CN1911949A - Method of chemical synthesizing hongjingtian glycoside - Google Patents

Abstract

The invention discloses a method for chemically synthesizing salidroside. The steps are: in the presence of molecular sieves, Lewis acid catalyzes the glycosylation reaction of pentaacetyl-β-D-glucose and p-hydroxyphenylethanol in an organic solvent to generate tetraacetyl Base salidroside, and then tetraacetyl salidroside deacetylated in NaOCH ₃ methanol solution to obtain salidroside. Compared with the traditional synthesis, the method of the invention has convenient sources of raw materials, short reaction steps, cheap and easy-to-obtain catalysts for the glycosidation reaction, and significantly reduces the preparation cost. The method of the invention is suitable for industrial production of salidroside.

Description

A method for chemically synthesizing salidroside

technical field

The invention belongs to the field of pharmaceutical chemical industry, in particular to a method for chemically synthesizing salidroside.

Background technique

Rhodiola belongs to the sedum family. There are nearly a hundred species in the world, mostly distributed in the alpine regions of the northern hemisphere, and most of them grow at an altitude of 3500-5000 meters. In the place where Rhodiola is produced, people use it as a tonic and strong medicine, and it is also used to eliminate fatigue and resist cold; it has anti-aging, anti-fatigue, anti-hypoxia, anti-adverse stimulation, two-way regulation of the body, and inhibition of blood sugar rise. In 1976, the Soviet Union used rhodiola as an "adaptogen" drug, which was widely used in anti-fatigue, anti-aging, and improving mental and physical functions. In my country, Rhodiola rosea plants have been used to successfully develop injection preparations, oral liquid preparations and a variety of health care products, and their demand is constantly expanding.

Rhodiola is a plant in the alpine region. Due to the fragile ecology of the plateau and poor regeneration ability, the natural regeneration is very slow. Generally, it takes 7-8 years to grow naturally before it can be used. However, the amount of medicinal resources consumed in production is quite large, and the reserves of wild resources are getting worse. less and less, there may soon be a problem of resource depletion. Salidroside is one of the main active ingredients of Rhodiola rosea. The extraction of natural salidroside not only requires a complex extraction process, but the general extraction rate can only reach 0.4-0.8% of the dry weight of the plant. Therefore, it is very important to develop alternative resources. The use of biotechnology and chemical synthesis methods is an important means of developing alternative resources.

The existing salidroside synthesis methods include biosynthesis and chemical synthesis. It is generally believed that biosynthesis has the characteristics of mild reaction conditions, high stereoselectivity, simple reaction process, and less environmental pollution, but it also has the problems of long reaction cycle and low titer. The biosynthesis method of salidroside is generally to directly use glucose as a sugar donor to carry out glycosylation reaction with p-hydroxyphenylethanol. The reported methods mainly include: using the glycosylation method of Rhodiola sachalinesis suspension culture solution to synthesize salidroside (Xu Jianfeng; Su Zhiguo; Feng Pusun Natural Product Research and Development 1998, 10 (2), 8-14; Xu Jianfeng; Su Zhiguo Botanical Journal, 1998, 40, 1129-1135; Wu, Shuangxiu; Zu, Yuangang; Wu, Madeline.J.Biotech.2003, 106, 33-43); or use the strain Absidia sp.MS2 to ferment the crude enzyme liquid Catalyze the glycosylation reaction of glucose and p-hydroxyphenylethanol to generate salidroside (Jia Yanping; Guo Hongyan; Zhang Chunzhi; Jin Fengxie; Journal of Dalian Institute of Light Industry, 2004, 23, 97-99). Recently, Chinese patent CN 1560268A disclosed a method of using apple seed powder as glucosidase to directly synthesize salidroside by glycosidation with glucose and p-hydroxyphenylethanol. Although the conversion rate of glucose in this method can reach 15.5%, p-hydroxyphenylethanol can be recycled, but there are problems that the single utilization rate of p-hydroxyphenylethanol is too low (1.6%) and the reaction cycle is long (5 days). Its potency is still low, and the cost of industrialized production is still high. The method (Wang Mengliang, Zhang Fang, Liu Diansheng Chinese Journal of Catalysis 2006,27 (3), 233-236) that utilizes microorganism to carry out glucosidation to synthesize salidroside has been reported again recently, but the conversion rate of p-hydroxyphenethyl alcohol only reaches 8.2%.

There have been many studies on the chemical synthesis of salidroside. As early as the end of the 1960s, Russian chemists used tetraacetyl-D-glucose-1-bromosugar and p-hydroxyphenylethyl alcohol to carry out glycosylation reaction under the catalysis of Lewis acid silver carbonate, and then deprotected with sodium methoxide to generate The method of salidroside [Troshchenko, A.T.; Juodvirsis, A.Khim.Prir.Soe.(1969), 5(4), 256-60.Synthesis of glycosides of 2-(p-hydroxyphenyl)ethanol], but the The synthesis yield of the method is low. Some methods reported later are similar to this condensation method, using tetraacetyl-D-glucose-1-bromosugar as the sugar donor, and the phenolic hydroxyl group in the glycoside p-hydroxyphenethyl alcohol needs to be protected in advance. For example, the p-hydroxyphenylethanol of phenolic hydroxyl benzylation is obtained by the reaction of p-hydroxyphenethyl ester (Li Guoqing, Li Zhan, Chinese Journal of Medicinal Chemistry, 1996, 6 (2), 136-138), or obtained by the reaction of p-bromophenol (Zhang Sanqi ; Shang Gangwei; Li Zhongjun; Wang Anbang; Cai Mengshen; Chinese Journal of Medicinal Chemistry, 1997, 7(4), 256-257), or obtained by the reaction of p-hydroxyphenylacetic acid (Zhang Lianji, Li Xuemei, Tian Guanrong; Journal of Yanbian University, Natural Science Edition , 2002, 28(2), 97-98), or obtained by the reaction of p-aminophenylacetic acid (Ji Shufang; Zhou Yaqing. Journal of Shenyang Pharmaceutical College 1987, 4(3), 192-193).

Tetraacetyl-D-glucose-1-bromosugar in the above method needs to be obtained by bromination of pentaacetyl-β-D-glucose and hydrobromic acid, and expensive precious metal salt silver carbonate is used as a glycosidation catalyst , In addition to the protection of the protective group on the sugar, the glycosidation product also needs to use palladium catalytic hydrogenation to remove the protective group on the phenolic hydroxyl group. Therefore, there are many procedures and the cost of industrialization is relatively high. Recently, Chinese patent CN 1403467A discloses a glycosylation reaction with tetraacetyl-α-D-glucosyl trichloroacetimidate as glycosylation reagent and p-acetoxyphenylethanol under the catalysis of a catalytic amount of Lewis acid. , and then remove the protecting group to synthesize the method of salidroside. This method has a higher yield, however, the raw material tetraacetyl-α-D-glucosyl trichloroacetimide ester in this method needs to be converted from pentaacetyl-β-D-glucose, p-hydroxyphenylethyl alcohol The phenolic hydroxyl group in also needs to be protected in advance.

Contents of the invention

The purpose of the present invention is to provide a method for chemically synthesizing salidroside which is beneficial to reduce the cost and is suitable for industrialization.

The method for chemically synthesizing salidroside of the present invention, its steps are as follows:

1) In the presence of molecular sieves, catalyzed by Lewis acid, glycosylate pentaacetyl-β-D-glucose and p-hydroxyphenylethanol in an organic solvent at a temperature of 10-35°C for 0.5-5.0 hours to generate tetraacetyl The molar concentration of salidroside and p-hydroxyphenylethanol is 0.1-1.0M, the equivalent ratio of pentaacetyl-β-D-glucose and p-hydroxyphenylethanol is 1.0-5.0, and the amount of molecular sieve is pentaacetyl-β-D- 0.5-3.0 times the weight of glucose, the equivalent ratio of Lewis acid and pentaacetyl-β-D-glucose is 0.5-3.0;

2) Add the tetraacetylsalidroside obtained in step 1) into the methanol solution of _NaOCH3 , the molar concentration of tetraacetylsalidroside is 0.05-0.5M, and the molar concentration of _NaOCH3 is 0.1-0.5M, at room temperature The reaction was carried out for at least 12 hours, and the acetyl group was removed to obtain salidroside.

In the glycosidation reaction of the present invention, if the amount of pentaacetyl-β-D-glucose decreases, the yield of glycosidation will decrease, and when the amount increases, the by-products will increase, preferably pentaacetyl-beta-D-glucose and p-hydroxyphenylethanol The equivalent ratio is 1.5-2.5.

If molecular sieves are not used in the glycosylation reaction, the yield of the glycosylation reaction will drop significantly. The molecular sieve used is preferably 4A molecular sieve. Preferably, the amount of molecular sieve used is 1.0-2.0 times the weight of pentaacetyl-β-D-glucose.

The glycosidation reaction in the present invention requires Lewis acid catalysis, and the Lewis used is tin tetrachloride SnCl ₄ or boron trifluoride BF ₃ , preferably SnCl ₄ . The equivalent ratio of Lewis acid to pentaacetyl-β-D-glucose is 0.5-3.0, preferably 1.0-2.0. If the amount is too small, the reaction will slow down and the yield will decrease obviously. If the dosage is too large, the reaction by-product 1-chlorotetraacetyl-β-D-glucose will increase significantly.

The organic solvent used in the present invention can be methylene dichloride or ethylene dichloride, or a mixed solvent of methylene chloride and ether or tetrahydrofuran, or a mixed solvent of ethylene dichloride and ether or tetrahydrofuran. The amount of organic solvent used is such that the molar concentration of p-hydroxyphenethyl alcohol reaches 0.1-1.0M, preferably 0.2-0.4M.

In the present invention, the glycosidation reaction temperature has a great influence on the reaction yield. When the temperature is too low, the reaction will proceed very slowly or even fail. When the temperature is too high, the glycosidic bond isomerization products will increase significantly. The reaction temperature is preferably 10-35°C, more preferably 15-30°C.

In the present invention, the reaction time has an obvious influence on the reaction yield. When the time is too short, the conversion of raw materials is not complete, and when the time is too long, the by-products increase obviously. The reaction time is preferably 0.5-5.0 hours, more preferably 1.0-2.5 hours.

The chemical reaction formula of chemically synthesizing salidroside of the present invention is as follows, wherein, structural formula I is salidroside, structure II is pentaacetyl-β-D-glucose, structure III is p-hydroxyphenethyl alcohol, and structural formula IV is tetraacetyl Base salidroside:

The beneficial effects of the present invention are: compared with the traditional synthetic method, there is no need to convert pentaacetyl-β-D-glucose into highly active tetraacetyl-D-glucose-1-bromosugar or tetraacetyl-α-D-glucose in advance -Glucosyl trichloroacetimidate, the phenolic hydroxyl group in p-hydroxyphenylethanol does not need to be protected and can be directly glycosylated to form glycosides, so the reaction steps are shortened; the catalyst in the condensation reaction only needs to be SnCl ₄ , BF ₃ which is relatively cheap Lewis acid, without using expensive silver carbonate, the preparation cost is significantly reduced. Therefore, this synthesis method can become a method suitable for industrial production of salidroside.

Detailed ways

Example 1

Add 2 g of 4A molecular sieves to a solution of pentaacetyl-β-D-glucose (2.93 g, 7.5 mmol) in dichloromethane (30 ml), and stir for 1 hour under nitrogen protection. Then, tin tetrachloride (0.585ml, 5.0mmol) was added, and immediately after the addition, a suspension of p-hydroxyphenethyl alcohol (0.69g, 5mmol) in dichloromethane (20ml) was added, and the reaction was stirred at room temperature for 2 hours. After the reaction was completed and allowed to stand, pour out the organic layer, then add ethyl acetate to the solid and stir for several minutes, pour out the organic layer, and repeat again. After the organic phases were combined, they were poured into saturated sodium bicarbonate (75ml) under stirring. After the organic layer was separated, the aqueous layer was extracted with dichloromethane (3 × 15ml), and the organic layers were combined and washed with water (2 × 30ml). Then it was filtered on celite, and the solvent was distilled off under reduced pressure to obtain a slurry. The slurry was separated by silica gel column chromatography (petroleum ether: dichloromethane), and the solvent was evaporated under reduced pressure to obtain 1.06 g of tetraacetyl salidroside as a white solid.

¹ H NMR (400MHz, CDCl ₃ ) δ7.03(d, J=8.4Hz, 2H), 6.74(d, J=8.4Hz, 2H), 5.64(s, 1H), 5.17(t, J=9.2Hz , 1H), 5.07(dd, J=10.0Hz, 9.2Hz, 1H), 4.98(dd, J=10.0Hz, 9.6Hz, 1H), 4.47(d, J=8.4Hz, 1H), 4.25(dd, J=12.4Hz, 4.4Hz, 1H), 4.14-4.06(m, 2H), 3.68-3.60(m, 2H), 2.81-2.77(m, 2H), 2.08(s, 3H), 2.01(s, 3H ), 1.99(s, 3H), 1.91(s, 3H).

Dissolve the above tetraacetyl salidroside in anhydrous methanol (12.5ml) containing sodium methoxide (0.27g, 5.0mmol), stir and react at room temperature for 24 hours, after the reaction is over, add acidic resin to neutralize, then filter The resin was removed, the filtrate was concentrated under reduced pressure, and separated and purified with a silica gel column to obtain 0.67 g of salidroside with a total yield of 45% and a melting point of 160-162°C.

¹ H NMR (500MHz, D ₂ O) 7.12 (d, J = 8.5Hz, 2H), 6.76 (d, J = 8.5Hz, 2H), 4.35 (d, J = 8.0Hz, 1H), 4.10-3.90 ( m, 1H), 3.81-3.70(m, 2H), 3.61(dd, J=12.5Hz, 5.5Hz, 1H), 3.38-3.25(m, 3H), 3.14(dd, J=9.0Hz, 8.0Hz, 1H), 2.78(t, J=7.0Hz, 2H).

Example 2

Add 2 g of 4A molecular sieves to a solution of pentaacetyl β-D-glucose (2.96 g, 7.5 mmol) in dichloromethane (30 ml), and stir for 1 hour under nitrogen protection. Then, boron trifluoride ether solution (0.63ml, 5.0mmol) was added, and immediately after the addition, a suspension of p-hydroxyphenylethanol (0.69g, 5mmol) in dichloromethane (20ml) was added, and the reaction was stirred at room temperature for 5 hours. 0.30 g of tetraacetyl salidroside was obtained.

The above-mentioned tetraacetyl salidroside was dissolved in anhydrous methanol (12.5 ml) containing sodium methoxide (0.07 g, 1.3 mmol), and stirred at room temperature for 12 hours. After the reaction was finished, an acidic resin was added to neutralize, and then the resin was filtered off. The filtrate was concentrated under reduced pressure, and separated and purified with a silica gel column to obtain 0.17 g of salidroside, with a total yield of 11%.

Example 3

Add 2 g of 4A molecular sieves to a solution of pentaacetyl β-D-glucose (3.90 g, 1.0 mmol) in dichloromethane (30 ml), and stir for 1 hour under nitrogen protection. Then, tin tetrachloride (0.88ml, 7.5mmol) was added, immediately after the addition, a suspension of p-hydroxyphenethyl alcohol (0.69g, 5mmol) in dichloromethane (20ml) was added, and the reaction was stirred at room temperature for 2 hours. 0.56 g of tetraacetyl salidroside was obtained.

The above tetraacetyl salidroside was dissolved in anhydrous methanol (12.5 ml) containing sodium methoxide (0.14 g, 2.5 mmol), and stirred at room temperature for 24 hours. After the reaction was completed, an acidic resin was added for neutralization, and then the resin was filtered off. The filtrate was concentrated under reduced pressure and separated and purified with a silica gel column to obtain 0.33 g of salidroside, with a total yield of 22%.

Example 4

Add 6 g of 4A molecular sieves to a solution of pentaacetyl β-D-glucose (2.96 g, 7.5 mmol) in dichloroethane (30 ml), and stir for 1 hour under nitrogen protection. Then, tin tetrachloride (0.585ml, 5.0mmol) was added, and immediately after the addition, a suspension of p-hydroxyphenethyl alcohol (0.69g, 5mmol) in dichloroethane (20ml) was added, and the reaction was stirred at 35°C for 4 hours. 0.42 g of tetraacetyl salidroside was obtained.

The above-mentioned tetraacetyl salidroside was dissolved in anhydrous methanol (12.5 ml) containing sodium methoxide (0.27 g, 5.0 mmol), and stirred at room temperature for 12 hours. After the reaction was completed, an acidic resin was added for neutralization, and then the resin was filtered off. The filtrate was concentrated under reduced pressure and separated and purified with a silica gel column to obtain 0.25 g of salidroside, with a total yield of 17%.

Example 5

Add 2 g of 4A molecular sieves to a solution of pentaacetyl β-D-glucose (2.96 g, 7.5 mmol) in dichloromethane (30 ml) and ether (15 ml), and stir for 1 hour under nitrogen protection. Then, cool to 10°C and add tin tetrachloride (0.585ml, 5.0mmol), add p-hydroxyphenethyl alcohol (0.69g, 5mmol) immediately after the dichloromethane (20ml) suspension, stir the reaction at 10°C 5 hours. 0.22 g of tetraacetyl salidroside was obtained.

The above tetraacetyl salidroside was dissolved in anhydrous methanol (12.5 ml) containing sodium methoxide (0.14 g, 2.5 mmol), and stirred at room temperature for 12 hours. After the reaction was completed, an acidic resin was added to neutralize, and then the resin was filtered off. The filtrate was concentrated under reduced pressure, and separated and purified by a silica gel column to obtain 0.14 g of salidroside, with a total yield of 9%.

Example 6

Add 4 g of 4A molecular sieves to a solution of pentaacetyl β-D-glucose (3.90 g, 1.0 mmol) in dichloromethane (30 ml), and stir for 1 hour under nitrogen protection. Then, tin tetrachloride (1.17ml, 1.0mmol) was added, and immediately after the addition, a suspension of p-hydroxyphenethyl alcohol (0.69g, 5mmol) in dichloromethane (20ml) was added, and the reaction was stirred at room temperature for 0.5 hours. 0.63 g of tetraacetyl salidroside was obtained.

The above tetraacetyl salidroside was dissolved in anhydrous methanol (12.5 ml) containing sodium methoxide (0.27 g, 5.0 mmol), and stirred at room temperature for 24 hours. After the reaction was completed, an acidic resin was added for neutralization, and then the resin was filtered off. The filtrate was concentrated under reduced pressure and separated and purified with a silica gel column to obtain 0.39 g of salidroside, with a total yield of 26%.

Claims (10)

1. a method for chemically synthesizing salidroside, its steps are as follows: 1) In the presence of molecular sieves, catalyzed by Lewis acid, glycosylate pentaacetyl-β-D-glucose and p-hydroxyphenylethanol in an organic solvent at a temperature of 10-35°C for 0.5-5.0 hours to generate tetraacetyl The molar concentration of salidroside and p-hydroxyphenylethanol is 0.1-1.0M, the equivalent ratio of pentaacetyl-β-D-glucose and p-hydroxyphenylethanol is 1.0-5.0, and the amount of molecular sieve is pentaacetyl-β-D- 0.5-3.0 times the weight of glucose, the equivalent ratio of Lewis acid and pentaacetyl-β-D-glucose is 0.5-3.0; 2) Add the tetraacetylsalidroside obtained in step 1) into the methanol solution of _NaOCH3 , the molar concentration of tetraacetylsalidroside is 0.05-0.5M, and the molar concentration of _NaOCH3 is 0.1-0.5M, at room temperature The reaction was carried out for at least 12 hours, and the acetyl group was removed to obtain salidroside. 2. The method for chemically synthesizing salidroside according to claim 1, characterized in that the equivalent ratio of pentaacetyl-β-D-glucose and p-hydroxyphenethyl alcohol is 1.5-2.5. 3. The method for chemically synthesizing salidroside according to claim 1, characterized in that said molecular sieve is 4A molecular sieve. 4. The method for chemically synthesizing salidroside according to claim 1, characterized in that the amount of molecular sieves is 1.0-2.0 times the weight of pentaacetyl-β-D-glucose. 5. The method for chemically synthesizing salidroside according to claim 1, characterized in that said Lewis acid is tin tetrachloride or boron trifluoride. 6. The method for chemically synthesizing salidroside according to claim 1, characterized in that the equivalent ratio of Lewis acid and pentaacetyl-β-D-glucose is 1.0-2.0. 7. the method for chemically synthesizing salidroside according to claim 1 is characterized in that said organic solvent is methylene dichloride or ethylene dichloride, or a mixed solvent of methylene chloride and ether or tetrahydrofuran, or It is a mixed solvent of dichloroethane and ether or tetrahydrofuran. 8. The method for chemically synthesizing salidroside according to claim 1, characterized in that the molar concentration of p-hydroxyphenylethanol is 0.2-0.4M. 9. The method for chemically synthesizing salidroside according to claim 1, characterized in that the condensation reaction temperature is 15-30°C. 10. The method for chemically synthesizing salidroside according to claim 1, characterized in that the condensation reaction time is 1.0-2.5 hours.