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Preparation of amyrolin and derivatives thereof

A technology for the synthesis of eralemisinin and its derivatives, which can solve the problems of harsh high-temperature cyclization conditions, many by-products, and difficult operations, and achieve short reaction time and high overall yield , The effect of simplifying the purification method

Inactive Publication Date: 2009-04-15
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Description
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Problems solved by technology

Other problems of the bibliographical method are harsh conditions for high-temperature cyclization, difficult operation, many by-products, and low yield [30% of the yield of 4-methyl carnivorous artemisinin (Xie L.et al., J.Med.Chem., 1999, 42: 2662)], therefore it is necessary to search for a synthetic horn-type artemisinin with high selectivity, simple operation, convenient purification, high yield, synthetic method and preparation process suitable for large-scale preparation and industrial production

Method used

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  • Preparation of amyrolin and derivatives thereof
  • Preparation of amyrolin and derivatives thereof
  • Preparation of amyrolin and derivatives thereof

Examples

Experimental program
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Embodiment 13

[0037] Embodiment 1.3, the preparation of 4-dimethyl-7-acetoxy coumarin (C1)

[0038] 9.5g (50mmol) of 3,4-dimethyl-7-hydroxycoumarin (B1), 20mL of acetic anhydride, heated to reflux for 90 minutes, cooled to about 50°C, poured into 150g of ice water under vigorous stirring, and continued to vigorously After stirring, a pale yellow solid precipitated, filtered with suction, and washed with water until neutral. The obtained solid was recrystallized with about 500 mL of ethanol to obtain 11.1 g of pale yellow needle crystals, with a yield of 95.7%. mp 164-165°C; 1 H NMR (CDCl 3 , 400MHz, δppm): 2.21 (3H, s, 3-CH 3 ), 2.34 (3H, s, 4-CH 3 ), 2.39 (3H, s, 7-CH 3 COO), 7.05 (1H, dd, J=2.4 & 8.4Hz, 6-H), 7.08 (1H, d, J=2.4Hz, 8-H), 7.60 (1H, d, J=8.4Hz, 5- h).

Embodiment 2

[0039] The preparation of embodiment 2.4-methyl-7-acetoxy coumarin (C2)

[0040] 8.8g (50mmol) of 4-methyl-7-hydroxycoumarin (B2), 20mL of acetic anhydride, heated to reflux for 90 minutes, cooled to about 50°C, poured into 150g of ice water under vigorous stirring, continued vigorous stirring, and precipitated Pale yellow solid, suction filtered, washed with water until neutral. The obtained solid was recrystallized with about 500 mL of ethanol to obtain 10.5 g of pale yellow needle crystals, with a yield of 96.3%. mp150-151°C (documentation: 150-151°C); 1 H NMR (CDCl 3 , δppm): 2.35 (3H, s, 4-CH 3 ), 2.44 (3H, s, 7-CH 3 COO), 6.28 (1H, s, 3-H), 7.09 (1H, dd, J=2.0 & 8.4Hz, 6-H), 7.12 (1H, d, J=2.0Hz, 8-H), 7.62 ( 1H, d, J=8.4Hz, 5-H).

Embodiment 3

[0041] Example 3.3, Preparation of 4-dimethyl-7-hydroxyl-8-acetylcoumarin (D1).

[0042] 11.02g (47.5mmol) of 3,4-dimethyl-7-acetoxycoumarin (C1) and 25g of anhydrous aluminum trichloride were placed in a mortar, fully ground and mixed, and the mixture was filled into 250mL in a round bottom flask. The oil bath was preheated to 130°C, and put into the flask. Slowly raise the temperature of the oil bath to 170-180°C over two hours and heat at this temperature for 2 hours. Cool to room temperature, add 60g of crushed ice, slowly add 150mL of 5% hydrochloric acid under vigorous stirring, and slowly heat to 110°C to obtain a suspension, keep it warm for 1 hour to complete the decomposition. Cool to room temperature, filter with suction, wash with water until neutral. The obtained solid was recrystallized with 300 mL of ethanol to obtain 9.1 g of yellow needle crystals with a yield of 82.6%. mp 175-176°C; 1 H NMR (CDCl 3 )δppm 2.21 (3H, s, 3-CH 3 ), 2.39 (3H, s, 4-CH 3 ), 2...

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Abstract

The invention relates to a synthesizing method and preparing process for seselin and the derivatives. The method takes substituted hydroxyphenol as a raw material, and after Pechmann reaction, acetylation, Fries rearrangement, cyclization, reduction and dehydration, the seselin compound can be obtained. The method has the advantages of simple operation of each step, controllable conditions, easily obtained reagent, convenient purification, single product and high yield. The synthesizing route overcomes the defects of low yield and being difficult to remove isomers of the existing methods. The seselin and the derivatives which are taken as the important bioactive substance and medical intermediate have good application prospect in anti-inflammatory, anti-fungus and anti-tumor aspects, particularly playing a key role in synthesizing candidate anti-HIV agents. The synthesizing route and the method have high application value and wide application prospect.

Description

technical field [0001] The invention relates to a synthesis method and a preparation process of Seselin and its derivatives. Background technique [0002] Artemisinin (1) and its derivatives are widely found in the roots of Rutaceae Citrus citrus, the fruit of Umbelliferae Artemisia indica and the bark of Zanthoxylum bungeanum, and more than 20 kinds of similar thing. The eralemisinin and its analogues isolated from natural products exhibit a variety of biological activities. For example, prosperidin has the effect of lowering blood pressure and relaxing coronary arteries, and its mechanism of action is calcium ion antagonism. According to existing literature, its biological activity is manifested in the following aspects: antifungal effect (Bandara B.M.R., et al., Phytochem., 1991, 29: 297; Norma C.C.O. et al. Asian Journal of PlantSciences, 2007, 6 (4): 712); antioxidant, anti-inflammatory, cytotoxic effects (TandanS.K.et al., Fitoterapia, 1990, 61: 360; Yang H.et al., P...

Claims

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Application Information

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IPC IPC(8): C07D493/04
CPCC07D493/04
Inventor 谢蓝郭焕芳
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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