Camptothecin and method for preparing analogues thereof

A technology of analogs and camptothecin, which is applied in the field of preparation of -camptothecin and its analogs, can solve the problems of harsh reaction conditions, poor product purity, and serious waste pollution, and achieve mild reaction conditions, good product quality, The effect of less pollution of three wastes

Inactive Publication Date: 2010-09-08
FUDAN UNIV
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Problems solved by technology

These methods all have the disadvantages of large amount of catalyst, serious pollution of three wastes, harsh reaction conditions, cumbersome reaction steps, complicated process and so on.
The Friedlander condensation reaction of compound (IV) and substituted o-aminobenzaldehyde (ketone) (V) is usually under the catalysis of p-toluenesulfonic acid, in anhydrous toluene / ethanol system azeotropic reaction with water for 5 to 10 hours to obtain hi Rectamine and its analogs (I), but this technology has shortcomings such as low reaction yield and poor product purity, which is not conducive to large-scale preparation
Chinese patent 101270123 has described that under the effect of trimethylsilane chloride, compound (IV) and compound (V) carry out Friedlander condensation to prepare compound (I), although the reaction yield and product purity of this technology have a little improvement, but still exist Disadvantages such as excessive dosage of trimethylsilyl chloride (4 to 5 times the stoichiometric ratio relative to the reaction substrate is optimal) and inconvenient operation of the reaction

Method used

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  • Camptothecin and method for preparing analogues thereof
  • Camptothecin and method for preparing analogues thereof
  • Camptothecin and method for preparing analogues thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Nitrogen in 3,10-dioxo-4-ethyl-6,6-disubstituted alkoxy(thio)yl-1,4,7,8-tetrahydro-4-hydroxypyran (3,4-f) Preparation of indene (III):

[0026] Compound 3,10-dioxo-4-ethyl-6,6-ethylenedioxy-1,4,7,8-tetrahydropyran (3,4-f) indolizine (II) ( 2.91g, 10mmol), 10% palladium / carbon (0.29g), triethylamine (0.10g, 1mmol) and methanol (30mL) were placed in a reaction flask, and oxygen was introduced at 20°C under normal pressure, and the reaction was stirred for 1 hour. After completion of the reaction, filter and spin the filtrate to dryness under reduced pressure, add dichloromethane (100 mL), and wash the organic layer with water (50 mL×2) and saturated brine (50 mL), respectively. Dry over anhydrous sodium sulfate, recover dichloromethane, and obtain off-white compound 3,10-dioxo-4-ethyl-6,6-ethylenedioxy-1,4,7,8-tetrahydro-4- Hydroxypyran (3,4-f) indolizine (III) 2.7g, yield 88%, mp 178.5-180°C, purity ≥ 98%.

Embodiment 2

[0028] Compound 3,10-dioxo-4-ethyl-6,6-ethylenedioxy-1,4,7,8-tetrahydropyran (3,4-f) indolizine (II) ( 0.29g, 1mmol), the 10% palladium / carbon (0.029g) recovered in Example 1, triethylamine (10.1mg, 0.1mmol) and methanol (3mL) were placed in a reaction flask, and passed through at 25°C under normal pressure Oxygen, stirred for 2 hours. After the reaction was completed, it was filtered, and the filtrate was spin-dried under reduced pressure, dichloromethane (50 mL) was added, and the organic layer was washed with water (20 mL×2) and saturated brine (20 mL), respectively. Dry over anhydrous sodium sulfate, recover dichloromethane, and obtain off-white compound 3,10-dioxo-4-ethyl-6,6-ethylenedioxy-1,4,7,8-tetrahydro-4- Hydroxypyran (3,4-f) indolizine (III) 0.26g, yield 85%, mp 177.3-180.5°C, purity ≥ 96%.

Embodiment 3

[0030]Compound 3,10-dioxo-4-ethyl-6,6-(2′,2′-dimethyl-1′,4′propylenedioxy)-1,4,7,8- Tetrahydropyran (3,4-f) indolizine (II) (3.33g, 10mmol), 10% palladium / carbon (0.33g), triethylamine (0.10g, 1mmol) and ethanol (30mL) were reacted In the bottle, at 25°C, oxygen was introduced under normal pressure, and the reaction was stirred for 2 hours. After completion of the reaction, filter and spin the filtrate to dryness under reduced pressure, add dichloromethane (100 mL), and wash the organic layer with water (50 mL×2) and saturated brine (50 mL), respectively. Dry over anhydrous sodium sulfate, recover dichloromethane, and obtain off-white compound 3,10-dioxo-4-ethyl-6,6-(2',2'-dimethyl-1',4'-propylene Dioxy)-1,4,7,8-tetrahydro-4-hydroxypyran (3,4-f) indolizine (III) 3.12g, yield 89%, mp 188~189.7℃, purity ≥ 98%.

[0031] Example 3

[0032] Preparation of 3,6,10-trioxy-4-ethyl-1,4,7,8-tetrahydro-4-hydroxypyran (3,4-f) indolizine (IV):

[0033] The compound 3,10-dioxo-4-ethyl-6...

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Abstract

The invention relates to camptothecin and a method for preparing analogues of the camptothecin, and belongs to the field of organic chemistry. The method comprises the following steps of: carrying out palladium / carbon catalytic oxidation on 3,10-dioxo-4-ethyl-6,6-disubstituted alkoxy (alkylthio)-1,4,7,8-tetrahydropyrane (3,4-f) indolizine serving as a starting material in the presence of catalytic amount of organic base or under an alkali-free condition to generate 3,10-dioxo-4-ethyl-6,6-disubstituted alkoxy (alkylthio)-1,4,7,8-tetralin-hydroxy-pyran(3,4-f) indolizine; and carrying out molecular iodine-catalyzed ketal deprotection and carrying out Friedlander condensation of substituted o-aminobenzaldehyde (o-aminobenzophenone) and the 3,0-dioxo-4-ethyl-6,6-disubstituted alkoxy (alkylthio)-1,4,7,8-tetralin-hydroxy-pyran(3,4-f) indolizine so as to obtain the camptothecin and the analogues thereof. In the invention, the catalyst palladium / carbon can be recycled for three times without reducing catalytic effect, and the whole synthetic route has the advantages of mild reaction conditions, simple operation, environmental friendliness, high yield and quality of products, and suitability for industrial production. In the formula, R1 refers to H, OH and OCH3, and R2 refers to H, and C1 to C5 alkyl.

Description

technical field [0001] The invention belongs to the field of organic chemistry, and in particular relates to a preparation method of (dl)-camptothecin and its analogues. Background technique [0002] Camptothecin (R 1 =R 2 =H, camptothecin, C PT) was first obtained from the Davidiaceae plant Camptothecin in 1966 by American Wall et al. An anti-tumor alkaloid containing a quinoline pentacyclic skeleton structure isolated from Since Hsiang et al. (Hsiang YH, Hertzberg R, Hecht S et al. J Bio Chem., 1985, 260: 14873) discovered the unique mechanism of action of camptothecin as a specific inhibitor of topoisomerase I in 1985, The research and development of such compounds has entered a stage of rapid development. For more than 20 years, the efficient chemical synthesis of camptothecin and its derivatives has been one of the hotspots in the field of medicinal chemistry research. Different research groups at home and abroad have successively reported more than 30 synthetic com...

Claims

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Application Information

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IPC IPC(8): C07D491/22B01J27/06B01J23/44
Inventor 陈芬儿匡云艳
Owner FUDAN UNIV
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