CN106518825B - A kind of chemoselective monomethylation method of coumarin catechol compound - Google Patents

Abstract

The invention provides a chemoselective monomethylation method of coumarin catechol compounds, which belongs to the field of natural medicine synthesis. In the method, catechol coumarin compounds are added into an organic reaction system with a suitable alkali catalyst, A highly selective methylation reaction occurs with a methylating agent to obtain a monomethylated product. The molar ratio of the base to the catechol-like coumarin compound is: 1.0-5.0:1; the methyl The molar ratio of the chemical reagent to the catechol-like coumarin compound is 1.0-2.0:1, the temperature of the reaction system is -20-10°C, and the reaction time is 0.5-3 hours. The method has the characteristics of simple operation, mild conditions, good selectivity, high yield, etc., and can be used for the preparation of monomethylated products of coumarin catechols with different types of substituent groups.

Description

A kind of chemoselective monomethylation method of coumarin catechol compound

technical field

The invention belongs to the field of natural medicine synthesis, and in particular relates to a chemoselective monomethylation method of coumarin catechol compounds.

Background technique

Scopoletin (6-methoxy-7-hydroxycoumarin), dalbene (4-phenyl-6-methoxy-7-hydroxycoumarin) and other catechol coumarin monomethylation products It is an important class of natural products with various pharmacological activities. Scopoletin is one of the main components of Dinggongteng (a traditional Chinese medicine for the treatment of rheumatic venereal diseases) [Bioorgan.Med.Chem.2013,84], which has a wide range of biological activities, such as: anti-inflammatory, lowering uric acid, anti-oxidation, anti-inflammatory Aging and anti-tumor and anti-angiogenesis and other pharmacological activities [Eur.J.Pharmacol.2007,555,218; Lett.Drug Des.Disc.2012,9,397]. Dalbergia is a Chinese herbal plant known for treating vascular diseases and inflammations, the active ingredient of which is Dalbergia [Phytochemistry.1997,46,947]. In addition, 7-hydroxy-8-methoxycoumarin has been reported to inhibit liver fibrosis and prevent liver cirrhosis [J.Nat.Med.2011,65,370]. However, the content of such compounds in plants is low, and the extraction process is complicated and time-consuming [Nat.Prod.Res.2015]. Therefore, it is very important to study the practical and efficient preparation methods of such compounds for their development and application. At present, most of the reported synthetic methods have many defects such as expensive experimental raw materials, advanced experimental equipment, poor selectivity, low yield, and harsh experimental conditions. Therefore, the development of a new and efficient selective alkylation technology to prepare catechol coumarin monomethylated products is of great value to the development and utilization of such compounds.

Contents of the invention

The purpose of the present invention is to address the above-mentioned deficiencies in the prior art and research, that is, for the different bond energies of the hydroxyl groups in different positions of catechol coumarins, select an appropriate base catalysis, and under a certain organic reaction system, react with methylation The reagent undergoes a highly selective monomethylation reaction to prepare a monomethylated product.

The present invention is a chemoselective monomethylation method of coumarin catechol compounds, in which the catechol coumarin compounds are added into an organic reaction system with a suitable alkali catalyst to undergo high selectivity with methylation reagents Methylation reaction, and then obtain the monomethylation product, the molar ratio of the base and the catechol-like coumarin compound is: 1.0～5.0:1; the methylation reagent and the catechol-like aroma The molar ratio of the soy bean compound to: 1.0-2.0:1, the temperature of the reaction system is -20°C-10°C, and the reaction time is 0.5-3 hours;

The structure of the catechol-like coumarin compound is as follows:

Wherein R is any one of H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, aryl, (C ₁ -C ₆ ) substituted alkyl;

The structural formula of the monomethylation product is:

Wherein R is any one of H, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) substituted alkyl, and aryl.

The methylating agent is any one or a combination of methyl iodide, dimethyl sulfate, methyl trifluoromethanesulfonate or methyl methanesulfonate.

The alkali catalyst is any one or combination of sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride.

The organic reaction system is a polar aprotic solvent, one or more selected from N,N-dimethylformamide, tetrahydrofuran, acetonitrile or dimethyl sulfoxide.

The molar ratio of the base to the catechol-like coumarin compound is preferably 2.5:1.

The molar ratio of the methylating agent to the catechol-like coumarin compound is preferably 1.1:1.

The reaction temperature is preferably -5-5°C.

The reaction time is preferably 0.5 to 1 hour.

The feature of the present invention is to use cheap and easy-to-get catechol coumarin (6,7/7,8-dihydroxy coumarin) or C4-substituted catechol coumarin as raw material, aiming at its different According to the difference in the dissociation energy of the phenolic hydroxyl group in the position, select the appropriate base to catalyze, and under a certain organic reaction system, a highly selective methylation reaction occurs with a methylating reagent to prepare a monomethylated product. The preparation method has the characteristics of highly selective monomethylation and also has the characteristics of simple process, convenient operation, cheap and practical. This preparation process not only provides a practical method for the preparation of catechol coumarin monomethylation products, but also provides technical guidance for the selective alkylation of other catechol compounds.

Description of drawings

Figure 1. The route diagram for the preparation of catechol-like coumarin selective monomethylation products;

Figure ^2.1 H-NMR spectrum of 6-methoxy-7-hydroxycoumarin (I-aa);

Figure ^3.1 H-NMR spectrum of 4-methyl-6-methoxy-7-hydroxycoumarin (I-ab);

Figure 4.1 H-NMR spectrum of ⁴ -phenyl-6-methoxy-7-hydroxycoumarin (I-ac);

Figure 5.1 H-NMR spectrum of ⁷ -hydroxy-8-methoxycoumarin (II-aa);

Figure 6.1 H-NMR spectrum of ⁴ -methyl-7-hydroxy-8-methoxycoumarin (II-ab);

Fig. 7. ¹ H-NMR spectrum of 4-phenyl-7-hydroxy-8-methoxycoumarin (II-ac).

Detailed ways

The following examples will further illustrate the present invention, but do not limit the present invention thereby. The route diagram for the preparation of chemoselective monomethylated products of catechol coumarins is shown in Figure 1, see the following examples for details.

Example 1

Preparation of 6-methoxy-7-hydroxycoumarin (Ⅰ-aa)

Weigh 500mg of 6,7-dihydroxycoumarin into a three-necked flask, add 5mL of N,N-dimethylformamide under the protection of argon to dissolve the sample, and add an ice bath to lower the temperature of the reaction system to -20°C. Add 280 mg of sodium hydride, and the reaction solution is viscous. After fully reacting for 15 minutes, add 250 μL of methyl iodide dropwise to maintain the temperature of the reaction system at -15 to 0 ° C. TLC monitors the progress of the reaction (V _CH2Cl2 : V _CH3OH = 50:1 ), after 0.5h, the reaction was completed, and the reaction solution was added dropwise to 40mL of ice water, and hydrochloric acid was added under stirring to adjust the pH. At about 3 o'clock, a precipitate was precipitated, filtered after 30min, and the filter cake was collected, which was the crude product. Recrystallize with 15 mL of ethyl acetate, heat to reflux for 1 h, cool to room temperature, filter, wash the filter cake twice with ethyl acetate, collect the filter cake to obtain 490 mg of white solid, its ¹ H NMR is shown in Figure 2.

¹ H NMR (500MHz, DMSO-d ₆ )δ: 3.82(s, 3H, OCH ₃ ), 6.22(d, J=9.5Hz, 1H, COCH=C), 6.78(s, 1H, Ar-H), 7.22 (s, 1H, Ar-H), 7.91 (d, J=9.5Hz, 1H, C=CH), 10.29 (d, br, 1H, Ar-OH)

Example 2

Preparation of 4-methyl-6-methoxy-7-hydroxycoumarin (Ⅰ-ab)

Weigh 500 mg of 4-methyl-6,7-dihydroxycoumarin into a three-necked flask, add 5 mL of N,N-dimethylformamide to dissolve the sample under the protection of argon, and add an ice-water bath to lower the temperature of the reaction system. When the temperature is below -10°C, add 660 mg of potassium hydroxide, and after fully reacting for 15 minutes, gradually add 210 μL of iodomethane dropwise to maintain the reaction temperature of the system at -10～0°C, TLC Monitor the progress of the reaction. After 2 hours, the reaction ends. Add the reaction solution dropwise to 40 mL of ice water with stirring, and adjust the pH to 3-4 with dilute hydrochloric acid. Precipitation occurs. After 30 minutes, filter and collect the filter cake, which is the crude product. The crude product was recrystallized from ethyl acetate, heated to reflux for 1 h, filtered after cooling, and the filter cake was collected and dried in vacuo to obtain 440 mg of a white solid, whose ¹ H NMR is shown in Figure 3 .

¹ H NMR (400MHz, DMSO-d ₆ )δ: 2.40(s,3H,CH ₃ ),3.85(s,3H,OCH ₃ ),6.13(s,1H,COCH＝C),6.90(s,1H, Ar-H),7.13(s,1H,Ar-H),10.53(s,1H,OH).

Example 3

Preparation of 4-phenyl-6-methoxy-7-hydroxycoumarin (Ⅰ-ac)

Weigh 500 mg of 4-phenyl-6,7-dihydroxycoumarin into a three-necked flask, add 5 mL of N,N-dimethylformamide to dissolve the sample under the protection of argon, and add an ice-water bath to lower the temperature of the reaction system. to 0°C, add 360 mg of sodium hydroxide, and after fully reacting for 15 minutes, gradually add 190 μL of iodomethane dropwise to maintain the reaction temperature of the system at 0-10°C, TLC Monitor the reaction process, the reaction is over after 3 hours, add the reaction solution drop by drop to 40mL ice water with stirring, add dilute hydrochloric acid to adjust the pH to 3-4, there is precipitation, filter after 30 minutes, and collect the filter cake, which is the crude product. The crude product was recrystallized from methanol, heated to reflux for 1 h, filtered after cooling, and the filter cake was collected and dried in vacuo to obtain 380 mg of white solid, whose ¹ H NMR is shown in Figure 4 .

¹ H NMR (500MHz, DMSO-d ₆ ) δ: 3.67(s,3H,OCH ₃ ), 6.17(s,1H,COCH=C), 6.83(s,1H,Ar-H), 6.89(s,1H ,Ar-H),7.58(s,5H,Ar-H),10.47(s,br,1H,Ar-OH).

Example 4

Preparation of 7-Hydroxy-8-methoxycoumarin (Ⅱ-aa)

Weigh 500 mg of 7,8-dihydroxycoumarin into a three-neck flask, add 5 mL of N,N-dimethylformamide under argon protection, add an ice bath to lower the temperature of the reaction system to -20 °C, add potassium hydride After reacting for 15 minutes, add 220 μL of methyl iodide dropwise to maintain the temperature of the reaction system at -20～-5 °C. TLC monitors the reaction process. After 0.5 hours, the reaction is completed. Add the reaction solution dropwise to 100 mL of ice water, add hydrochloric acid Adjust the pH to about 3, extract with ethyl acetate (50mL×3), combine the ethyl acetate phases, wash with saturated brine twice, and distill the organic phase under reduced pressure to remove ethyl acetate, which is the crude product, which is separated by a silica gel column, and the mobile phase V _{petroleum ether} : V _{dichloromethane} : V _acetone = 2:1:0.15, distilled off the solvent under reduced pressure, and dried in vacuo to obtain 370 mg of white solid, whose ¹ H NMR is shown in Figure 5.

¹ H NMR (400MHz, DMSO-d ₆ )δ: 3.82(s, 3H, OCH ₃ ), 6.22(d, J=9.2Hz, 1H, COCH=C), 6.85(d, 1H, J=8.4Hz, Ar-H), 7.26(d, 1H, J=8.4Hz, Ar-H), 7.92(d, J=9.2, 1H, C=CH), 10.38(s, 1H, Ar-OH).

Example 5

Preparation of 4-methyl-7-hydroxy-8-methoxycoumarin (Ⅱ-ab)

Weigh 500 mg of 4-methyl-7,8-dihydroxycoumarin into a three-necked flask, add 5 mL of N,N-dimethylformamide under the protection of argon to dissolve the substrate, add an ice bath, and bring the temperature of the reaction system to When the temperature drops below -10°C, add 380 mg of potassium hydroxide. After 20 minutes of reaction, add 280 μL of iodomethane dropwise to maintain the temperature of the reaction system at about -10 to 0°C. TLC monitors the reaction process. After 0.5 hours, the reaction is completed. The liquid was added dropwise to 100 mL of ice water, hydrochloric acid was added to adjust the pH to about 3, extracted with ethyl acetate (50 mL×3), the ethyl acetate phase was combined, washed twice with saturated brine, and the organic phase was distilled under reduced pressure to remove the ethyl acetate, which was Crude product, the crude product was separated by a silica gel column, the mobile phase was V _{petroleum ether} : V _{dichloromethane} : V _acetone = 2:1:0.15, the solvent was distilled off under reduced pressure, and dried in vacuo to obtain 326 mg of a white solid. Its ¹ H NMR is shown in Figure 6 shown.

¹ H NMR (400MHz, DMSO-d ₆ ) δ: 2.36(s,3H,CH ₃ ), 3.82(s,3H,OCH ₃ ), 6.16(s,1H,COCH=C), 6.88(d,J= 8,1H,Ar-H),7.35(d,J=8,1H,Ar-H),10.33(s,1H,OH).

Example 6

Preparation of 4-phenyl-7-hydroxy-8-methoxycoumarin (Ⅱ-ac)

Weigh 500 mg of 4-phenyl-7,8-dihydroxycoumarin into a three-necked flask, add 5 mL of N,N-dimethylformamide under the protection of argon to dissolve the substrate, add an ice bath, and bring the temperature of the reaction system to Drop to 0°C, add 240 mg of sodium hydroxide, and react for 25 minutes, then add 250 μL of methyl iodide dropwise to maintain the temperature of the reaction system at 0-10°C, monitor the progress of the reaction by TLC. Add hydrochloric acid to adjust the pH to about 3 in 100mL of ice water. After 30 minutes, filter and collect the filter cake, which is the crude product. The crude product was separated on a silica gel column, the mobile phase was V _{petroleum ether} : V _{ethyl acetate} : V _methanol = 4:1:0.1, and the organic solvent was removed by distillation under reduced pressure to obtain 280 mg of a white slightly yellow needle-like solid. Its ¹ H NMR is shown in the figure 7.

¹ H NMR (500MHz, DMSO-d _{6 )} δ: 3.87 (s, 3H, OCH ₃ ), 6.18 (s, 1H, COCH＝C), 6.86 (d, J＝9Hz, 1H, Ar-H), 7.02 (d,J=9Hz,1H,Ar-H),7.50-7.57(m,5H,Ar-H),10.49(s,br,1H,Ar-OH)

Claims (1)

1. a kind of preparation method of Scopolean, which is characterized in that

Esculetin 500mg is weighed in there-necked flask, argon gas protection is lower to be added n,N-Dimethylformamide 5mL dissolution Sample, bath on the rocks make the temperature of reaction system drop to -20 DEG C, sodium hydride 280mg are added, reaction solution is in thick, sufficiently reaction After 15min, 250 μ L of iodomethane is added dropwise, maintains the temperature of reaction system at -15~0 DEG C, TLC monitors reaction process, 0.5h Reaction terminates afterwards, and reaction solution is added drop-wise in 40mL ice water, and it is 3 that salt acid for adjusting pH is added under stirring action, there is Precipitation, It being filtered after 30min, collects filter cake, as crude product is cooled to room temperature after being heated to reflux 1h with 15mL re-crystallizing in ethyl acetate, Filtering, filter cake are washed twice with ethyl acetate, collect filter cake, obtain white solid 490mg.