, washing with water, filtering to obtain 38g of intermediate labeled14C about 5.2g of chloroacetaldehyde;
(2) 6g of 70% sodium hydrosulfide hydrate was added to a dry 25m L single-neck flask, dissolved in 7m L water, and the intermediate obtained in step (1) was added dropwise at-10 deg.C14Marking chloroacetaldehyde solution with C, generating solid in the dropping process, stopping dropping when the pH value of the reaction solution is 8 when 15g of chloroacetaldehyde solution is added, and filtering to obtain 800mg of intermediate 2 (which is not dried);
(3) 10g of 70% sodium hydrosulfide hydrate was added to a dry 25m L single-neck flask, dissolved in 14m L water, and the intermediate obtained in step (1) was added dropwise at-10 deg.C14Marking chloroacetaldehyde solution with C, generating solid in the dropping process, stopping dropping when the pH value of the reaction solution is 8 when the solution is added to 21g, and filtering to obtain 1.4g of intermediate 3 (which is not dried);
(4) mixing the intermediate 2 obtained in step (2) and the intermediate 3 obtained in step (3), adding 6m L methanol at-10 deg.C, pulping, filtering, washing the filter cake with glacial methanol, filtering, and drying the filter cake to obtain 1.9g14C-labeled 1, 4-dithio-2, 5-diol, yield 18%, chemical purity 98%, isotopic abundance 99 Atom%14C。
Claims (7)
1. Stable isotope13The method for synthesizing the C-marked 1, 4-dithio-2, 5-diol is characterized by comprising the following steps: the method comprises the following steps:
(1) adding into a dry single-neck flask13C-labeled chloroethanol is used as a raw material, dichloromethane is added, an oxidant is added at the temperature of minus 10 ℃, the natural temperature rise reaction is carried out after the addition is finished, after the reaction is completed, diatomite is added into obtained reaction liquid, the reaction liquid is stirred and filtered, filter cakes are washed by the dichloromethane, washing liquid and filtrate are combined, isovolumetric diethyl ether is added into the obtained solution, a saturated sodium bicarbonate solution is added into an ice water bath to adjust the pH value to be 7-8, the filtration is carried out, the filter cakes are washed by the diethyl ether, the washing liquid and the filtrate are combined, the obtained solution is dried in a spinning mode at the temperature of 10 ℃, crude products are obtained, the diethyl ether is added, the crude products are pulped and filtered, the filtrate is directly subjected to silica gel column chromatography, the diethyl ether is used for passing13C, marking chloroacetaldehyde solution;
(2) adding sodium hydrosulfide into a dry single-neck flask, adding water for dissolving, and dropwise adding the intermediate obtained in the step (1) at the temperature of minus 10 DEG C13Marking chloroacetaldehyde solution with C, generating solid in the dropping process, stopping dropping when the pH value of the reaction solution is 8-9, and filtering to obtain an intermediate 2;
(3) adding sodium hydrosulfide into a dry single-neck flask, adding water for dissolving, and dropwise adding the intermediate obtained in the step (1) at the temperature of minus 10 DEG C13Marking chloroacetaldehyde solution with C, generating solid in the dropping process, stopping dropping when the pH value of the reaction solution is 8-9, and filtering to obtain an intermediate 3;
(4) mixing the intermediate 2 obtained in the step (2) and the intermediate 3 obtained in the step (3), adding methanol to pulp at-10 ℃, filtering, washing a filter cake with glacial methanol, filtering, and drying the obtained filter cake to obtain the product13C marks 1, 4-dithio-2, 5-diol.
2. The stable isotope of claim 113The method for synthesizing the C-marked 1, 4-dithio-2, 5-diol is characterized by comprising the following steps: in the step (1), the13Feeding mol ratio of the C-marked chloroethanol, the dichloromethane and the oxidant is 1: 18-22: 0.8-1.2.
3. The stable isotope of claim 1 or 213The method for synthesizing the C-marked 1, 4-dithio-2, 5-diol is characterized by comprising the following steps: in the step (1), the oxidant is at least one of dess-martin oxidant, pyridinium chlorochromate, sulfur trioxide pyridine or 9-BBN.
4. The stable isotope of claim 1 or 213The method for synthesizing the C-marked 1, 4-dithio-2, 5-diol is characterized by comprising the following steps: in the step (1), the amount of the diatomaceous earth added is 1/3-2/3 of the reaction solution.
5. The stable isotope of claim 1 or 213The method for synthesizing the C-marked 1, 4-dithio-2, 5-diol is characterized by comprising the following steps: in the step (2), the sodium hydrosulfide accounts for 70% by mass and is a dihydrate.
6. The stable isotope of claim 1 or 213The method for synthesizing the C-marked 1, 4-dithio-2, 5-diol is characterized by comprising the following steps: in the step (3), the sodium hydrosulfide accounts for 70% by mass and is a dihydrate.
7. A stable isotope as claimed in any of claims 1 to 613Method for synthesizing C-labeled 1, 4-dithio-2, 5-diol in radioactive isotope14The application of the method for synthesizing C-marked 1, 4-dithio-2, 5-diol.
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| DE3149653A1 (en) * | 1981-12-15 | 1983-06-23 | Wacker-Chemie GmbH, 8000 München | Process for the preparation of pure 2,5-dihydroxy-1,4-dithiane |
| CN104860951A (en) * | 2010-05-21 | 2015-08-26 | Abbvie公司 | Modulators of 5-HT receptors and methods of use thereof |
| CN109608433A (en) * | 2018-11-30 | 2019-04-12 | 潍坊汇韬化工有限公司 | A kind of preparation method of 2,5- dihydroxy -1,4- dithiane |
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| IBRAHIM SHALAYEL等: "Cysteine Chemistry in Connection with Abiogenesis", 《EUR. J. ORG. CHEM.》 * |
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Denomination of invention: A Synthesis Method for Stable Isotope13C-Labeled 1,4-Disulfide-2,5-diol Effective date of registration: 20230616 Granted publication date: 20221115 Pledgee: Jiangsu Jiangyin Rural Commercial Bank Co.,Ltd. high tech Zone sub branch Pledgor: WUXI BEITA PHARMATECH Co.,Ltd. Registration number: Y2023980044515 |