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Medicinal bulk drug for resisting tumors

A technology of raw materials and medicinal salts, applied in the field of medicine

Inactive Publication Date: 2014-01-01
李友香
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It has been found that during the long-term storage of the raw materials of the compound of formula I or its pharmaceutically acceptable salts or its preparations, some specific impurities show a tendency to increase with the prolongation of the sample retention time. This phenomenon is necessary for the strict requirements of "quality control "It is very unfavorable for the medicine

Method used

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  • Medicinal bulk drug for resisting tumors
  • Medicinal bulk drug for resisting tumors
  • Medicinal bulk drug for resisting tumors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0167] Embodiment 1: Preparation of eribulin / eribulin mesylate bulk drug

[0168] Step (1)——synthesis of the compound of formula I: According to CN1216051C (Chinese patent ZL99809658.X) instruction page 28, line 11, starting from L-arabinose synthesis triol 1, to instruction page 62, line 7, to obtain compound B1939, which is the formula I of the present invention Compound (free base form), the product obtained is a compound of formula I (crude product). It was determined by 【HPLC-A】, RRT1.07 content = 4.17%, RRT1.29 content = 0.73%.

[0169] Step (2)——salt formation: at a temperature of 20 to 25°C, add 50 grams of the product obtained in step (1) and 70 mmol of methanesulfonic acid to a mixed solution of 1400 ml of water and 1300 ml of acetonitrile, stir to react, and react The product was concentrated under reduced pressure; the resulting residue was dissolved in 400ml of dichloromethane, filtered, and 3000ml of n-pentane was added to the filtrate; the precipitate was fil...

Embodiment 2

[0171] Embodiment 2: Preparation of eribulin / eribulin mesylate bulk drug

[0172] Take the product obtained in step (2) of Example 1, and carry out recrystallization and purification with reference to the operation mode of step (3) of Example 1.

[0173] At a temperature of 30-35°C, dissolve 1.0 g of the product obtained in step (2) of Example 1 in 10 ml of anhydrous ethanol-ethyl acetate mixed solvent (1:3, v / v), and slowly add 60ml of n-hexane, let it stand still to allow sufficient precipitation (about 6 hours), filter out the precipitate, wash with n-hexane, and vacuum-dry to obtain (recrystallization yield 91.4%). It was determined by 【HPLC-A】, RRT1.07 content = 0.76%, RRT1.29 content = 0.33%. After one recrystallization purification, the content of RRT1.07 was reduced by 77.4%. It can be used as the eribulin mesylate bulk drug of the present invention.

Embodiment 3

[0174] Embodiment 3: Preparation of eribulin / eribulin mesylate bulk drug

[0175] Take the product obtained in step (2) of Example 1, and carry out recrystallization and purification with reference to the operation mode of step (3) of Example 1.

[0176] At a temperature of 35-40°C, 2.0 g of the product obtained in step (2) of Example 1 was dissolved in 10 ml of anhydrous ethanol-ethyl acetate mixed solvent (1:7, v / v), and slowly added dropwise 120ml of n-hexane, let it stand still to allow sufficient precipitation (about 36 hours), filter out the precipitate, wash with n-hexane, and vacuum-dry to obtain (recrystallization yield 95.2%). It was determined by [HPLC-A], RRT1.07 content = 0.91%, RRT1.29 content = 0.44%. After one recrystallization purification, the content of RRT1.07 was reduced by 72.9%. It can be used as the eribulin mesylate bulk drug of the present invention.

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Abstract

The invention relates to a medicinal bulk drug for resisting tumors, and in particular relates to a bulk drug for medicines. The active component of the bulk drug is a compound in the formula I or pharmaceutical salt thereof, wherein each substituent is described as the specification. The invention also relates to a medicinal composition containing the compound in the formula I or salt thereof, a preparation method of the medicinal composition and pharmaceutical application thereof. The bulk drug has excellent characteristics, such as stability and safety, when serving as an anti-tumor drug.

Description

technical field [0001] The invention relates to the technical field of medicine, and relates to a macrolide drug compound with antitumor activity. Background technique [0002] Halichondrin B, a potent anticancer agent, was originally isolated from the marine sponge Halichondria okadai and subsequently found in Axinella sp., Phakellia carteri, and Lissondendryxsp. .) found in . The total synthesis of halichondrin B was published in 1992 (Aicher, T, D. et al., J. Am. Chem. Soc. 114:3162-3164). Halichondrin B has been shown to inhibit tubulin polymerization, microtubule assembly, β s - Tubulin cross-linking, binding of GTP and vinblastine to tubulin and tubulin-dependent hydrolysis of GTP, and has shown anticancer properties in vitro and in vivo. [0003] Halichondrin analogues or pharmaceutically acceptable salts thereof, such as the mesylate salt shown in the following formula Ia, are known with the following formula I structure: [0004] [0005] Having defined pharm...

Claims

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Application Information

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IPC IPC(8): C07D493/22C07C309/04A61K31/357A61P35/00
CPCC07D493/22
Inventor 李友香孙俊
Owner 李友香
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