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Asymmetric synthesis method for tanshinol ester derivative

A technology of danshensu ester and synthesis method, which is applied in the field of asymmetric synthesis of danshensu ester derivatives and achieves the effects of high yield, high enantioselectivity and simple operation

Inactive Publication Date: 2015-11-25
SHANGHAI JIAO TONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with the prior art, the present invention is special in that it solves the problem of reaction selectivity caused by substrate specificity (containing phenolic hydroxyl groups, alcoholic hydroxyl groups, etc. with similar reactivity) in the Danshensu sodium molecule

Method used

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  • Asymmetric synthesis method for tanshinol ester derivative
  • Asymmetric synthesis method for tanshinol ester derivative
  • Asymmetric synthesis method for tanshinol ester derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Embodiment 1, the asymmetric rhodium-catalyzed oxidation of (Z)-2-acetamido-3-(4-hydroxyphenyl) acrylic acid

[0026] Add (Z)-2-acetamido-3-(4-hydroxyphenyl)acrylic acid to a 10mL reaction test tube, catalyst [Rh((R,R)-QuinoxP*)(cod)]SbF6 (the amount is dehydroamino acid 1 / 10000 of the molar equivalent), vacuumize and change the hydrogen for 3 times, then add degassed MeOH (2mL) under the protection of hydrogen, and finally adjust the hydrogen pressure to 20atm and stir vigorously for 48 hours. After the reaction was completed, MeOH was distilled off under reduced pressure to obtain (R)-2-acetylamino-3-(4-hydroxyphenyl)propionic acid.

[0027] 1 HNMR (CD 3 OD, 400MHz): δ7.25(d, J=8.6Hz, 2H), 7.02(d, J=8.6Hz, 2H), 4.65(dd, J=9.2Hz, 5.2Hz, 1H), 3.20(dd, J=13.8Hz, 5.2Hz, 1H), 2.96(dd, J=13.8Hz, 9.2Hz, 1H), 2.25(s, 3H), 1.91(s, 3H).

[0028] HPLC (with (CH 3 ) 3 SiCHN 2 Determination after methyl esterification): DaicelCHIRALCELOD-H, 1.0mL / min, 2-propanol / hexane=10 / ...

Embodiment 2

[0029] Embodiment 2, the asymmetric rhodium catalytic hydrogenation of (Z)-2-acetamido-3-(4-acetoxyphenyl) methyl acrylate

[0030]Add (Z)-2-acetamido-3-(4-acetoxyphenyl)methyl acrylate to a 10mL reaction test tube, catalyst [Rh((S, S)-QuinoxP*)(cod)]SbF6 (amount of 1 / 10000 of the molar equivalent of dehydroamino acid), vacuumize the hydrogen for 3 times, then add degassed MeOH (2mL) under the protection of hydrogen, and finally adjust the hydrogen pressure to 5atm and stir vigorously for 20 hours. After the reaction was completed, MeOH was distilled off under reduced pressure to obtain (S)-methyl 2-acetamido-3-(4-acetoxyphenyl)propionate.

[0031] 1 HNMR (CD 3 OD, 400MHz): δ7.23(d, J=8.6Hz, 2H), 7.02(d, J=8.6Hz, 2H), 4.87(s, 3H), 4.66(dd, J=8.8Hz, 5.8Hz, 1H), 3.14(dd, J=14.0Hz, 5.8Hz, 1H), 2.97(dd, J=14.0Hz, 8.8Hz, 1H), 2.56(s, 3H), 1.91(s, 3H).

[0032] HPLC: Daicel CHIRALCELOD-H, 1.0 mL / min, 2-propanol / hexane=10 / 90, 210 nm. Rt(major)=15.3min, Rt(minor)=19.9min.

Embodiment 3

[0033] The synthesis of embodiment 3, (R)-tyrosine

[0034] In a 500ml single-necked bottle, add (R)-2-acetylamino-3-(4-hydroxyphenyl)propionic acid and hydrochloric acid, stir to dissolve, and heat to reflux. The reaction was monitored by a TLC plate, and after 3 hours the raw material spot disappeared, and the heating was stopped. Add ammonia water to the hydrolyzed solution to adjust the pH value to 3.5, add 1% activated carbon, stir and boil for 10 minutes, stir and heat in a water bath at 90°C for 30 minutes, filter while hot, wash the activated carbon layer with distilled water 3 times, and combine the filtrate and lotion. Place it below 10°C for 24 hours, and the crystalline (R)-tyrosine (ee>99%) will precipitate out.

[0035] 1 HNMRofhydrochloridesaltof5(D 2 (0, 400MHz): δ7.13(d, J=8.4Hz, 2H), 6.83(d, J=8.4Hz, 2H), 4.23(dd, J=7.6Hz, 5.6Hz, 1H), 3.21(dd, J=14.4Hz, 5.6Hz, 1H), 3.09 (dd, J=14.4Hz, 7.6Hz, 1H).

[0036] HPLC: DaicelCHIRALCELCR(+), 0.8mL / min, pH=2.0HC...

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Abstract

The invention discloses an asymmetric synthesis method for a tanshinol ester derivative. The method comprises: carrying out direct reaction on (R)- or (S)-sodium tanshinol (the formula is shown in the description) and halogenated hydrocarbon, sulphonate, sulphate or carbonic ester to obtain an (R)- or (S)-tanshinol ester derivative (the formula is shown in the description) with high optical activity, wherein R is C1-C7 alkyl or bornyl. The method disclosed by the invention is free of complex separation steps in the whole course, is simple in preparation process, does not pass through chromatographic column, is low in production cost, and is quite suitable for industrialized batch production.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to an asymmetric synthesis method of danshensu ester derivatives. Background technique [0002] Danshensu has the effects of dilating blood vessels, increasing coronary blood flow, anti-myocardial ischemia and hypoxia, anti-thrombosis, and improving microcirculation. It has unique curative effects in the treatment of coronary heart disease and angina pectoris. The active ingredients of injections are currently one of the important treatment and maintenance drugs for cardiovascular and cerebrovascular diseases with clear curative effects. However, the large polar carboxylic acid group contained in the Danshensu structure makes Danshensu too water-soluble and difficult to enter the cell membrane composed of lipid bilayers, resulting in a very low absolute bioavailability when administered orally. . In addition, the exposed carboxyl group is easy to combine wit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/732C07C67/10
Inventor 张万斌张振锋王志惠王兴广
Owner SHANGHAI JIAO TONG UNIV
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