Asymmetric synthesis method of (+)-tanshinol

A synthetic method and asymmetric technology, applied in the field of medicine and chemical industry, can solve the problems of unseen chemical synthesis of natural (+)-danshensu, chiral resolution of refractory racemic danshensu, etc., and achieve high optical purity and easy operation Effect

Inactive Publication Date: 2013-02-13
FOURTH MILITARY MEDICAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because there are two phenolic hydroxyl groups that are easily oxidized in the structure of Danshensu, it is difficult to perform chiral resolution of racemic Danshensu
So far, there is no report on the chemical synthesis of natural ( + )-danshensu

Method used

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  • Asymmetric synthesis method of (+)-tanshinol

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Example 1 Synthesis of 2-methyl-4-(3,4-methylenedioxybenzylidene)oxazolone (1)

[0017] Add 6.00 g (40 mmol) of piperonal, 5.76 g (50 mmol) of acetylglycine, 4.16 g (50 mmol) of anhydrous sodium acetate and 20 mL of acetic anhydride into a 250 mL three-necked flask, stir and react in a water bath at 80°C for 3 hours, then raise the temperature Continue the reaction at 100°C for 1 hour, stir and cool until the reaction mixture solidifies, add 30 mL of ice water and stir vigorously, a large number of yellow crystals precipitate, filter with suction, wash with ice water, and dry to obtain 6.80 g of bright yellow crystals, m.p.182.5°C-183.0 °C (literature value 178°C-179°C) (Wong, H. Synthesis, 1992, 793-797), yield: 75%. 1 H NMR (300 MHz, DMSO): δ 2.38 (s, 3H), 6.13 (s, 2H), 7.06(d, J = 8.1 Hz, 1H), 7.16 (s, 1H), 7.66(d, J = 8.1 Hz, 1H), 7.91 (s, 1H).

Embodiment 2

[0018] Example 2 Synthesis α -Acetylamino- β -(3,4-methylenedioxyphenyl)acrylic acid (2)

[0019] Add 4.62 g (20 mmol) of 2-methyl-4-(3,4-methylenedioxybenzylidene) oxazolone, 40 mL of water, 80 mL of acetone and 3.0 mL of concentrated hydrochloric acid into a 250 mL one-necked flask , reflux for 3h. Activated carbon decolorization, suction filtration while hot, after the filtrate was placed at room temperature, it was cooled in a refrigerator to complete the crystallization. Suction filtration, washing with ice water, and drying gave 3.06 g of loose beige crystalline powder, m.p. Rate: 75.5%. 1 H NMR (300 MHz, DMSO): δ 1.98 (s, 3H), 6.06 (s, 2H), 6.95(d, J = 8.0 Hz, 1H), 7.11~7.22 (m, 3H), 9.32 (s, 1H).

Embodiment 3

[0020] Example 3 Synthesis β -(3,4-methylenedioxyphenyl)pyruvate (3)

[0021] Add to a 250 mL one-necked flask α -Acetylamino- β -(3,4-methylenedioxyphenyl)acrylic acid 4.98 g (20 mmol) and 50 mL 3 mol L -1 Hydrochloric acid solution, reflux for 10 h. Decolorize with activated carbon, filter with suction, concentrate the filtrate until crystals are precipitated, and put it in the refrigerator to cool to complete the crystallization. Suction filtration, washing with ice water, and drying yielded 3.40 g of loose crystals, m.p. 1 H NMR (500 MHz, DMSO): δ 6.01(s, 2H), 6.77 (s, 1H), 6.90(d, J = 8.1 Hz, 1H), 7.14(d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 9.08 (s, 1H), 13.08 (s, 1H); 13 C NMR (125 MHz, DMSO): δ100.99, 108.29, 108.89, 109.86, 123.83, 129.20, 140.36, 146.37, 147.21, 166.38.

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Abstract

The invention relates to an asymmetric synthesis method of (+)-tanshinol, which comprises the following steps: carrying out Knoevenagel condensation on the raw material heliotropin, hydrolyzing for ring opening to obtain beta-(3,4-3,4-methylenedioxyphenyl)pyruvic acid, carrying out key asymmetric reduction reaction to obtain R-beta-(3,4-dibenzyloxyphenyl)-alpha-hydracrylic acid, and finally, deprotecting to obtain the (+)-tanshinol. The method has the advantages of accessible raw material and high optical purity of the product, is simple to operate, and can implement large-scale preparation.

Description

technical field [0001] The invention relates to an asymmetric synthesis method of natural (+)-danshensu, which belongs to the technical field of medicine and chemical industry. Background technique [0002] Natural Danshensu is the main water-soluble component of Salvia miltiorrhiza in Labiatae, and its chemical name is R-( + )- β -3,4-dihydroxyphenyl lactic acid. Pharmacological research results show that Danshensu can inhibit platelet synthesis, improve myocardial hypoxia resistance, protect myocardium, increase coronary artery flow, has anti-oxidation, anti-myocardial ischemia, blood lipid regulation, anti-thrombosis, nerve cell protection, and prevention of liver fibrosis. It has multiple functions such as anti-cancer and anti-tumor, and is an active ingredient of compound Danshen dripping pills and Danshen injection. Because the substance directly extracted from Danshen is a mixture of water-soluble components, not only the purity is low, but also the content of Dansh...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/52C07C51/347
Inventor 姜茹陈惠刘雪英田海林张馨源
Owner FOURTH MILITARY MEDICAL UNIVERSITY
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