阅读说明：本技术 一种磷酸酯类化合物及其制备方法和应用 (Phosphate compound and preparation method and application thereof ) 是由 区颖聪 陈迁 何圳林 黄远婷 余国典 霍延平 于 2020-05-27 设计创作，主要内容包括：本发明公开了一种磷酸酯类化合物及其制备方法和应用,所述的磷酸酯类化合物具有如式(I)所示分子结构：<Image he="347" wi="248" file="DDA0002512074300000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中R<Sub>1</Sub>为苯基、联苯基、氟代苯基、二甲氧基取代苯基、萘基中的一种；R<Sub>2</Sub>为苯基、联苯基、氟代苯基、二甲氧基取代苯基、萘基中的一种；R<Sub>3</Sub>为(3S,5S,8R,9S,10S,13R,14S,17R)-10,13-二甲基-17-((R)-6-甲基庚烷-2-基)十六氢-1H-环戊烷[a]菲-3-基、二甲氧基取代苯基、2,3-二羟丙基、甲基中的一种,其中当R<Sub>3</Sub>为甲基时,R<Sub>1</Sub>和R<Sub>2</Sub>不为苯基。本发明以一定配比的氧化膦化合物与羟基取代有机物为原料,在温和条件下制得磷酸酯类化合物,产率高,可应用于药物合成领域。(The invention discloses a phosphate compound and a preparation method and application thereof, wherein the phosphate compound has a molecular structure shown in a formula (I): wherein R is 1 Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r 2 Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r 3 Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]One of phenanthrene-3-yl, dimethoxy substituted phenyl, 2, 3-dihydroxypropyl and methyl, wherein when R is 3 When it is methyl, R 1 And R 2 Is not phenyl. The invention uses certain proportion of phosphine oxide compound and hydroxyl group to substituteThe organic matter is used as the raw material, the phosphate compound is prepared under mild conditions, the yield is high, and the method can be applied to the field of drug synthesis.)

1. A phosphate ester compound is characterized by having a molecular structure shown as a formula (I):

formula (I) wherein R₁Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r₂Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r₃Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]One of phenanthrene-3-yl, dimethoxy substituted phenyl, 2, 3-dihydroxypropyl and methyl, wherein when R is₃When it is methyl, R₁And R₂Is not phenyl.

2. The phosphate ester based compound according to claim 1, wherein R is₁Is one of fluorophenyl, dimethoxy substituted phenyl and naphthyl; r₂Is one of fluorophenyl, dimethoxy substituted phenyl and naphthyl; r₃Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]Phenanthrene-3-yl, dimethoxy substituted phenyl and 2, 3-dihydroxypropyl.

3. The phosphate ester-based compound according to claim 1 or 2, wherein R is₁Is one of 3-fluorophenyl, 3, 5-dimethoxy substituted phenyl and 1-naphthyl; r₂Is one of 3-fluorophenyl, 3, 5-dimethoxy substituted phenyl and 1-naphthyl; r₃Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]Phenanthrene-3-yl, 3, 4-dimethoxy substituted phenyl and 2, 3-dihydroxypropyl.

4. The phosphate ester compound according to claim 3, having a molecular structure represented by formula (II) to formula (VIII):

5. the method for producing a phosphate ester compound according to any one of claims 1 to 4, comprising the steps of:

dissolving a phosphine oxide compound and a hydroxyl substituted organic matter in a molar ratio of 1: 1-10 in an organic solvent, adding a halide and an alkali, reacting at 10-40 ℃ for 2-5 h, and performing nucleophilic substitution to generate a phosphate compound; the phosphine oxide compoundThe molar ratio of the compound to the halide is 1: 0.1 to 1.5; the molar ratio of phosphine oxide compound to base is 1: 0.5 to 3; the molecular structure of the phosphine oxide compound isThe molecular structure of the hydroxyl-substituted organic matter is R₃-OH, wherein R₁Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r₂Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r₃Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]One of phenanthrene-3-yl, dimethoxy substituted phenyl, 2, 3-dihydroxypropyl and methyl, wherein when R is₃When it is methyl, R₁And R₂Is not phenyl.

6. The production method according to claim 5, wherein the molar ratio of the phosphine oxide compound to the hydroxyl-substituted organic compound is 1:1 to 5.

7. The production method according to claim 5, wherein the molar ratio of the phosphine oxide compound to the halide is 1:1 to 1.5.

8. The production method according to claim 5, wherein the molar ratio of the phosphine oxide compound to the base is 1: 1.5 to 2.

9. The method of claim 5, wherein the halide is one of carbon tetrachloride, chloroform, methylene bromide, methylene iodide, and 1, 2-dibromoethane.

10. The use of the phosphate compound of any one of claims 1 to 4 in the synthesis of a medicament.

Technical Field

The invention relates to the technical field of organic synthesis, and particularly relates to a phosphate compound and a preparation method and application thereof.

Background

The phosphate ester compound has certain medicinal activity, is widely applied in the aspect of medicine, and can also be used for preventing and treating various plant diseases and insect pests in agriculture. Chinese patent CN107522741A proposes a phosphate ester compound, which is synthesized by taking alcohol and H-phosphite ester compounds as raw materials, taking oxygen as an oxidant, taking divalent cobalt salt and N-hydroxyphthalimide as a co-catalyst, and reacting at 80-110 ℃ for 12-18H to obtain the phosphate ester compound, but the preparation method uses toxic cobalt salt as a catalyst, needs to react at high temperature for a long time, has large energy consumption and low yield, is not beneficial to energy conservation and environmental protection, and is not beneficial to industrial production. Therefore, there is a need for a new phosphate compound and a new preparation method thereof, which has milder reaction conditions and higher yield, and does not require toxic salts as a catalyst.

Disclosure of Invention

The invention aims to solve the technical problems of the preparation of the existing phosphate compound that toxic salts are used as catalysts, high-temperature conditions are needed, energy consumption is high, and the yield is low, and provides the phosphate compound.

The invention also aims to provide a preparation method of the phosphate compound.

The invention also aims to provide application of the phosphate compound.

The above purpose of the invention is realized by the following technical scheme:

a phosphate ester compound has a molecular structure shown in a formula (I):wherein R is₁Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r₂Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r₃Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]One of phenanthrene-3-yl, dimethoxy substituted phenyl, 2, 3-dihydroxypropyl and methyl, wherein when R is₃When it is methyl, R₁And R₂Is not phenyl.

Preferably, said R is₁Is one of fluorophenyl, dimethoxy substituted phenyl and naphthyl; r₂Is one of fluorophenyl, dimethoxy substituted phenyl and naphthyl; r₃Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]Phenanthrene-3-yl, dimethoxy substituted phenyl and 2, 3-dihydroxypropyl.

More preferably, said R₁Is one of 3-fluorophenyl, 3, 5-dimethoxy substituted phenyl and 1-naphthyl; r₂Is one of 3-fluorophenyl, 3, 5-dimethoxy substituted phenyl and 1-naphthyl; r₃Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]Phenanthrene-3-yl, 3, 4-dimethoxy substituted phenyl and 2, 3-dihydroxypropyl.

Further preferably, the molecular structure has a molecular structure represented by the formulae (II) to (VIII):

the invention protects the preparation method of the phosphate compound, which comprises the following steps:

in a molar ratio of1: 1-10 phosphine oxide compound and hydroxyl substituted organic matter are dissolved by organic solvent, and then halide and alkali are added to react for 2-5 h at 10-40 ℃, and nucleophilic substitution is carried out to generate phosphate compound; the molar ratio of phosphine oxide compound to halide is 1: 0.1 to 1.5; the molar ratio of phosphine oxide compound to base is 1: 0.5 to 3; the molecular structure of the phosphine oxide compound isThe molecular structure of the hydroxyl-substituted organic matter is R₃-OH, wherein R₁Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r₂Is one of phenyl, biphenyl, fluorophenyl, dimethoxy substituted phenyl and naphthyl; r₃Is (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopentane [ a ]]One of phenanthrene-3-yl, dimethoxy substituted phenyl, 2, 3-dihydroxypropyl and methyl, wherein when R is₃When it is methyl, R₁And R₂Is not phenyl.

The invention designs and synthesizes a phosphate compound, the preparation method takes phosphine oxide compound and hydroxyl substituted organic matter with a certain proportion as raw materials, oxygen as oxidant, trace halide and alkali as co-catalyst, phosphorus free radical with higher activity is generated by reaction, and finally the phosphate compound is prepared by nucleophilic substitution reaction, the reaction condition is mild, and the phosphate compound has wide substrate adaptability and high yield.

Preferably, the molar ratio of the phosphine oxide compound to the hydroxyl-substituted organic substance is 1: 1-5.

Preferably, the molar ratio of phosphine oxide compound to halide is 1:1 to 1.5.

Preferably, the molar ratio of phosphine oxide compound to base is 1: 1.5 to 2.

Preferably, the halide is one of carbon tetrachloride, chloroform, methylene bromide, diiodomethane and 1, 2-dibromoethane.

More preferably, the halide is one of carbon tetrachloride, chloroform and methylene bromide.

Further preferably, the halide is chloroform.

Preferably, the base is one of sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, potassium phosphate, triethylamine, 1, 8-diazabicycloundecen-7-ene.

More preferably, the base is one of sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, 1, 8-diazabicycloundec-7-ene.

Further preferably, the base is 1, 8-diazabicycloundecen-7-ene.

Preferably, the organic solvent is one of N, N-dimethylformamide, acetonitrile, polyethylene glycol 200, polyethylene glycol 40, dichloromethane, water, nitromethane, 1, 2-dichloroethane, tetrahydrofuran, and dimethylsulfoxide.

Preferably, the reaction temperature is 25 ℃ and the reaction time is 3 h.

Preferably, the preparation method further comprises the following steps of post-treatment:

after the reaction is finished, ethyl acetate is added to quench the reaction, saturated sodium sulfate solution is used for washing, an organic phase is separated, a water phase is extracted for 3 times by ethyl acetate, the organic phase is combined, and column chromatography separation is carried out to obtain the phosphate compound.

The invention also protects the application of the phosphate compound in synthesizing medicaments.

Furthermore, the medicine is anti-AIDS medicine, antifungal medicine, anticancer medicine, and pesticide.

The phosphate ester compound has pharmaceutical activity, is mostly used as a skeleton of a drug molecule, not only can be used for treating various diseases such as viruses and cancers, but also can be used for preventing and treating various plant diseases and insect pests in agriculture.

Compared with the prior art, the invention has the beneficial effects that:

the invention synthesizes a new phosphate compound, the preparation method is more efficient and environment-friendly, specifically, phosphine oxide compound and hydroxyl substituted organic matter with a certain proportion are used as raw materials, halide and alkali are used as co-catalysts, the reaction is carried out in the air atmosphere, oxygen is used as an oxidant, the phosphine oxide compound and the hydroxyl substituted organic matter are subjected to nucleophilic substitution reaction at normal pressure and low temperature to generate the phosphate compound, and the selection of substrates is wide; compared with the traditional method, the method has the advantages of mild conditions, less waste discharge, simple reaction equipment, easy industrial production and the like; the method does not need toxic salts as a catalyst, utilizes oxygen in the air for oxidation, has mild reaction conditions and high yield which can reach 100 percent at most, and is environment-friendly; and the method can be applied to the field of drug synthesis, and provides more phosphate compounds as choices for the research of synthetic drugs.

Drawings

FIG. 1 shows the nuclear magnetic H spectrum of 3, 4-dimethoxyphenyldiphenylphosphinate prepared in example 1.

FIG. 2 shows the nuclear magnetic C spectrum of 3, 4-dimethoxyphenyl diphenylphosphinate prepared in example 1.

FIG. 3 is a nuclear magnetic P spectrum of 3, 4-dimethoxyphenyldiphenylphosphinate prepared in example 1.

FIG. 4 is a nuclear magnetic H spectrum of 2, 3-dihydroxypropyldiphenylphosphinate prepared in example 2.

FIG. 5 is a nuclear magnetic C spectrum of 2, 3-dihydroxypropyldiphenylphosphinate prepared in example 2.

FIG. 6 is a nuclear magnetic P spectrum of 2, 3-dihydroxypropyldiphenylphosphinate prepared in example 2.

FIG. 7 is a nuclear magnetic H spectrum of methyl bis [ [1,1' -biphenyl ] -4-yl ] phosphinate obtained in example 3.

FIG. 8 is a nuclear magnetic C spectrum of methyl bis [ [1,1' -biphenyl ] -4-yl ] phosphinate obtained in example 3.

FIG. 9 is a nuclear magnetic P spectrum of methyl bis [ [1,1' -biphenyl ] -4-yl ] phosphinate obtained in example 3.

FIG. 10 is a nuclear magnetic H spectrum of methyl bis (3-fluorophenyl) phosphinate obtained in example 4.

FIG. 11 is a nuclear magnetic C spectrum of methyl bis (3-fluorophenyl) phosphinate obtained in example 4.

FIG. 12 is a nuclear magnetic P spectrum of methyl bis (3-fluorophenyl) phosphinate obtained in example 4.

FIG. 13 is a nuclear magnetic H spectrum of methyl bis (3, 5-dimethoxyphenyl) phosphinate prepared in example 5.

FIG. 14 is a nuclear magnetic C spectrum of methyl bis (3, 5-dimethoxyphenyl) phosphinate prepared in example 5.

FIG. 15 is a nuclear magnetic P spectrum of methyl bis (3, 5-dimethoxyphenyl) phosphinate prepared in example 5.

FIG. 16 is a nuclear magnetic H spectrum of methyl bis (naphthalen-1-yl) phosphinate prepared in example 6.

FIG. 17 is a nuclear magnetic C spectrum of methyl bis (naphthalen-1-yl) phosphinate prepared in example 6.

FIG. 18 is a nuclear magnetic P spectrum of methyl bis (naphthalen-1-yl) phosphinate prepared in example 6.

FIG. 19 is a nuclear magnetic H spectrum of (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthreneanthracene-3-diphenylphosphinate prepared in example 7.

FIG. 20 is a nuclear magnetic C spectrum of (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthreneanthracene-3-diphenylphosphinate prepared in example 7.

FIG. 21 is a nuclear magnetic P spectrum of (3S, 5S, 8R, 9S, 10S, 13R, 14S, 17R) -10, 13-dimethyl-17- ((R) -6-methylheptan-2-yl) hexadecahydro-1H-cyclopenta [ a ] phenanthreneanthracene-3-diphenylphosphinate prepared in example 7.

Detailed Description

The present invention will be further described with reference to specific embodiments, but the present invention is not limited to the examples in any way. The starting reagents employed in the examples of the present invention are, unless otherwise specified, those that are conventionally purchased.