CN111423410B - A synthetic method for labeling 1,4-dithio-2,5-diol with stable isotope 13C - Google Patents

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

A synthetic method for labeling 1,4-dithio-2,5-diol with stable isotope 13C

technical field

The present invention relates to a method for synthesizing 1,4-dithio-2,5-diol with isotope labeling, in particular to a method for synthesizing 1,4-dithio-2,5-diol labeled with stable isotope ¹³ C .

Background technique

1,4-dithio-2,5-diol is an important organic chemical raw material and intermediate. It has a wide market in pharmaceutical, fragrance, organic synthesis and other industries, especially in fragrance compounds. prospect. At present, there are few methods for producing 1,4-dithio-2,5-diol in China, and the reaction of synthesizing 1,4-dithio-2,5-diol generally has a single and fixed starting material. It is costly or even difficult to synthesize 1,4 _- dithio-2,5-diol _- ^13C4 and 1,4-dithio-2,5-diol- ^14C4 with isotope labeling, which is very important for 1,4 -Dithio-2,5-diol and its derivatives are very unfavorable for the synthesis of the corresponding isotope-labeled compounds required for more in-depth pharmacological, environmental and metabolic studies.

The existing methods for synthesizing 1,4-dithio-2,5-diol mainly include: such as ZongqiangWang (Chem. Commun., 2014, 50, 7004--7006), using chloroacetaldehyde to dropwise add sodium hydrosulfide aqueous solution Among them, the reaction obtains mercaptoaldehyde intermediate, the reaction is simple to operate, and the product yield can reach 75.3%. Mercaptoaldehyde needs to be further synthesized to obtain 1,4-dithio-2,5-diol. In mercaptoaldehyde In the process of converting into 1,4-dithio-2,5-diol, the process operation is complicated and the by-products increase. For example, in 2003, Chen Haitao, Sun Baoguo, Liang Menglan, etc. published the paper "Synthesis of 1,4-dithiane spice compounds and their application in food" in the "Journal of Beijing Technology and Business University", mentioning 1,4-dithio- The broad application prospects of 2,5-diol, it is mentioned in the article that chloroacetaldehyde will be added dropwise to sodium hydrosulfide aqueous solution to react to obtain 1,4-dithio-2,5-diol, but there is no detailed reaction data , and the reaction uses chloroacetaldehyde as a raw material, which is not suitable for laboratory and industrial synthesis of isotope-labeled compounds.

Contents of the invention

The technical problem to be solved by the present invention is to overcome the above-mentioned defects in the prior art, and provide a stable isotope ¹³ C labeling 1, which is cheap and easy to obtain, mild reaction conditions, simple reaction device, easy to operate, and convenient for product purification. 4-dithio-2,5-diol synthesis method, the resulting isotope-labeled synthetic products and various stable isotope-labeled intermediates have not been reported in the literature, and the isotope abundance will not be diluted during the synthesis process, effectively reducing production costs .

The technical solution adopted by the present invention to solve the technical problem is as follows: a method for synthesizing 1,4-dithio-2,5-diol labeled with stable isotope ¹³ C, comprising the following steps:

(1) Add ¹³ C labeled chloroethanol in a dry single-necked flask as a raw material, add dichloromethane, add an oxidizing agent at -10°C, and naturally heat up after the addition is completed. After the reaction is complete, add diatomaceous earth to the resulting reaction solution and stir , filter, and wash the filter cake with dichloromethane, the washing liquid and the filtrate are combined, add an equal volume of ether to the resulting solution, add saturated sodium bicarbonate solution to the ice-water bath to adjust the pH value = 7-8, filter, and wash the filter cake with ether, wash The liquid and the filtrate were combined, and the obtained solution was spin-dried at 10°C to obtain a crude product, which was then slurried by adding ether, filtered, and the filtrate was directly subjected to silica gel column chromatography, passed through the column with ether, the chromatographic liquid was collected, added water, and spin-dried to obtain a white solid containing The crude product is washed with water and filtered to obtain intermediate ¹³ C labeled chloroacetaldehyde solution;

(2) Add sodium hydrosulfide to a dry single-necked flask, add water to dissolve, and add dropwise the ^13C -labeled chloroacetaldehyde solution of the intermediate obtained in step (1) at -10°C. During the dropwise addition, solids are formed. When the reaction solution The pH value=8-9, stop dropping, filter, get intermediate 2;

(3) Add sodium hydrosulfide to a dry one-necked flask, add water to dissolve, and add dropwise the ¹³ C-labeled chloroacetaldehyde solution of the intermediate obtained in step (1) at -10°C. During the dropping process, solids are formed, and when the reaction solution The pH value=8-9, stop dropping, filter, obtain intermediate 3;

(4) Mix the intermediate 2 obtained in step (2) with the intermediate 3 obtained in step (3), add methanol to beat at -10°C, filter, wash the filter cake with ice methanol, filter, and dry the obtained filter cake to obtain ¹³ C labeled 1,4-dithio-2,5-diol.

Preferably, in step (1), the molar ratio of the ¹³ C-labeled chloroethanol, dichloromethane and 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, pyridine sulfur trioxide or 9-BBN.

Preferably, in step (1), the input amount of diatomaceous earth is 1/3-2/3 of the reaction solution.

Preferably, in step (2), the sodium hydrosulfide mass fraction is 70%, which is a dihydrate.

Preferably, in step (3), the sodium hydrosulfide mass fraction is 70%, which is a dihydrate.

The synthesis method of stable ^isotope13C -labeled 1,4-dithio-2,5-diol of the present invention is applied to the synthesis of radioactive ^isotope14C -labeled 1,4-dithio-2,5-diol.

The reaction process of the present invention is as follows:

Note: * is stable isotope ¹³ C or radioactive isotope ¹⁴ C.

Compared with the prior art, the beneficial effects of the present invention are as follows: avoiding the use of complex or difficult-to-obtain labeled compounds as starting materials, and directly using labeled acetic acid that is easily available on the market as starting materials, greatly reducing the synthesis cost; the synthesized ¹³ C The purity of labeled 1,4-dithio-2,5-diol is ≥98%, and the abundance of labeling points is ≥99%. It can not only fill the gap in China, but also can be used to label 1,4-dithio-2 with radioactive isotope ¹⁴ C , the synthesis of 5-diol; it also helps to meet the huge needs of the domestic and international markets; the process reaction conditions are mild, which can maximize the high-purity 1,4-dithio-2,5-diol, and directly by Chloroacetaldehyde is synthesized in one step, which greatly shortens the reaction time, saves time and effort, effectively reduces production costs, and is suitable for industrial production.

Detailed ways

The present invention will be further described below in conjunction with embodiment.

The chemical reagents used in the examples of the present invention were obtained through conventional commercial channels unless otherwise specified.

Example 1

This embodiment includes the following steps:

(1) Add 1g (12.1mmoL, 1.0eq) of commercially available stable isotope-labeled [1,2- ¹³ C ₂ ]-chloroethanol into a dry 50mL single-necked flask as a raw material, add 15ml of dichloromethane, and Add 6g of Dess-Martin oxidant, after adding, naturally heat up and react for 20min, after reacting for 3h, add diatomaceous earth equivalent to 1/3 of the mass of the reaction solution, stir for 5min, filter, and wash the filter cake with dichloromethane, wash liquid and the filtrate were combined, and an equal volume of diethyl ether was added to the resulting solution, and saturated sodium bicarbonate solution was added to an ice-water bath at 0°C to adjust the pH value to 7 (the organic phase or the organic phase plus water was used to measure the aqueous phase), filtered, and the filter cake was washed with diethyl ether, washed The liquid and the filtrate were combined, and the obtained solution was spin-dried at 10°C to obtain 3.5 g of the crude product, which was slurried by adding 7 mL of diethyl ether, filtered, and the filtrate was directly subjected to silica gel column chromatography, passed through the column with diethyl ether, and 150 mL of the chromatographic liquid was collected, and 1.0 g of water was added. Spin-dry at 10°C to obtain 2.6 g of a crude product containing a white solid, wash with water, and filter to obtain 7 g of an intermediate-labeled chloroacetaldehyde solution, of which ¹³ C-labeled chloroacetaldehyde is about 0.9 g;

(2) Add 1 g of hydrated 70% sodium hydrosulfide to a dry 25 mL single-necked flask, add 1.3 mL of water to dissolve, and add the intermediate ¹³ C-labeled chloroacetaldehyde solution obtained in step (1) dropwise at -10 ° C. The dropwise addition process There is solid generation in the middle, the pH value of reaction solution=8 when adding to 2.6g, stop dripping, filter, obtain 139mg intermediate 2 (not pulled dry);

(3) Add 1.9g of 70% sodium hydrosulfide hydrate in a dry 25mL single-necked flask, add 2.4mL of water to dissolve, add dropwise the intermediate ^13C labeled chloroacetaldehyde solution obtained in step (1) at -10°C, and add dropwise A solid is generated during the process, and the pH value of the reaction solution when added to 4.4g=8, the dropwise addition is stopped and filtered to obtain 230mg of intermediate 3 (not dried);

(4) Mix the intermediate 2 obtained in step (2) with the intermediate 3 obtained in step (3), add 1.5mL of methanol to beat at -10°C, filter, wash the filter cake with ice methanol, filter, and pull the obtained filter cake dry. 310 mg ¹³ C labeled 1,4-dithio-2,5-diol was obtained with a yield of 17%, a chemical purity of 98%, and an isotope abundance of 99atom% ¹³ C.

Example 2

This embodiment includes the following steps:

(1) Add 2.7g (32.7mmol, 1.0eq) of commercially available stable isotope-labeled [1,2- ¹³ C ₂ ]-chloroethanol into a dry 50mL single-necked flask as a raw material, add 40ml of dichloromethane, and store at -10°C Add 16g (1.2eq) of Dess-Martin oxidant at the same time, after the addition, naturally heat up and react for 20min, after reacting for 3h, add diatomaceous earth equivalent to 1/3 of the mass of the reaction solution, stir for 5min, filter, and dichloromethane Wash the filter cake, combine the washing liquid with the filtrate, add an equal volume of diethyl ether to the resulting solution, add saturated sodium bicarbonate solution to an ice-water bath at 0°C to adjust the pH value = 7 (the organic phase or the organic phase plus water to measure the aqueous phase), filter, and diethyl ether Wash the filter cake, combine the washing liquid and the filtrate, spin dry the obtained solution at 10°C to obtain 9.5 g of the crude product, add 20 mL of diethyl ether to beat the crude product, filter, and directly apply the filtrate to silica gel column chromatography, pass through the column with diethyl ether, and collect 300 mL of the chromatographic liquid, Add 2.0 g of water and spin dry at 10°C to obtain 7.0 g of a crude product containing a white solid, wash with water, and filter to obtain 18.86 g of an intermediate-labeled chloroacetaldehyde solution, of which ¹³ C-labeled chloroacetaldehyde is about 2.5 g;

(2) Add 3g of 70% sodium hydrosulfide hydrate in a dry 25mL single-necked flask, add 3.5mL of water to dissolve, and add the intermediate ^13C labeled chloroacetaldehyde solution obtained in step (1) dropwise at -10°C, and the dropwise addition process There is solid generation in the middle, and the pH value of reaction solution=8 when adding 7.0g, stops dropping, filters, and obtains 375mg intermediate 2 (not pulled dry);

(3) Add 5g of 70% sodium hydrosulfide hydrate in a dry 25mL single-necked flask, add 6.5mL of water to dissolve, and add the intermediate ^13C labeled chloroacetaldehyde solution obtained in step (1) dropwise at -10°C, and the dropwise addition process There is solid generation in the middle, the pH value of reaction solution=8 when adding to 11.86g, stop dripping, filter, obtain 620mg intermediate 3 (not pulled dry);

(4) Mix the intermediate 2 obtained in step (2) with the intermediate 3 obtained in step (3), add 4 mL of methanol to make a slurry at -10°C, filter, wash the filter cake with ice methanol, filter, and pull the obtained filter cake dry to obtain 870mg ¹³ C labeled 1,4-dithio-2,5-diol, the yield is 18%, the chemical purity is 98%, and the isotope abundance is 99atom% ¹³ C.

Example 3

This embodiment includes the following steps:

(1) Add 5.4g (65.5mmol, 1.0eq) of commercially available stable isotope-labeled [1,2- ¹⁴ C ₂ ]-chloroethanol into a dry 50mL single-necked flask as a raw material, add 70ml of dichloromethane, and store at -10°C Add 32g (1.2eq) of Dess-Martin oxidant at the same time, after adding, naturally heat up and react for 20min, after reacting for 3h, add diatomaceous earth equivalent to 1/3 of the mass of the reaction solution, stir for 5min, filter, and dichloromethane Wash the filter cake, combine the washing liquid with the filtrate, add an equal volume of diethyl ether to the resulting solution, add saturated sodium bicarbonate solution to an ice-water bath at 0°C to adjust the pH value = 7 (the organic phase or the organic phase plus water to measure the aqueous phase), filter, and diethyl ether Wash the filter cake, combine the washing liquid and the filtrate, and spin dry the obtained solution at 10°C to obtain 20 g of the crude product, add 30 mL of diethyl ether to beat the crude product, filter, and directly apply the filtrate to silica gel column chromatography, pass through the column with diethyl ether, collect 500 mL of the chromatographic liquid, add 4.0 g of water was spin-dried at 10°C to obtain 15 g of a crude product containing a white solid, which was washed with water and filtered to obtain 38 g of an intermediate labeled chloroacetaldehyde solution, of which ¹⁴ C-labeled chloroacetaldehyde was about 5.2 g;

(2) Add 6g of hydrated 70% sodium hydrosulfide to a dry 25mL single-necked flask, add 7mL of water to dissolve, add the intermediate ^14C labeled chloroacetaldehyde solution obtained in step (1) dropwise at -10°C, during the dropwise addition A solid is generated, and when the pH value of the reaction solution is added to 15g=8, the dropwise addition is stopped and filtered to obtain 800mg of intermediate 2 (not dried);

(3) Add 10g of hydrated 70% sodium hydrosulfide to a dry 25mL single-necked flask, add 14mL of water to dissolve, and add the intermediate ^14C labeled chloroacetaldehyde solution obtained in step (1) dropwise at -10°C, during the dropwise addition A solid was generated, and when the pH value of the reaction solution was added to 21g=8, the dropwise addition was stopped and filtered to obtain 1.4g of intermediate 3 (not dried);

(4) Mix the intermediate 2 obtained in step (2) with the intermediate 3 obtained in step (3), add 6 mL of methanol to make a slurry at -10 ° C, filter, wash the filter cake with ice methanol, filter, and pull the obtained filter cake dry to obtain 1.9g ¹⁴ C labeled 1,4-dithio-2,5-diol, yield 18%, chemical purity 98%, isotope abundance 99atom% 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.