CN104610098B - A kind of synthetic method of isotope marks MTMC D3 - Google Patents

Abstract

The present invention relates to a kind of isotope marks MTMC D₃Synthetic method, by monomethyl amine hydrochloride D₃The aqueous solution be added dropwise to carboxylic acid dimethyl dithiocarbamate's solution, obtain intermediate S methyl N methyl carboxylic acids dimethyl esters after reaction, above-mentioned intermediate is slowly introducing Cl at low temperature₂, acid binding agent and metacresol is added successively, label MTMC D is prepared₃.Compared with prior art, the deuterated isotope process is simple of present invention mark, yield are higher, and isotope abundance is undiluted, is suitable for Laboratory Production MTMC D₃.

Description

A kind of synthetic method of isotope-labeled metiocarb-D3

technical field

The invention relates to a preparation method of a stable isotope-labeled organic compound, in particular to a synthesis method of isotope-labeled amethicarb- _D3 .

Background technique

Methiocarb is a moderately toxic insecticide. No carcinogenic, teratogenic, mutagenic effects, but toxic to fish, highly toxic to bees. Due to the widespread use of Methiocarb, food, fruit, water and soil have been polluted. In order to inspect Methiocarb in agricultural products, inspection and quarantine departments often use isotope-labeled Methiocarb-D ₃ as an internal standard, and use isotope dilution mass spectrometry (IDMS) for accurate quantitative analysis to synthesize Methiocarb-D ₃ It is of great significance to the establishment of China's food safety system.

The synthesis of deuterium-labeled amethicarb does not have relevant documents at present, and the non-isotope-labeled amethicarb mainly has the following methods: (1) chloroformate method: take highly toxic phosgene as raw material, after the alcoholysis of m-cresol and Methylamine amination reaction obtains amodicarb; (2) isocyanate method: with tertiary amine as catalyst, excess methyl isocyanate and m-cresol reaction can be synthesized to obtain amethacarb. The above methods have their own advantages, but the use of the above methods to synthesize isotope-labeled metiocarb- _D3 has shortcomings, and it is difficult to introduce deuterated isotope labels. For example, Chinese patent CN101167468A discloses a method for synthesizing Memocarb insecticide, which does not disclose labeling with isotope.

Contents of the invention

The purpose of the present invention is to effectively and accurately detect the pesticide residues of Methiocarb, prepare isotope-labeled Methiocarb- _D3 as the internal standard of pesticide residues, and provide a reliable basis for the inspection of pesticide residues. Provided is an organic synthesis method of isotope-labeled amethacarb- _D3 which is simple, feasible and suitable for mass production.

The purpose of the present invention can be achieved through the following technical solutions:

A kind of synthetic method of isotope labeling amethicarb _{- D3} , the aqueous solution of monomethylamine hydrochloride-D3 is added dropwise to dimethyl dithiocarboxylate solution, obtains intermediate S-methyl-N- Dimethyl methyl carboxylate, the above-mentioned intermediate is slowly passed into Cl ₂ at low temperature, and acid-binding agent and m-cresol are added successively to prepare the marker Memocarb-D ₃ , the specific steps are as follows:

(1) Under the protection of _N2 , dissolve monomethylamine hydrochloride- _D3 in water, add it dropwise to the dimethyl dithiocarboxylate solution within 5-10 minutes, and keep the pH of the reaction solution at 8-9 with alkali , the reaction is mild and exothermic, maintain the reaction temperature at 30-60 ° C, react for 4-8 hours until the raw materials disappear, extract with dichloromethane and combine the organic phases, dry overnight with anhydrous Na ₂ SO ₄ , and concentrate to obtain the intermediate without Color oil S-methyl-N-methyl dimethyl carboxylate-D ₃ ;

(2) Dissolve the intermediate S-methyl-N-methylcarboxylate- _D3 in dimethyldithiocarboxylate, cool to -30～-15°C, and slowly introduce Cl under stirring _2. During the process, the mixture turns light yellow, gradually fades until the color of the reaction solution is colorless, stir and react for 1-4 hours;

(3) Under the protection of _N2 , an acid-binding agent was added to the reaction solution to keep the pH of the reaction solution at 9-10, and a white solid precipitated immediately, and the reaction temperature was raised to 0-20°C, m-cresol was added, and stirred for 2-20°C. 6h, the reaction solution was monitored by TLC (PE:EA=3:1), showing that m-cresol completely disappeared, the reaction solution was extracted with ethyl acetate, washed with saturated NaCl, dried overnight with anhydrous Na ₂ SO ₄ , and concentrated to obtain a colorless Solid Medicarb-D ₃ .

Preferably, the molar ratio of monomethylamine hydrochloride- _D3 to dimethyl dithiocarboxylate in step (1) is 1:1 to 10, and the base is selected from _NaOH , _Na2CO3 or _NaHCO3 one or more of.

More preferably, in step (1), the molar ratio of monomethylamine hydrochloride- _D3 to dimethyl dithiocarboxylate is 1:5-6, the reaction temperature is 40-50°C, and the reaction time is 5-5 6h.

Preferably, the cooling temperature in step (2) is -25 to -20°C, and the stirring reaction time is 2 to 3 hours.

Preferably, in step ( ₃ ), the molar ratio of the amount of m-cresol to monomethylamine hydrochloride-D3 is 1:0.5～2, and the acid-binding agent used is one of triethylamine, DIEA or pyridine. One or several kinds, the dosage is to keep the pH of the reaction solution=9-10.

More preferably, in step ( ₃ ), the molar ratio of m-cresol to monomethylamine hydrochloride-D3 is 1:1-1.2, the reaction temperature is 5-10°C, and the reaction time is 3-4h.

Preferably, the entire reaction is carried out under _N2 protection.

Compared with the prior art, the present invention uses monomethylamine hydrochloride- _D3 as a raw material to prepare the intermediate S-methyl-N-methylcarboxylic acid dimethyl ester through reaction. The intermediate is slowly passed through Cl ₂ at low temperature, and the acid-binding agent and m-cresol are added successively to prepare isotope-labeled amecarb-D ₃ . The total yield is greater than 85% (in terms of monomethylamine hydrochloride-D ₃ ), the abundance of deuterium isotopes is greater than 99% (measured by Shimadzu LC-MS 2020), and the chemical purity is greater than 99% (Waters liquid chromatography external standard method), this method has simple process for labeling deuterium isotope, high yield, undiluted isotope abundance, and is suitable for laboratory production of Methiocarb-D ₃ . This is because the reaction of monomethylamine and dimethyl dithiocarboxylate is through the substitution reaction of the first methylthio group on the dimethyl dithiocarboxylate with tetrahedral structure, and due to the second A methylthio group must have a very high reaction temperature to carry out nucleophilic substitution, so a methylthio substitution reaction has higher selectivity, higher yield and easy separation of intermediates. In the second step reaction, chlorine gas is more likely to undergo nucleophilic substitution reaction, and can easily replace the second methylthio group to form an acid chloride structure. After the acid-binding agent is formed to form a quaternary ammonium salt to remove ^Cl- , the reaction solution is condensed with m-cresol. Methiocarb- _D3 is available. This method introduces deuterium isotopes conveniently through the commonly used deuterium reagent methylamine hydrochloride- _D3 , avoiding the necessary deuterium-labeled isocyanate in the current route, and deuterium-labeled isocyanate is very active, difficult to store stably, and not easy to separate and purify.

detailed description

The synthetic method of isotope-labeled amethicarb _{- D3} , the aqueous solution of monomethylamine hydrochloride-D3 is added dropwise to the dimethyl dithiocarboxylate solution, and the intermediate S-methyl-N-methyl is obtained after the reaction Dimethyl carboxylate, the above-mentioned intermediate is slowly passed into Cl ₂ at low temperature, and acid-binding agent and m-cresol are added successively to prepare the marked substance Medicarb-D ₃ , the specific steps are as follows:

(1) Under the protection of _N2 , dissolve monomethylamine hydrochloride- _D3 in water, add it dropwise to the dimethyl dithiocarboxylate solution within 5-10 minutes, and keep the pH of the reaction solution at 8-9 with alkali , the reaction is mild and exothermic, maintain the reaction temperature at 30-60 ° C, react for 4-8 hours until the raw materials disappear, extract with dichloromethane and combine the organic phases, dry overnight with anhydrous Na ₂ SO ₄ , and concentrate to obtain the intermediate without Color oil S-methyl-N-methyl dimethyl carboxylate-D ₃ ;

(2) Dissolve the intermediate S-methyl-N-methylcarboxylate- _D3 in dimethyldithiocarboxylate, cool to -30～-15°C, and slowly introduce Cl under stirring _2. During the process, the mixture turns light yellow, gradually fades until the color of the reaction solution is colorless, stir and react for 1-4 hours;

(3) Under the protection of _N2 , an acid-binding agent was added to the reaction solution to keep the pH of the reaction solution at 9-10, and a white solid precipitated immediately, and the reaction temperature was raised to 0-20°C, m-cresol was added, and stirred for 2-20°C. 6h, the reaction solution was monitored by TLC (PE:EA=3:1), showing that m-cresol completely disappeared, the reaction solution was extracted with ethyl acetate, washed with saturated NaCl, dried overnight with anhydrous Na ₂ SO ₄ , and concentrated to obtain a colorless Solid Medicarb-D ₃ .

Wherein, in the step (1), the molar ratio of monomethylamine hydrochloride-D ₃ to dimethyl dithiocarboxylate is 1: 1～10, and the alkali wherein is selected from NaOH, Na ₂ CO ₃ or NaHCO ₃ one or several. If better results are needed, the molar ratio of monomethylamine hydrochloride- _D3 to dimethyl dithiocarboxylate is 1:5~6, the reaction temperature is 40~50°C, and the reaction time is 5~6h .

In step (2), the cooling temperature is -25 to -20° C., and the stirring reaction time is 2 to 3 hours.

In step ( ₃ ), the molar ratio of the amount of m-cresol to monomethylamine hydrochloride-D3 is 1: 0.5～2, and the acid-binding agent used is one or more of triethylamine, DIEA or pyridine. species, the dosage is to keep the pH of the reaction solution = 9-10. If a better effect is needed, the molar ratio of the amount of m-cresol to monomethylamine hydrochloride- _D3 is 1:1~1.2, the reaction temperature is 5~10°C, and the reaction time is 3~4h.

The whole reaction is carried out under _N2 protection, and the reaction scheme is as follows:

The present invention will be described in detail below in conjunction with specific embodiments.

Example 1

Under the protection of _N2 , dissolve 15mmol of monomethylamine hydrochloride- _D3 with a small amount of water, add dropwise to 50mmol of dimethyl dithiocarboxylate solution within 5 to 10 minutes, and use NaOH to keep the pH of the reaction solution from 8 to 8. 9. The reaction was mildly exothermic, and the reaction was maintained at 30°C for 8 hours until the raw materials disappeared and the reaction ended. Extract with dichloromethane, combine the organic phases, dry over anhydrous Na ₂ SO ₄ overnight, and concentrate to obtain the intermediate colorless oily S-methyl-N-methylcarboxylate-D ₃ .

Dissolve the intermediate S-methyl-N-methyl dimethyl carboxylate- _D3 in dimethyl dithiocarboxylate, cool to -30°C, and slowly introduce Cl ₂ under stirring. During the process, the mixture Turn pale yellow, and gradually fade until the color of the reaction solution is colorless, stirring and reacting for 1h.

Under the protection of N ₂ , triethylamine was added to the reaction solution to keep the pH of the reaction solution at 9-10, and a white solid precipitated out immediately. Raise the reaction temperature to 0°C, add m-cresol (18mmol), and stir for 4h. TLC analysis of the reaction solution (PE:EA=3:1) showed that m-cresol completely disappeared. The reaction solution was extracted with ethyl acetate (3×50ml), washed with saturated NaCl, dried overnight with anhydrous Na ₂ SO ₄ , and concentrated to give 2.18g (13.0mmol) of colorless solid Medicarb-D ₃ . The total yield is 86.7% (calculated as monomethylamine-D ₃ hydrochloride), the purity is 99.0%, and the deuterium isotope abundance is 99.1%.

Example 2

Under the protection of _N2 , dissolve 15mmol monomethylamine hydrochloride- _D3 with a small amount of water, add dropwise to 15mmol dimethyl dithiocarboxylate solution within _5-10min , and use _Na2CO3 to maintain the pH of the reaction solution =8~9. The reaction was mildly exothermic, and the reaction was maintained at 60°C for 6 hours until the raw materials disappeared, and the reaction ended. Extract with dichloromethane, combine the organic phases, dry over anhydrous Na ₂ SO ₄ overnight, and concentrate to obtain the intermediate colorless oily S-methyl-N-methylcarboxylate-D ₃ .

Dissolve the intermediate S-methyl-N-methylcarboxylate- _D3 in dimethyldithiocarboxylate, cool to -20°C, and slowly introduce Cl ₂ under stirring, and the mixture Turn pale yellow, gradually fade until the color of the reaction solution is colorless, stirring reaction for 4h.

Under the protection of N ₂ , DIEA was added to the reaction solution to keep the pH of the reaction solution at 9-10, and a white solid precipitated immediately. Raise the reaction temperature to 20°C, add m-cresol (30mmol), and stir for 2h. TLC analysis of the reaction solution (PE:EA=3:1) showed that m-cresol completely disappeared. The reaction solution was extracted with ethyl acetate (3×50ml), washed with saturated NaCl, dried overnight with anhydrous Na ₂ SO ₄ , and concentrated to give 2.30 g (13.7 mmol) of colorless solid Medicarb-D ₃ . The total yield is 91.3% (calculated as monomethylamine-D ₃ hydrochloride), the purity is 99.3%, and the deuterium isotope abundance is 99.5%.

Example 3

Under the protection of _N2 , dissolve 15mmol monomethylamine hydrochloride- _D3 with a small amount of water, add dropwise to 150mmol dimethyl dithiocarboxylate solution within 5-10min, and use _NaHCO3 to keep the pH of the reaction solution at 8 ~9. The reaction was mildly exothermic, and the reaction was maintained at 45°C for 4 hours until the raw materials disappeared, and the reaction ended. Extract with dichloromethane, combine the organic phases, dry over anhydrous Na ₂ SO ₄ overnight, and concentrate to obtain the intermediate colorless oily S-methyl-N-methylcarboxylate-D ₃ .

Dissolve the intermediate S-methyl-N-methylcarboxylate- _D3 in dimethyldithiocarboxylate, cool to -15°C, and slowly introduce Cl ₂ under stirring. During the process, the mixture Turn pale yellow, gradually fade until the color of the reaction solution is colorless, stirring reaction for 2h.

Under the protection of N ₂ , pyridine was added to the reaction solution to keep the pH of the reaction solution at 9-10, and a white solid precipitated out immediately. Raise the reaction temperature to 10°C, add m-cresol (7.5mmol), and stir for 6h. TLC analysis of the reaction solution (PE:EA=3:1) showed that m-cresol completely disappeared. The reaction solution was extracted with ethyl acetate (3×50ml), washed with saturated NaCl, dried overnight with anhydrous Na ₂ SO ₄ , concentrated to give 2.15g (12.8mmol) of colorless solid Medicarb-D ₃ . The total yield is 85.2% (calculated as monomethylamine-D ₃ hydrochloride), the purity is 99.5%, and the deuterium isotope abundance is 99.2%.

Example 4

The synthetic method of isotope-labeled amethicarb _{- D3} , the aqueous solution of monomethylamine hydrochloride-D3 is added dropwise to the dimethyl dithiocarboxylate solution, and the intermediate S-methyl-N-methyl is obtained after the reaction Dimethyl carboxylate, the above-mentioned intermediate is slowly passed into Cl ₂ at low temperature, and acid-binding agent and m-cresol are added successively to prepare the marked substance Medicarb-D ₃ , the specific steps are as follows:

(1) Under the protection of _N2 , dissolve monomethylamine hydrochloride- _D3 in water, and dropwise add it to the solution of dimethyl dithiocarboxylate within 5min. Monomethylamine hydrochloride- _D3 and disulfide The molar ratio of dimethyl carboxylate is 1:5. NaOH is used to keep the pH of the reaction solution = 8. The reaction is mild and exothermic. The reaction temperature is maintained at 40 ° C. React for 6 hours until the raw materials disappear. After extraction with dichloromethane, the organic Phase, using anhydrous Na ₂ SO ₄ dried overnight, concentrated to give the intermediate colorless oil S-methyl-N-methyl carboxylate-D ₃ ;

(2) Dissolve the intermediate S-methyl-N-methylcarboxylate-D ₃ in dimethyl dithiocarboxylate, cool to -25°C, slowly introduce Cl ₂ under stirring, and During the process, the mixture turned pale yellow, and gradually faded until the color of the reaction solution was colorless, and the reaction was stirred for 2h;

(3) Under the protection of _N2 , acid-binding agent DIEA is added in the reaction solution to keep the pH of the reaction solution=9, and a white solid is precipitated immediately, and the reaction temperature is raised to 5° C., and m-cresol is added. The amount of m-cresol is the same as The molar ratio of monomethylamine hydrochloride- _D3 was 1:1, stirred for 4h, and the reaction solution was monitored by TLC (PE:EA=3:1), showing that m-cresol completely disappeared, and the reaction solution was extracted with ethyl acetate, Wash with saturated NaCl, dry overnight with anhydrous Na ₂ SO ₄ , and concentrate to obtain a colorless solid of amethacarb-D ₃ .

Example 5

The synthetic method of isotope-labeled amethicarb _{- D3} , the aqueous solution of monomethylamine hydrochloride-D3 is added dropwise to the dimethyl dithiocarboxylate solution, and the intermediate S-methyl-N-methyl is obtained after the reaction Dimethyl carboxylate, the above-mentioned intermediate is slowly passed into Cl ₂ at low temperature, and acid-binding agent and m-cresol are added successively to prepare the marked substance Medicarb-D ₃ , the specific steps are as follows:

(1) Under the protection of N ₂ , dissolve monomethylamine hydrochloride- _D3 in water, add dropwise to the solution of dimethyl dithiocarboxylate within 10min, monomethylamine hydrochloride- _D3 and disulfide The molar ratio of dimethyl carboxylate is 1:6. Use Na ₂ CO ₃ and NaHCO ₃ to keep the pH of the reaction solution = 9. The reaction is mild and exothermic. Keep the reaction temperature at 50°C for 5 hours until the raw materials disappear. After extraction with methyl chloride, the organic phases were combined, dried overnight with anhydrous Na ₂ SO ₄ , and concentrated to obtain the intermediate colorless oily substance S-methyl-N-methyl dimethyl carboxylate-D ₃ ;

(2) Dissolve the intermediate S-methyl-N-methylcarboxylate-D ₃ in dimethyl dithiocarboxylate, cool to -20°C, slowly introduce Cl ₂ under stirring, and During the process, the mixture turned pale yellow, and gradually faded until the color of the reaction solution was colorless, and the reaction was stirred for 3h;

(3) Under the protection of _N2 , the acid-binding agent pyridine is added to the reaction solution in an amount to keep the pH of the reaction solution = 10, and a white solid is precipitated immediately, and the reaction temperature is raised to 10°C, and m-cresol is added in an amount similar to that of monomethyl The molar ratio of amine hydrochloride-D ₃ was 1:1.2, stirred for 3 hours, and the reaction solution was monitored by TLC (PE:EA=3:1), which showed that m-cresol had completely disappeared. The reaction solution was extracted with ethyl acetate, saturated with NaCl Washed, dried overnight with anhydrous Na ₂ SO ₄ , and concentrated to obtain a colorless solid Memethacarb-D ₃ .

Claims (9)

1. a kind of synthetic method of isotope-labeled amethicarb _- D, it is characterized in that, the method drips the aqueous solution of monomethylamine hydrochloride- _D dimethyl dithiocarboxylate solution, obtains intermediate after the reaction Dimethyl S-methyl-N-methyl carboxylate, the above intermediate is slowly introduced into Cl ₂ at low temperature, and acid-binding agent and m-cresol are added successively to prepare the marker Medicarb-D ₃ , specifically Take the following steps: (1) Under the protection of _N2 , dissolve monomethylamine hydrochloride- _D3 in water, add it dropwise to the dimethyl dithiocarboxylate solution within 5-10 minutes, and keep the pH of the reaction solution at 8-9 with alkali , the reaction is mild and exothermic, maintain the reaction temperature at 30-60 ° C, react for 4-8 hours until the raw materials disappear, extract with dichloromethane and combine the organic phases, dry overnight with anhydrous Na ₂ SO ₄ , and concentrate to obtain the intermediate without Color oil S-methyl-N-methyl dimethyl carboxylate-D ₃ ; (2) Dissolve the intermediate S-methyl-N-methylcarboxylate- _D3 in dimethyldithiocarboxylate, cool to -30～-15°C, and slowly introduce Cl under stirring _2. During the process, the mixture turns light yellow, gradually fades until the color of the reaction solution is colorless, stir and react for 1-4 hours; (3) Under the protection of _N2 , an acid-binding agent was added to the reaction solution to keep the pH of the reaction solution at 9-10, and a white solid precipitated immediately, and the reaction temperature was raised to 0-20°C, m-cresol was added, and stirred for 2-20°C. 6h, the reaction solution was monitored by TLC, PE:EA=3:1, showing the complete disappearance of m-cresol, the reaction solution was extracted with ethyl acetate, washed with saturated NaCl, dried overnight with anhydrous Na ₂ SO ₄ , and concentrated to obtain a colorless solid Meprocarb-D ₃ . 2. the synthetic method of a kind of isotope-labeled amethicarb- _D3 according to claim 1 is characterized in that, in step (1), monomethylamine hydrochloride- _D3 and dimethyl dithiocarboxylate The molar ratio is 1:1～10. 3. according to claim 1 and 2 described a kind of synthetic method of isotope-labeled amethicarb- _D3 , it is characterized in that, in step (1), monomethylamine hydrochloride- _D3 and dithiocarboxylic acid two The molar ratio of methyl ester is 1:5-6, the reaction temperature is 40-50°C, and the reaction time is 5-6h. 4. the synthetic method of a kind of isotope-labeled amethicarb _- D according to claim 1, is characterized in that, the alkali in step (1) is selected NaOH, Na ₂ CO ₃ or NaHCO ₃ one or more kind. 5 . The method for synthesizing isotope-labeled Methiocarb-D ₃ according to claim 1 , wherein the cooling temperature in step (2) is -25 to -20° C., and the stirring reaction time is 2 to 3 hours. 6. the synthetic method of a kind of isotope-labeled amethicarb- _D3 according to claim 1, is characterized in that, in step ( ₃ ), the consumption of m-cresol and the mole of monomethylamine hydrochloride-D3 The ratio is 1:0.5~2. 7. according to claim 1 or 6 described a kind of synthetic method of isotope-labeled amethicarb- _D3 , it is characterized in that, in step (3), the consumption of m-cresol and monomethylamine hydrochloride- _D3 The molar ratio is 1:1~1.2, the reaction temperature is 5~10°C, and the reaction time is 3~4h. 8. the synthetic method of a kind of isotope-labeled amethicarb- _D3 according to claim 1, is characterized in that, described acid-binding agent is one or more in triethylamine, DIEA or pyridine, consumption To keep the pH of the reaction solution = 9-10. 9. the synthetic method of a kind of isotope-labeled amecarb _- D according to claim ₁ , is characterized in that, whole reaction is all carried out under N protection.