CN111116645A - A kind of synthetic method of phosphorothioate compound - Google Patents

A kind of synthetic method of phosphorothioate compound Download PDF

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CN111116645A
CN111116645A CN201911291209.7A CN201911291209A CN111116645A CN 111116645 A CN111116645 A CN 111116645A CN 201911291209 A CN201911291209 A CN 201911291209A CN 111116645 A CN111116645 A CN 111116645A
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沈振陆
陈莺莺
李美超
胡宝祥
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Zhejiang University of Technology ZJUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
    • C07F9/165—Esters of thiophosphoric acids
    • C07F9/18—Esters of thiophosphoric acids with hydroxyaryl compounds
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
    • C07F9/165—Esters of thiophosphoric acids
    • C07F9/1653—Esters of thiophosphoric acids with arylalkanols
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    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
    • C07F9/165—Esters of thiophosphoric acids
    • C07F9/17—Esters of thiophosphoric acids with hydroxyalkyl compounds without further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
    • C07F9/165—Esters of thiophosphoric acids
    • C07F9/177—Esters of thiophosphoric acids with cycloaliphatic alcohols
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
    • C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring

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Abstract

本发明公开了一种硫代磷酸酯类化合物的合成方法，以硫醇为反应底物，三氯异氰尿酸(TCCA)为促进剂，反应底物和促进剂在有机溶剂中，于常温常压条件下反应10～20min，然后加入亚磷酸三酯，继续反应10～20min，反应结束后经分离处理得到所述的硫代磷酸酯类化合物。本发明所述的合成方法，反应在常温常压下进行，没有特殊要求；反应时间短；反应底物普适性好。The invention discloses a method for synthesizing phosphorothioate compounds. Thiol is used as a reaction substrate, trichloroisocyanuric acid (TCCA) is used as an accelerator, and the reaction substrate and accelerator are in an organic solvent at room temperature and normal temperature. The reaction is carried out under pressure conditions for 10-20 min, then the phosphite triester is added, and the reaction is continued for 10-20 min. After the reaction, the phosphorothioate compound is obtained by separation and treatment. In the synthesis method of the invention, the reaction is carried out at normal temperature and normal pressure without special requirements; the reaction time is short; and the reaction substrate has good universality.

Description

Synthesis method of thiophosphate compound
Technical Field
The invention relates to a synthetic method of a thiophosphate compound.
Background
The organic compound containing phosphorus and sulfur has special properties and wide application. Thiophosphate compounds are important in sulfur-phosphorus-containing organic compounds, and the compounds have wide application in various fields such as medicines, pesticides, biology, materials and the like. The conventional synthesis of these compounds is carried out by reacting halogenated phosphates with thiols, but with halogenated phosphorusThe preparation method of the acid ester compound is complex and inconvenient to operate. In recent years, the use of diphosphorous acid diesters (H-P (O) (OR))2) The synthesis of phosphorothioate compounds by cross-dehydrocoupling (CDC) reaction with thiols has been developed. In 2013, the literature reports that CuI can catalyze the reaction of hydrogen phosphorous acid diester and aryl mercaptan to synthesize phosphorothioate compounds in the presence of triethylamine (Synthesis2013, 45, 2323); in 2014, the literature reports the reaction for preparing the thiophosphate compound by taking hydrogen phosphorous acid diester and thiol promoted by NCS as raw materials (Green chem.2014, 16, 357); in 2016, a reaction for preparing a thiophosphate compound by taking Pd-catalyzed diphosphorous acid diester and mercaptan as raw materials is reported (J.Am.chem.Soc.2016, 138, 5825); in 2017, Cs is reported in literature2CO3A reaction for preparing a thiophosphate compound by using catalytic diphosphorous diester and mercaptan as raw materials (Angew. chem. int. Ed.2017, 56, 2487); the NHCs catalyst can catalyze the reaction of the diphosphorus acid diester and the disulfide to synthesize the thiophosphate compound (chem.Eur.J.2017, 23, 6259).
The phosphite triester compound has low price and strong nucleophilic ability. Therefore, K has been reported2CO3The reaction for preparing the thiophosphate compound by taking the phosphite triester and the mercaptan as raw materials is promoted, and the reaction time is generally 5-12h (RSCAdv.2017, 7, 45416). However, this reaction is only applicable to aryl thiols, and aliphatic thiols are not. Chinese patent CN10884260 reports a method for preparing thiophosphate compounds by reacting phosphite triester and disulfide, and the reaction does not need catalyst or promoter. However, this reaction is only applicable to diaryl disulfides, and it is well known that disulfide compounds still need to be prepared from thiols. The above methods have advantages but disadvantages, such as the use of a transition metal catalyst in some methods, limited substrate in some methods, relatively high raw material cost in some methods, and long reaction time in some methods.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a method for preparing a thiophosphate compound at room temperature by using phosphite triester and mercaptan as raw materials.
In order to achieve the purpose, the invention adopts the following technical scheme: a method for synthesizing a thiophosphate compound comprises the steps of taking mercaptan as a reaction substrate, taking trichloroisocyanuric acid (TCCA) as an accelerant, reacting the reaction substrate and the accelerant in an organic solvent for 10-20 min under the conditions of normal temperature and normal pressure, then adding phosphite triester, continuing to react for 10-20 min, and separating after the reaction is finished to obtain the thiophosphate compound.
The structural formula of the phosphite triester compound is shown as a formula (II), the structure of the thiol compound is shown as a formula (III), and the structural formula of the corresponding obtained thiophosphate compound is shown as a formula (I);
Figure BDA0002319133920000021
in the formula (I) or formula (II), R1Is C1-C8 alkyl, preferably methyl, ethyl, isopropyl or n-butyl.
In the formula (I) or formula (III), R2Is C1-C12 alkyl, benzyl, substituted benzyl, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, naphthyl or substituted naphthyl. The heteroaryl group may be an aromatic group containing a heteroatom such as N, O, S in the ring. The substituted benzyl, substituted phenyl, substituted heteroaromatic group and substituted naphthyl refer to that hydrogen on a benzene ring, a heteroaromatic ring or a naphthalene ring is substituted by one or more substituents, and each substituent is independently selected from one of the following groups: halogen, alkyl of C1-C4, alkoxy of C1-C4, amino and hydroxyl. Preferably R2Cyclohexyl, 2-methylbutyl, dodecyl, benzyl, halogenated phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, amino substituted phenyl, naphthyl or thienyl.
In the invention, the quantity ratio of the mercaptan compound to the substances of the phosphite triester and TCCA is 100: 90-250: 30-60, preferably 100: 100-200: 33 to 50.
In the invention, the organic solvent is dichloromethane, tetrahydrofuran, N-dimethylformamide, toluene and acetonitrile, preferably acetonitrile or N, N-dimethylformamide; the mass usage of the solvent is recommended to be 7-30 times of that of the thiol compound.
The post-treatment method of the reaction liquid comprises the following steps: after the reaction is finished, filtering, evaporating the filtrate under reduced pressure to remove the solvent, and then performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting the eluent containing the target compound, and evaporating the solvent to obtain the product, i.e. the thiophosphate compound.
The invention specifically recommends that the method for synthesizing the thiophosphate compound by taking the phosphite triester and the mercaptan as raw materials is carried out according to the following steps: adding mercaptan and TCCA into an organic solvent, reacting for 10-20 min at normal temperature and normal pressure, adding phosphite triester into a reaction system, continuing to react for 10-20 min, filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether to ethyl acetate is 20: 1 as eluent, collecting the eluent containing the target compound, and evaporating the solvent to obtain the product, i.e. the thiophosphate compound. The organic solvent is acetonitrile or N, N-dimethylformamide; the quantity ratio of the mercaptan compound to the substances of the phosphite triester and TCCA is 100: 100-200: 33 to 50.
The synthesis method has the beneficial effects that:
(1) the reaction is carried out at normal temperature and normal pressure, and has no special requirement.
(2) The reaction time is short.
(3) The reaction substrate has good universality.
Detailed Description
The invention is further illustrated by the following specific examples, without limiting the scope of the invention thereto.
The following examples show the structural formulas of the phosphorothioate compounds shown in formulas (1) to (23), respectively:
Figure BDA0002319133920000041
example 1: preparation of O, O-diethyl-S-p-tolylthiophosphate (formula (1))
In a 15mL reaction tube equipped with a magnetic stirrer, p-toluenesulphonol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL acetonitrile were added, and the reaction was stirred at room temperature for 10min, then triethyl phosphite (1.2mmol) was added, and stirring was continued at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting eluent containing target compound, evaporating solvent to obtain product O, O-diethyl-S-p-tolyl thiophosphate with separation yield of 94%.
Example 2: preparation of O, O-diethyl-S-p-tolylthiophosphate (formula (1))
The reaction procedure was as in example 1, except that the reaction solvent was changed to methylene chloride and the isolated yield of O, O-diethyl-S-p-tolylthiophosphate was 67%.
Example 3: preparation of O, O-diethyl-S-p-tolylthiophosphate (formula (1))
The procedure was as in example 1, except that the reaction solvent was changed to tetrahydrofuran, and the isolated yield of O, O-diethyl-S-p-tolylthiophosphate was 83%.
Example 4: preparation of O, O-diethyl-S-p-tolylthiophosphate (formula (1))
The reaction procedure was as in example 1, except that the reaction solvent was changed to N, N-dimethylformamide, and the isolated yield of O, O-diethyl-S-p-tolylthiophosphate was 93%.
Example 5: preparation of O, O-diethyl-S-p-tolylthiophosphate (formula (1))
The reaction procedure was as in example 1, except that the reaction solvent was changed to toluene, and O, O-diethyl-S-p-tolylthiophosphate was isolated in a yield of 50%.
Example 6: preparation of O, O-diethyl-S-p-tolylthiophosphate (formula (1))
The reaction procedure was as in example 1, except that the amount of trichloroisocyanuric acid was changed to 0.33mmol, and the isolated yield of O, O-diethyl-S-p-tolylthiophosphate was 90%.
Example 7: preparation of O, O-diethyl-S-m-tolyl phosphorothioate (formula (2))
In a 15mL reaction tube equipped with a magnetic stirrer, m-tolylthiophenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL of acetonitrile were added, and the reaction was stirred at room temperature for 10min, then triethyl phosphite (1.2mmol) was added, and stirring was continued at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting eluent containing target compound, evaporating solvent to obtain product O, O-diethyl-S-m-tolyl thiophosphate with separation yield of 75%.
Example 8: preparation of O, O-diethyl-S-O-tolylthiophosphate (formula (3))
In a 15mL reaction tube equipped with a magnetic stirrer, o-tolylthiophenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL of acetonitrile were added, and the reaction was stirred at room temperature for 10min, then triethyl phosphite (1.2mmol) was added, and stirring was continued at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting eluent containing target compound, evaporating solvent to obtain product O, O-diethyl-S-O-tolyl thiophosphate with separation yield of 60%.
Example 9: preparation of O, O-diethyl-S-p-isopropylphenyl phosphorothioate (formula (4))
In a 15mL reaction tube equipped with a magnetic stirrer, p-isopropylthiophenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL of acetonitrile were added, and the reaction was stirred at room temperature for 10min, then triethyl phosphite (1.2mmol) was added, and stirring was continued at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting the eluent containing the target compound, evaporating the solvent to obtain the product O, O-diethyl-S-p-isopropylphenyl thiophosphate, with the separation yield of 80%.
Example 10: preparation of O, O-diethyl-S-p-tert-butylphenyl thiophosphate (formula (5))
To a 15mL reaction tube equipped with a magnetic stirrer, p-tert-butylphenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL acetonitrile were added, and the reaction was stirred at room temperature for 10min, followed by the addition of triethyl phosphite (1.2mmol) and continued stirring at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting the eluent containing the target compound, evaporating the solvent to obtain the product O, O-diethyl-S-p-tert-butylphenyl thiophosphate, with a separation yield of 84%.
Example 11: preparation of O, O-diethyl-S-p-methoxyphenyl phosphorothioate (formula (6))
A15 mL reaction tube equipped with a magnetic stirrer was charged with p-methoxythiophenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL acetonitrile, stirred at room temperature for 10min, then triethyl phosphite (1.2mmol) was added, and stirring was continued at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting eluent containing target compound, evaporating solvent to obtain product O, O-diethyl-S-p-methoxyphenyl thiophosphate, and separating yield is 85%.
Example 12: preparation of O, O-diethyl-S-O-methoxyphenyl phosphorothioate (formula (7))
In a 15mL reaction tube equipped with a magnetic stirrer, o-methoxythiophenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL acetonitrile were added, and the reaction was stirred at room temperature for 10min, then triethyl phosphite (1.2mmol) was added, and stirring was continued at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting the eluent containing the target compound, evaporating the solvent to obtain the product O, O-diethyl-S-O-methoxyphenyl thiophosphate, wherein the separation yield is 72 percent.
Example 13: preparation of O, O-diethyl-S- (2, 4-dimethylphenyl) thiophosphate (formula (8))
2, 4-Dimethylthiophenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL acetonitrile were added to a 15mL reaction tube equipped with a magnetic stirrer, and the reaction was stirred at room temperature for 10min, followed by the addition of triethyl phosphite (1.2mmol) and continued stirring at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting eluent containing target compound, evaporating solvent to obtain O, O-diethyl-S- (2, 4-dimethylphenyl) thiophosphate, and separating yield is 72%.
Example 14: preparation of O, O-diethyl-S-p-chlorophenyl thiophosphate (formula (9))
P-chlorothiophenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL acetonitrile were added to a 15mL reaction tube equipped with a magnetic stirrer, and the reaction was stirred at room temperature for 10min, followed by the addition of triethyl phosphite (1.2mmol) and continued stirring at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting the eluent containing the target compound, evaporating the solvent to obtain the product O, O-diethyl-S-p-chlorophenyl thiophosphate, with the separation yield of 93%.
Example 15: preparation of O, O-diethyl-S-m-chlorophenyl phosphorothioate (formula (10))
In a 15mL reaction tube equipped with a magnetic stirrer, m-chlorothiophenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL acetonitrile were added, and the reaction was stirred at room temperature for 10min, then triethyl phosphite (1.2mmol) was added and stirring was continued at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting the eluent containing the target compound, evaporating the solvent to obtain the product O, O-diethyl-S-m-chlorophenyl thiophosphate, wherein the separation yield is 87%.
Example 16: preparation of O, O-diethyl-S-O-chlorophenyl thiophosphate (formula (11))
To a 15mL reaction tube equipped with a magnetic stirrer, o-chlorothiophenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL acetonitrile were added, and the reaction was stirred at room temperature for 10min, followed by the addition of triethyl phosphite (1.2mmol) and continued stirring at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting the eluent containing the target compound, evaporating the solvent to obtain the product O, O-diethyl-S-O-chlorophenyl thiophosphate, wherein the separation yield is 90%.
Example 17: preparation of O, O-diethyl-S-p-bromophenyl phosphorothioate (formula (12))
In a 15mL reaction tube equipped with a magnetic stirrer, p-bromothiophenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL acetonitrile were added, and the reaction was stirred at room temperature for 10min, then triethyl phosphite (1.2mmol) was added, and stirring was continued at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting eluent containing target compound, evaporating solvent to obtain O, O-diethyl-S-p-bromophenyl thiophosphate, and separating yield is 82%.
Example 18: preparation of O, O-diethyl-S-p-fluorophenyl phosphorothioate (formula (13))
P-fluorophenylthiophenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL of acetonitrile were added to a 15mL reaction tube equipped with a magnetic stirrer, and the reaction was stirred at room temperature for 10min, followed by addition of triethyl phosphite (1.2mmol) and further stirring at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting eluent containing target compound, evaporating solvent to obtain product O, O-diethyl-S-p-fluorophenyl thiophosphate, and separating yield is 88%.
Example 19: preparation of O, O-diethyl-S-p-aminophenyl phosphorothioate (formula (14))
In a 15mL reaction tube equipped with a magnetic stirrer, p-aminophenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL of acetonitrile were added, and the reaction was stirred at room temperature for 10min, then triethyl phosphite (1.2mmol) was added, and stirring was continued at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting the eluent containing the target compound, evaporating the solvent to obtain the product O, O-diethyl-S-p-aminophenyl thiophosphate, wherein the separation yield is 48%.
Example 20: preparation of O, O-diethyl-S- (thien-2-yl) thiophosphate (formula (15))
Thiophene-2-thiophenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL acetonitrile were added to a 15mL reaction tube equipped with a magnetic stirrer, and the reaction was stirred at room temperature for 10min, followed by the addition of triethyl phosphite (1.2mmol) and continued stirring at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting eluent containing target compound, evaporating solvent to obtain O, O-diethyl-S- (thiophene-2-yl) thiophosphate with separation yield of 50%.
Example 21: preparation of O, O-diethyl-S- (naphthalen-2-yl) thiophosphate (formula (16))
Naphthalene-2-thiophenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL acetonitrile were added to a 15mL reaction tube equipped with a magnetic stirrer, and the reaction was stirred at room temperature for 10min, followed by the addition of triethyl phosphite (1.2mmol) and continued stirring at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting eluent containing target compound, evaporating solvent to obtain O, O-diethyl-S- (naphthalene-2-yl) thiophosphate with separation yield of 56%.
Example 22: preparation of O, O-diethyl-S-benzylthiophosphate (formula (17))
To a 15mL reaction tube equipped with a magnetic stirrer, benzylthiol (1mmol), trichloroisocyanuric acid (0.5mmol) and 2mL acetonitrile were added, and the reaction was stirred at room temperature for 10min, followed by the addition of triethyl phosphite (2mmol) and continued stirring at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting eluent containing target compound, evaporating solvent to obtain O, O-diethyl-S- (naphthalene-2-yl) thiophosphate with separation yield of 74%.
Example 23: preparation of O, O-diethyl-S- (2-methylbutyl) thiophosphate (formula (18))
2-Methylbutanethiol (1mmol), trichloroisocyanuric acid (0.5mmol) and 2mL acetonitrile were added to a 15mL reaction tube equipped with a magnetic stirrer, and the reaction was stirred at room temperature for 10min, followed by the addition of triethyl phosphite (2mmol) and continued stirring at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting eluent containing target compound, evaporating solvent to obtain product O, O-diethyl-S- (2-methylbutyl) thiophosphate, and separating yield is 70%.
Example 24: preparation of O, O-diethyl-S-cyclohexyl thiophosphate (formula (19))
A15 mL reaction tube equipped with a magnetic stirrer was charged with cyclohexyl thiol (1mmol), trichloroisocyanuric acid (0.5mmol) and 2mL acetonitrile, stirred at room temperature for 10min, then triethyl phosphite (2mmol) was added, and stirring was continued at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting eluent containing target compound, evaporating solvent to obtain product O, O-diethyl-S-cyclohexyl thiophosphate, and separating yield is 72%.
Example 25: preparation of O, O-diethyl-S-dodecylthiophosphate (formula (20))
A15 mL reaction tube equipped with a magnetic stirrer was charged with dodecylmercaptan (1mmol), trichloroisocyanuric acid (0.5mmol) and 2mL acetonitrile, stirred at room temperature for 10min, then triethyl phosphite (2mmol) was added, and stirring was continued at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting the eluent containing the target compound, evaporating the solvent to obtain the product O, O-diethyl-S-dodecyl thiophosphate, wherein the separation yield is 64%.
Example 26: preparation of O, O-diethyl-S-dodecylthiophosphate (formula (20))
The reaction procedure was as in example 26 except that dodecylmercaptan and trichloroisocyanuric acid were stirred at room temperature for 20min and then stirred at room temperature for 20min after triethyl phosphite was added, and the isolation yield of O, O-diethyl-S-dodecylthiophosphate was 80%.
Example 26: preparation of O, O-dimethyl-S-p-tolylthiophosphate (formula (21))
P-methylthiophenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL acetonitrile were added to a 15mL reaction tube equipped with a magnetic stirrer, and the reaction was stirred at room temperature for 10min, followed by the addition of trimethyl phosphite (1.2mmol) and continued stirring at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting eluent containing target compound, evaporating solvent to obtain product O, O-dimethyl-S-p-tolyl thiophosphate, with separation yield of 95%.
Example 27: preparation of O, O-diisopropyl-S-p-tolylthiophosphate (formula (22))
P-methylthiophenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL of acetonitrile were added to a 15mL reaction tube equipped with a magnetic stirrer, and the reaction was stirred at room temperature for 10min, followed by the addition of triisopropyl phosphite (1.2mmol) and further stirring at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting eluent containing target compound, evaporating solvent to obtain product O, O-diisopropyl-S-p-tolyl thiophosphate, and separating yield is 86%.
Example 28: preparation of O, O-di-n-butyl-S-p-tolylthiophosphate (formula (23))
In a 15mL reaction tube equipped with a magnetic stirrer, p-methylthiophenol (1mmol), trichloroisocyanuric acid (0.35mmol) and 2mL acetonitrile were added, and the reaction was stirred at room temperature for 10min, then tri-n-butyl phosphite (1.2mmol) was added, and the stirring was continued at room temperature for 10 min. Filtering, evaporating the filtrate under reduced pressure to remove the solvent, and performing column chromatography separation, wherein the volume ratio of petroleum ether/ethyl acetate is 20: 1 as eluent, collecting eluent containing target compound, evaporating solvent to obtain product O, O-di-n-butyl-S-p-tolyl thiophosphate with separation yield of 86%.

Claims (5)

1.一种硫代磷酸酯类化合物的合成方法，其特征在于：以硫醇为反应底物，三氯异氰尿酸为促进剂，反应底物和促进剂在有机溶剂中，于常温常压条件下反应10～20min，然后加入亚磷酸三酯，继续反应10～20min，反应结束后经分离处理得到所述的硫代磷酸酯类化合物；1. a synthetic method of phosphorothioate compound, it is characterized in that: take mercaptan as reaction substrate, trichloroisocyanuric acid is accelerator, reaction substrate and accelerator are in organic solvent, in normal temperature and normal pressure The reaction is carried out under the conditions for 10-20 min, then the phosphite triester is added, and the reaction is continued for 10-20 min. After the reaction is completed, the phosphorothioate compound is obtained by separation and treatment; 所述亚磷酸三酯化合物的结构式如式(II)所示，硫醇化合物的结构如式(III)所示，得到的硫代磷酸酯类化合物的结构式如式(I)所示；The structural formula of the phosphorous acid triester compound is shown in formula (II), the structure of the thiol compound is shown in formula (III), and the structural formula of the obtained phosphorothioate compound is shown in formula (I);
Figure FDA0002319133910000011
Figure FDA0002319133910000011
 式(I)或式(II)中，R1为C1～C8烷基；式(I)或式(III)中，R2为C1～C12烷基、苄基、取代的苄基、苯基、取代的苯基、杂芳香基、取代的杂芳香基、萘基或取代的萘基，所述的杂芳香基可以是环内含N、O、S等杂原子的芳香基，所述的取代的苄基、取代的苯基、取代的杂芳香基和取代的萘基是指苯环、杂芳香环或萘环上的氢被一个或多个取代基取代，所述的取代基各自独立选自下列之一：卤素、C1～C4的烷基、C1-C4的烷氧基、氨基和羟基。In formula (I) or formula (II), R 1 is C1-C8 alkyl; in formula (I) or formula (III), R 2 is C1-C12 alkyl, benzyl, substituted benzyl, phenyl , substituted phenyl, heteroaryl, substituted heteroaryl, naphthyl or substituted naphthyl, the heteroaryl group can be an aromatic group containing heteroatoms such as N, O, S, etc. Substituted benzyl, substituted phenyl, substituted heteroaryl and substituted naphthyl means that the hydrogen on the benzene ring, heteroaromatic ring or naphthalene ring is substituted by one or more substituents, each of which is independent One of the following: halogen, C1-C4 alkyl, C1-C4 alkoxy, amino and hydroxy. 2.如权利要求1所述的方法，其特征在于：优选R1为甲基、乙基、异丙基或正丁基；优选R2为环己基、2-甲基丁基、十二烷基、苄基、卤代苯基、烷基取代苯基、烷氧基取代苯基、氨基取代苯基、萘基或噻吩基。2. The method of claim 1, wherein: preferably R 1 is methyl, ethyl, isopropyl or n-butyl; preferably R 2 is cyclohexyl, 2-methylbutyl, dodecane phenyl, benzyl, halophenyl, alkyl substituted phenyl, alkoxy substituted phenyl, amino substituted phenyl, naphthyl or thienyl. 3.如权利要求2所述的方法，其特征在于：所述硫醇类化合物与亚磷酸三酯和三氯异氰尿酸的物质的量比为100：90～250：30～60，优选100：100～200：33～50；所述有机溶剂为二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、甲苯、乙腈，溶剂质量用量为硫醇类化合物的7～30倍。3. The method according to claim 2, characterized in that: the material ratio of the thiol compound to the phosphite triester and trichloroisocyanuric acid is 100:90～250:30～60, preferably 100 : 100-200: 33-50; the organic solvent is dichloromethane, tetrahydrofuran, N,N-dimethylformamide, toluene, acetonitrile, and the quality and dosage of the solvent is 7-30 times that of the thiol compound. 4.如权利要求3所述的方法，其特征在于：所述硫醇类化合物与亚磷酸三酯和三氯异氰尿酸的物质的量比为100：100～200：33～50；所述有机溶剂优选为乙腈或者N,N-二甲基甲酰胺。4. The method according to claim 3, characterized in that: the material ratio of the thiol compound to the phosphite triester and trichloroisocyanuric acid is 100:100-200:33-50; The organic solvent is preferably acetonitrile or N,N-dimethylformamide. 5.如权利要求4所述的方法，其特征在于：所述反应液后处理的方法为：反应结束后，过滤，滤液减压蒸除溶剂，再进行柱层析分离，以石油醚/乙酸乙酯体积比20：1的混合液为洗脱剂，收集含目标化合物的洗脱液，蒸除溶剂即得产物硫代磷酸酯类化合物。5. method as claimed in claim 4 is characterized in that: the method for described reaction solution post-processing is: after reaction finishes, filter, filtrate decompression evaporates solvent, then carry out column chromatography separation, with petroleum ether/acetic acid The mixed solution with a volume ratio of ethyl esters of 20:1 was used as the eluent, the eluent containing the target compound was collected, and the solvent was evaporated to obtain the product phosphorothioate compound.
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