CN110066255B - Synthetic method of stable isotope deuterium-labeled 5-chloro-2-methyl-4-isothiazole-3-ketone - Google Patents
Synthetic method of stable isotope deuterium-labeled 5-chloro-2-methyl-4-isothiazole-3-ketone Download PDFInfo
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- C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
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Abstract
The invention provides a synthesis method of stable isotope deuterium-labeled 5-chloro-2-methyl-4-isothiazole-3-ketone, which comprises the following steps: step 1: 3,3 '-dimercaptodipropionic acid and thionyl chloride are taken as reaction raw materials, and are catalyzed by a catalyst to react to obtain 3,3' -dimercaptodipropionyl chloride; step 2: sequentially adding sodium hydroxide and potassium carbonate into deuterated methylamine hydrochloride, then adding the 3,3' -dimercaptodipropionyl chloride obtained in the step 1, and reacting to obtain deuterated amide; and step 3: adding a reaction solvent and sulfonyl chloride into the deuterated amide obtained in the step 2, continuously stirring the reaction system in an ice-water bath for reaction for 1 hour, and then continuously stirring the reaction system for about 23 hours at 35 ℃ to obtain deuterium-labeled 5-chloro-2-methyl-4-isothiazole-3-ketone, wherein the molar ratio of the deuterated amide to the sulfonyl chloride is 1. The reaction yield of the invention can reach 48%. The purity of the target product can reach 98%, and the deuteration rate is more than 99%.
Description
Technical Field
The invention relates to the technical field of isotope deuterium labeled compound synthesis, and particularly relates to a synthesis method of stable isotope deuterium labeled 5-chloro-2-methyl-4-isothiazole-3-ketone.
Background
Methylisothiazolinone and chloro-compound thereof are commonly called Kathon or Kathon (Kathon CG), and the active ingredients are 5-chloro-2-methyl-4-isothiazolin-3-one (CMI) and 2-methyl-4-isothiazolin-3-one (MIT), and the two are generally mixed according to the mass ratio of 3:1, the composition is widely used in the industries of cosmetics, personal care products, papermaking, coatings and the like, and is used as an antiseptic bactericide to protect products from microbial pollution and prolong the service life of the products. The method has important practical significance for quickly and accurately detecting the relative content of the CMI in the substance.
In recent years, along with the development of instruments, the sensitivity of mass spectrometry instruments is higher and higher to ng level, and the combination of mass spectrometry and liquid phase and gas phase instruments enables the qualitative and quantitative detection of the content of the compound to be more sensitive. To further improve the sensitivity of detection, excluding instrumental and human subjective influences, stable isotope dilution (stable isotopes as internal standards) is receiving increasing attention from analysts. Stable Isotope Dilution Mass Spectrometry (IDMS) adopts a stable isotope labeled compound with the same molecular structure as a detected substance as an internal standard substance, a high resolution liquid chromatography-mass spectrometry (LC/MS) is used for detection, the mass spectrometer is used for measuring the ratio of ions with corresponding mass numbers, and the ratio is compared with the standard ratio, so that the aim of accurate quantification is fulfilled. The isotope internal standard can effectively eliminate the recovery rate difference of the sample in the chemical and physical pretreatment steps, thereby avoiding the deviation of the detection result caused by the loss of the sample treatment process. This property of stable isotope dilution mass spectrometry combined with the high sensitivity of LC/MS and the ability to process complex samples makes the chromatography/isotope dilution mass spectrometry technique well recognized as a benchmark method for measuring trace and trace amounts of organic matter.
At present, isotope deuterium labeling 5-chloro-2-methyl-4-isothiazole-3-ketone in China depends on import, a synthetic route of the isotope deuterium labeling 5-chloro-2-methyl-4-isothiazole-3-ketone is not disclosed at home and abroad, and the invention develops stable isotope labeling CMI internal standard (CMI-d 3) and provides a standard reagent for more accurately determining the nature and quantity of CMI.
Disclosure of Invention
The invention provides a synthesis method of stable isotope deuterium-labeled 5-chloro-2-methyl-4-isothiazole-3-ketone, which aims to solve the problem of synthesis of stable isotope deuterium-labeled 5-chloro-2-methyl-4-isothiazole-3-ketone.
The invention adopts the following technical scheme:
the invention provides a synthesis method of stable isotope deuterium-labeled 5-chloro-2-methyl-4-isothiazole-3-ketone, which comprises the following steps:
step 1: 3,3 '-dimercaptodipropionic acid and thionyl chloride are used as reaction raw materials, and are catalyzed by a catalyst to react to obtain 3,3' -dimercaptodipropionyl chloride;
step 2: adding alkali into deuterated methylamine hydrochloride, then adding the 3,3' -dimercaptodipropionyl chloride obtained in the step 1, and reacting to obtain deuterated amide;
and step 3: and (3) adding a reaction solvent and sulfonyl chloride into the deuterated amide obtained in the step (2), continuously stirring the reaction system at the temperature of 0 ℃ for 1 hour, and then continuously stirring the reaction system at the temperature of 35 ℃ for 23 hours to react to obtain deuterium-labeled 5-chloro-2-methyl-4-isothiazole-3-one, wherein the molar ratio of the deuterated amide to the sulfonyl chloride is 1 (5-8).
Further, the catalyst in step 1 is N, N-dimethylformamide.
Further, the molar ratio of 3,3' -dimercaptodipropionic acid to thionyl chloride in step 1 is 1.
Further, the reaction of step 1 is carried out under an inert gas atmosphere.
Further, the reaction described in step 1 was a vigorous stirring reaction at 30 ℃ for 12 hours.
Further, the molar ratio of the deuterated methylamine hydrochloride to the 3,3' -dimercaptodipropionyl chloride in the step 2 is 3.
Further, the reaction in step 2 is a stirring reaction at 0 ℃ for 2 hours.
Further, the deuterated methylamine hydrochloride and the OH in the base in the step 2 - 1, and the base is sodium hydroxide.
Further, step 2 adds a carbonate after the addition of the alkali to neutralize the acid generated in the reaction, and step 3 adds a carbonate after the reaction for 15 hours to neutralize the acid generated in the reaction.
Further, the reaction solvent in step 3 is dichloromethane.
The invention has the following beneficial effects:
in step 3 of the scheme of the invention, the deuterated amide reacts with sulfonyl chloride to generate deuterium-labeled 5-chloro-2-methyl-4-isothiazol-3-one. If 3 equivalents of sulfonyl chloride are used, the product MIT-d is formed 3 And if the amount of sulfonyl chloride is greater than 3 equivalents, excess sulfonyl chloride will follow CMI-d 3 The chlorination reaction is continued to generate CMI-d 3 When 6 equivalents of sulfonyl chloride are used as the reaction raw material, CMI-d 3 The yield is highest.
Drawings
FIG. 1 is CMI-d prepared in example 1 3 Hydrogen spectrum of (2).
Detailed Description
The invention is further described with reference to the following figures and detailed description.
Example 1
A synthetic method of stable isotope deuterium labeled 5-chloro-2-methyl-4-isothiazol-3-ketone comprises the following steps:
step 1: a 100mL schlenk tube was placed on a flame blower and dried under vacuum followed by cooling under nitrogen. A stir bar and 3,3' -dimercaptodipropionic acid (6.3 g, 30mmol) were then added under nitrogen and thionyl chloride (4.4 mL, 60mmol) was quickly injected into the schlenk tube using a 5mL syringe. 6 drops (about 0.3 mL) of N, N-dimethylformamide was added dropwise to the reaction mixture as a catalyst to accelerate the reaction. The schlenk tube was placed in an oil bath pan with the temperature of the oil bath steadily controlled at 30 ℃ and with vigorous stirring for 12 hours. The reaction solution slowly changed from colorless to yellow. Cooling the reaction system to room temperature, removing volatile matters in the solution by using an oil pump in a vacuum environment to obtain a dry crude product 3,3' -dimercaptodipropionyl chloride, wherein the product can be directly used for the next reaction without further purification;
the reaction formula of step 1 is as follows:
step 2: deuterated methylamine hydrochloride (201mg, 3mmol) is weighed by a balance and placed in a 25mL round-bottom flask, the round-bottom flask is placed in an ice-water bath, and 3mL of 1M sodium hydroxide is slowly added dropwise to the round-bottom flask. Potassium carbonate (138mg, 1mmol) was additionally weighed and poured into the reaction system to neutralize the acid generated in the reaction, and the reaction system was continuously stirred in an ice-water bath for about 20 minutes. After the stirring is finished, 3' -dimercaptodipropionyl chloride (247mg, 1mmol) prepared before is weighed and slowly dripped into a reaction system in an ice water bath at the speed of 3mL/min, and if the adding speed is too high, a large amount of by-products are generated to influence the product yield. After the addition, the reaction system was stirred for 2 hours, and the reaction system was in the form of a white suspension. Water in the reaction system was removed by a rotary evaporator to obtain a white solid, and the solid at this time contained an inorganic salt such as sodium chloride. Adding 5mL of absolute ethyl alcohol, fully stirring to enable the organic matter to be fully dissolved in the ethyl alcohol, filtering the obtained suspension, washing filter residues twice with 10mL of ethyl alcohol, filtering, combining organic phases, and spin-drying the ethyl alcohol by using a rotary evaporator to obtain a product deuterated amide which is a white solid, wherein the product is not required to be further purified and can be directly used for the next reaction;
the reaction formula of step 2 is as follows:
and step 3: the deuterated amide prepared in step 2 (242mg, 1mmol) was placed in a 25mL round bottom flask and 3mL dichloromethane solvent was added to the reaction flask. The round-bottomed flask was placed in an ice-water bath, and sulfuryl chloride (810mg, 6mmol) was slowly dropped into the flask, at which time the solid in the system was slowly dissolved, and a relatively uniform suspension was obtained. The reaction was stirred continuously in an ice-water bath for about 1 hour, then the round-bottom flask was placed in an oil bath and stirring was continued for about 23 hours while the temperature was controlled at 35 ℃ whereupon the reaction became a white suspension, an appropriate amount of potassium carbonate was added to the reaction until no bubbles were formed (potassium carbonate was added to neutralize the acid formed in the reaction) and stirring was continued for 10 minutes. Silica gel (2g, 200-300 m) was added to the reaction system, the volatiles were removed from the system using a rotary evaporator, and the silica gel in the round bottom flask was swirled to a granular form. Selecting column chromatography column with proper size, filling thin layer chromatography silica gel (HG/T2354-2010, H grade, chemical purity) in the column, wetting the silica gel with redistilled petroleum ether, transferring the well-mixed silica gel to the upper layer silica gel of the column chromatography column, and adding a layer of quartz sand. Firstly, using a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 4 as an eluent to separate a sample by column chromatography, wherein the eluted component is impurity and is discarded. However, the device is not suitable for use in a kitchenThen ethyl acetate is used as eluent to collect the eluted sample. The eluted sample was placed in a test tube, and the sample in the test tube was checked by TLC thin layer chromatography plate and UV lamp until all the sample was run out. Pouring the test tube containing the target product into a round-bottom flask, and removing volatile organic matters by using a rotary evaporator to obtain the target product CMI-d 3 (72 mg) was obtained, showing a reaction yield of 48%. The purity of the target product is 98 percent, and the deuteration rate is>99％；
The reaction formula of step 3 is as follows:
example 2
A synthetic method of stable isotope deuterium labeled 5-chloro-2-methyl-4-isothiazole-3-ketone comprises the following steps:
The difference lies in that:
and 3, step 3: the deuterated amide prepared in step 2 (242mg, 1mmol) was placed in a 25mL round bottom flask, and 3mL of dichloromethane solvent was added to the round bottom flask. The round-bottomed flask was placed in an ice-water bath, and sulfuryl chloride (675mg, 5mmol) was slowly added dropwise to the round-bottomed flask, at which time the solid in the system was slowly dissolved to give a uniform suspension. The reaction was stirred continuously in an ice water bath for about 1 hour, then the round bottom flask was placed in an oil bath and the temperature was controlled at 35 ℃ and stirring was continued for about 23 hours, at which time the reaction was a white suspension, an appropriate amount of potassium carbonate was added to the reaction until no bubbles were formed and stirring was continued for 10 minutes. Silica gel (2g, 200 to 300 m) was added to the reaction system, the volatile matter in the system was removed with a rotary evaporator, and the silica gel in the round-bottomed flask was swirled into a granular form. Selecting column chromatography column with proper size, filling thin layer chromatography silica gel (HG/T2354-2010, H grade, chemical purity) in the column, wetting the silica gel with redistilled petroleum ether, transferring the mixture system with silica gel to the thin layer silica gel on the upper layer of the column chromatography column, and adding a layer of quartz sand. Preparing a mixture of petroleum ether and ethyl acetate in a volume ratio of 4Using solvent as eluent, separating mixed sample in column chromatography, placing eluted sample into test tube, and detecting sample in the test tube by TLC thin layer chromatography plate and ultraviolet lamp until all samples are used up. Pouring the test tube containing the target product into a round-bottom flask, and removing volatile organic matters by using a rotary evaporator to obtain the target product CMI-d 3 (49 mg) in reaction yield 33%.
Example 3
A synthetic method of stable isotope deuterium labeled 5-chloro-2-methyl-4-isothiazol-3-ketone comprises the following steps:
The difference lies in that:
and step 3: deuterated amide prepared in step 2 (242mg, 1mmol) was placed in a 25mL round bottom flask and 3mL dichloromethane solvent was added to the round bottom flask. The round-bottomed flask was placed in an ice-water bath, and sulfuryl chloride (1080mg, 8mmol) was slowly dropped into the round-bottomed flask, at which time the solid in the system was slowly dissolved to give a uniform suspension. The reaction was stirred continuously in an ice-water bath for about 1 hour, then the round-bottomed flask was placed in an oil bath, the temperature was controlled at 35 ℃ and stirring was continued for about 23 hours, at which time the reaction was a white suspension, an appropriate amount of potassium carbonate was added to the reaction until no bubbles were present, and stirring was continued for 10 minutes. Silica gel (2g, 200 to 300 m) was added to the reaction system, the volatile matter in the system was removed with a rotary evaporator, and the silica gel in the round-bottomed flask was swirled into a granular form. Selecting column chromatography column with appropriate size, filling thin layer chromatography silica gel (HG/T2354-2010, H grade, chemical purity) in the column, wetting the silica gel with redistilled petroleum ether, transferring the mixture system with silica gel to the thin layer silica gel on the upper layer of the column chromatography column, and adding a layer of quartz sand. Preparing a mixed solvent of petroleum ether and ethyl acetate with a volume ratio of 4 as an eluent, separating a mixed sample in column chromatography, putting an eluted sample into a test tube, and detecting the sample in the test tube by using a TLC thin-layer chromatography plate and an ultraviolet lamp until all samples are used up. Pouring the test tube containing the target product into a round-bottom flask, and removing volatile organic substances by using a rotary evaporator to obtain the productTo the target product CMI-d 3 (24 mg) in a reaction yield of 16%.
The above-mentioned embodiments are only preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, and it is obvious to those skilled in the art that other embodiments can be easily made by replacing or changing the technical contents disclosed in the present specification, and therefore, the changes and modifications made by the principles and process conditions of the present invention should be included in the claims of the present invention.
Claims (8)
1. A synthetic method of stable isotope deuterium labeled 5-chloro-2-methyl-4-isothiazol-3-one is characterized by comprising the following steps:
step 1: 3,3 '-dimercaptodipropionic acid and thionyl chloride are used as reaction raw materials, and are catalyzed by a catalyst to react to obtain 3,3' -dimercaptodipropionyl chloride;
step 2: adding alkali into deuterated methylamine hydrochloride, adding an acid-binding agent after adding the alkali, then dropwise adding the 3,3' -dimercapto dipropionyl chloride obtained in the step 1 in an ice water bath at the rate of 3mL/min, and reacting to obtain deuterated amide; the molar ratio of the deuterated methylamine hydrochloride to the 3,3' -dimercaptodipropionyl chloride is 3; OH in the deuterated methylamine hydrochloride and the base - In a molar ratio of 1;
and step 3: adding a reaction solvent and sulfonyl chloride into the deuterated amide obtained in the step 2, and reacting the reaction system under the condition of 0 ℃ for 1 hour under continuous stirring, and then reacting under the condition of 35 ℃ for 23 hours under continuous stirring to obtain deuterium-labeled 5-chloro-2-methyl-4-isothiazole-3-ketone, wherein the molar ratio of the deuterated amide to the sulfonyl chloride is 1.
2. The method for synthesizing 5-chloro-2-methyl-4-isothiazol-3-one labeled with deuterium as a stable isotope according to claim 1, wherein the catalyst in step 1 is N, N-dimethylformamide.
3. The method for synthesizing deuterium-labeled 5-chloro-2-methyl-4-isothiazol-3-one as claimed in claim 1, wherein the molar ratio of 3,3' -dimercaptodipropionic acid to thionyl chloride in step 1 is 1.
4. The method for synthesizing 5-chloro-2-methyl-4-isothiazol-3-one labeled with deuterium as a stable isotope according to claim 1, wherein the reaction of step 1 is performed under an inert gas atmosphere.
5. The method for synthesizing 5-chloro-2-methyl-4-isothiazol-3-one labeled with deuterium as a stable isotope according to claim 4, wherein the reaction in step 1 is performed by stirring vigorously at 30 ℃ for 12 hours.
6. The method for synthesizing 5-chloro-2-methyl-4-isothiazol-3-one labeled with deuterium as a stable isotope of claim 1, wherein the reaction in step 2 is performed by stirring at 0 ℃ for 2 hours.
7. The method for synthesizing 5-chloro-2-methyl-4-isothiazol-3-one labeled with deuterium as a stable isotope according to claim 1, wherein an acid-binding agent is added after the reaction for 15 hours in step 3.
8. The method as claimed in claim 1, wherein the reaction solvent in step 3 is dichloromethane.
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| CN102675018A (en) * | 2011-03-17 | 2012-09-19 | 苏州泽璟生物制药有限公司 | Method for preparing deuterated diphenyl urea |
| CN102816129A (en) * | 2011-06-07 | 2012-12-12 | 中国人民解放军军事医学科学院毒物药物研究所 | Isothiazoline(alkane)ketone-substituted benzendicarboxylic acid derivative, and purposes thereof as beta-secretase inhibitor |
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