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

Synthesis method of cinacalcet hydrochloride and intermediate thereof

A technology of cinacalcet hydrochloride and synthetic method, which is applied in the field of drug synthesis, can solve the problems of high price, high price of ethylamine, and low yield, and achieve the effects of reducing production cost, low price, and high yield

Active Publication Date: 2015-08-12
CHANGZHOU SUNLIGHT PHARMA
View PDF13 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The deficiency of this class method is: (R)-1-(naphthalene-1-yl) ethylamine price is higher, thereby makes production cost higher
The disadvantages of this method are: (1) Obtaining the racemate first and then resolving it will cause half of the optical isomers to be discarded, resulting in a large amount of waste, resulting in higher production costs
(2) The starting material 3-(3-(trifluoromethyl)phenyl)propan-1-amine has limited commercial sources and high price
The deficiency of this method is: starting material 2-(3-(trifluoromethyl) phenyl) acetaldehyde is difficult to obtain from commercial way, and price is higher
The deficiency of this method is: starting material 3-(3-(trifluoromethyl)phenyl) acrylic acid is unstable, and is not easy to obtain from commercial route, and synthetic route is long, and yield is low, and cost is high
The deficiency of this method is: starting material 3-(trifluoromethyl) benzaldehyde and Wittig reagent price are all more expensive, and yield is lower

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1）

[0035] The synthetic method of the cinacalcet hydrochloride of the present embodiment has the following steps:

[0036] ①Under nitrogen protection, mix 22.5g of 1-bromo-3-(trifluoromethyl)benzene (0.1mol), 5.3g of acrylonitrile (0.1mol), 0.78g of palladium acetate (0.0035mol) and 200mL of Tris Add ethanolamine into a four-neck flask, heat to 100°C in an oil bath, stir for 10 hours, control in the sampling center until the raw materials disappear, stop heating, cool to room temperature (20±2°C, the same below), add 200mL methyl tert-butyl ether, Stir for 10 min, separate the liquids, discard the aqueous phase, wash the organic phase with 200 mL of water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 17.5 g of light yellow solid 3-(3-(trifluoromethyl)phenyl)propene Nitrile, yield 87.9%, purity 98.9% (HPLC).

[0037] 2. Add 16.5g of 3-(3-(trifluoromethyl)phenyl)acrylonitrile, 82.5mL of methanol and 0.8g of 5wt% palladium-carbon catalyst prep...

Embodiment 2～ Embodiment 5）

[0040] Each embodiment is basically the same as embodiment 1, the difference lies in step ①, see Table 1 for details.

[0041] Table 1

[0042] Example 1 Example 2 Example 3 Example 4 Example 5 catalyst 0.78g palladium acetate 0.23g palladium acetate 1.12g palladium acetate 4.0 g tetrakis(triphenylphosphine)palladium 3.2 DBA Palladium product weight 17.5g 16.9g 17.2g 16.8g 16.5g yield 87.9% 84.2% 86.2% 83.4% 81.7% purity 98.9% 98.2% 98.7% 97.8% 97.6%

Embodiment 6～ Embodiment 9）

[0044] Each embodiment is basically the same as embodiment 1, the difference lies in step ③, see Table 2 for details.

[0045] Table 2

[0046] Example 1 Example 6 Example 7 Example 8 Example 9 Hans ester 20.0g 20.0g 20.0g 18.6g 25.0g (R)-TRIP 0.5g 0.25g 1.25g 0.5g 0.5g product weight 16.5g 15.5g 16.2g 15.3g 16.3g yield 56.7% 53.1% 55.7% 52.5% 56.0% purity 99.5% 99.1% 99.5% 99.2% 99.4% ee value 99.2% 98.7% 99.1% 98.9% 99.2%

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 synthesis method of cinacalcet hydrochloride and an intermediate thereof. The cinacalcet hydrochloride is prepared by carrying out asymmetric reduction ammonification on 3-(3-(trifluoromethyl)phenyl)propyl-1-amine and 1-(naphthyl-1-yl)ethyl ketone. The asymmetric reduction ammonification is performed by carrying out asymmetric induction by combining a Hantzsch ester and a chiral phosphine ligand. The 3-(3-(trifluoromethyl)phenyl)propyl-1-amine is prepared by the following steps: carrying out Heck coupling reaction on 3-bromo-1-trifluoromethyl benzene and acrylonitrile to obtain 3-(3-(trifluoromethyl)phenyl)acrylonitrile, and carrying out catalytic hydrogenation. The catalyst of the Heck coupling reaction is tetra(triphenylphosphine) palladium, DBA palladium or palladium acetate. The method for synthesizing cinacalcet hydrochloride greatly lowers the production cost, and is suitable for industrialized mass production. The method for synthesizing the 3-(3-(trifluoromethyl)phenyl)propyl-1-amine greatly lowers the production cost, and has higher yield.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a synthesis method of cinacalcet hydrochloride and an intermediate thereof. Background technique [0002] Cinacalcet hydrochloride is a calcimimetics developed by NPS Pharmaceuticals in the United States. It activates the calcium receptors in the parathyroid glands, thereby reducing the secretion of parathyroid hormone (PTH), regulates the behavior of the calcium receptors in the parathyroid glands, and reduces the thyroid gland by enhancing the sensitivity of the receptors to calcium levels in the blood stream. Levels of parathyroid hormone, calcium, phosphorus, and calcium-phosphorus complex. It is mainly used for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on dialysis and hypercalcemia in patients with parathyroid carcinoma. [0003] The chemical name of cinacalcet hydrochloride is: (R)-N-(1-(naphthalen-...

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): C07C211/30C07C211/03C07C209/28C07C209/48
Inventor 胡锦平胡国宜郑建龙王永成李宏成
Owner CHANGZHOU SUNLIGHT PHARMA
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