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Two novel crystal forms of 9-nitrocamptothecin and preparation methods thereof

A technology of nitrocamptothecin and crystal form, which is applied in the field of 9-nitrocamptothecin, can solve the problem that the solubility of 9-nitrocamptothecin crystal form is not significantly improved, it is difficult to ensure that the residual amount of organic solvent is qualified, and the preparation process cumbersome and other problems, to achieve the effect of easy industrial production, simple operation and simple preparation method

Active Publication Date: 2015-05-20
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The solubility of the 9-nitrocamptothecin crystal form obtained by the above-mentioned several technologies has not been significantly improved, and the preparation process is relatively cumbersome, and a large amount of organic solvents are used, which causes environmental pollution and is difficult to ensure that the residual amount of organic solvents in the product is qualified.

Method used

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  • Two novel crystal forms of 9-nitrocamptothecin and preparation methods thereof
  • Two novel crystal forms of 9-nitrocamptothecin and preparation methods thereof
  • Two novel crystal forms of 9-nitrocamptothecin and preparation methods thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0038] Preparation of 9-nitrocamptothecin crystal form I: Accurately measure 20ml DCM and 80ml EtOH to prepare a mixed solvent, accurately weigh 110mg 9-nitrocamptothecin, and dissolve it in the above mixed solvent to form a solution. In the control software, set the temperature of the settling tank to 45° C., the pressure to 125 bar, and the flow rate of carbon dioxide injected into the settling tank to be 20 g / min. Open the steel cylinder, pass carbon dioxide into the settling kettle with a high-pressure pump, and when the temperature and pressure in the still reach the set value, use another high-pressure pump to pass the mixed solvent into the settling kettle at a rate of 1.2ml / min. After 15 minutes, stop the flow. Into the mixed solvent, inject the 9-nitrocamptothecin solution at the same rate. After the sample injection is completed, continue to feed carbon dioxide for 40 minutes, stop the carbon dioxide pump, lower the pressure of the settling tank to atmospheric pressu...

Embodiment 2

[0042] Preparation of 9-nitrocamptothecin crystal form I: Accurately measure 20ml DCM and 80ml EtOH to prepare a mixed solvent, accurately weigh 90mg 9-nitrocamptothecin, and dissolve it in the above mixed solvent to form a solution. In the control software, set the temperature of the settling tank to be 40° C., the pressure to be 110 bar, and the flow rate of carbon dioxide injected into the settling tank to be 20 g / min. Open the steel cylinder, pass carbon dioxide into the settling kettle with a high-pressure pump, and when the temperature and pressure in the still reach the set value, use another high-pressure pump to pass the mixed solvent into the settling kettle at a rate of 0.9ml / min. After 15 minutes, stop the flow. Into the mixed solvent, inject the 9-nitrocamptothecin solution at the same rate. After the sample injection is completed, continue to feed carbon dioxide for 40 minutes, stop the control system, and take it out when the pressure of the settling tank is red...

Embodiment 3

[0045] Preparation of 9-nitrocamptothecin crystal form I: Accurately measure 20ml DCM and 80ml EtOH to prepare a mixed solvent, accurately weigh 50mg 9-nitrocamptothecin, and dissolve it in the above mixed solvent to form a solution. In the control software, set the temperature of the settling tank to be 40° C., the pressure to be 125 bar, and the flow rate of carbon dioxide injected into the settling tank to be 20 g / min. Open the steel cylinder, pass carbon dioxide into the settling kettle with a high-pressure pump, and when the temperature and pressure in the still reach the set value, use another high-pressure pump to pass the mixed solvent into the settling kettle at a rate of 0.6ml / min. After 15 minutes, stop the flow. Into the mixed solvent, inject the 9-nitrocamptothecin solution at the same rate. After the sample injection is completed, continue to feed carbon dioxide for 40 minutes, stop the control system, and take it out when the pressure of the settling tank is red...

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Abstract

The invention discloses two novel crystal forms of 9-nitrocamptothecin and preparation methods thereof. In the X-ray powder diffraction pattern with copper target as a radiation source, the crystal form I has characteristic diffraction peaks at the diffraction angle 2theta of 5.8+ / -0.1 degrees, 7.4+ / -0.1 degrees, 8.8+ / -0.1 degrees, 10.5+ / -0.1 degrees, 11.3+ / -0.2 degrees, 11.7+ / -0 degrees, 15.7+ / -0.2 degrees, 17.8+ / -0.1 degrees, 18.7+ / -0.1 degrees, 21.1+ / -0.1 degrees, 24.1+ / -0.1 degrees and 26.2+ / -0.1 degrees and the crystal form II has the characteristic diffraction peaks at the diffraction angle 2theta is 6.1+ / -0.2 degrees, 6.7+ / -0.1 degrees, 7.5+ / -0.2 degrees, 9.4+ / -0.1 degrees, 11.4+ / -0.2 degrees, 12.4+ / -0.1 degrees, 14.1+ / -0.1 degrees, 15.1+ / -0.1 degrees, 17.6+ / -0.1 degrees, 19.7+ / -0.1 degrees, 22.6+ / -0.1 degrees, 23.8+ / -0.1 degrees, 25.2+ / -0.1 degrees, 27.3+ / -0.1 degrees and 29.2+ / -0.2 degrees. The preparation methods of the two novel crystal forms of 9-nitrocamptothecin are based on a supercritical anti-solvent process. The solubility of the prepared novel crystal forms I and II of 9-nitrocamptothecin is higher than that of the existing crystal forms of 9-nitrocamptothecin, and the thermal stability of the prepared novel crystal forms I and II of 9-nitrocamptothecin is more excellent than that of the existing crystal forms of 9-nitrocamptothecin.

Description

technical field [0001] The invention relates to 9-nitrocamptothecin, in particular to two new crystal forms of 9-nitrocamptothecin and a preparation method thereof; the preparation method is a preparation method of supercritical anti-solvent technology. Background technique [0002] 9-nitrocamptothecin (9-nitrocamptothecin, 9-NC, rubitecan) is a semi-synthetic derivative of camptothecin, developed by Super Gene Company of the United States, the trade name is rubitecan, the chemical name is 4(S)-Ethyl-4-hydroxy-10-nitro-1H-pyrano[3',4':6,7]indeno[1,2-b]quinoline-3,14 (4H,12H)-Diketone, the molecular formula is C 20 h 15 N 3 0 6 , the molecular weight is 393, and its chemical structure is as follows: [0003] [0004] 9-nitrocamptothecin is a topoisomerase Ⅰ inhibitor, which can selectively inhibit topoisomerase Ⅰ, through the nucleophilic part of topoisomerase Ⅰ and the 9-nitrocamptothecin lactone ring The interaction of acyl groups interferes with DNA replication an...

Claims

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Application Information

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IPC IPC(8): C07D491/22
CPCC07B2200/13C07D491/22Y02P20/54
Inventor 江燕斌黄银霞刘贵金汪红娣
Owner SOUTH CHINA UNIV OF TECH
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