Mirabegron metabolite synthesis method

A synthetic method and metabolite technology, applied in the field of drug metabolism, can solve the problems of Mirabegron’s short time to market and achieve the effects of large application research value, reasonable process design, and strong operability

Inactive Publication Date: 2019-06-21
TLC NANJING PHARMA RANDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, because Mirabegron has been on the market for a relatively short time, there will be many side effects during the drug treatment process, and it has not been fully popularized for some specific groups of people, so there is still a lot of work to be done in its research, especially for Its metabolite research is even more meaningful
At present, there is no relevant report on the synthesis method of this mirabegron metabolite

Method used

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  • Mirabegron metabolite synthesis method
  • Mirabegron metabolite synthesis method

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Such as figure 1 Shown, a kind of synthetic method of mirabegron metabolite comprises the following steps:

[0028] (1) Take a 1-liter flask and add 750 ml of methanol, add 5 g of solid sodium hydroxide, add 100 g of glucuronolactone in batches while stirring at 0°C, react at 28°C for 2 hours, TLC (sampling, DCM dilution spot plate) , the raw material reaction is complete, the reaction solution is concentrated to dryness by rotary evaporation at 20°C, and the foam is pulled dry with an oil pump, and 250 ml of triethylamine is added to stand for 10 minutes, and 380 ml of acetic anhydride is slowly added in an ice bath, and it is left to stand for 15 minutes after the addition is completed. The reaction solution turned black, stirred and reacted overnight in an ice bath, a large amount of solids precipitated in the reaction mixture the next day, filtered with suction, rinsed with n-hexane: DCM volume ratio 4:1, rinsed with 100 ml each time for 3 times, and transferred the...

Embodiment 2

[0040] Such as figure 1 Shown, a kind of synthetic method of mirabegron metabolite comprises the following steps:

[0041] (1) Take a 1-liter flask, add 600 ml of methanol, add 3 g of solid sodium hydroxide, stir at 0°C in batches (after dissolving, add 100 g of glucuronolactone, react at 28°C for 3 hours, TLC (sampling, DCM dilution point plate), the raw materials reacted completely, the reaction solution was evaporated and concentrated to dryness at 20 ° C, and the oil pump was used to dry the foam, and 250 ml of triethylamine was added to stand for 10 minutes, and 380 ml of acetic anhydride was slowly added in an ice bath. Let it stand for 15 minutes after the addition, the reaction solution turns black, stir the reaction overnight in an ice bath, a large amount of solids precipitate out of the reaction mixture the next day, filter with suction, rinse with n-hexane:DCM volume ratio 4:1 (100 ml x 3), and transfer the solids Diethyl ether was dissolved in DCM to recrystalliz...

Embodiment 3

[0053] Such as figure 1 Shown, a kind of synthetic method of mirabegron metabolite comprises the following steps:

[0054](1) Take a 1-liter flask and add 750ml of methanol (newly opened), add 5g of lithium hydroxide solid, stir at 0°C in batches (after dissolving, add another batch), add 100g of glucuronolactone, and react at 28°C 2 hours, TLC (sampling, DCM dilution spot plate), the reaction of the raw materials is complete, the reaction solution is concentrated to dryness by rotary evaporation at 20 ° C, and then dried with an oil pump to foam, add 250 ml of triethylamine and let it stand for 10 minutes, slowly add 380 After the addition, let it stand for 15 minutes. The reaction solution turned black. Stir the reaction overnight in an ice bath. A large amount of solids precipitated in the reaction mixture the next day. Suction filtration, n-hexane: DCM volume ratio 4:1 rinse (100 ml x3 ), the solid was transferred to DCM to dissolve ether for recrystallization, suction fi...

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Abstract

The invention discloses a mirabegron metabolite synthesis method and belongs to the field of drug metabolism. The mirabegron metabolite synthesis method can prepare a mirabegron metabolite from glucurolactone (1R)-2-2[2-(4-nitrophenyl)ethylamino]-1-phenylethanol as starting materials through eight-step reaction. The mirabegron metabolite synthesis method has the advantages that the synthesis method is reasonable in process design and strong in operability on the basis of optimal preparation steps and reaction conditions screened by a great number of experiments; the synthesis method is high inyield and can reach high chemical purity above 99% and therefore can be applied to industrial production of mirabegron metabolite; the mirabegron metabolite can provide a standard substance for metabolic mechanism research of the mirabegron drug, can be used for exploring the metabolic process of the drugs in vivo, and has high application research value in clinical pharmacokinetic study.

Description

technical field [0001] The invention belongs to the field of drug metabolism, in particular to a method for synthesizing mirabegron metabolites. Background technique [0002] Mirabegron (mirabegron) tablets were developed by Japan's Astellas Pharmaceutical Company and were launched in Japan on September 16, 2011, and approved by the US Food and Drug Administration (FDA) on June 28, 2012 For the treatment of overactive bladder (OAB) in adults, the trade name is Myrbetriq. Chinese chemical name of Mirabegron: ( R) - 2-( 2-amino-1,3-thiazol-4-yl) - 4'-[2-[(2-Hydroxy-2-phenethyl)amino ] Ethyl] phenylacetamide; English chemical name: ( R) - 2-( 2-aminothiazol- 4-yl) - 4'-[ 2-[( 2-hydroxy- 2-phenylethyl) amino] ethyl] acetanilide; Molecular Formula: C21H24N4 O2 S; Molecular Weight: 396; CAS Registry Number: 223673-61-8. [0003] Mirabegron is the first β3 adrenergic receptor agonist drug for the treatment of overactive bladder, and its successful marketing has filled the gap of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H1/00C07H13/12
Inventor 魏德胜张池刘春徐一鸣
Owner TLC NANJING PHARMA RANDD CO LTD
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