阅读说明：本技术 一种有机中间体化合物的合成方法 (Synthetic method of organic intermediate compound ) 是由 曹晗 刘雪静 韩迎 别福升 闫鹏 孙蕊蕊 石鹏诚 于 2019-10-24 设计创作，主要内容包括：本发明提供了一种有机中间体化合物的合成方法,该方法包括以式(II)化合物为起始原料合成式(I)化合物：<Image he="205" wi="700" file="DDA0002246248700000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中,R选自被选自氢、卤素、C<Sub>1</Sub>-C<Sub>3</Sub>烷基、C<Sub>1</Sub>-C<Sub>3</Sub>烷氧基和硝基中的一个或多个取代基所取代的苯基。所述方法快速高效,产率稳定,有效的解决了现有合成方法单一的问题。(The invention provides a synthesis method of an organic intermediate compound, which comprises the following steps of synthesizing a compound of a formula (I) by taking a compound of a formula (II) as a starting material: wherein R is selected from phenyl substituted by one or more substituents selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy and nitro. The method is rapid and efficient, has stable yield, and effectively solves the problem of single existing synthetic method.)

1. a method of synthesizing a compound of formula (I) comprising starting with a compound of formula (II);

Wherein R is selected from phenyl substituted by one or more substituents selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy and nitro.

2. The process according to claim 1, wherein the R group is a mono-or di-substituted phenyl group and the substituents are selected from the group consisting of hydrogen, Br, Cl, I, methyl, methoxy and nitro.

3. The method according to claim 1 or 2, wherein R is selected from the group consisting of:

4. The process according to claim 1 or 2, characterized in that the compound of formula (I) is prepared by the following reaction:

Wherein R is as defined in any one of claims 1 to 3.

5. The method according to claim 4, wherein the molar ratio of the compound of formula (II) to the Meldrum's acid is 1:1 to 1: 2; preferably 1:1 to 1: 1.5.

6. The process according to claim 4, wherein the reaction is carried out in a solvent selected from one or more of methanol, ethanol, tetrahydrofuran, dichloromethane, acetonitrile, toluene, acetic acid, 1, 4-dioxane;

Preferably, the solvent contains at least acetic acid;

Preferably, the solvent is acetic acid, acetic acid/toluene or acetic acid/1, 4-dioxane.

7. The process according to claim 4, wherein the reaction temperature is 0 ℃ to 120 ℃ and the reaction time is 0.08 to 8 hours, preferably 80 to 100 ℃ and the reaction time is 0.08 to 6 hours.

8. the process according to claim 4, wherein the reaction is carried out under heating by oil bath heating or microwave heating.

9. The process of claim 8, wherein the oil bath conditions are 100 ℃ for 3 to 6 hours.

10. The method as claimed in claim 8, wherein the microwave heating condition is microwave power of 100-200W, the reaction temperature is 80-100 ℃, and the reaction time is 0.08-0.25 hour.

Technical Field

The invention relates to the field of organic synthesis, in particular to a synthetic method of an organic intermediate compound.

Background

the information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.

2, 2-dimethyl-5- ((arylamino) methylene) -1, 3-dioxane-4, 6-diketone is an important organic intermediate and has wide application in the field of medicines. For example, patent US9550735B2 reports a synthetic route for its use in the synthesis of drug Ivacaftor for the treatment of cystic fibrosis. Patent US20100041024 reports the synthesis of RIP2 kinase inhibitors therewith. The patent US8017779 reports the use thereof for the synthesis of CB-1 inverse agonists. Patent US8232391 reports the use thereof for the synthesis of bicyclic pyrazole antibacterial compounds.

Many documents are reported for synthesizing 2, 2-dimethyl-5- ((phenylamino) methylene) -1, 3-dioxane-4, 6-dione, but the existing method for synthesizing 2, 2-dimethyl-5- ((phenylamino) methylene) -1, 3-dioxane-4, 6-dione is very limited, the existing technology mainly utilizes triethyl orthoformate HC (OEt3), Medit acid and amine to carry out reaction, and the yield is unstable and varies from 20% to 86%, and the reaction route is as follows:

disclosure of Invention

Therefore, the invention aims to provide a method for synthesizing 2, 2-dimethyl-5- ((arylamino) methylene) -1, 3-dioxane-4, 6-diketone intermediate compounds, which is rapid and efficient, is slightly influenced by the change of an amine source, has stable yield and can maintain the yield at 80-95 percent, and effectively solves the problem of single existing synthetic method.

Specifically, the technical scheme of the invention is as follows:

The invention provides a method for synthesizing a compound shown in a formula (I), which comprises the following steps of taking a compound shown in a formula (II) as a starting material;

Wherein R is selected from phenyl substituted by one or more substituents selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy and nitro.

in some embodiments of the invention, the R group is a mono-or di-substituted phenyl, said substituent being selected from the group consisting of hydrogen, Br, Cl, I, methyl, methoxy and nitro.

In still other embodiments, R is selected from the group consisting of:

In the embodiment of the present invention, the yield of the process of the present invention is stable, and is less affected by the change of the amine source, and when R is the above group, the yield can be stable and can be maintained at 75% or more.

In an embodiment of the invention, the compound of formula (I) is prepared by the following reaction:

Wherein the R groups are as defined above.

The method disclosed by the invention is mild and simple in reaction and can be carried out without harsh conditions.

In an embodiment of the invention, the molar relationship between the compound of formula (II) and mucic acid is: 1: 1-1: 2, the influence of different amine sources on yield can be obviously reduced by adjusting the dosage of the Meldrum's acid; in some embodiments, when the molar ratio of the compound of formula (II) to the meldrum's acid is 1:1 to 1:1.5, the effect of the amine source on the yield can be reduced to a greater extent.

In an embodiment of the invention, the reaction is carried out in a solvent selected from one or more of methanol, ethanol, tetrahydrofuran, dichloromethane, acetonitrile, toluene, acetic acid, 1, 4-dioxane. The reaction of the present invention can be carried out in the above-mentioned solvent or a combination of solvents, but the rates of the reactions are different, and in the present invention, when the solvent contains at least acetic acid, satisfactory and stable yields can be obtained, and particularly when the solvent is acetic acid, acetic acid/toluene or acetic acid/1, 4-dioxane, the reaction is easier to carry out and the yield is higher.

In an embodiment of the present invention, the reaction temperature is 0 ℃ to 120 ℃ and the reaction time is 0.08 to 8 hours, preferably 80 to 100 ℃ and the reaction time is 0.08 to 6 hours. The present invention can react at a temperature not higher than 120 ℃, but the reaction rates have large differences, and in some embodiments of the present invention, the reaction is stable and the yield is high when the reaction temperature is 80-100 ℃, and the reaction rate is reduced and the yield is reduced when the reaction temperature is lower than 80 ℃ or higher than 100 ℃.

In an embodiment of the invention, the reaction is carried out under heating, which is oil bath heating or microwave heating.

In some embodiments of the present invention, the oil bath condition is 100 ℃ for 3-6 hours, in the present invention, too low or too high oil bath temperature is not good for stable reaction, for example, when the oil bath temperature is lower than 100 ℃, for example, 80 ℃, the reaction time is greatly prolonged, and the yield is reduced; when the reaction temperature is higher than 100 ℃, for example, 120 ℃, the reaction time is not shortened compared with 100 ℃, but the yield is reduced.

in the embodiment of the invention, the microwave heating condition is that the microwave power is 100-200W, the reaction temperature is 80-100 ℃, and the reaction time is 0.08-0.25 h. The reaction rate is greatly accelerated by a microwave heating mode, compared with oil bath heating, the reaction time is shortened by 12-100 times, and the reaction yield is stable.

The invention also provides application of the compound of the formula (I) synthesized by the synthesis method in synthesizing medicaments for treating cystic fibrosis, such as Ivacaftor or bicyclic pyrazole antibacterial compounds and the like as an intermediate.

The compound of formula (I) is an important organic intermediate, and has wide application in the field of medicine, and compared with the compound of formula (I), the compound of formula (I) can be used for synthesizing a medicament Ivacaftor for treating cystic fibrosis, and the specific preparation process can be seen in US patent 9550735B 2; the compound of formula (I) can be used for the synthesis of RIP2 kinase inhibitors, and specific preparation processes can be found in US patent US 20100041024; the compound of formula (I) can be used for synthesizing CB-1 inverse agonist, and the specific preparation process can be seen in US 8017779; the compound shown in the formula (I) can be used for synthesizing bicyclic pyrazole antibacterial compounds, and the specific preparation process can be seen in an aesthetic patent US 8232391. The disclosures of all patent documents cited herein are hereby incorporated by reference in their entirety. Therefore, the method has great significance for quickly, stably and high-yield obtaining of the compound of the formula (I).

Detailed Description

the invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.

unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or starting materials used in the present invention can be purchased from conventional sources, and unless otherwise specified, the reagents or starting materials used in the present invention can be used in a conventional manner in the art or in accordance with the product specifications. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

the method of the invention is carried out according to the following reaction:

Wherein the solvent is selected from methanol, ethanol, tetrahydrofuran, dichloromethane, acetonitrile, toluene, acetic acid, 1, 4-dioxane; temperature: 0 ℃ to 120 ℃; the reaction time is 0.5-8 hours. The heating mode is selected from oil bath heating or microwave heating.

The R group is selected from the following structures;

Wherein, the compound can be prepared by the method described in Ying H, Lisheng C.an effective and conventional Synthesis of formalmides [ J ]. Tetrahedron Letters,1997,38(31):5423-5426. or other known methods, and the general formula of the compound is as follows:

For example, when R is respectively, the raw materials in the following example examples can be respectively prepared, and the yield is between 80 and 95 percent.