Crystalline form of thymidine phosphorylase inhibitor and preparation method thereof

A technology of trifluorothymidine and crystal form, applied in the directions of organic chemistry, organic chemistry, pharmaceutical formulations, etc., to achieve the effects of short cycle, good stability and simple operation

Active Publication Date: 2014-05-14
QILU PHARMA HAINAN +1
View PDF4 Cites 21 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The 5-chloro-6-(1-(2-iminopyrrolidinyl) methyl) uracil hydrochloride as TAS-102 effective drug component has the chemical structure shown in formula I, and for its high crystallinity, There are no reports in the literature about pharmaceutical crystal forms with

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Crystalline form of thymidine phosphorylase inhibitor and preparation method thereof
  • Crystalline form of thymidine phosphorylase inhibitor and preparation method thereof
  • Crystalline form of thymidine phosphorylase inhibitor and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0044] Preparation Example 1: Preparation of 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride

[0045] A. Preparation of 5-chloro-6-chloromethyluracil:

[0046]

[0047] Add 100ml of acetic acid to 20.0g of 6-chloromethyluracil, add 22ml of sulfuryl chloride dropwise within 20 minutes under stirring condition, after the dropwise addition is completed, stir and react at 30-35°C, TLC monitors that the reaction of raw materials is complete, and slowly pour the reaction solution into 200ml Suction filter in ice water, wash with 10-15ml of methanol, and air-dry at 50°C to obtain 16.0g of off-white solid with a yield of 66.0%.

[0048] ESI-MS (m / z): [M+H] 195.0; 1 HNMR (600MHz, DMSO-d 6 , δppm): 4.47 (S, 2H), 11.58 (S, 1H), 11.72 (S, 1H).

[0049] b. Preparation of 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride

[0050]

[0051] In the reaction bottle, add 150ml N, N-dimethylformamide (DMF), 19.5g 2-aminopyrrolidine hydrochloride, 18.0g sodium...

Embodiment 1

[0053] Example 1: Preparation of 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride crystal form I

[0054] Add 1.0 g of the solid product obtained by the method of Preparation Example 1 into a mixed solvent composed of 3.0 ml of water and 15 ml of isopropanol, heat and stir until dissolved, then cool down to 15°C within 1.5 to 2 hours while stirring, continue stirring for 2 hours, and filter. After washing and drying, 0.94 g of the crystal form I described in the title was obtained in the form of 0.94 g of white crystals, with a yield of 94% and a purity of 100.0% by HPLC;

[0055] After testing, its X-ray powder diffraction pattern is as follows figure 1 As described, the differential scanning calorimetry (DSC) spectrum is as figure 2 Shown; its infrared absorption spectrum as image 3 As shown, the polarizing microscope image as Figure 4 shown.

Embodiment 2

[0056] Example 2: Preparation of 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride crystal form I

[0057] Add 1.0 g of the solid product obtained by the method of Preparation Example 1 into a mixed solvent composed of 3.0 ml of water and 10 ml of isopropanol, heat and stir until dissolved, then cool down to 20°C within 1.5 to 2 hours while stirring, continue stirring for 2 hours, and filter. After washing and drying, 0.92 g of the crystal form I described in the title was obtained in the form of 0.92 g of white crystals, with a yield of 92% and a purity of 100.0% by HPLC;

[0058] After testing, its X-ray powder diffraction pattern is consistent with figure 1 Basically the same, differential scanning calorimetry (DSC) spectrum and figure 2 Basically the same, the infrared absorption spectrum and image 3 Basically the same, the scanning electron microscope image and Figure 4 Basically the same.

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

PUM

No PUM Login to view more

Abstract

The invention specifically discloses a new crystalline form of 5-chlorine-6-(1-(2-iminopyrrolidyl)methyl)uracil hydrochloride, and discloses a preparation method thereof. The crystalline form has the advantages of good stability, high crystallinity, easiness in preparation and the like, and can be used as a thymidine phosphorylase inhibitor for preparing colorectal cancer treating drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, in particular to a new crystal form of thymidine phosphorylase inhibitor 5-chloro-6-(1-(2-iminopyrrolidinyl)methyl)uracil hydrochloride and its preparation method. Background technique [0002] Colorectal cancer, also known as colorectal cancer, is one of the most common malignant tumors in the world. There are about 1 million new cases every year in the world, accounting for 10-15% of all tumors, and the incidence rate is still rising. The incidence rate in developed countries in North America is the highest, reaching 35-50 / 100,000 population. Its incidence rate and mortality rate rank second only to lung cancer in the United States, while the incidence rate in my country ranks fourth among all tumor diseases. There are 15.7 patients per 100,000 people, and 4.7 people per 100,000 people die from colorectal cancer, and the death rate during this period ranks fifth among can...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to view more

Application Information

Patent Timeline
no application Login to view more
IPC IPC(8): C07D403/06A61K31/513A61P35/00
CPCA61K31/513C07B2200/13C07D403/06A61K2300/00
Inventor 李燕刘建波李华玉王艳蕾初乐玲范传文田振平
Owner QILU PHARMA HAINAN
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap