Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Sitagliptin synthesis method

A synthetic method and step-by-step technology, applied in the field of medicine and chemical industry, can solve the problems of resource waste, many steps, expensive raw materials, etc., and achieve the effects of avoiding toxic and dangerous chemical reagents, mild reaction conditions, and easy-to-obtain raw materials

Inactive Publication Date: 2018-06-19
安庆奇创药业有限公司
View PDF6 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method needs to obtain a single chiral intermediate by resolution, which is a great waste of resources for industrial production, and there are also expensive raw materials and more steps for the synthesis of formula IV compounds. question

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
  • Sitagliptin synthesis method
  • Sitagliptin synthesis method
  • Sitagliptin synthesis method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1, the preparation of formula II compound

[0035] In a 50mL single-necked bottle, add 2,4,5-trifluorobromobenzene (I) (2.10g, 10mmol), diethyl malonate (4.80g, 30mmol), cuprous iodide (0.19g, 1mmol), L-proline (0.23g, 2mmol), potassium phosphate (7.43g, 35mmol) and 20mL of anhydrous DMSO, and the reaction system was replaced with nitrogen three times. Raise the temperature to 90°C and react for 24h. After that, spread a layer of diatomaceous earth on the filter paper, filter, and wash the filter cake with 10 mL of ethyl acetate to obtain the mother liquor. Add 70 mL of ethyl acetate to dilute the mother liquor, wash three times with saturated ammonium chloride aqueous solution, once with saturated sodium chloride aqueous solution, and finally wash once with water, and spin evaporate the ethyl acetate under reduced pressure to obtain the crude product. The crude product was recrystallized from methanol at 0° C. to obtain 2.28 g of a light yellow solid, name...

Embodiment 2

[0036] Embodiment 2, the preparation of formula III compound

[0037] Into a 50 mL single-necked flask, 1-tert-butoxycarbonylpiperazine (1.87 g, 10 mmol), trifluoroacetic anhydride (3.15 g, 15 mmol) and 15 mL of anhydrous dioxane were sequentially added, and stirred at room temperature for one hour. Then hydrazine hydrate (80%, 1.25g, 20mmol), tetrabutylammonium iodide (0.37g, 1mmol) and morpholine (0.17g, 2mmol) were added successively, and then the temperature was raised to 70°C. Hydrogen peroxide (30%, 4.53g, 40mmol) was dissolved in 5mL of dioxane, and the hydrogen peroxide solution was slowly added dropwise to the above reaction solution for 4h, and then the reaction was continued for 2h. Afterwards, 80 mL of ethyl acetate was added to dilute the mother liquor, washed three times with saturated aqueous sodium sulfite solution, once with saturated aqueous sodium chloride solution, and finally washed once with water, and the ethyl acetate was rotary evaporated under reduced p...

Embodiment 3

[0038] Embodiment 3, the preparation of formula IV compound

[0039] In a 100 mL single-necked bottle, potassium tert-butoxide (2.24 g, 20 mmol) was dissolved in 40 mL of tetrahydrofuran, and stirred at room temperature for one minute. Then compound III (1.91 g, 10 mmol) and compound II (2.60 g, 10 mmol) were added sequentially, and stirring was continued at room temperature for 60 min. Afterwards, the reaction solvent tetrahydrofuran was distilled off under reduced pressure, and 50 mL of water and 50 mL of dichloromethane were added to extract an organic phase. The organic phase was dried with anhydrous sodium sulfate, and then distilled under reduced pressure to obtain a yellow crude product solid. The crude product was recrystallized from dichloromethane and cyclohexane to obtain 3.33 g of compound IV with a yield of 82% and a purity of 99%.

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 sitagliptin synthesis method, which comprises: carrying out a reaction on a compound represented by a formula IV, (R)-(+)-tert-butyl sulfinamide and hydrogen under the catalysis of a catalyst to obtain a compound represented by a formula V; and carrying out a hydrolysis reaction on the compound represented by the formula V to obtain a compound represented by a formula VI,ie., sitagliptin. According to the present invention, the method has advantages of easily available raw materials, simple steps, high yield and mild reaction conditions, and is suitable for industrial production. The formulas IV, V and VI are defined in the specification.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a synthesis method of sitagliptin. Background technique [0002] The chemical name of sitagliptin is 7-[(3R)-3amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetra Hydrogen-3-trifluoromethyl-1,2,4-triazolo[4,3-a]pyrazine is an oral DPP-IV inhibitor for the treatment of type II diabetes. Sitagliptin was approved for marketing in 2006 and is the best-selling variety. In 2015, the total sales of Januvia and Janumet reached US$6.29 billion, making it the largest variety among DPP-IV inhibitors. [0003] Initially, Merck applied for the patent CN1761642 for the preparation method of the compound, which disclosed that 2,4,5-trifluorophenylacetic acid was used as the starting material, and first reacted with cyclo(ethylene)isopropyl malonate to form The corresponding enol compound is followed by substitution and decarboxylation with the corresponding pyraz...

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): C07D487/04
Inventor 吴学平邢继刚严东洋陈耀
Owner 安庆奇创药业有限公司
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com