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Salt of 5-fluorouracil and metformin as well as preparation method and crystal structure of salt

A technology of fluorouracil-metformin salt and fluorouracil, which is applied in the field of medicinal chemistry, can solve the problems of single therapeutic target, low bioavailability, and poor selectivity, and achieve the effects of simple process, high yield and purity, and low cost

Active Publication Date: 2018-12-28
OCEAN UNIV OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in clinical use, it is found that 5-Fu mainly has two problems: one is that the 5-Fu therapeutic target is single and the selectivity is poor, leading to tumor drug resistance and side effects; the other is that 5-Fu is water-soluble and Both are poorly fat soluble, resulting in low bioavailability
However, due to the huge difference in the physical and chemical properties of 5-Fu and Met and the incompatibility, traditional physical mixing compound preparations cannot overcome this problem

Method used

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  • Salt of 5-fluorouracil and metformin as well as preparation method and crystal structure of salt
  • Salt of 5-fluorouracil and metformin as well as preparation method and crystal structure of salt
  • Salt of 5-fluorouracil and metformin as well as preparation method and crystal structure of salt

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Experimental program
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specific Embodiment approach 1

[0023] Specific embodiment one: In this embodiment, 5-fluorouracil metformin salt has a chemical structure shown in formula (I), and its molecular formula is C 8 h 14 FN 7 o 2 , consisting of a metformin cation and a 5-fluorouracil anion:

[0024]

[0025] Structural formula (I) of 5-fluorouracil metformin.

specific Embodiment approach 2

[0026] Specific embodiment two: In this embodiment, 5-fluorouracil metformin salt belongs to the monoclinic crystal system, and the space group is P 2 1 / n , the unit cell parameters are: a = 9.1294 Å, b = 12.3129 Å, c = 11.0216 Å, α = γ = 90°, β = 113.691°. Its PXRD characteristic diffraction peaks appear at 12.798°, 14.378°, 16.242°, 17.940°, 21.919°, 22.762°, 24.143°, 25.279°, 27.301°, 30.258°.

[0027] The 5-fluorouracil metformin salt described in this embodiment consists of a metformin cation and a 5-fluorouracil anion. Such as figure 2 As shown, the proton on the 1-position nitrogen atom in the 5-fluorouracil molecule is transferred to the nitrogen atom of metformin to form 5-fluorouracil anion and metformin cation, respectively. Each metformin cation in the crystal forms hydrogen bonds with five adjacent 5-fluorouracil anions, and vice versa. Among them, metformin forms two kinds of R through unsubstituted guanidine group and 5-fluorouracil 2 2 (6) A cyclic hy...

specific Embodiment approach 3

[0028] Specific embodiment three: the preparation method of the present embodiment 5-fluorouracil metformin salt is implemented according to the following steps:

[0029] Under the protection of nitrogen, put the 5-fluorouracil raw material drug and metformin free base in a round bottom flask with a molar ratio of 1:1, add a mixed solvent of methanol and acetonitrile to completely dissolve the mixed powder, stir until there is precipitation, continue to stir After 12 to 48 hours, filter, wash and precipitate with methanol, acetonitrile and ether for several times to obtain the crude product, recrystallize with alcohol solvent, and dry in vacuum to obtain 5-fluorouracil metformin salt.

[0030] This embodiment prepares a 5-fluorouracil metformin salt with good chemical stability and high purity.

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Abstract

The invention discloses a salt of 5-fluorouracil and metformin as well as a preparation method and a crystal structure of the salt and relates to the field of medicinal chemistry. The molecular formula of the 5-fluorouracil metformin salt is C8H14FN7O2; and a basic structural unit is formed by a metformin anion and a 5-fluorouracil anion. The salt belongs to a monoclinic crystal system with a space group of P21 / n. The preparation method comprises the following steps: taking a 5-fluorouracil crude drug and metformin free alkali as raw materials; mixing the 5-fluorouracil crude drug and the metformin free alkali according to the molar ratio of 1 to 1 and dissolving a mixture into a mixed solvent of methanol and acetonitrile for reacting; and taking ethanol as a solvent and recrystallizing toobtain high-purity 5-fluorouracil metformin salt. The 5-fluorouracil metformin salt disclosed by the invention has the advantages that the solubility of the 5-fluorouracil is improved and bioavailability of the 5-fluorouracil is favorably improved. The salt structure has no crystallized solvent molecules, so that a framework structure of the crystal of the salt can be kept after the salt is stored under the condition of room temperature for a long term and no denaturation phenomenon is caused.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a salt of 5-fluorouracil and metformin, a preparation method and a crystal structure thereof. Background technique [0002] With the development of society and changes in lifestyle, the spectrum of human diseases has undergone major changes, and cancer has always been one of the major diseases that seriously endanger human health. According to the World Health Organization cancer development research report, there are more than 10 million new cancer cases and more than 9 million deaths worldwide every year, and the trend is increasing. Although drug chemotherapy is still one of the main options for cancer treatment, however, most of the anti-tumor drugs currently used clinically have a relatively single site of action and only have high affinity and selectivity for a single target; while cancer In most cases, the occurrence of cancer is caused by the transduction of multiple s...

Claims

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Application Information

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IPC IPC(8): C07D239/553C07C279/26C07C277/08
CPCC07B2200/13C07C279/26C07D239/553
Inventor 李延团王凌阳刘方宋昱焉翠蔚管华诗吴智勇
Owner OCEAN UNIV OF CHINA