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Asymmetric synthesis method of optically pure tanshinol and derivative of tanshinol

A synthesis method and technology of derivatives, applied in the fields of organic synthesis and pharmaceutical synthesis, can solve the problems of high reaction pressure of catalyst hydrogenation method, unsuitable for large-scale synthesis, harsh reaction conditions, etc., and achieve mature synthesis method, high yield and selectivity. , the effect of simple operation

Inactive Publication Date: 2014-06-04
XIAN UNIV OF SCI & TECH
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  • Abstract
  • Description
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AI Technical Summary

Problems solved by technology

The racemate resolution method is to pass an equal amount of (R) and (S)-danshensu mixture through a chiral environment to obtain a single (R)-danshensu, which undoubtedly wastes general raw materials; enzyme specificity The reduction method can obtain higher optical purity, but its adaptability to substrates is poor; the introduction of chiral centers by raw materials is a low-cost synthesis method, but racemization is prone to occur during the synthesis process, that is, the optical purity is low; Catalyst hydrogenation generally requires higher reaction pressure and harsher reaction conditions, and is not suitable for large-scale synthesis

Method used

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  • Asymmetric synthesis method of optically pure tanshinol and derivative of tanshinol
  • Asymmetric synthesis method of optically pure tanshinol and derivative of tanshinol
  • Asymmetric synthesis method of optically pure tanshinol and derivative of tanshinol

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Experimental program
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Effect test

preparation example Construction

[0035] see figure 1 , the asymmetric synthesis method of above-mentioned optically pure Danshensu and its derivatives comprises the following steps:

[0036] (1) Using benzaldehyde or benzaldehyde derivatives (compound 3) as the starting material, the oxazolone compound (compound 4 );

[0037] (2) Oxazolone compounds (compound 4) were hydrolyzed into enamine compounds (compound 5) in acetone / water system;

[0038] (3) The enamine compound (compound 5) is further hydrolyzed in dilute hydrochloric acid to obtain the pyruvate compound (compound 6);

[0039] (4) Pyruvate compounds (compound 6) are reduced to α-hydroxypropionic acid compounds (compound 1) under phase transfer conditions, and the phase transfer catalysts are cinchona phase transfer catalysts (PTCs);

[0040] (5) Pyruvate compounds (compound 6) can also react with alcohols to form α-keto ester compounds (compound 7) under Steglich esterification reaction (DCC / DMAP) conditions;

[0041] (6) α-hydroxypropionic acid...

Embodiment 1

[0049] 1) Protection of 3,4-dihydroxybenzaldehyde (R 1 =R 2 =OH)

[0050] Add 200mL of N,N-dimethylformamide, 17.22g (0.126mol) of 3,4-dihydroxybenzaldehyde, and 86.8g (0.63mol) of potassium carbonate to a 500mL three-necked flask equipped with a constant pressure funnel and a reflux condenser. Add 36.3 mL (0.315 mol) of benzyl bromide to the constant pressure funnel; raise the temperature to 65°C, slowly drop in benzyl bromide (about 30 min), and continue the reaction for 6 h after the drop is complete. The reaction was detected by TLC. After the reaction was completed, it was filtered with suction, and the filtrate was distilled off under reduced pressure to remove N,N-dimethylformamide. The residue was poured into ice water to obtain a pale yellow precipitate, which was filtered and dried to obtain 38.3 g of a yellow solid (see formula 1 for the structure). , yield 96%. melting point, 1 The HNMR and MS data are consistent with those reported in the literature.

[0051]...

Embodiment 2

[0063] Step 1) to step 5) are the same as in Example 1;

[0064] 6) Isopropyl (R)-β-(3,4-methylenedioxyphenyl)-α-hydroxypropionate (Compound 2, R 1 =R 2 =OBn) synthesis

[0065] Add 1.88g (5mmol) of compound 1, 2.06g (10mmol) of N,N'-dicyclohexylcarbodiimide (DCC), 0.732g (6mmol) of 4-dimethyl to a 100mL three-necked flask Aminopyridine (DAMP), 1.5mL isopropanol, 40mL dichloromethane, stirred at room temperature for 24h. TLC detection reaction, after the reaction is completed, filter, add 50mL of water, after vigorous stirring, separate the organic phase, extract the water phase with ethyl acetate 3*20mL, combine the organic phase, dry over anhydrous sodium sulfate, distill off the solvent under reduced pressure, 200 -300 mesh silica gel column chromatography to obtain 1.94 g of a white solid (see formula III for the structure), with a yield of 94%. melting point, 1 The HNMR and MS data are consistent with those reported in the literature.

[0066]

[0067] 7) Synthes...

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Abstract

The invention discloses an asymmetric synthesis method of optically pure tanshinol and a derivative of the tanshinol. The optically pure tanshinol and the derivative thereof are obtained by performing Knoevenagel condensation and hydrolysis based on benzaldehyde or a benzaldehyde derivative as an initial raw material to obtain a pyruvic acid compound and performing asymmetric reduction reaction and simple functional group conversion. The method is available in raw materials, low in chiral secondary alcohol construction cost, good in three-dimensional selectivity, simple to operate, environmental friendly and applicable to on-scale production, and has the technical advantages of high yield, high selectivity and relatively low chiral construction cost, and is simple to operate.

Description

technical field [0001] The invention belongs to the fields of medicine synthesis and organic synthesis, and relates to an asymmetric synthesis method of optically pure danshensu and its derivatives. Background technique [0002] Danshensu is the main medicinal ingredient in Salvia miltiorrhiza Bge, which has a wide range of physiological and pharmacological activities. It is clinically used to dilate coronary arteries, inhibit platelet aggregation and cardiomyocyte apoptosis, antithrombotic and prevent arterial Atherosclerosis, liver protection, anti-inflammation and enhancement of body immunity, etc. [0003] A large number of studies have shown that chemically synthesized (±)-danshensu is significantly different from natural (R)-danshensu in terms of pharmacology, efficacy and pharmacokinetics, and even exhibits opposite activities. At the same time, according to the standards for new drug application, different isomers (including enantiomers and diastereomers) of compoun...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/52C07C51/367C07B53/00
CPCC07B53/00C07B2200/07C07C51/367C07C67/31C07C231/10C07D263/42C07C59/52C07C69/734C07C233/47
Inventor 陈福欣王兰龚频周安宁李刚
Owner XIAN UNIV OF SCI & TECH
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