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Homocamptothecin compound and synthesis method thereof

A technology of homocamptothecin and its synthesis method, which is applied in the field of camptothecin and can solve the problems of poor solubility and bioavailability of homocamptothecin

Active Publication Date: 2017-03-08
SUNDIA MEDITECH COMPANY LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The purpose of the present invention is to provide a homocamptothecin compound with improved solubility and bioavailability and its synthesis method, mainly to solve the existing technical problems of poor solubility and bioavailability of homocamptothecin

Method used

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  • Homocamptothecin compound and synthesis method thereof
  • Homocamptothecin compound and synthesis method thereof
  • Homocamptothecin compound and synthesis method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Embodiment 1: ( S Synthesis of )-10-((dibutoxyphosphate)oxo)camptothecin (2)

[0040] Under an ice bath, slowly add elemental iodine (75.0 g, 0.30 mol) to a dichloromethane solution (200 mL) dissolved with tributyl phosphite (94.0 g, 0.38 mol), and the reaction system was maintained at this temperature Stir for half an hour, then remove the ice bath and gradually warm to room temperature. To the above reaction system, slowly dropwise add 10-hydroxycamptothecin (1,50.0 g, 0.14 mol) and 4-dimethylaminopyridine (42.0 g, 0.34 mol) in dichloromethane solution (600 mL) . The reactant was stirred at room temperature overnight. The organic phase was washed successively with 1M hydrochloric acid (200 mL x3), brine (200 mL x3), dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was subjected to column chromatography (DCM:CH 3 OH=200:1-60:1) purified to obtain 47.0 g (yield: 60%) ( S )-10-((dibutoxyphosphate)oxo)camptothecin (1), as a yellow solid. ...

Embodiment 2

[0041] Example 2: Dibutyl (4-ethyl-3,4-dihydroxy-14-oxo-3,4,12,14-tetrahydro-1H-pyranoindole-o-[1,2-b Synthesis of ]quinolin-9-yl)phosphate (3)

[0042] Xiang Rongyou ( S )-10-((dibutoxyphosphate) oxo)camptothecin (2, 47.0 g, 84.5 mmol) in anhydrous methanol solution (300 mL), under ice-cooling, within 10 minutes, add the solid Sodium borohydride (3.2 g, 84.5 mmol). The reaction was reacted at room temperature for half an hour, then quenched with saturated aqueous ammonium chloride (200 mL), and concentrated to dryness. The residue was dissolved in ethyl acetate (300 mL), then washed with saturated brine (100 mLx3), then dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 37.7 g (yield: 80.0%) of dibutyl ( 4-Ethyl-3,4-dihydroxy-14-oxo-3,4,12,14-tetrahydro-1H-pyranoindole-o[1,2-b]quinolin-9-yl) Phosphate ester synthesis (3), was pale yellow solid.

Embodiment 3

[0043] Example 3: {3-[1-(4-chloro-benzyl)-3-(2-cyano-thiophen-3-yl)-1 H Synthesis of -indol-2-yl]-phenoxy}-acetic acid (4)

[0044] In an ice bath, dibutyl (4-ethyl-3,4-dihydroxy-14-oxo-3,4,12,14-tetrahydro-1H-pyranoindole-o-[1,2 -b] quinoline-9-yl) phosphate (3, 2.00 g, 3.58 mmol) in acetone (30 mL) suspension liquid, slowly dropwise add sodium periodate aqueous solution (1.5 g, 11.7 mmol, 6 mL) . After the dropwise addition, the reaction solution rose to 50 o C, stirred for 5 hours. The reaction solution was concentrated to dryness, and the residue was dissolved in ethyl acetate (50 mL), washed with saturated brine (30mLx3), dried over anhydrous sodium sulfate and concentrated to dryness. The crude product was purified by column chromatography (DCM: CH 3 OH=100:1-40:1), to obtain 1.50 g (yield: 75%) {3-[1-(4-chloro-benzyl)-3-(2-cyano-thiophen-3-yl) -1 H -Indol-2-yl]-phenoxy}-acetic acid (4) as pale yellow solid.

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Abstract

The invention relates to camptothecin, in particular relates to homocamptothecin compounds and a synthesis method thereof, and mainly solves the technical problems of poor solubility and bioavailability of homocamptothecin in the prior art. Structural formulas of the homocamptothecin compounds are as shown in I and II, and the homocamptothecin compounds comprise racemic compounds and (S)-and (R)-stereisomers corresponding to the racemic compounds. The invention specifically relates to derivation of 10-hydroxyl homocamptothecin compound, the 10-hydroxyl homocamptothecin is used as a mother nucleus for synthesis of a series of homocamptothecin ester and amide compounds. The invention provides a new synthetic route, and according to the path, a full synthesis ring enlargement method is not needed, and protection and deprotection are not needed.

Description

technical field [0001] The present invention relates to camptothecin, in particular to a homocamptothecin compound and a synthesis method thereof. Background technique [0002] Camptothecin (CPT, 1) is a natural alkaloid with a five-ring fused ring system. Its (20S)-absolute configuration compound was first reported in 1966 and was extracted from the bark of Camptotheca acuminata by American scientist Wall. Experiments have proved that it has good lethality to rat leukemia cells (leukemia L1210), and has significant anti-tumor activity (Monroe E. Wall, M. C. Wani, C. E. Cook, et al. J. Am. Chem. Soc. 1966, 88, 3888-3889.). According to literature reports (K. Mross1, H.Richly, N. Schleucher, et al., Annals of Oncology , 2004, 15, 1284-1294.), he can prevent the direct interaction between topoisomerase I and DNA, thereby hindering the DNA replication of virus cells and apoptosis. [0003] However, due to its poor solubility in water, camptothecin (CPT, 1) is poorly absorb...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/22
CPCC07D491/22
Inventor 李尚丰马秀光何志敏陈炯
Owner SUNDIA MEDITECH COMPANY LTD
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