Method for preparing high-yield and high-purity agomelatine crystal I

An agomelatine, high-purity technology, applied in the field of medicinal chemistry synthesis, can solve the problems of poor stability, low crystal form purity, poor reproducibility, etc., to improve yield and yield, reduce reagent cost and energy consumption , the effect of simple operation

Active Publication Date: 2014-05-21
SICHUAN OPEN MEDICINE CO LTD
View PDF10 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The present invention overcomes the disadvantages of low purity, poor reproducibility and poor stability of the crystal form in the prior art, and invents a method for preparing crystal form I of agomelatine with high yield and high purity different from the prior art, and the operation procedure of the method Detailed and clear experimental conditions, agomelatine crystal form I with high process purity (HPLC content greater than 99.5%) was obtained. This method has good reproducibility, high success rate, and high yield (more than 94%), which is suitable for industrialization Production

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
  • Method for preparing high-yield and high-purity agomelatine crystal I
  • Method for preparing high-yield and high-purity agomelatine crystal I
  • Method for preparing high-yield and high-purity agomelatine crystal I

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Dissolve 20g of agomelatine in a mixed solvent of 50mL of DMF and 25mL of purified water (the dissolution reaction temperature is 50°C); suction filtration under a pressure of -0.09MPa; slowly add the filtrate dropwise to 400mL while stirring at 180r / min Frozen purified water at 1°C, add dropwise for 2 hours; stir at constant temperature at 1°C for 1 hour after dropping; filter under -0.09MPa pressure; rinse with 40mL purified water, and put the obtained filter cake into a vacuum oven with 100g of phosphorus pentoxide After heat preservation at 40°C and drying for 72 hours, 18.92 g of white solid powder was obtained with a melting point of 98.3°C to 99.3°C and a yield of 94.6%. The white solid powder was verified as agomelatine crystal form I, with a purity of 99.96% (HPLC content), and a single impurity of 9ppm. Its HPLC test result is shown in Table 1 and attached image 3 , see the attached DSC test results figure 2 , XRPD test results are shown in Table 2 and att...

Embodiment 2

[0042] Dissolve agomelatine 16g in a mixed solvent of DMF 40mL and purified water 20mL (dissolution reaction temperature is 45°C); filter under -0.09MPa pressure; slowly add the filtrate dropwise to 320mL with stirring at 190r / min Frozen and purified water at 1°C, dropwise for 110min; after dropping, stir at 1°C for 1h; filter under -0.09MPa pressure; rinse with 30mL of purified water, and put the obtained filter cake into a vacuum oven with 80g of phosphorus pentoxide After heat preservation at 45°C and drying for 48 hours, 18.80 g of white solid powder was obtained with a melting point of 98.2°C to 99.1°C and a yield of 94%. The white solid powder was verified as agomelatine crystal form I, with a purity of 99.94% (HPLC content), and a single impurity of 9ppm. Its XRPD test result is shown in Table 3 and attached Figure 4 .

[0043]

[0044] The XRPD test data of table 3 embodiment two

[0045]

Embodiment 3

[0047]Dissolve 8g of agomelatine in a mixed solvent of DMF 20mL and purified water 8mL (dissolution reaction temperature is 50°C); filter under -0.09MPa pressure; slowly add the filtrate dropwise to 160mL with stirring at 180r / min Frozen purified water at 1°C, dropwise for 110 minutes; after dropping, stir at 0°C for 1 hour; filter under -0.09MPa pressure; rinse with 20mL of purified water, and put the obtained filter cake into a vacuum oven with 50g of phosphorus pentoxide After heat preservation at 45°C and drying for 72 hours, 18.84 g of white solid powder was obtained, with a melting point of 98.3°C to 99.3°C and a yield of 94.2%. The white solid powder was verified as agomelatine crystal form I, with a purity of 99.95% (HPLC content), and a single impurity of 8ppm. Its XRPD test result is shown in Table 4 and attached Figure 5 .

[0048] The XRPD test data of table 4 embodiment three

[0049]

[0050] The present invention has mild reaction conditions, simple opera...

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 discloses a method for preparing high-yield and high-purity agomelatine crystal I. The method comprises the following steps: firstly, dissolving agomelatine into a mixed solvent of dimethyl formamide (DMF) and purified water, wherein the ratio of the DMF to the purified water in dosage is (3:1)-(1:1), the ratio of the agomelatine to the mixed solvent in dosage is 1g:(3-4)mL, and the dissolution temperature is 45-60 DEG C; carrying out suction filtration; slowly adding the obtained filtrate to 20fold frozen purified water at 0-5 DEG C under the agitation at the rotation speed of 180-200r/min; slowly adding for 1.5-2.5 hours; agitating for an hour under the condition at constant temperature of 0-5 DEG C; carrying out suction filtration; rinsing a filter cake by using the purified water; putting the filter cake into a vacuum oven which contains phosphorus pentoxide under the temperature condition at 30-50 DEG C to dry for 36-72 hours, so as to obtain white solid powder. X-Ray-powder diffraction (XRPD) validates that the generated crystal I is agomelatine crystal I, the yield is 93.8-94.9%, the melting point is 98.3-99.3 DEG C, and the purity is greater than 99.5%. The method is mild in reaction condition, detailed in operating procedure, and explicit in experiment condition, the cost and the energy consumption of the reagent are reduced, the condition for achieving industrial production is controllable by controlling each critical process parameter, and large-scale industrialization is facilitated.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a preparation method of agomelatine crystal form I. Background technique [0002] Agomelatine (agomelatine), the chemical name is N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide, and its structural formula is as follows: [0003] [0004] Agomelatine is a new type of antidepressant, which is not only a melatonin (melatonin, MT) receptor agonist, but also a 5-hydroxytryptamine (5-HT) 2C receptor antagonist. Agomelatine can effectively treat adult depression, especially for major depressive disorder (MMD), and can effectively improve sleep parameters and maintain sexual function. The preparation method and therapeutic use of agomelatine have been reported in European patent specification EP0447285. Agomelatine crystal form I was described in detail by Tinant et al. (Actacryst, 1994, c50, 907-910). [0005] CN200910228683.5 records the prepar...

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
Patent Type & Authority Applications(China)
IPC IPC(8): C07C233/18C07C231/24
Inventor 刘波骆俊清魏岚范有平但汉兴黄明辉宛燕飞丁昭莉
Owner SICHUAN OPEN MEDICINE CO LTD
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