CN111423410B - Stable isotope 13 Synthesis method of C-labeled 1,4-disulfide-2,5-diol - Google Patents
Stable isotope 13 Synthesis method of C-labeled 1,4-disulfide-2,5-diol Download PDFInfo
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Abstract
Stable isotope 13 C-labeled 1,4-dithio-2,5-diol, and a preparation method thereof 13 Reacting C-labeled chloroethanol serving as raw material with an oxidant to obtain an intermediate 13 C marking chloroacetaldehyde solution, and then adding the obtained intermediate 13 C-labeled chloroacetaldehyde solution reacts with sodium hydrosulfide to obtain 13 C-Mark 1,4-disulfide-2,5-diol. The invention not only provides a 1,4-dithio-2,5-diol synthesis method with mild reaction conditions, simple reaction device, convenient process control and convenient product purification, but also provides a stable isotope 13 The synthesis of C-labeled 1,4-dithio-2,5-diol provides a convenient method, and is also applicable to radioisotopes 14 C-labeled 1,4-disulfide-2,5-diol synthesis.
Description
Technical Field
The invention relates to a method for synthesizing 1,4-disulfide-2,5-diol by isotope labeling, in particular to a stable isotope 13 C label 1,4-dithio-2,5-diol synthesis method.
Background
1,4-dithio-2,5-diol is an important organic chemical raw material and intermediate, and has a wide market in the industries of medicine, spice, organic synthesis and the like, and especially has a great development prospect in spice compounds. At present, the domestic production method of 1,4-disulfide-2,5-diol is few, the reaction for synthesizing 1,4-disulfide-2,5-diol generally has the phenomenon of single fixed initial raw material, and the phenomenon of single fixed initial raw material exists in the reactionThe situation led to isotopic labeling synthesis of 1,4-dithio-2,5-diol- 13 C 4 And 1,4-disulfide-2,5-diol- 14 C 4 The cost is high and even difficult to realize, which is very unfavorable for the synthesis of corresponding isotope labeled compound required by 1,4-dithio-2,5-diol and the derivative thereof for further pharmacological, environmental and metabolic research.
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), chloroacetaldehyde is added dropwise to sodium hydrosulfide aqueous solution to react to obtain 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 byproducts are increased in the process of converting mercaptoacetaldehyde into 1,4-dithio-2,5-diol. For example, chen Haitao, sun Baoguo, liang Menglan, etc., published in "1,4-dithiane flavor compound synthesis and its use in food" the paper published in "journal of Beijing university of Industrial products", mentions the broad application prospect of 1,4-disulfide-2,5-diol, mentions that the reaction using chloroacetaldehyde dropwise added to sodium hydrosulfide aqueous solution gave 1,4-disulfide-2,5-diol, but has no detailed reaction data, and the reaction uses chloroacetaldehyde as 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 isotope which has the advantages of cheap and easily available reaction raw materials, mild reaction conditions, simple reaction device, convenient operation and convenient product purification 13 The synthesis method of the C-labeled 1,4-disulfide-2,5-diol has the advantages that the obtained isotope-labeled synthetic products and various stable isotope-labeled intermediates are not reported in documents, the isotope abundance cannot be diluted in the synthesis process, and the production cost is effectively reduced.
The technical scheme adopted by the invention for solving the technical problem is as follows: stable isotope 13 The synthesis process of C-mark 1,4-dithio-2,5-diol includes the following steps:
(1) In a dry single-neck flaskAdding therein 13 C-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, equal volume of diethyl ether is added into the obtained solution, saturated sodium bicarbonate solution is added into ice water bath to adjust the pH value to be =7-8, the filter cakes are filtered, 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, diethyl ether is added, the crude products are pulped and filtered, the filtrate is directly applied to silica gel column chromatography, the chromatographic solution is collected, water is added and dried in a spinning mode, crude products containing white solids are obtained, the crude products are washed by water and filtered, and the intermediate is obtained 13 C, marking chloroacetaldehyde solution;
(2) Adding sodium hydrosulfide into a dry single-neck flask, adding water to dissolve, and dropwise adding the intermediate obtained in the step (1) at the temperature of minus 10 DEG C 13 Marking 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 C 13 Marking chloroacetaldehyde solution by 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 product 13 C marker 1,4-dithio-2,5-diol.
Preferably, in step (1), the 13 Feeding 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 oxidant is at least one of dess-martin oxidant, pyridinium chlorochromate, pyridine trioxide or 9-BBN.
Preferably, in the step (1), the amount of the diatomaceous earth to be charged is 1/3 to 2/3 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 invention 13 Synthesis method of C-labeled 1,4-disulfide-2,5-diol applied to radioisotope 14 C-labeled 1,4-disulfide-2,5-diol synthesis.
The reaction process of the invention is as follows:
note: * As stable isotopes 13 C or radioactive isotopes 14 C。
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; synthesized 13 The purity of C-marked 1,4-disulfide-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; can fill up the domestic blank, and can also be applied to radioactive isotopes 14 C-mark 1,4-dithio-2,5-diol synthesis; but also helps to meet the huge demands of domestic and international markets; the process has mild reaction conditions, can realize the maximized preparation of the high-purity 1,4-dithio-2,5-diol, and is directly synthesized by chloroacetaldehyde in one step, thereby greatly shortening the reaction time, saving time and labor, effectively reducing the production cost and being suitable for industrial production.
Detailed Description
The present invention will be further described with reference to the following examples.
The chemicals used in the examples of the present invention were obtained from conventional commercial sources unless otherwise specified.
Example 1
The embodiment comprises the following steps:
(1) A dry 50mL single-neck flask was charged with 1g (12.1 mmoL,1.0 eq) of a commercially available stable isotope-labeled [1,2- 13 C 2 ]-chloroethanol as raw material, 15mlDichloromethane, 6g of dess-martin oxidant is added at the temperature of-10 ℃, the mixture is naturally heated to react for 20min after the addition, after the reaction is carried out for 3h, diatomite which is equal to 1/3 of the mass of the reaction liquid is added into the obtained reaction liquid, the mixture is stirred for 5min, the filtration is carried out, a filter cake is washed by dichloromethane, a washing liquid is combined with a filtrate, the obtained solution is added with aether with equal volume, a saturated sodium bicarbonate solution is added into an ice water bath at the temperature of 0 ℃, the pH value is adjusted to be =7 (an organic phase or the organic phase is added to measure water phase), the filtration is carried out, the filter cake is washed by aether, the washing liquid is combined with the filtrate, the obtained solution is dried in a spinning mode at the temperature of 10 ℃, 3.5g of crude product is obtained, 7mL of aether pulping crude product is added, the filtrate is directly subjected to silica gel column chromatography, the diethyl ether is used for passing through a column, 150mL of chromatographic liquid is collected, 1.0g of water is added, the 10 ℃ is dried in a spinning mode, 2.6g of crude product containing white solid is obtained, the crude product is washed by water, the filtration is obtained, 7g of intermediate labeled chloral solution, and the intermediate is obtained, the intermediate is filtered, wherein the 7g of chloral solution, and the intermediate is obtained, and the chloral solution, and the intermediate is obtained by the intermediate, and the intermediate is obtained by the reaction solution, and the method is obtained by the method 13 C about 0.9g of chloroacetaldehyde;
(2) 1g of 70% sodium hydrosulfide hydrate was added to a dry 25mL single-neck flask, dissolved in 1.3mL of water, and the intermediate obtained in step (1) was added dropwise at-10 deg.C 13 Marking 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 2.6g, and filtering to obtain 139mg of intermediate 2 (not dried);
(3) 1.9g of 70% sodium hydrosulfide hydrate was added to a dry 25mL single-neck flask, dissolved in 2.4mL of water, and the intermediate obtained in step (1) was added dropwise at-10 deg.C 13 Marking 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 4.4g, and filtering to obtain 230mg of intermediate 3 (not dried);
(4) Mixing the intermediate 2 obtained in step (2) and the intermediate 3 obtained in step (3), adding 1.5mL of methanol at-10 deg.C, pulping, filtering, washing the filter cake with glacial methanol, filtering, and drying the filter cake to obtain 310mg 13 C-labeled 1,4-dithio-2,5-diol, 17% yield, 98% chemical purity, 99Atom% isotopic abundance 13 C。
Example 2
The embodiment comprises the following steps:
(1) A dry 50mL single-neck flask was charged with 2.7g (32.7mmol, 1.0eq) of a commercially available stable isotope-labeled [1,2- 13 C 2 ]Adding 40mL of dichloromethane into chloroethanol serving as a raw material, adding 16g (1.2 eq) of dess-martin oxidant at-10 ℃, naturally heating to react for 20min after adding, adding kieselguhr which is 1/3 of the mass of the reaction solution into the obtained reaction solution after reacting for 3h, stirring for 5min, filtering, washing a filter cake with dichloromethane, combining washing liquid with 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 (organic phase or organic phase water phase is measured), filtering, washing the filter cake with diethyl ether, combining the washing liquid with the filtrate, spin-drying the obtained solution at 10 ℃ to obtain 9.5g of crude product, adding 20mL of diethyl ether into the crude product to pulp, filtering, directly coating the filtrate on silica gel, passing through a column with diethyl ether, collecting 300mL 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 solution, wherein 13 C about 2.5g of chloroacetaldehyde;
(2) Adding 3g of 70% sodium hydrosulfide hydrate into a dry 25mL single-neck flask, dissolving with 3.5mL of water, and dropwise adding the intermediate obtained in the step (1) at-10 DEG C 13 Marking chloroacetaldehyde solution with C, generating solid in the dropping process, stopping dropping when the pH value of the reaction solution is =8 when 7.0g of chloroacetaldehyde solution is added, and filtering to obtain 375mg of intermediate 2 (not dried);
(3) 5g of 70% sodium hydrosulfide hydrate was added to a dry 25mL single-neck flask, dissolved in 6.5mL of water, and the intermediate obtained in step (1) was added dropwise at-10 deg.C 13 Marking chloroacetaldehyde solution with C, generating solid in the dropping process, stopping dropping when the pH value of the reaction solution is =8 when 11.86g is added, and filtering to obtain 620mg of intermediate 3 (not dried);
(4) Mixing the intermediate 2 obtained in step (2) and the intermediate 3 obtained in step (3), adding 4mL of methanol at-10 ℃, pulping, filtering, washing a filter cake with glacial methanol, filtering, and drying the obtained filter cake to obtain 870mg of 870mg 13 C-labeled 1,4-dithio-2,5-diol, 18% yield, 98% chemical purity, 99Atom% isotopic abundance 13 C。
Example 3
The embodiment comprises the following steps:
(1) In a dry 50mL single-neck flask was added 5.4g (65.5mmol0 eq) commercially available stable isotope labeling [1,2- 14 C 2 ]-chloroethanol as a raw material, adding 70mL of dichloromethane, adding 32g (1.2 eq) of dess-martin oxidant at-10 ℃, naturally heating to react for 20min after adding, after reacting for 3h, adding diatomite with the mass 1/3 of the reaction solution into the obtained reaction solution, stirring for 5min, filtering, washing a filter cake with dichloromethane, combining washing liquid with the 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 =7 (organic phase or organic phase and water phase), filtering, washing the filter cake with diethyl ether, combining the washing liquid with the filtrate, spin-drying the obtained solution at 10 ℃ to obtain 20g of crude product, adding 30mL of diethyl ether to pulp the crude product, filtering, directly performing silica gel column chromatography on the filtrate, passing through a diethyl ether column, collecting 500mL of chromatography liquid, adding 4.0g of water, spin-drying at 10 ℃ to obtain 15g of crude product containing white solid, washing with water, filtering, obtaining 38g of intermediate labeled chloroacetaldehyde solution, wherein 14 C about 5.2g of chloroacetaldehyde;
(2) Adding 6g of 70% sodium hydrosulfide hydrate into a dry 25mL single-neck flask, adding 7mL of water for dissolving, and dropwise adding the intermediate obtained in the step (1) at the temperature of minus 10 DEG C 14 Marking 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 (not dried);
(3) Adding 10g of 70% sodium hydrosulfide hydrate into a dry 25mL single-neck flask, dissolving the mixture in 14mL of water, and dropwise adding the intermediate obtained in the step (1) at the temperature of minus 10 DEG C 14 Marking chloroacetaldehyde solution with C, generating solid in the dropping process, stopping dropping when the pH value of the reaction solution is =8 when the amount of chloroacetaldehyde 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 the step (2) and the intermediate 3 obtained in the step (3), adding 6mL of methanol to pulp at-10 ℃, filtering, washing a filter cake with glacial methanol, filtering, and drying the obtained filter cake to obtain 1.9g of filter cake 14 C-labeled 1,4-dithio-2,5-diol, 18% yield, 98% chemical purity, 99Atom% isotopic abundance 14 C。
Claims (7)
1. Stable isotope 13 C-tag 1,4-disulfide-2,5-diolThe method is characterized in that: the method comprises the following steps:
(1) Adding into a dry single-neck flask 13 Adding dichloromethane into C-labeled chloroethanol as a raw material, adding an oxidant at the temperature of-10 ℃, naturally heating for reaction after the addition is finished, adding diatomite into obtained reaction liquid for stirring after the reaction is completed, filtering, washing a filter cake with dichloromethane, combining washing liquid with filtrate, adding equal volume of diethyl ether into obtained solution, adding saturated sodium bicarbonate solution into ice water bath to adjust the pH value to be =7-8, filtering, washing the filter cake with diethyl ether, combining the washing liquid with the filtrate, spin-drying the obtained solution at the temperature of 10 ℃ to obtain a crude product, adding diethyl ether for pulping, filtering, directly performing silica gel column chromatography on the filtrate, passing through a column with diethyl ether, collecting chromatography liquid, adding water, spin-drying to obtain a crude product containing white solid, washing with water, and filtering to obtain an intermediate 13 C, marking chloroacetaldehyde solution;
(2) Adding sodium hydrosulfide into a dry single-neck flask, adding water to dissolve, and dropwise adding the intermediate obtained in the step (1) at the temperature of minus 10 DEG C 13 Marking 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 C 13 Marking 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 product 13 C marker 1,4-dithio-2,5-diol.
2. The stable isotope of claim 1 13 The synthesis method of C-labeled 1,4-dithio-2,5-diol is characterized in that: in the step (1), the 13 Feeding mol ratio of the C-marked chloroethanol, the dichloromethane and the oxidant is 1:18-22:0.8-1.2.
3. According to claim 1 or2 the stable isotope 13 The synthesis method of the C-marked 1,4-disulfide-2,5-diol is characterized in that: 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 2 13 The synthesis method of the C-marked 1,4-disulfide-2,5-diol is characterized in that: in the step (1), the amount of the diatomaceous earth added is 1/3 to 2/3 of the reaction solution.
5. The stable isotope of claim 1 or 2 13 The synthesis method of the C-marked 1,4-disulfide-2,5-diol is characterized in that: in the step (2), the sodium hydrosulfide accounts for 70% by mass and is a dihydrate.
6. The stable isotope of claim 1 or 2 13 The synthesis method of the C-marked 1,4-disulfide-2,5-diol is characterized in that: in the step (3), the sodium hydrosulfide accounts for 70% in mass percent and is a dihydrate.
7. A stable isotope as claimed in any of claims 1 to 6 13 Method for synthesizing C-labeled 1,4-dithio-2,5-diol in radioisotope 14 C mark 1,4-dithio-2,5-diol synthesis method.
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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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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 |