Method for preparing intermediate of colchicine derivatives

A technology for colchicine and derivatives, which is applied in the field of preparation of colchicine derivative intermediates, can solve the problems of restricting new drug research and development, failing to obtain products, reducing product yields, etc., and achieve large-scale industrial production and reaction conditions Gentle, Process-Controlled Effects

Active Publication Date: 2012-07-25
ZHEJIANG UNIV
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  • Abstract
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Problems solved by technology

However, the yield of the Schmidt rearrangement reaction catalyzed with concentrated sulfuric acid is lower than 30%. If the temperature is too high or the reaction time is too long, the product yield will be significantly reduced, and even the product cannot be obtained. Moreover, the amount of solvent used in the reaction is large. The harsh conditions of the synthesis process make it difficult to achieve large-scale synthesis, which greatly limits the development of new drugs based on this compound

Method used

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  • Method for preparing intermediate of colchicine derivatives
  • Method for preparing intermediate of colchicine derivatives

Examples

Experimental program
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Effect test

Embodiment 1

[0025] 7.0g colchicic acid was added to 70g PPA (85%P 2 o 5 ), that is, polyphosphoric acid (containing 85% phosphorus pentoxide), heated to 100°C, and 8.5g of sodium azide was added in batches while vigorously stirring. The gas generated during the reaction can be absorbed with cold alkaline solution.

[0026] After reacting until there is basically no gas evolution, follow the reaction with TLC (chloroform / methanol volume ratio 10:1) until the colchicic acid is consumed. Cool in a water bath to 60°C, add 100ml of water, stir until the PPA solution is completely dissolved, pour it into a beaker containing 500 grams of crushed ice, and adjust the pH to neutral or weakly alkaline with an aqueous solution with a molar concentration of 5M NaOH.

[0027] Suction filtration was performed after adjusting the pH value, and the obtained solid was washed with water until the water phase was neutral, and 4.2 g of solid was obtained after drying;

[0028] The filtrate obtained by suct...

Embodiment 2

[0031] Adopt the experimental condition identical with embodiment 1, only PPA (85%P 2 o 5 ) to PPA (80%P 2 o 5 ). The resulting solid crude product was recrystallized with methanol-water at a volume ratio of 2:1, and dried to obtain (5S)-N-(3-amino-9,10,11-trimethoxy-6,7-dihydro-5H - Dibenzo[a,c]cyclohepten-5-yl)acetamide 4.2 g.

Embodiment 3

[0033] 7g P 2 o 5 Add 5g 90% H in 3 PO 4 , Heated and stirred at 120 ° C, now made of polyphosphoric acid. Add 4.5 g of colchicic acid, then dropwise add 60 mL of 0.5 mol / L azide in benzene solution, heat to reflux, follow the reaction with TLC (chloroform / methanol volume ratio 10:1), until the colchicic acid is consumed , the solvent benzene was removed by rotary evaporation, and 80ml of water was added to make the polyphosphoric acid solution fully dissolved, and the follow-up treatment was the same as in Example 1 to obtain (5S)-N-(3-amino-9,10,11-trimethoxy-6, 2.8 g of 7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl)acetamide.

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Abstract

The invention discloses a method for preparing an intermediate of colchicine derivatives, namely (5S)-N-(3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo [a, c] cycloheptene-5-yl) acetamide. The method comprises the steps of rearranging colchicine under the action of sodium methylate to generate allo-colchicine, hydrolyzing the allo-colchicine under alkaline conditions to obtain colchicinic acid and carrying out Schmidt rearrangement on the colchicinic acid and an azide reagent under the catalysis of polyphosphoric acid to obtain the intermediate of the colchicine derivatives, namely the (5S)-N-(3-amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cycloheptene-5-yl)acetamide. The method has the advantages that the polyphosphoric acid is adopted to catalyze the Schmidt rearrangement; the reaction condition is mild; the process is simple; the product purification is easy; the yield is high; and large-scale industrial production is easy to realize.

Description

technical field [0001] The invention relates to a method for preparing a derivative intermediate, in particular to a method for preparing a colchicine derivative intermediate. Background technique [0002] (5S)-N-(3-Amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl)acetamide, structural formula As shown in (I), [0003] [0004] It is an important intermediate for the synthesis of colchicine derivatives. The current synthesis mainly adopts the method disclosed by Fernholz in Liebigs Ann. Alkaline hydrolysis to obtain colchicic acid (Colchinoic acid, also known as allocolchicine), which is directly reacted with sodium azide through Schmidt rearrangement under the catalysis of concentrated sulfuric acid to obtain the intermediate of colchicine derivatives (5S)-N-(3-Amino-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-5-yl)acetamide. [0005] The synthesis yield of colchicic acid in the method can reach more than 80%, and is suitable for lar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/41C07C231/12
Inventor 钟建华沈莉萍王彦广
Owner ZHEJIANG UNIV
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