阅读说明：本技术 一种1,3-噁嗪类氟化物的合成方法 (Synthetic method of 1, 3-oxazine fluoride ) 是由 牟学清 陈永正 龙艳 于 2020-06-29 设计创作，主要内容包括：一种1,3-噁嗪类氟化物的合成方法,包括以下步骤：1)酰亚胺高烯丙酯和氟化剂依次加入到有机溶剂中,2)加热至适当温度下得到氟代1,3-噁嗪类化合物。本发明使用了酰亚胺高烯丙酯和氟源反应制备1,3-噁嗪类氟化物,原料简单易得,反应操作方便。本发明有良好的实用价值和社会经济效率,对氟取代1,3-噁嗪及下游产品的工艺开发具有重要的借鉴意义。(A synthetic method of 1, 3-oxazine fluoride comprises the following steps: 1) sequentially adding imide high allyl ester and a fluorinating agent into an organic solvent, and 2) heating to a proper temperature to obtain the fluoro 1, 3-oxazine compound. The invention uses imide high allyl ester to react with fluorine source to prepare 1, 3-oxazine fluoride, the raw material is simple and easy to obtain, and the reaction operation is convenient. The invention has good practical value and social and economic efficiency, and has important reference significance for the process development of fluorine substituted 1, 3-oxazine and downstream products.)

1. a synthetic method of 1, 3-oxazine fluoride is characterized in that: it comprises the following steps: 1) sequentially adding imide high allyl ester and a fluorinating agent into an organic solvent, and 2) heating to a proper temperature to obtain a fluoro-1, 3-oxazine compound, wherein the chemical reaction formula is as follows:

in the above formulas:

R¹substituted by one or more of methyl, ethyl, propyl, butyl, phenyl, p-methylphenyl, m-methylphenyl, p-ethylphenyl, m-ethylphenyl, p-chlorophenyl, m-chlorophenyl, p-bromophenyl, m-bromophenyl, p-iodophenyl, m-tert-butylphenyl, p-tert-butylphenyl and naphthyl;

R²is substituted by one or more of hydrogen atom, methyl, ethyl, propyl, butyl, phenyl, p-methylphenyl, m-methylphenyl, p-ethylphenyl, m-ethylphenyl, p-chlorophenyl, m-chlorophenyl, p-bromophenyl, m-bromophenyl, p-iodophenyl, m-tert-butylphenyl, p-tert-butylphenyl and naphthyl.

2. The method for synthesizing 1, 3-oxazine fluoride according to claim 1, wherein: the fluorinating agent is selected from 1-chloromethyl-4-fluoro-1, 4-diazotized bicyclo 2.2.2 octane bis-salts, namely tetrafluoroborate and N-fluorobisbenzenesulfonamide.

3. The method for synthesizing 1, 3-oxazine fluorides according to claim 1 or 2, wherein: the fluorinating agent is selected from 1-chloromethyl-4-fluoro-1, 4-diazotized bicyclo 2.2.2 octane bis-salt, namely tetrafluoroborate.

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

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

6. The method for synthesizing 1, 3-oxazine fluoride according to claim 1, wherein: the heating temperature is 10-120 deg.C, and the maintaining time is 0-30 hr.

7. The method for synthesizing 1, 3-oxazine fluoride according to claim 1 or 6, wherein: the heating is suitably carried out at a temperature of 80 ℃ for a period of 12 hours.

8. The method for synthesizing 1, 3-oxazine fluoride according to claim 1, wherein: the molar weight ratio of the imide high allyl ester to the fluorinating reagent is as follows: 1: 1-1: 10.

9. the method for synthesizing 1, 3-oxazine fluorides according to claim 1 or 8, wherein: the molar weight ratio of imide homoallyl ester to fluorinating agent is preferably 1: 2.

Technical Field

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

Background

1, 3-oxazine is an important chemical skeleton structure, and has wide application in organic synthesis chemistry, pharmaceutical chemistry and material chemistry, for example, BACE-1 (beta-secretase, also known as beta-amyloid precursor protein lyase) inhibitory active molecules contain 1, 3-oxazine structures. In addition, fluorine atoms have larger electronegativity and smaller atomic radius, and the fluorocarbon bond formed with carbon atoms has stronger bond energy and chemical stability. Thus, the introduction of fluorine atoms into biologically active molecules can significantly alter the dipole moment, lipophilicity and chemical stability of the parent molecule and is an important strategy for altering the activity of the parent structure. The traditional synthesis method of fluoro-1, 3-oxazine compounds is to use fluoro-compounds for condensation preparation, and the reaction steps are relatively complicated (J.Med.chem,2013,56, 3980).

Disclosure of Invention

The invention aims to solve the technical problems that the imide high allyl ester is used for reacting with a fluorine source to prepare the 1, 3-oxazine fluoride, the raw materials are simple and easy to obtain, and the reaction operation is convenient.

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

a synthetic method of 1, 3-oxazine fluoride comprises the following steps: 1) sequentially adding imide high allyl ester and a fluorinating agent into an organic solvent, and 2) heating to a proper temperature to obtain a fluoro-1, 3-oxazine compound, wherein the chemical reaction formula is as follows:

in the above formulas:

R¹substituted by one or more of methyl, ethyl, propyl, butyl, phenyl, p-methylphenyl, m-methylphenyl, p-ethylphenyl, m-ethylphenyl, p-chlorophenyl, m-chlorophenyl, p-bromophenyl, m-bromophenyl, p-iodophenyl, m-tert-butylphenyl, p-tert-butylphenyl and naphthyl;

R²is substituted by one or more of hydrogen atom, methyl, ethyl, propyl, butyl, phenyl, p-methylphenyl, m-methylphenyl, p-ethylphenyl, m-ethylphenyl, p-chlorophenyl, m-chlorophenyl, p-bromophenyl, m-bromophenyl, p-iodophenyl, m-tert-butylphenyl, p-tert-butylphenyl and naphthyl.

The fluorinating agent is selected from 1-chloromethyl-4-fluoro-1, 4-diazotized bicyclo 2.2.2 octane bis-salts, namely tetrafluoroborate and N-fluorobisbenzenesulfonamide.

The fluorinating agent is preferably 1-chloromethyl-4-fluoro-1, 4-diazobicyclo 2.2.2 octane bis salt, i.e., tetrafluoroborate.

The organic solvent is selected from N, N-dimethylformamide, N-heptane, 1, 2-dichloroethane, acetonitrile, N-hexane, cyclohexane, N-nonane and tetrahydrofuran.

The organic solvent is preferably acetonitrile.

The heating temperature is 10-120 deg.C, and the maintaining time is 0-30 hr.

The appropriate temperature for the heating is preferably 80 ℃ and the holding time is 12 hours.

The molar weight ratio of the imide high allyl ester to the fluorinating reagent is as follows: 1: 1-1: 10.

the molar weight ratio of imide homoallyl ester to fluorinating agent is preferably 1: 2.

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

1. the invention uses imide high allyl ester to react with fluorine source to prepare 1, 3-oxazine fluoride, the raw material is simple and easy to obtain, and the reaction operation is convenient.

2. The invention has good practical value and social and economic efficiency, and has important reference significance for the process development of fluorine substituted 1, 3-oxazine and downstream products.

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.