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

The method for making candixatan ester and intermediates thereof

A compound, the technology of methoxycarbonyl, applied in the field of preparation of candesartan cilexetil and its intermediates, can solve the problem of low total yield, and achieve the effect of simple operation and easy availability of raw materials

Inactive Publication Date: 2012-05-30
SUZHOU VIGONVITA LIFE SCIENCES CO LTD
View PDF2 Cites 4 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But this method still needs to use trialkyl tin chloride and sodium azide, and total yield is not high

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
  • The method for making candixatan ester and intermediates thereof
  • The method for making candixatan ester and intermediates thereof
  • The method for making candixatan ester and intermediates thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Example 1: 2-[N-(tert-butoxycarbonyl)-[4-[2'-(1-trityl-1H-tetrazol-5-yl)biphenylmethyl]amino]-3 - Preparation of ethyl nitrobenzoate (formula V, R1 = tert-butoxycarbonyl, R2 = trityl)

[0072] Ethyl 2-tert-butoxycarbonylamino-3-nitrobenzoate (1.06g, 3.41mmol), 2-(1-trityl-1H-tetrazol-5-yl)biphenylmethyl bromide (1.91mg, 3.42mmol), potassium carbonate (0.7g, 5.07mmol) and dry DMF (15ml) were mixed and fully reacted at 30°C-120°C (60°C for 2 hours was specifically selected). After cooling, pour into ice water (30ml), stir for half an hour, extract with ethyl acetate (20ml×3), wash the organic phase with water (20ml×2), wash with saturated brine (20ml), and dry over anhydrous sodium sulfate. Concentration gave a yellow oil, which was recrystallized from acetone-water to give 2-[N-(tert-butoxycarbonyl)-[4-[2′-(1-trityl-1H-tetrazolium- 5-yl)biphenylmethyl]amino]-3-nitrobenzoic acid ethyl ester (V, R1 = tert-butoxycarbonyl, R2 = trityl) (2.3 g, 90%).

Embodiment 2

[0073] Example 2: 2-[N-(tert-butoxycarbonyl)-[4-[2'-(1-trityl-1H-tetrazol-5-yl)biphenylmethyl]amino]-3 - Preparation of nitrobenzoic acid (formula IV, R1 = tert-butoxycarbonyl, R2 = trityl)

[0074] The compound (2.01g, 2.56mmol) represented by the formula V (R1 = tert-butoxycarbonyl, R2 = trityl) was dissolved in THF (5ml) / water (1ml) solution, and sodium hydroxide (113mg, 2.83 mmol), fully react under the condition of 40°C-70°C (specifically choose 60°C for 24 hours). The THF was evaporated under reduced pressure, the residue was dissolved in water (20ml), and the pH value was adjusted to 5 with 1N hydrochloric acid. A large amount of white precipitates precipitated out. The precipitates were collected and dried to obtain 2-[N-(tert-butoxycarbonyl)- [4-[2′-(1-trityl-1H-tetrazol-5-yl)biphenylmethyl]amino]-3-nitrobenzoic acid (IV, R1=tert-butoxycarbonyl, R2 =trityl) (1.85 g, 98%). 1 H NMR (CDCl 3 -d6, 300MHz), δ1.6 (2s, 9H), 4.5 (d+d, 2H), 6.8-7.9 (m, 26H).

Embodiment 3

[0075] Example 3 (±) 2-[N-(tert-butoxycarbonyl)-[4-[2′-(1-trityl-1H-tetrazol-5-yl)biphenylmethyl]amino] - Preparation of 3-nitrobenzoic acid-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester (formula III, R1=tert-butoxycarbonyl, R2=trityl)

[0076] Compound (1.85g, 2.4mmol), 1-chloroethylcyclohexyl carbonate (700mg, 3.4mmol), potassium carbonate (500mg, 3.4mmol) and dry DMF (10ml) were mixed, and the reaction was complete under the condition of 20°C-60°C (specifically choose 50°C for 4 hours). After cooling, pour into ice water (30ml), stir for half an hour, extract with ethyl acetate (20ml×3), wash the organic phase with water (20ml×2), wash with saturated brine (20ml), and dry over anhydrous sodium sulfate. (±) 2-[N-(tert-butoxycarbonyl)-[4-[2′-(1-trityl-1H-tetrazol-5-yl)biphenylmethyl) in white semi-solid ]amino]-3-nitrobenzoic acid-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl ester (III, R1 = tert-butoxycarbonyl, R2 = trityl) (1.78g, 80 %). 1 H NMR (DMSO-d6, 300MHz), δ1.1-2.0 (m, 1...

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 method for making candixatan ester and intermediates thereof and a compound of formula III, wherein R1 is triphenylmethyl, methxoycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzoxycarbonyl, trimethylsilane, triethylsliane or tritertbutylsilane protect group, and R2 is triphenylmethyl, methxoycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzoxycarbonyl, trimethylsilane, triethylsliane ortritertbutylsilane protect group. The method for making candixatan ester by the said compound of formula III is also provided. The invention is a completely new synthesis route of candixatan ester which is shorter than ever, and the raw material is easily obtained, and the operation is simple. The new synthesis route of candixatan ester of the invention shortens the reaction route and simplifies the operation procedure. Furthermore, the new synthesis route of candixatan ester of the invention avoids the use of organo-tin and nitrine compounds, and which is safety and protects the environment.

Description

technical field [0001] The invention relates to a preparation method of candesartan cilexetil and an intermediate thereof. Background technique [0002] Candesartan cilexetil is a good active ingredient of antihypertensive drugs. [0003] As a prodrug form, candesartan cilexetil is absorbed through the intestinal tract in vivo, and is completely hydrolyzed into the active metabolite of candesartan, which highly selectively binds to the angiotensin II subtype I receptor (AT1) Combined, produce antihypertensive effect. [0004] Candesartan cilexetil was developed by Takeda Corporation of Japan, and then Astra joined in the joint development. It was first launched in Sweden in December 1997 under the trade name Atacand. [0005] [0006] The preparation method of candesartan cilexetil can be found in EP459136; J.Med.Chem., 1993, 36(15), 2182-2195; J.Med.Chem., 1993, 36(16), 2343-2349; EP881212; CN1800179A; CN1361101A; CN1425654A; CN1510031A; CN1666989A, etc. [0007] Amo...

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): C07D257/04C07D403/10
CPCC07D257/04C07D403/10
Inventor 李海泓杨池刘正李剑锋沈敬山
Owner SUZHOU VIGONVITA LIFE SCIENCES CO LTD
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