A kind of preparation method of chiral four-membered ring taxane side chain compound

A compound and four-membered ring technology, which is applied in the field of preparation of chiral four-membered ring taxane side chain compounds, can solve the problems of unfavorable market promotion, high price, and high cost of the four-membered ring taxane side chain, and can reach the price The effect of low cost, simple operation and easy industrial production

Active Publication Date: 2017-08-18
无锡紫杉药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] The prior art discloses a variety of preparation methods of four-membered ring taxane side chain compounds. The basic scheme is to use hydroxyl-protected (2R,3S)-phenylisoserine methyl ester as a starting material, and in the presence of an organic base , a cyclization reaction occurs under low temperature conditions to obtain a four-membered ring side chain, but the price of (2R,3S)-phenylisoserine methyl ester used is relatively high, and the cost of the prepared chiral four-membered ring taxane side chain is relatively high. Not conducive to marketing

Method used

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  • A kind of preparation method of chiral four-membered ring taxane side chain compound
  • A kind of preparation method of chiral four-membered ring taxane side chain compound
  • A kind of preparation method of chiral four-membered ring taxane side chain compound

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Experimental program
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Effect test

Embodiment 1

[0021] Add (-)-cytisine (2mmol) into tetrahydrofuran (20mL), cool to -30°C, add butyllithium (2mmol), then add the compound represented by formula II (2mmol), and react for 1 hour , TLC showed that the reaction of the raw materials was complete, the reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered with suction, and concentrated to obtain a crude product. The crude product is purified by petroleum ether / ethyl acetate silica gel column chromatography, and the yield is 34%. figure 1 shown.

[0022] The control of the reaction temperature of the present embodiment is accomplished under the protection of nitrogen.

[0023] 1H-NMR (400MHz, d6-DMSO): 0.44 (m, 6H); 0.76 (t, J = 7.9, 9H); 4.79 (d, J = 4.7, 1H); 5.08 (dd, J = 4.7, J = 2.7,1H); 6.17(br,s,1H); 7.28-7.38(m,5H)

[0024]

Embodiment 2

[0026] Add (-)-cytisine (10mmol) into tetrahydrofuran (20mL), at 25°C, after adding butyl lithium (10mmol), add the compound shown in formula II (2mmol), and react for 1 hour, TLC shows After the reaction of the raw materials was complete, the reaction solution was poured into a saturated aqueous ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered with suction, and concentrated to obtain a crude product. Crude product obtains refined product with sherwood oil / ethyl acetate silica gel column chromatography, and yield is 45%, and the obtained product, i.e. the chiral four-membered ring taxane side chain compound shown in formula I, the proton nuclear magnetic resonance spectrum as shown in figure 1 shown.

[0027] The control of the reaction temperature of the present embodiment is accomplished under the protection of nitrogen.

[0028]

Embodiment 3

[0030] Add (-)-cytisine (3mmol) to tetrahydrofuran (20mL), put it in an ice-water bath, cool to 0°C, add butyllithium (3mmol), and then add the compound shown in formula II (2mmol) , After reacting for 1 hour, TLC showed that the reaction of the raw materials was complete. The reaction solution was poured into a saturated ammonium chloride aqueous solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered with suction, and concentrated to obtain a crude product. The crude product is purified by petroleum ether / ethyl acetate silica gel column chromatography, and the yield is 92%. figure 1 shown.

[0031] The control of the reaction temperature of the present embodiment is accomplished under the protection of nitrogen.

[0032]

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Abstract

The invention relates to a preparation method of a chiral four-membered-ring taxane side chain compound and belongs to the field of pharmaceutical synthesis. The chiral four-membered-ring taxane side chain compound as shown in the formula I is prepared from a compound as shown in the formula II through a cyclization reaction. The method overcomes the defects of the relatively high cost of (2R,3S)-phenyl isoserine methyl ester in the prior art, and has the advantages of low cost of the used achiral material, simple equipment, easiness in operation, higher yield, and easiness in industrial production.

Description

technical field [0001] The invention relates to a preparation method of a chiral four-membered ring taxane side chain compound, belonging to the field of drug synthesis. Background technique [0002] The prior art discloses a variety of preparation methods for four-membered ring taxane side chain compounds. The basic scheme is to use hydroxyl-protected (2R,3S)-phenylisoserine methyl ester as a starting material, and in the presence of an organic base , a cyclization reaction occurs under low temperature conditions to obtain a four-membered ring side chain, but the price of (2R,3S)-phenylisoserine methyl ester used is relatively high, and the cost of the prepared chiral four-membered ring taxane side chain is relatively high. Not conducive to marketing. Contents of the invention [0003] The technical problem to be solved by the present invention is to provide a preparation method of a chiral four-membered ring taxane side chain compound with low production cost in view of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F7/18
Inventor 赵洪涛陈磊葛月兰
Owner 无锡紫杉药业股份有限公司
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