阅读说明：本技术 一种三氟甲基化1,3-噁嗪类化合物的合成方法 (Synthetic method of trifluoromethyl 1, 3-oxazine compound ) 是由 牟学清 陈永正 单静 于 2020-06-29 设计创作，主要内容包括：一种三氟甲基化1,3-噁嗪类化合物的合成方法,包括以下步骤：1)选芳甲酰亚胺高烯丙酯、三氟甲基亚磺酸钠、银盐和铜盐依次加入到有机溶剂中；2)加热至适合温度制得三氟甲基取代的1,3-噁嗪类化合物。本发明以芳甲酰亚胺高烯丙酯为底物,使用廉价的三氟甲基亚磺酸钠为三氟甲基试剂,在铜盐和银盐的作用下,合成三氟甲基取代的1,3-噁嗪类化合物,为该类化合物提供一条经济的合成路线。(A synthetic method of a trifluoromethyl 1, 3-oxazine compound comprises the following steps: 1) sequentially adding aryl formyl imine high allyl ester, sodium trifluoromethyl sulfinate, silver salt and copper salt into an organic solvent; 2) heating to a proper temperature to prepare the trifluoromethyl substituted 1, 3-oxazine compound. The invention takes the arylformimide high allyl ester as a substrate, uses the cheap sodium trifluoromethanesulfonate as a trifluoromethyl reagent, and synthesizes the trifluoromethyl substituted 1, 3-oxazine compound under the action of copper salt and silver salt, thereby providing an economic synthetic route for the compound.)

1. a synthetic method of a trifluoromethyl 1, 3-oxazine compound is characterized in that: it comprises the following steps: 1) sequentially adding aryl formyl imine high allyl ester, sodium trifluoromethyl sulfinate, silver salt and copper salt into an organic solvent; 2) heating to a proper temperature to obtain the trifluoromethyl substituted 1, 3-oxazine compound, wherein the chemical reaction formula is as follows:

in the above formulas:

ar is substituted by one or more of phenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, m-ethylphenyl, p-chlorophenyl, m-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, m-fluorophenyl, p-fluorophenyl, m-tert-butylphenyl, p-tert-butylphenyl, naphthyl, 3, 5-dimethylphenyl, p-methoxyphenyl, m-methoxyphenyl, 3,4, 5-trimethoxyphenyl, m-trifluoromethylphenyl and p-trifluoromethylphenyl.

2. The method for synthesizing the trifluoromethylated 1, 3-oxazine compound according to claim 1, wherein: the copper salt is selected from copper acetylacetonate, copper acetate, copper trifluoromethanesulfonate, copper bromide and copper chloride; the silver salt is selected from silver oxide, silver trifluoromethanesulfonate, silver acetate, silver sulfate, silver bromide, silver chloride, silver iodide and silver nitrate.

3. The method for synthesizing trifluoromethylated 1, 3-oxazines according to claim 1 or 2, wherein: the copper salt is selected from copper acetate; the silver salt is selected from silver acetate.

4. The method for synthesizing the trifluoromethylated 1, 3-oxazine compound according to claim 1, wherein: the organic solvent is selected from dichloroethane, ethyl acetate, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, N-hexane, N-heptane and cyclohexane.

5. The method for synthesizing trifluoromethylated 1, 3-oxazines according to claim 1 or 4, wherein: the organic solvent is selected from acetonitrile.

6. The method for synthesizing the trifluoromethylated 1, 3-oxazine compound according to claim 1, wherein: the heating temperature is 40-100 deg.C, and the maintaining time is 1-60 hr.

7. The method for synthesizing trifluoromethylated 1, 3-oxazines according to claim 1 or 6, wherein: the appropriate temperature for the heating is preferably 80 ℃ and the holding time is 24 hours.

8. The method for synthesizing the trifluoromethylated 1, 3-oxazine compound according to claim 1, wherein: the arylcarboximide high allyl ester: sodium trifluoromethanesulfonate: copper salt: the molar weight ratio of the silver salt is as follows: 1: 1-5: 0.01-0.5: 1 to 3.

9. The method for synthesizing trifluoromethylated 1, 3-oxazines according to claim 1 or 8, wherein: the arylcarboximide high allyl ester: sodium trifluoromethanesulfonate: copper salt: the molar weight ratio of silver salt is preferably 1: 2: 0.2: 2.

Technical Field

The invention relates to a synthetic method of a trifluoromethyl 1, 3-oxazine compound, belonging to the technical field of organic synthesis.

Background

Trifluoromethyl is a relatively special fluorine-containing group, and the structure contains three carbon fluorine (C-F) bonds, so that the trifluoromethyl has the property of containing many fluorine atoms. The special properties of trifluoromethyl are utilized to introduce trifluoromethyl into active medicine molecules, and the dipole moment, acidity, lipophilicity, polarity and chemical stability of parent molecules are changed, so that the metabolic stability and lipid solubility of the parent medicine molecules can be obviously enhanced, and the absorption, distribution, interaction with targets and the like of the medicine in vivo can be influenced. For example, after the methyl groups at C12 and C13 of the tumor inhibitor epothilone D with better market prospect are changed into trifluoromethyl, the stability of drug molecules is enhanced, the action time of the drug is prolonged, and the toxic and side effects are reduced. Given that 1, 3-oxazines are the core backbone structure of some beta-amyloid precursor protein lyase inhibitors, the introduction of trifluoromethyl groups possessing specific properties into such molecules would facilitate the development of novel bioactive molecules. In the existing synthesis method of the compound, expensive 3, 3-dimethyl-1- (trifluoromethyl) -1, 2-benzo iodooxa-lane) is used as a trifluoromethyl source (Org Lett 2019,21,4657), and the economical efficiency of reaction atoms is poor, so that the industrial application of the molecule is limited.

Disclosure of Invention

The invention aims to solve the technical problem of providing an economic synthesis route for the trifluoromethyl substituted 1, 3-oxazine compound by using cheap sodium trifluoromethyl sulfinate as a trifluoromethyl reagent and synthesizing the trifluoromethyl substituted 1, 3-oxazine compound under the action of copper salt and silver salt.

In order to solve the technical problems, the invention adopts the following technical scheme:

a synthetic method of a trifluoromethyl 1, 3-oxazine compound comprises the following steps: 1) sequentially adding aryl formyl imine high allyl ester, sodium trifluoromethyl sulfinate, silver salt and copper salt into an organic solvent;

2) heating to a proper temperature to obtain the trifluoromethyl substituted 1, 3-oxazine compound, wherein the chemical reaction formula is as follows:

in the above formulas:

ar is substituted by one or more of phenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, m-ethylphenyl, p-chlorophenyl, m-chlorophenyl, o-bromophenyl, m-bromophenyl, p-bromophenyl, m-fluorophenyl, p-fluorophenyl, m-tert-butylphenyl, p-tert-butylphenyl, naphthyl, 3, 5-dimethylphenyl, p-methoxyphenyl, m-methoxyphenyl, 3,4, 5-trimethoxyphenyl, m-trifluoromethylphenyl and p-trifluoromethylphenyl.

The copper salt is selected from copper acetylacetonate, copper acetate, copper trifluoromethanesulfonate, copper bromide and copper chloride.

The copper salt is preferably copper acetate.

The silver salt is selected from silver oxide, silver trifluoromethanesulfonate, silver acetate, silver sulfate, silver bromide, silver chloride, silver iodide and silver nitrate.

The silver salt is preferably silver acetate.

The organic solvent is selected from dichloroethane, ethyl acetate, 1, 2-dichloroethane, tetrahydrofuran, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, N-hexane, N-heptane and cyclohexane. The organic solvent is preferably acetonitrile.

The heating temperature is 40-100 deg.C, and the maintaining time is 1-60 hr.

The appropriate temperature for the heating is preferably 80 ℃ and the holding time is 24 hours.

The arylcarboximide high allyl ester: sodium trifluoromethanesulfonate: copper salt: the molar weight ratio of the silver salt is as follows: 1: 1-5: 0.01-0.5: 1 to 3.

The arylcarboximide high allyl ester: sodium trifluoromethanesulfonate: copper salt: the molar weight ratio of silver salt is preferably 1: 2: 0.2: 2.

the beneficial effect of adopting above-mentioned technical scheme is:

the invention takes the arylformimide high allyl ester as a substrate, uses the cheap sodium trifluoromethanesulfonate as a trifluoromethyl reagent, and synthesizes the trifluoromethyl substituted 1, 3-oxazine compound under the action of copper salt and silver salt, thereby providing an economic synthetic route for the compound.

Detailed Description

The present invention will be further described with reference to specific examples, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples, and that all the technologies implemented based on the above-described contents of the present invention belong to the scope of the present invention.