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Related substances F and G of pemetrexed disodium as well as preparation and detection method thereof

A technology for pemetrexed disodium and related substances is applied to the related substances of pemetrexed disodium and the fields of preparation and detection thereof to achieve the effect of promoting further development, economy and technology

Active Publication Date: 2016-12-14
SUZHOU LIXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] From the published analysis of the above five related substances and their production mechanism, the research does not involve the impurities produced by the oxidation process, but the oxidation factor is an unavoidable factor in the storage and use of raw materials

Method used

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  • Related substances F and G of pemetrexed disodium as well as preparation and detection method thereof
  • Related substances F and G of pemetrexed disodium as well as preparation and detection method thereof
  • Related substances F and G of pemetrexed disodium as well as preparation and detection method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1: Preparation of Pemetrexed Disodium Related Substance F and Related Substance G

[0030] At room temperature, add pemetrexed disodium (4.7g, 10mmol) and 50mL of water into the reaction bottle, stir until dissolved, add 3.5mL of 18% hydrogen peroxide, keep at 20-30°C, stir for 3-5 hours, TLC detection , the reaction is complete.

[0031] Add 50 mL of dichloromethane, adjust the pH to 3-4 with hydrochloric acid, stir for 30 minutes, separate layers, concentrate the organic phase, and separate the resulting oily matter by column chromatography (ethyl acetate / methanol=5 / 1) to obtain pemetrex 3.1 g of off-white solids of related substance F and related substance G of disodium disodium, yield 70.0%. 1H NMR (DMSO-d6) δ8.43(s, 4H,), 8.16(m, 1H), 7.73(m, 2H), 7.54(s, 2H), 7.25(d, J=6.8Hz, 2H), 4.17(m, 1H), 3.30(m, 1H), 2.68(m, 2H), 2.20(m, 2H), 2.02(m, 2H), 1.94(m, 2H); EI-MS m / z443(M +H).

[0032] The synthetic route involved therein is as follows:

[0033]

Embodiment 2

[0034] Example 2: High-performance liquid chromatography detection method of pemetrexed disodium related substance F and related substance G

[0035] Adopt high performance liquid chromatography (HPLC), the pemetrexed disodium related substance F and related substance G related to the present invention are detected, and it comprises the steps:

[0036] (1) Chromatographic column C8 / 150×4.6mm / 3.5μm, column temperature 25 degrees, wavelength 250nm and flow rate 1.0mL / min;

[0037] (2) prepare mobile phase A to be the ammonium formate solution of 12mmol / L of 95% volume and mix with the acetonitrile of 5% volume and adjust pH value to 3.5 with formic acid; Preparation mobile phase B is the ammonium formate of 12mmol / L of 70% volume After the solution is mixed with 30% volume of acetonitrile, the pH is adjusted to 3.5 with formic acid; the gradient time program of the mobile phase is determined to be 100%-0% / 0-55min;

[0038] The detailed gradient design is:

[0039]

[0040] ...

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Abstract

The invention discloses related substances F and G of pemetrexed disodium as well as preparation and detection researches on the two substances. Remarkable economic and technical benefits can be made for improvement of the quality and the safety of medicines of pemetrexed disodium. The chemical formulae of the two substances are as shown in the specification.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a related substance of pemetrexed disodium and a preparation and detection method thereof. Background technique [0002] Pemetrexed disodium (Pemetrexed disodium) is a new type of multi-target folic acid blocker containing pyrrole pyrimidine group. It can block various enzymes needed in the process of cancer cell division and proliferation, so as to achieve anti-tumor effect. The drug was developed by Eli Lilly (Eli Lilly) of the United States and first launched in the United States in 2004. It was approved to be used in combination with cisplatin for the treatment of malignant pleural mesothelioma and non-small cell lung cancer. The trade name is Alimta (Libitai). The drug was launched in China in December 2005, and the approved indication is malignant pleural mesothelioma. [0003] The chemi...

Claims

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Application Information

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IPC IPC(8): C07D487/04G01N30/74
CPCC07D487/04G01N30/74
Inventor 许学农包志坚苏健舒亮谢玲玲冷秀云黄栋梁范红
Owner SUZHOU LIXIN PHARMA
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