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Intermediate, preparation method and application of intermediate in synthesis of vincamine

An intermediate, vincamine technology, applied in the field of chemical drug synthesis, can solve the problems of low total yield, long steps, and low industrial value, and achieve the effect of simple operation, simple reaction, and easy scale production

Active Publication Date: 2021-08-31
SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, most of the above-mentioned total synthetic routes have long steps, low overall yield, and low industrial value

Method used

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  • Intermediate, preparation method and application of intermediate in synthesis of vincamine
  • Intermediate, preparation method and application of intermediate in synthesis of vincamine
  • Intermediate, preparation method and application of intermediate in synthesis of vincamine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0097] The synthesis of embodiment 1 compound 2, reaction scheme is as follows:

[0098]

[0099] Include the following steps:

[0100]Compound 1 (98%ee) (1.73g, 6.4mmol) was dissolved in 100mL of dichloromethane, and ozone was passed through at -78°C for 10 minutes, and the reaction solution turned blue. Oxygen was introduced into the reaction solution for 10 minutes, and excess ozone was discharged, and triphenylphosphine (3.34 g, 12.8 mmol) was added, and the mixture was heated to room temperature and stirred. After TLC detection showed that the reaction was complete, the reaction solution was directly concentrated, and the obtained crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 to 4:1) to obtain yellow oil 2 (1.63 g, yield 97 %).

[0101] Compound 2: 1 H NMR (400MHz, CDCl 3 )δ9.67(s,1H),7.51(d,J=7.2Hz,2H),7.48–7.41(m,1H),7.41–7.31(m,2H),4.06–3.91(m,1H),3.88 –3.70(m,1H),2.97(d,J=17.6Hz,1H),2.47 (d,J=17.6Hz,1H),2....

Embodiment 2

[0102] The synthesis of embodiment 2 compound 4, reaction scheme is as follows:

[0103]

[0104] Include the following steps:

[0105] Disperse (methoxymethyl)triphenylphosphine chloride (3.01 g, 8.8 mmol) in dry tetrahydrofuran (50 mL) under the protection of argon, and after cooling to 0 °C, slowly add potassium tert-butoxide ( 1.0M in THF, 6.59mL, 6.6mmol), after the addition, the reaction solution was stirred at 0°C for 30 minutes. Then it was cooled to -78°C, and 10 mL of dry tetrahydrofuran solution of compound 2 (1.20 g, 4.4 mmol) was added thereto, reacted under the protection of argon for 2 hours, then opened for reaction, and gradually rose to room temperature for reaction. After TLC detection showed that the reaction was complete, saturated ammonium chloride solution was added to quench the reaction, the organic layer was separated, the aqueous layer was extracted with ethyl acetate (20mL×2), the organic layers were combined, and the organic layer was washed on...

Embodiment 3

[0107] The synthesis of embodiment 3 compound 5, reaction scheme is as follows:

[0108]

[0109] Include the following steps:

[0110] Compound 4 (1.16g, 4.0mmol) was dissolved in 23mL of dichloromethane, pinacol (716mg, 6.1mmol) and p-toluenesulfonic acid (76.8mg, 0.404mmol) were added to react at room temperature. After the complete disappearance of the raw material was detected by TLC, the reaction solution was directly concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain yellow oil 5 (1.49 g, yield 97%).

[0111] Compound 5: 1 H NMR (400MHz, CDCl 3 )δ7.50(d,J=7.6Hz,2H),7.47–7.41(m,1H),7.40–7.31(m,2H),5.01(t,J=5.2Hz,1H),3.76(t,J =6.4Hz,2H),2.06–1.93(m,2H),1.88–1.81(m,2H),1.81–1.63(m,4H),1.62–1.51(m,2H),1.25–1.08(m,12H ),0.88(t,J=7.6Hz,3H). 13 C NMR (100MHz, CDCl 3 )δ178.1, 175.6, 136.8, 131.1, 128.0, 127.4, 100.8, 81.7, 81.7, 47.0, 46.9, 31.1, 30.9, 30.7, 29.8, 24.3, 24.2, 22.0, 22.0,...

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Abstract

The invention relates to the technical field of chemical drug synthesis, and discloses an intermediate, a preparation method and application of the intermediate in synthesis of vincamine. A modular synthesis strategy is adopted, and a compound 1 with a D ring structure and a C20 quaternary carbon center and a tryptophol derivative 7 (namely the compound 7) with an indole ring are adopted as synthesis blocks for synthesis. The synthesis method is efficient; each step of the synthesis route is simple in reaction; the used reagent and solvent are cheap and easy to obtain; the operation is simple and convenient; the yield is high; and large-scale production is easy.

Description

technical field [0001] The invention relates to the technical field of chemical drug synthesis, in particular to an intermediate, a preparation method and its application in synthesizing vincamine. Background technique [0002] Vincamine ((+)-vincamine) is a monoterpene indole alkaloid that was first isolated from Vinca minor L. by Zabolatnaya et al. in the 1950s. Vincamine can pass through the blood-brain barrier, has significant activity in dilating cerebral blood vessels, can restore normal blood flow in ischemic areas, improve blood oxygen utilization, improve cerebral blood flow, and has a regulating effect on arterial blood pressure, cardiac output, heart rate, etc. , It is often used clinically to treat cardiovascular and cerebrovascular diseases such as cerebral ischemia. In addition, vincamine is also a key raw material for the synthesis of vinpocetine, a drug for treating cerebral infarction, so this natural product has important research value. [0003] [00...

Claims

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Application Information

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IPC IPC(8): C07D405/06C07D461/00
CPCC07D405/06C07D461/00C07B2200/07Y02P20/55
Inventor 宋颢薛芳琳秦勇
Owner SICHUAN UNIV
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