Preparation method of maropitant free alkali

A technology of free base and reaction, which is applied in the field of preparation of raw material drug Maropitant free base, can solve the problems of low yield, long route and high cost, and achieve short synthesis route, simple process operation and high total yield Effect

Active Publication Date: 2019-02-12
WISDOM PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] 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

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  • Preparation method of maropitant free alkali
  • Preparation method of maropitant free alkali
  • Preparation method of maropitant free alkali

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 is complete , 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 ...

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...

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Abstract

The invention relates to a preparation method of maropitant free alkali. The reaction of the preparation method relates to a reaction between (2S,3R)-2-benzhydryl quinuclidine-3-alcohol and R1SO2Cl or(CF2SO2)2O; by means of the reaction, a hydroxyl protected compound formula IV can be obtained; the formula IV can react with 2-methoxy-5-tert butyl-benzylamine under the existence of an alkali and asolvent to obtain the maropitant free alkali. (The formula is shown in the description).

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 anticaking agent that acts on the central nervous system by inhibiting substance P, the 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

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Application Information

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Patent Type & Authority Applications(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
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