A kind of preparation method of maropitant free base

A technology of free base and reaction formula, which is applied in the field of preparation of raw material drug maropitant free base, can solve the problems of consuming a large amount of solvent and adsorbent, high cost, and long route

Active Publication Date: 2021-04-27
WISDOM PHARM CO LTD
View PDF7 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The above-mentioned method for synthesizing maropitant free base not only has a long route and low yield (the total yield of the 8-step reaction is only about 10%), but also involves the use of various precious metals, such as Ti, Pt, Pd, etc. , not only the cost is high, but also the removal of these precious metal residues requires a large amount of solvents and adsorbents

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 maropitant free base
  • A kind of preparation method of maropitant free base
  • A kind of preparation method of maropitant free base

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Embodiment one: the preparation of (2S, 3R)-2-benzhydrylquinuclidin-3-alcohol (formula II)

[0024] Add (S)-2-benzhydrylquinuclidin-3-one (Formula I) (130g, 446mmol, 1.0eq.) and toluene (1.8L) into a 5L reaction flask, and heat the system under reflux to separate water after the addition , to remove a small amount of water in the reaction system. Then metal Na (50 g, 2175 mmol) cut into small pieces was slowly added under reflux, and i-PrOH (450 mL) was slowly added under reflux after the addition was complete. After the system was refluxed for 1.5 hours, the temperature was naturally cooled to room temperature, and methanol (1 L) was added to the reaction system to quench the reaction. The system was concentrated under high vacuum and reduced pressure to remove the solvent, and the residue was added to H 2 O(2L) and CH 2 Cl 2 (1L), the system was stirred for 3 hours and left to stand, the organic phase was separated, and the aqueous phase was CH 2 Cl 2 (3 × 500mL...

Embodiment 2

[0025] Embodiment two: (2S, 3R)-2-benzhydryl-3-methanesulfonyloxy-quinine (formula IV, R 2 = Preparation of Ms)

[0026] Add (2S,3R)-2-benzhydrylquinuclidin-3-ol (Formula II) (5.0 g, 17 mmol) and CH to the reaction flask 2 Cl 2 (15 mL). The reaction system was cooled to 5°C in an ice-salt bath, and then Pyridine (25 mL) and MsCl (4.0 g, 34.9 mmol) were slowly added through the dropping funnel. After the addition, the system was naturally warmed to room temperature and stirred for 5 hours, then heated to reflux for 2 hours, and then the system was naturally cooled to room temperature. Add HCl solution (2N in H 2 O) adjust the pH value of the system to 8-9, then add CHCl 3 (3×120mL) was extracted three times, the organic phases were combined, the organic phase was concentrated under high vacuum to remove the solvent, and the residue was purified by column chromatography to obtain (2S,3R)-2-benzhydryl-3-methanesulfonyloxy- Quinine (formula IV, R 2 =Ms) (5.15 g, 81.5%).

Embodiment 3

[0027] Embodiment three: the preparation of maropitant free base

[0028] Add (2S, 3R)-2-benzhydryl-3-methanesulfonyloxy-quinine (formula IV, R) in the reaction flask 2 =Ms) (4.5 g, 12.11 mol) and DMF (20 mL). After the addition was complete, triethylamine (4.9 g, 48.42 mmol, 4.0 eq.) and 2-methoxy-5-tert-butyl-benzylamine (3.50 g, 18.11 mol) were added to the system. After the addition, the temperature of the system was raised to 100°C to react until the disappearance of the starting material was tracked by TLC. The system was naturally cooled to room temperature, the organic solvent was removed under high vacuum, and the residue was added with CH 2 Cl 2 (60mL) and H 2 O (60mL), the organic phase was separated, and the aqueous phase was separated with CH 2 Cl 2 Extract (3 x 30 mL). The organic phases were combined, and the organic phase was washed with saturated brine (50mL), anhydrous Na 2 SO 4 After drying, the solvent was precipitated under reduced pressure, and t...

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 present invention relates to the preparation method of maropitant free base, and the reaction involves (2S,3R)-2-benzhydrylquinuclidine-3-alcohol and R 1 SO 2 Cl or (CF 3 SO 2 ) 2 O reacts to obtain hydroxyl-protected compound formula IV, and formula IV reacts with 2-methoxy-5-tert-butyl-benzylamine in the presence of a base and a solvent to obtain maropitant free base.

Description

technical field [0001] The invention belongs to the technical field of methods for synthesizing raw materials, and in particular relates to the preparation of raw materials Maropitant free base. Background technique [0002] Maropitant citrate is a type 1 neurokinin (NK1) receptor anti-caking agent that acts on the central nervous system by inhibiting substance P, a key neurotransmitter that causes vomiting. Maropitant citrate is one of the alternative quinine drugs. Due to its remarkable curative effect, the drug was approved by the FDA in 2007 for the prevention and treatment of acute vomiting in dogs, and it was subsequently approved for prescription external use in cats. There are two dosage forms of maropitant citrate, maropitant citrate for injection is used to prevent and treat acute vomiting in dogs; tablet maropitant citrate is used to prevent acute vomiting in dogs and caused by motion sickness vomiting; both are available as a prescription topical drug for cats. ...

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): C07D453/02
CPCC07D453/02
Inventor 邱小龙刘文博邹平胡林储玲玲张新刚王平王东辉曹雷陈俊
Owner WISDOM PHARM 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