Method for synthesizing CA4P

The technology of conbutastatin and mixed solvent, which is applied to a preparation field of conbutastatin, can solve the problems of complicated operation, harsh conditions and high reagent price, and achieves the advantages of cheap and easy-to-obtain raw materials, mild reaction conditions, and simple and feasible operation. Effect

Active Publication Date: 2010-11-17
SHANGHAI ECUST BIOMEDICINE CO LTD
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  • Abstract
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Problems solved by technology

The document WO0249994 reports the Perkin method, which uses 3,4,5-trimethoxyphenylacetic acid and isovanillin as raw materials for preparation. The problem with this method is that the Penkin reaction step does not give the ratio of high cis-trans isomers; finally The one-step decarboxylation reaction temperature is relatively high, requiring more than 230°C, which is not suitable for industrial production; in addition, the double bond in CA4 is prone to side reactions such as oxidation, polymerization, and isomerization at a temperature of 200°C, so this route is not ideal.
The raw materials are expensive and the conditions are harsh. It takes two resin exchanges to wait for the sodium salt of CA4P, which has great limitations in operation and industrialization.
The separation and purification operations are complicated and the yield is low, which is not suitable for large-scale production and cannot meet the needs of clinical trials
Chinese Journal of Pharmaceutical Industry, 2001, 32: 531-532 provides the method of N, N-diethylamino-di-tert-butyl phosphonate, the method reagent price is relatively high, and the cost is too high

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  • Method for synthesizing CA4P

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Effect test

Embodiment 1

[0020] 1.1 3-trityloxy-4-methoxybenzaldehyde

[0021] Into a 500 mL flask, 50 g of isovanillin, 104 g of trityl chloride, 65 mL of triethylamine, and 180 mL of dry tetrahydrofuran were added. Raise the temperature to reflux, and react for 4 to 5 hours. TLC showed the reaction was complete. Add 100 mL of water to the reaction system to stop the reaction, and lower the temperature to 20-25°C. Ethyl acetate / n-heptane (1:1) 80 mL was added, and a granular light yellow solid was formed. The precipitate was filtered. The filter cake was washed with purified water. After vacuum drying, 100 g of 3-trityloxy-4-methoxybenzaldehyde was obtained with a yield of 77%.

[0022] 1.2 3'-trityloxy-3,4,4',5-tetramethoxystilbene

[0023] In a 500 mL four-necked flask, under argon protection, 65 g of trimethoxyphenylmethylenetriphenylphosphine bromide and 112 mL of anhydrous tetrahydrofuran were added. Cool to -25°C, add 70mL of n-butyl lithium in n-hexane solution (2.4M) dropwise to the sy...

Embodiment 2

[0040] 2.13-trityloxy-4-methoxybenzaldehyde

[0041] Into a 500 mL flask, 50 g of isovanillin, 104 g of trityl chloride, 65 mL of triethylamine, and 180 mL of dry methylene chloride were added. The temperature was raised to reflux, and the reaction was followed by TLC. Add 100 mL of water to the reaction system to stop the reaction, and lower the temperature to normal temperature 20-25°C. Ethyl acetate / n-heptane (1:1) 80 mL was added, and a granular light yellow solid was formed. The precipitate was filtered, and the filter cake was washed with purified water. After vacuum drying, 95 g of 3-trityloxy-4-methoxybenzaldehyde was obtained with a yield of 74%.

[0042] 2.23'-trityloxy-3,4,4',5-tetramethoxystilbene

[0043] In a 500 mL four-necked flask, under argon protection, 65 g of trimethoxyphenylmethylenetriphenylphosphine bromide and 112 mL of anhydrous tetrahydrofuran were added. Cool to -15°C, add 70mL of n-butyl lithium in n-hexane solution (2.4M) dropwise to the syst...

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Abstract

The invention belongs to the field of chemical synthesis and relates to a method for preparing CA4P, in particular to a method for synthesizing CA4P by the following steps that: isovanillin and trityl chloride, which serve as raw materials, are used to form 3- triphenylmethoxy-4-methoxybenzaldehyde which is an intermediate isovanillin protector; the 3- triphenylmethoxy-4-methoxybenzaldehyde and 3,4,5-trimethoxy-triphenyl benzylidene bromide phosphine salt undergo a Wittig reaction , and the protective group is removed by hydrolysis to obtain CA4; and the CA4 and phosphonic acid bis(phenylmethyl)ester react to form benzyl phosphate, and the benzyl group is removed to form a sodium salt to obtain the target compound, namely CA4P.

Description

technical field [0001] The invention relates to a preparation method of comprastatin (CA4P), which belongs to the field of chemical synthesis. In particular, it involves using isovanillin and trityl chloride as raw materials to obtain the intermediate isovanillin protected body 3-trityloxy-4-methoxybenzaldehyde; 3-trityloxy-4- Methoxybenzaldehyde and 3,4,5-trimethoxybenzyl bromide triphenylphosphine salt undergo Wittig reaction, hydrolysis and deprotection to obtain CA4; through CA4 and dibenzyl phosphite to form benzyl phosphate, debenzylation to form sodium The salt obtains the synthesis method of the target compound combrestatin. Background technique [0002] Combretastatin (CA4P) is a new type of anti-tumor prodrug developed by the American OXIGENE company. Its original drug is CA4 (Combretastatin A4), which is a polyhydroxy stilbene isolated from the bark of the African shrub Combretum Caffrum. natural product. CA4P is a tubulin binding agent, which can interfere wit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/12
CPCC09B23/148
Inventor 吴范宏肖繁花周卫国徐方明熊杨苏敏
Owner SHANGHAI ECUST BIOMEDICINE CO LTD
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