阅读说明：本技术 一种合成苯并吡喃3醇衍生物类化合物的方法 (Method for synthesizing benzopyran 3 alcohol derivative compound ) 是由 娄绍杰 郝宏艳 毛羊杰 许丹倩 徐振元 于 2019-12-03 设计创作，主要内容包括：本发明涉及化合物制备技术领域,公开了一种合成苯并吡喃3醇衍生物类化合物的方法,包括如下步骤：(1)将化合物I与钯催化剂、氧化剂和溶剂混合,在70~130℃下密闭搅拌反应1~24h；对步骤(1)所得混合液进行后处理得到中间产物II；将中间产物II与催化剂、乙腈和水混合,用氮气置换空气后,在85~95℃下密闭搅拌反应1~24h；对步骤(3)所得混合液进行后处理得到终产物III苯并吡喃3醇衍生物类化合物。本发明通过交叉脱氢偶联直接进行分子内C(sp<Sup>3</Sup>)-H芳基化,合成苯并吡喃3醇衍生物类化合物,路线简单,收率较高,普适性好,反应条件温和,选择性高。(The invention relates to the technical field of compound preparation, and discloses a method for synthesizing benzopyran 3 alcohol derivative compounds, which comprises the following steps: (1) mixing the compound I with a palladium catalyst, an oxidant and a solvent, and carrying out closed stirring reaction for 1-24 h at the temperature of 70-130 ℃; carrying out post-treatment on the mixed solution obtained in the step (1) to obtain an intermediate product II; mixing the intermediate product II with a catalyst, acetonitrile and water, replacing air with nitrogen, and carrying out closed stirring reaction at 85-95 ℃ for 1-24 h; and (4) carrying out post-treatment on the mixed solution obtained in the step (3) to obtain a final product III benzopyran 3 alcohol derivative compound. The invention directly carries out intramolecular C (sp) through cross dehydrogenation coupling 3 ) the-H arylation is carried out to synthesize the benzopyran 3 alcohol derivative compound, the route is simple, the yield is high, the universality is good, the reaction condition is mild, and the selectivity is high.)

1. A method for synthesizing benzopyran-3-alcohol derivative compounds is characterized by comprising the following steps:

(1) mixing a compound I with a palladium catalyst, an oxidant and a solvent, and carrying out closed stirring reaction for 1-24 hours at the temperature of 70-130 ℃, wherein the structural formula of the compound I is as follows:

wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹Respectively selecting one from hydrogen, C1-C6 straight chain or branched chain aliphatic alkyl, C1-C6 alkoxy, halogen and C6-C10 aryl, wherein the halogen is selected from one from F, Cl, Br and I;

(2) carrying out post-treatment on the mixed solution obtained in the step (1) to obtain an intermediate product II;

(3) mixing the intermediate product II with a catalyst, acetonitrile and water, replacing air with nitrogen, and carrying out closed stirring reaction at 70-130 ℃ for 1-24 h;

(4) and (4) carrying out post-treatment on the mixed solution obtained in the step (3) to obtain a final product III benzopyran-3-alcohol derivative compound.

2. The method as claimed in claim 1, wherein R in the compound I is¹Is one of hydrogen and C1-C6 straight chain or branched chain fatty alkyl; r²Is one of hydrogen, halogen, straight chain or branched chain aliphatic alkyl of C1-C6, aryl of C6-C10 and aromatic acyl; r³Is one of hydrogen, C1-C6 straight chain or branched chain aliphatic alkyl, C1-C6 alkoxy and halogen; r⁴Is one of hydrogen and halogen; r⁵Is one of hydrogen, halogen, C1-C6 straight chain or branched chain aliphatic alkyl or R⁵And R⁶To form a pyridine ring; r⁶Is one of hydrogen, halogen and trifluoromethyl or R⁵And R⁶To form a pyridine ring; r⁷Is one of hydrogen, C1-C6 straight chain or branched chain aliphatic alkyl, halogen and trifluoromethyl; r⁸Is one of hydrogen, halogen and trifluoromethyl; r⁹Is one of hydrogen, halogen and C1-C6 straight chain or branched chain fatty alkyl.

3. A process for the synthesis of benzopyran-3-ol derivatives, as claimed in claim 1 or 2, wherein R is¹Is hydrogen or methyl; r²Is one of hydrogen, methyl, fluorine, chlorine, bromine, phenyl and benzoyl; r³Is one of hydrogen, methyl and chlorine; r⁴Is hydrogen or bromine; r⁵Is one of hydrogen, fluorine and methyl or R⁵And R⁶To form a pyridine ring; r⁶Is one of hydrogen, fluorine and trifluoromethyl or R⁵And R⁶To form a pyridine ring; r⁷Is one of hydrogen, methyl, fluorine and trifluoromethyl; r⁸Is one of hydrogen, fluorine and trifluoromethyl; r⁹Is one of hydrogen, fluorine and methyl.

4. The method according to claim 1, wherein the palladium catalyst in step (1) is selected from one of palladium acetate, palladium dichloride, palladium trifluoroacetate, bis (benzonitrile) palladium dichloride, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium and bis (triphenylphosphine) palladium dichloride, and the ratio of the amount of the compound I to the amount of the palladium catalyst material is 1: (0.05-0.15).

5. The method for synthesizing benzopyran-3-ol derivatives according to claim 1, wherein in the step (1), the oxidizing agent is selected from one of iodobenzene acetate, potassium persulfate, tert-butyl hydroperoxide, N-fluoro-bis-benzenesulfonamide and Selectfluor, and the ratio of the amount of the compound I to the oxidizing agent is 1: (1.0-3.0).

6. The method for synthesizing benzopyran-3-ol derivative compounds according to claim 1, wherein the solvent in step (1) is one selected from toluene, trifluorotoluene, chlorobenzene, xylene, nitromethane, acetic acid, ethyl acetate, 1, 2-dichloroethane, acetonitrile, chloroform, tetrahydrofuran, 1, 4-dioxane, N-hexane, and N, N-dimethylformamide, and the volume of the solvent is 0.5-5 m L/mmol based on the substance of compound I.

7. The method for synthesizing benzopyran-3-ol derivatives according to claim 1, wherein the post-treatment method in the step (2) comprises the following steps: adding ethyl acetate into the mixed solution obtained in the step (1) for dilution, filtering, distilling the filtrate under reduced pressure to remove the solvent, separating the residue by column chromatography, taking the mixed solution of petroleum ether and ethyl acetate as an eluent, collecting the eluent containing the product, and distilling the eluent to remove the solvent to obtain an intermediate product II.

8. The method for synthesizing benzopyran-3-ol derivatives according to claim 1, wherein the catalyst in step (3) is molybdenum hexacarbonyl, and the mass ratio of the intermediate product II to the catalyst is 1 (1.0-5.0).

9. The method for synthesizing benzopyran-3-ol derivatives as claimed in claim 1 or 8, wherein the volume of acetonitrile used in step (3) is 1-5 m L/mmol and the volume of water used in step (3) is 1-10 rops/mmol based on the substance of intermediate product II.

10. The method for synthesizing benzopyran-3-ol derivatives as claimed in claim 1, wherein the post-treatment method in step (4) is: and (3) distilling the mixed solution obtained in the step (3) under reduced pressure to remove the solvent, adding water, extracting with ethyl acetate, drying the organic phase, distilling under reduced pressure to remove the solvent, separating the residue by column chromatography, collecting the eluent containing the product by taking the mixed solution of petroleum ether and ethyl acetate as an eluent, and evaporating the eluent to remove the solvent to obtain the final product III.

Technical Field

The invention relates to the technical field of compound preparation, in particular to a method for synthesizing benzopyran-3-alcohol derivative compounds.

Background

C(sp³)-C(sp²) The bond is a basic chemical bond in organic chemistry, constructionC(sp³)-C(sp²) Have long been receiving extensive attention and research. Construction of C (sp) in the prior art³)-C(sp²) The key method mainly comprises the following steps: 1. Friedel-Crafts reaction, but the method has relatively poor regioselectivity and narrow substrate application range, so the method limits the application of the method in the later functionalization of aromatic hydrocarbon (especially mono-substituted aromatic hydrocarbon) to some extent. 2. Construction of C (sp) by transition metal catalyzed cross-coupling reaction³)-C(sp²) Keys, for example: although these methods are widely used, they usually require two cross-coupled moieties for pre-functionalization, by Suzuki-Miyama coupling, Negishi arylation, Kumada reaction and Hiyama reaction, among others. And direct cross-coupling reaction to construct C (sp)³)-C(sp²) The manner of bonding has not been extensively studied at present.

Benzopyran-3-ol derivatives have various biological activities such as analgesic, anticancer, antibacterial, antioxidant, etc., and are widely present in various bioactive compounds, for example: antioxidant and antibacterial catechin (Epicatechin) and chromancalin (Cromakalim) for treating hypertension, angina pectoris and asthma contain benzopyran-3-ol derivative skeleton structure. The methods for synthesizing benzopyran-3-ol derivatives reported in the prior art, such as CN105219815A and CN 1214675 disclosed in Chinese patent literature, generally adopt the above-mentioned method for constructing C (sp) in benzopyran-3-ol derivatives³)-C(sp²) The bond method has the defects of difficult obtainment of reaction raw materials, low yield of key intermediates, harsh reaction conditions and the like. Therefore, a method for synthesizing benzopyran-3-alcohol derivative compounds with simple route, higher yield and good universality is needed to be found.

Disclosure of Invention

The invention aims to solve the problems of difficult obtainment of reaction raw materials, low yield of key intermediates and harsh reaction conditions of the synthetic method of the benzopyran-3-alcohol derivative compounds in the prior art, and provides a method for synthesizing the benzopyran-3-alcohol derivative compounds by directly carrying out cross dehydrogenation couplingIntramolecular C (sp)³) The benzopyran-3-alcohol derivative compound is synthesized by-H arylation, and has the advantages of simple route, higher yield, good universality, mild reaction conditions and high selectivity.

In order to achieve the purpose, the invention adopts the following technical scheme:

a method for synthesizing benzopyran-3-alcohol derivative compounds comprises the following steps:

(1) mixing a compound I with a palladium catalyst, an oxidant and a solvent, and carrying out closed stirring reaction for 1-24 hours at the temperature of 70-130 ℃, wherein the structural formula of the compound I is as follows:

wherein R is¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹Respectively selecting one from hydrogen, C1-C6 straight chain or branched chain aliphatic alkyl, C1-C6 alkoxy, halogen and C6-C10 aryl, wherein the halogen is selected from one from F, Cl, Br and I;

(2) carrying out post-treatment on the mixed solution obtained in the step (1) to obtain an intermediate product II;

(3) mixing the intermediate product II with a catalyst, acetonitrile and water, replacing air with nitrogen, and carrying out closed stirring reaction at 85-95 ℃ for 1-24 h;

(4) and (4) carrying out post-treatment on the mixed solution obtained in the step (3) to obtain a final product III benzopyran-3-alcohol derivative compound.

The invention firstly adopts the mode of cross dehydrogenation coupling to directly carry out intramolecular C (sp) on the compound I through the steps (1) and (2)³) -H arylation to give intermediate II of formula:

then, the guiding group in the intermediate product II is replaced by hydrogen through the steps (3) and (4), and finally, a final product III with the structural formula as follows is obtained:

the structural formula shows that the final product III is the benzopyran-3-alcohol derivative compound. The benzopyran-3-alcohol derivative compound is prepared by directly arylating in a cross dehydrogenation coupling mode, and the method has the advantages of simple route, higher yield, good universality, mild reaction conditions and high selectivity.

Preferably, R in the compound I¹Is one of hydrogen and C1-C6 straight chain or branched chain fatty alkyl; r²Is one of hydrogen, halogen, straight chain or branched chain aliphatic alkyl of C1-C6, aryl of C6-C10 and aromatic acyl; r³Is one of hydrogen, C1-C6 straight chain or branched chain aliphatic alkyl, C1-C6 alkoxy and halogen; r⁴Is one of hydrogen and halogen; r⁵Is one of hydrogen, halogen, C1-C6 straight chain or branched chain aliphatic alkyl or R⁵And R⁶To form a pyridine ring; r⁶Is one of hydrogen, halogen and trifluoromethyl or R⁵And R⁶To form a pyridine ring; r⁷Is one of hydrogen, C1-C6 straight chain or branched chain aliphatic alkyl, halogen and trifluoromethyl; r⁸Is one of hydrogen, halogen and trifluoromethyl; r⁹Is one of hydrogen, halogen and C1-C6 straight chain or branched chain fatty alkyl.

Most preferably, R¹Is hydrogen or methyl; r²Is one of hydrogen, methyl, fluorine, chlorine, bromine, phenyl and benzoyl; r³Is one of hydrogen, methyl and chlorine; r⁴Is hydrogen or bromine; r⁵Is one of hydrogen, fluorine and methyl or R⁵And R⁶To form a pyridine ring; r⁶Is one of hydrogen, fluorine and trifluoromethyl or R⁵And R⁶To form a pyridine ring; r⁷Is one of hydrogen, methyl, fluorine and trifluoromethyl; r⁸Is one of hydrogen, fluorine and trifluoromethyl; r⁹Is one of hydrogen, fluorine and methyl.

Preferably, in step (1), the palladium catalyst is selected from one of palladium acetate, palladium dichloride, palladium trifluoroacetate, bis (benzonitrile) palladium dichloride, tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium and bis (triphenylphosphine) palladium dichloride, and the ratio of the amount of compound I to the amount of palladium catalyst material is 1: (0.05-0.15).

More preferably, in the step (1), the palladium catalyst is palladium acetate, and the ratio of the amount of the compound I to the amount of the palladium catalyst substance is 1 (0.05-0.1).

Preferably, in the step (1), the oxidizing agent is selected from one of iodobenzene acetate, potassium persulfate, tert-butyl hydroperoxide, N-fluoro-bis-benzenesulfonamide and Selectfluor, and the ratio of the amount of the compound I to the oxidizing agent is 1: (1.0-3.0).

More preferably, the oxidizing agent in step (1) is N-fluorobisbenzenesulfonamide, and the ratio of the amount of the substance of compound I to the oxidizing agent is 1: (1.0-2.0).

Preferably, in the step (1), the solvent is one selected from toluene, trifluorotoluene, chlorobenzene, xylene, nitromethane, acetic acid, ethyl acetate, 1, 2-dichloroethane, acetonitrile, chloroform, tetrahydrofuran, 1, 4-dioxane, N-hexane and N, N-dimethylformamide, and the volume of the solvent is 0.5-5 m L/mmol based on the substance of the compound I.

More preferably, the solvent in the step (1) is 1, 2-dichloroethane, and the volume usage amount of the solvent is 0.75-2 m L/mmol.

Preferably, the reaction temperature in the step (1) is 75 to 90 ℃.

Preferably, the reaction time in the step (1) is 4-24 h, and more preferably 6-24 h.

Preferably, the post-treatment method in step (2) is: adding ethyl acetate into the mixed solution obtained in the step (1) for dilution, filtering, distilling the filtrate under reduced pressure to remove the solvent, separating the residue by column chromatography, taking the mixed solution of petroleum ether and ethyl acetate as an eluent, collecting the eluent containing the product, and distilling the eluent to remove the solvent to obtain an intermediate product II.

Preferably, the catalyst in the step (3) is molybdenum hexacarbonyl, and the mass ratio of the intermediate product II to the catalyst is 1 (1.0-5.0).

More preferably, the ratio of the amount of the intermediate product II to the amount of the catalyst substance in the step (3) is 1 (1.0 to 2.0).

Preferably, in the step (3), the volume usage of acetonitrile is 1-5 m L/mmol and the volume usage of water is 1-10 rops/mmol based on the mass of the intermediate product II.

More preferably, in the step (3), the volume usage of acetonitrile is 1-3 m L/mmol and the volume usage of water is 2-8 rops/mmol based on the mass of the intermediate product II.

Preferably, the reaction time in the step (3) is 12-24 h.

Preferably, the post-treatment method in step (4) is: and (3) distilling the mixed solution obtained in the step (3) under reduced pressure to remove the solvent, adding water, extracting with ethyl acetate, drying the organic phase, distilling under reduced pressure to remove the solvent, separating the residue by column chromatography, collecting the eluent containing the product by taking the mixed solution of petroleum ether and ethyl acetate as an eluent, and evaporating the eluent to remove the solvent to obtain the final product III.

Therefore, the beneficial effects of the invention are as follows: the benzopyran-3-alcohol derivative compound is prepared by adopting the following technical route, and has the advantages of simple route, higher yield, good universality, mild reaction conditions and high selectivity:

drawings

FIG. 1 is a drawing of intermediate II of example 1¹HNMR spectrogram;

FIG. 2 is a drawing of intermediate II of example 1¹³CNMR spectrogram;

FIG. 3 is the intermediate II of example 2¹HNMR spectrogram;

FIG. 4 is the intermediate II of example 2¹³CNMR spectrogram;

FIG. 5 is a drawing of intermediate II of example 3¹HNMR spectrogram;

FIG. 6 is intermediate II of example 3¹³CNMR spectrogram;

FIG. 7 is the intermediate II of example 4¹HNMR spectrogram;

FIG. 8 is the intermediate product II of example 4¹³CNMR spectrogram;

FIG. 9 is a drawing of intermediate II of example 5¹HNMR spectrogram;

FIG. 10 is the intermediate product II of example 5¹³CNMR spectrogram;

FIG. 11 is intermediate II of example 6¹HNMR spectrogram;

FIG. 12 is intermediate II of example 6¹³CNMR spectrogram;

FIG. 13 is intermediate II of example 7¹HNMR spectrogram;

FIG. 14 is a drawing of intermediate II of example 7¹³CNMR spectrogram;

FIG. 15 is of intermediate II of example 8¹HNMR spectrogram;

FIG. 16 is the intermediate product II of example 8¹³CNMR spectrogram;

FIG. 17 is intermediate II of example 9¹HNMR spectrogram;

FIG. 18 is intermediate II of example 9¹³CNMR spectrogram.

Detailed Description

The invention is further described with reference to the following detailed description and accompanying drawings. The structural formula of the compound I in each embodiment of the invention is as follows:

wherein R is⁵、R⁷、R⁹Is hydrogen, R⁶And R⁸Is trifluoromethyl to form a guide group DG of the formula^Al：

That is, the structural formula of compound I in the examples of the present invention is: