Unlock instant, AI-driven research and patent intelligence for your innovation.

A kind of preparation method of minodronic acid

A technology of minodronic acid and acetic acid, applied in chemical instruments and methods, compounds of group 5/15 elements of the periodic table, organic chemistry, etc., can solve the problems of difficult removal and low yield, and reduce the generation of impurities , improved yield, good effect of atom economy

Active Publication Date: 2017-02-08
SHANDONG LUOXIN PHARMA GRP CO LTD
View PDF4 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method 4-bromoacetoacetate ethyl has no industrial raw materials, needs further synthesis to use liquid bromine, and the yield of the cyclization process is low, and produces the relatively large impurity 2-(imidazo[1,2-a]pyridine -2-yl) acetic acid, difficult to remove

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
  • A kind of preparation method of minodronic acid
  • A kind of preparation method of minodronic acid
  • A kind of preparation method of minodronic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Example 1: Synthesis of 2-(imidazo[1,2-a]pyridin-3-yl) ethyl acetate

[0036]Dissolve 23.5g (250mmol) of 2-aminopyridine in 100mL of absolute ethanol, add 35.4g of triethylamine and 2.4g of copper trifluoromethanesulfonate to the solution, and add dropwise 47.3 g of trifluoromethanesulfonate dissolved in 100mL of absolute ethanol to the solution while stirring. g of ethyl 4-chloroacetoacetate, heated to 55-60°C, reacted for 4-5 hours, TLC (developer: chloroform: methanol = 2:1) monitored the reaction solution until the 2-aminopyridine spots disappeared, and added 1% citric acid solution to the pH of the solution is 7.6, and the insolubles are removed by filtration, the filtrate is extracted with ethyl acetate, the organic layer is collected, dried and filtered, concentrated to give 47.4 g of light yellow viscous liquid, yield 92.8% ( Calculated as 2-aminopyridine), the purity is 97.57%, and the impurity 2-(imidazo[1,2-a]pyridin-2-yl)ethyl acetate is 0.43% (HPLC normaliz...

Embodiment 2

[0037] Example 2: Synthesis of 2-(imidazo[1,2-a]pyridin-3-yl) ethyl acetate

[0038] Dissolve 23.5g (250mmol) 2-aminopyridine with 100mL absolute ethanol, add 35.4g triethylamine, 2.4g copper trifluoroacetate in the solution, under stirring, add dropwise 49.5g 4 -Ethyl chloroacetoacetate, heated to 55-60°C, reacted for 4-5 hours, TLC (developing agent: chloroform:methanol=2:1) ​​monitored the reaction solution until the 2-aminopyridine spots disappeared, and added 1% citric acid solution until the pH of the solution was 7.7, filtered to remove insoluble matter, the filtrate was extracted with ethyl acetate, the organic layer was collected, dried and filtered, and concentrated to obtain 47.0 g of a light yellow solid with a yield of 92.1%, a purity of 97.60%, and impurities 2-(imidazo[1,2-a]pyridin-2-yl)ethyl acetate 0.40% (HPLC normalization method).

Embodiment 3

[0039] Example 3: Synthesis of 2-(imidazo[1,2-a]pyridin-3-yl) ethyl acetate

[0040] Dissolve 23.5g (250mmol) 2-aminopyridine in 100mL of absolute ethanol, add 37.9g ​​of triethylamine and 2.8g of copper acetate to the solution, and add dropwise 51.5g of 4-chloropyridine dissolved in 100mL of absolute ethanol under stirring. Ethyl acetoacetate, heated to maintain the temperature at 55-60°C, reacted for 4-5 hours, TLC (developing agent: chloroform: methanol = 2:1) monitored the reaction solution until the 2-aminopyridine spots disappeared, and added 1% to the solution citric acid solution until the pH of the solution was 7.7, filtered to remove insoluble matter, the filtrate was extracted with ethyl acetate, the organic layer was collected, dried and filtered, concentrated to give 45.7 g of light yellow viscous liquid, yield 89.7%, purity 95.87 %, impurity 2-(imidazo[1,2-a]pyridin-2-yl) ethyl acetate 0.55% (HPLC normalization method)

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 relates to the technical field of drug synthesis, in particular to a minodronic acid preparing method. The method mainly includes the following steps that 2-aminopyridine is dissolved through organic solvent, organic alkali, copper catalyst and 4-chloroacetoacetic acid ethyl ester are added to the solution, reaction is conducted, and 2-(imidazo [1,2-a] pyridine-3-base) ethyl acetate is obtained; the 2-(imidazo [1,2-a] pyridine-3-base) ethyl acetate is dissolved through organic solvent, hydrolysis is conducted on the 2-(imidazo [1,2-a] pyridine-3-base) ethyl acetate through sodium hydroxide, and 2-(imidazo [1,2-a] pyridine-3-base) acetic acid is obtained; minodronic acid is prepared through phosphorylation in the prior art. According to the method, the copper catalyst is utilized, the yield of ring closing reaction is increased, generation of impurities is reduced, the operation steps are concise and easy to control, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of minodronic acid. Background technique [0002] Minodronic acid (minodronic acid), the chemical name is [1-hydroxy-2-(imidazo[1,2-a]pyridin-3-yl)ethylidene]bisphosphonic acid, manufactured by Japan Yamanouchi Pharmaceutical Co., Ltd. Jointly developed by Ono Pharmaceutical Co., Ltd., its oral preparations were launched in Japan under the trade names Recalbon and Bonoteo by Ono and Astellas in 2009. Compared with the existing bisphosphonic acid drugs, this product exhibits good anti-bone resorption ability, inhibits bone density and bone strength reduction at a lower dose, has a preventive effect on fractures, and is clinically used for the treatment of osteoporosis. [0003] Existing many papers have reported the preparation method of minodronic acid at present, all relate to the synthesis of key intermediate 2-(imidazo[1,2-a]pyridin-3-yl)acetic aci...

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 Patents(China)
IPC IPC(8): C07F9/6561
Inventor 张锋李志滨朱全明
Owner SHANDONG LUOXIN PHARMA GRP CO LTD