CN110016050B - Stable isotope labeled chlorpyrifos, derivative thereof and synthetic preparation method - Google Patents
Stable isotope labeled chlorpyrifos, derivative thereof and synthetic preparation method Download PDFInfo
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- CN110016050B CN110016050B CN201910277096.9A CN201910277096A CN110016050B CN 110016050 B CN110016050 B CN 110016050B CN 201910277096 A CN201910277096 A CN 201910277096A CN 110016050 B CN110016050 B CN 110016050B
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Abstract
The invention discloses a stable isotope labeled chlorpyrifos and derivatives thereof and a synthesis preparation method, wherein the stable isotope labeled chlorpyrifos and derivatives thereof are obtained by reacting trichlorothion serving as a raw material with a stable isotope labeled 3,5, 6-trichloropyridine-2-alcohol sodium salt and a stable isotope labeled short-chain alcohol in sequence by utilizing an organic synthesis method; the stable isotope labeled chlorpyrifos and the derivative thereof prepared by the invention have the chemical purity of more than 99 percent and the isotope abundance of more than 99 percent after simple separation and purification, can be applied to the fields of biological metabolism, food safety, environmental monitoring and the like, and have the advantages of good quality and low cost compared with foreign products.
Description
Technical Field
The invention relates to a stable isotope labeled compound and a synthetic preparation method thereof, in particular to a stable isotope labeled chlorpyrifos, a derivative thereof and a synthetic preparation method.
Background
Chlorpyrifos, chemical name O, O-diethyl-O (3,5, 6-trichloro-2-pyridyl) thiophosphate, international common name chlorerpifos. The insecticide and acaricide is an efficient, low-toxicity, broad-spectrum, low-residue and low-drug-resistance organophosphorus insecticide and acaricide developed by Dow company in 1965, has the effects of contact poisoning, stomach poisoning and fumigation, and can effectively control more than one species of pests such as stem borers, leaf rollers, armyworms, scale insects, aphids, leafhoppers and pest mites in the aspects of rice, wheat, corn, cotton, sugarcane, tea, fruit trees, flowers, livestock and the like. The chlorpyrifos derivatives such as methyl chlorpyrifos, propyl chlorpyrifos, etc. are also applied in pesticides.
But chlorpyrifos is volatile, has low solubility in water, is easily adsorbed by particles in soil, has a degradation half-life period of 9.8-63 d in soil and has low degradation speed. The plants are as follows: the green vegetables can absorb the chlorpyrifos in the soil, and the content of the chlorpyrifos in the plant tissues of the green vegetables is increased along with the increase of the residual quantity of the chlorpyrifos in the soil, so that potential danger is possibly caused to the human health. Furthermore, chlorpyrifos is an acetylcholinesterase inhibitor, and even a low dose may cause injury to the human body, possibly affecting the central nervous system, cardiovascular system, respiratory system. Children are more susceptible to chlorpyrifos than adults and are more vulnerable. Derivatives of chlorpyrifos are similarly harmful to humans.
Therefore, the detection and monitoring of chlorpyrifos in food are very necessary. However, the complex matrix effect in food needs to be accurately detected by a stable isotope internal standard method. Meanwhile, the metabolism and degradation research of the chlorpyrifos and the derivatives thereof in the field of biological metabolism also urgently needs the products of the chlorpyrifos and the derivatives thereof marked by stable isotopes.
At present, the synthetic literature of chlorpyrifos and derivatives thereof marked by stable isotopes is rarely reported at home and abroad, and most of the synthetic literature of natural chlorpyrifos is to prepare O, O-diethyl thiophosphoryl chloride by reacting trichlorothion with excessive ethanol and then react with 3,5, 6-trichloro-2-pyridinol or sodium salt under the action of a phase transfer catalyst to prepare the chlorpyrifos. The synthesis of chlorpyrifos by a natural method needs two-step preparation, the consumption of ethanol is large when O, O-diethyl thiophosphoryl chloride is prepared in the first step, the byproduct O, O, O-triethyl thiophosphate is easily generated, and the energy consumption of the product which needs rectification and purification is high. The second step reaction can prepare chlorpyrifos only by long-time high-temperature reaction under the conditions of aqueous phase, alkalinity, phase transfer catalyst and the like, and a byproduct thiotepa is easy to generate. The reaction route and the reaction conditions thereof are difficult to be applied to the synthesis of stable isotope labeled chlorpyrifos and derivatives thereof, excessive ethanol input and subsequent aqueous phase, acid-base and high-temperature reaction not only reduce the atom economy of isotope utilization, but also easily dilute the isotope abundance, and the stable isotope labeled chlorpyrifos and derivatives thereof with high abundance, good purity and high atom economy cannot be obtained.
Disclosure of Invention
The invention aims to provide stable isotope labeled chlorpyrifos, derivatives thereof and a synthetic preparation method thereof, raw materials are cheap and easy to obtain, the reaction process is simple, the utilization rate of stable isotope atoms is high, no waste water is generated, and the obtained target product has high chemical purity and isotope abundance.
The purpose of the invention can be realized by the following technical scheme: a stable isotope labeled chlorpyrifos and its derivatives have the following structural formula:
r is methyl, ethyl, propyl, isopropyl or butyl, at least one of the groups a, b, c, d, e, f, g, R is independently13C、D、15N or18And (4) labeling with an O isotope.
Further, a is18And marking by O.
Further, the b, c, e or f is13And C, marking.
Further, the group d or R is13C label, D label or both labels.
Further, the g is15And marking by N.
The invention also provides a synthetic method of the stable isotope labeled chlorpyrifos and the derivatives thereof, wherein the method comprises the following steps: the trichloro-sulfur phosphorus is used as a raw material and sequentially reacts with 3,5, 6-trichloropyridine-2-alcohol sodium salt marked by stable isotope and short-chain alcohol marked by stable isotope under the liquid-phase alkaline condition to obtain the trichloro-sulfur phosphorus.
Further, the molar ratio of the trichlorothiophosphor to the stable isotope labeled 3,5, 6-trichloropyridine-2-alcohol sodium salt to the stable isotope labeled short-chain alcohol is 1: 1: 1-1: 5: 5, the reaction temperature is-50-200 ℃.
Further, the molar ratio of the trichlorothiophosphor to the stable isotope labeled 3,5, 6-trichloropyridine-2-alcohol sodium salt to the stable isotope labeled short-chain alcohol is 1: 1: 1-1: 2: 3, the reaction temperature is-20-80 ℃.
Further, the liquid phase is one or a combination of toluene, ethylbenzene, xylene and cumene.
Further, one or a combination of tert-butylamine, n-butylamine and isopropylamine is added into the liquid phase.
Compared with the prior art, the invention has the following beneficial effects: the invention takes trichlorfon as a raw material, and the trichlorfon reacts with 3,5, 6-trichloropyridine-2-alcohol sodium salt marked by stable isotope and short-chain alcohol marked by stable isotope in sequence under the liquid phase alkaline condition to obtain chlorpyrifos marked by stable isotope and derivatives thereof. The method has the advantages of cheap and easily-obtained raw materials, simple reaction process, mild conditions, high yield, high utilization rate of stable isotope atoms and no waste water generation, is a synthesis method suitable for stable isotope labeled chlorpyrifos and derivatives thereof, and the successful development of the stable isotope labeled chlorpyrifos and the derivatives thereof, provides a metabolic standard for metabolic research of the chlorpyrifos and the derivatives thereof in the field of biological metabolism, and provides a standard reagent for more accurate quantitative detection of the chlorpyrifos and the derivatives thereof, thereby effectively providing services for the fields of biological metabolism, food safety and environmental monitoring.
Detailed Description
The invention is further described below with reference to the following examples.
The invention provides stable isotope labeled chlorpyrifos and derivatives thereof, which have the following structural formula:
r is methyl, ethyl, propyl, isopropyl or butyl, at least one of the groups a, b, c, d, e, f, g, R is independently13C、D、15N or18And (4) labeling with an O isotope. Specifically, the labeling substituted by the stable isotope of the tracer atom at each atom in the above-mentioned compound is as follows:
at a position of18O-label or non-label;
at the position b is13C is labeled or unlabeled;
at the position c is13C is labeled or unlabeled;
at d is13One or both of C-label, D (deuterium) label or non-label;
at the position e is13C is labeled or unlabeled;
at f is13C is labeled or unlabeled;
at g is15N-labeled or non-labeled;
the R group is13One or both of C-label, D (deuterium) or non-label.
Example 1
Stable isotope labeled chlorpyrifos-D10The preparation method comprises the following steps:
adding 17.0 g of trichloro-sulfur phosphorus into a 250 mL three-neck flask, adding 100mL of toluene at-5 ℃, adding 22.1g of 3,5, 6-trichloropyridine-2-sodium alkoxide in batches under stirring, controlling the temperature to be 0 ℃ to react for 1 hour after the addition is finished, and adding ethanol-D6 10.4g of isopropylamine and 11.8g of isopropylamine, heating to 40 ℃, reacting for 2 hours, filtering, and removing the solventThis gave 34.8g of chlorpyrifos-D10Solid, yield 96.7%, GC detection, purity 99.5%; mass spectrum detection, abundance 99.6atom% D.
Example 2
Stable isotope labeled methyl chlorpyrifos-D6The preparation method comprises the following steps:
adding 8.5 g of trichloro-sulfur phosphorus into a 250 mL three-neck flask, adding 70mL of dimethylbenzene at-15 ℃, adding 12.1g of 3,5, 6-trichloropyridine-2-sodium alkoxide in batches under stirring, controlling the temperature to be 0 ℃ after the addition, reacting for 1 hour, and adding methanol-D4 7.5g of tert-butylamine and 7.8g of tert-butylamine are heated to 60 ℃ to react for 1 hour, and after the solvent is removed, 15.0g of methyl chlorpyrifos-D is obtained6Solid, yield 91.5%, GC detection, purity 99.5%; mass spectrum detection, abundance 99.7atom% D.
Example 3
Stable isotope labeled chlorpyrifos-13C5The preparation method comprises the following steps:
adding 17.0 g of trichloro-sulfur phosphorus into a 250 mL three-neck flask, adding 80mL of ethylbenzene at-20 ℃, and adding 3,5, 6-trichloropyridine-2-sodium alcoholate in batches under stirring13C5 22.1g, controlling the temperature to be 0 ℃ after the addition to react for 1 hour, then adding 12.4g of ethanol and 11.8g of isopropylamine, heating to 60 ℃ to react for 1.5 hours, performing suction filtration, and removing the solvent to obtain 34.9g of chlorpyrifos-13C5Solid, yield 97.7%, GC detection, purity 99.5%; mass spectrum detection, the abundance is 99.6atom%13C。
Example 4
Stable isotope labeled chlorpyrifos-13C9D11 15N18O3The preparation method comprises the following steps:
adding 8.5 g of trichloro-sulfur into a 250 mL three-neck flask, adding 100mL of isopropyl benzene at-10 ℃, and adding 3,5, 6-trichloropyridine-2-sodium alcoholate in batches under stirring13C5D15N18O11.6g, after the addition, controlling the temperature to 0 ℃ for reaction for 1.5 hours, and then adding ethanol-13C2D6 1811.5g of O and 8.8g of tert-butylamine, heating to 70 ℃ for reaction for 1.5 hours,filtering, removing the solvent to obtain 17.9g of chlorpyrifos-13C9D11 15N18O3Solid, yield 98.7%, GC detection, purity 99.5%; mass spectrum detection, the abundance is 99.6atom%13CD15N18O。
Example 5
Stable isotope labeled propylchlorpyrifos-13C5The preparation method comprises the following steps:
mixing a mixture of 1: 1.1 Trithiophosphoryl chloride and 3,5, 6-trichloropyridin-2-ol sodium salt-13C5Mixing at 0 ℃, reacting for 0.5 hour, then adding 2.1 equivalent of propanol and isopropylamine, controlling the temperature to 80 ℃, and reacting for 3 hours to obtain the propyl chlorpyrifos-13C5。
Example 6
Stable isotope labeled isopropyl chlorpyrifos-D14The preparation method comprises the following steps:
mixing a mixture of 1: 1.2 mixing trichlorothion and 3,5, 6-trichloropyridine-2-sodium alcoholate at 5 deg.C, reacting for 2.5 hr, adding 2.5 equivalents of isopropanol and n-butylamine, controlling temperature at 50 deg.C, reacting for 4 hr to obtain isopropyl chlorpyrifos-D14。
Example 7
Stable isotope labeled n-butyl chlorpyrifos-13C8The preparation method comprises the following steps:
mixing a mixture of 1: 1.5 parts of phosphorus trichloride and 3,5, 6-trichloropyridine-2-alcohol sodium salt are mixed at the temperature of minus 15 ℃, after reaction for 1.5 hours, 2.1 equivalent of n-butyl alcohol is added13C4T-butylamine, controlling the temperature at 40 ℃, and reacting for 5 hours to obtain n-butyl chlorpyrifos-13C8。
Example 8
Stable isotope labeled chlorpyrifos-methyl-13C7D7 15N18O3The preparation method comprises the following steps:
mixing a mixture of 1: 1.2 Trithiophosphoryl chloride and 3,5, 6-trichloropyridine-2-ol sodium salt-13C5D15N18After mixing at the temperature of O-5 ℃, reacting for 1 hour, and then adding 2.3 equivalent of methanol-13CD4 18O and isopropylamine, controlling the temperature at 40 ℃ and reacting for 3 hours to obtain the chlorpyrifos-methyl-13C7D7 15N18O3。
The invention uses an organic synthesis method, takes trichlorosulfur as a raw material, and sequentially reacts with 3,5, 6-trichloropyridine-2-alcohol sodium salt marked by stable isotope and short-chain alcohol marked by stable isotope to obtain chlorpyrifos marked by stable isotope and derivatives thereof; the stable isotope labeled chlorpyrifos and the derivative thereof prepared by the invention have high chemical purity and isotope abundance after simple separation and purification, can be applied to the fields of biological metabolism, food safety, environmental monitoring and the like, and have the advantages of good quality and low cost compared with foreign products. The method has the following specific advantages: 1) the invention adopts a synthetic method, has cheap and easily obtained raw materials, simple reaction process, mild conditions, high yield, high utilization rate of stable isotope atoms and no wastewater generation. 2) The product of the invention is easy to separate and purify, the chemical purity of the product is more than 99 percent, and the isotopic abundance is more than 99 percent. 3) The invention has good economical efficiency and use value.
Although the present invention has been described with respect to the preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (2)
1. Stable isotope labeled chlorpyrifos-D10The preparation method is characterized by comprising the following steps:
adding 17.0 g of trichloro-sulfur phosphorus into a 250 mL three-neck flask, adding 100mL of toluene at-5 ℃, adding 22.1g of 3,5, 6-trichloropyridine-2-sodium alkoxide in batches under stirring, controlling the temperature to be 0 ℃ to react for 1 hour after the addition is finished, and adding ethanol-D6 10.4g of isopropyl amine and 11.8g of isopropylamine, heating to 40 ℃ for reaction for 2 hours, performing suction filtration, and removing the solvent to obtain 34.8g of chlorpyrifos-D10And (3) a solid.
2. Stable isotope labeled chlorpyrifos-D6The preparation method is characterized by comprising the following steps:
adding 8.5 g of trichloro-sulfur phosphorus into a 250 mL three-neck flask, adding 70mL of dimethylbenzene at-15 ℃, adding 12.1g of 3,5, 6-trichloropyridine-2-sodium alkoxide in batches under stirring, controlling the temperature to be 0 ℃ after the addition, reacting for 1 hour, and adding methanol-D4 7.5g of tert-butylamine and 7.8g of tert-butylamine are heated to 60 ℃ to react for 1 hour, and after the solvent is removed, 15.0g of methyl chlorpyrifos-D is obtained6And (3) a solid.
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