Unlock instant, AI-driven research and patent intelligence for your innovation.

A kind of preparation method of rivaroxaban intermediate

A technology for rivaroxaban and intermediates, applied in the direction of organic chemistry and the like, can solve the problems of low atom utilization rate, unobtainable raw materials, and high cost, and achieve the effects of convenient industrial production, readily available raw materials, and short reaction routes.

Active Publication Date: 2022-04-26
SHANGHAI HISOAR PHARMA TECH & DEV CO LTD +1
View PDF5 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In general, the existing synthetic routes of rivaroxaban have disadvantages such as unavailable raw materials, long route, high cost, and low utilization rate of atoms, and the total yield generally reaches 20-50%.

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 rivaroxaban intermediate
  • A kind of preparation method of rivaroxaban intermediate
  • A kind of preparation method of rivaroxaban intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] (1) Add successively the compound shown in 20.0g formula I (R is benzyl, 0.061mol), 7.44g lithium tert-butoxide (0.093mol), 3.93g lithium chloride (0.093mol) to the three-necked reaction flask ) and 60mL tetrahydrofuran, using nitrogen to replace the air in the reaction system three times, adding 14.84g of the compound of formula II (0.093mol) to the reaction system at one time, and then heating the system to 50°C for 4 hours until the compound I disappeared under HPLC monitoring , stop the reaction and generate the intermediate compound of formula III;

[0060] Wherein, the NMR (DMSO-d6) data of the compound of formula III is as follows:

[0061] 1 H NMR: (400MHz, DMSO-d6), δ8.47(s, 1H), 7.72(d, J=9.2Hz, 2H), 7.58(d, J=9.2Hz, 2H), 7.49-7.39(m, 5H),5.05-5.00(m,1H),4.24(t,J=9.2Hz,1H),4.20(s,2H),4.01-3.96(m,3H),3.92-3.91(m,2H),3.71 (t, J=9.2Hz, 2H).

[0062] (2) The reaction system is cooled to 5° C., and 80 mL of dilute hydrochloric acid with a mass percent concentra...

Embodiment 2

[0067] (1) Add successively the compound shown in 20.0g formula I that makes (R is benzyl, 0.061mol), 14.88g lithium tert-butoxide (0.186mol), 8.00g lithium bromide (0.093mol) and 60mL of tetrahydrofuran, use nitrogen to replace the air in the reaction system three times, add 19.64g of the compound of formula II (0.122mol) to the reaction system at one time, then heat the system to 40°C and react for 6 hours until the HPLC monitors that compound I disappears, stop Reaction generates intermediate formula III compound;

[0068] (2) The reaction system is cooled to 10°C, and 120mL of dilute hydrochloric acid with a mass percentage concentration of 10% is added dropwise under stirring under heat preservation, so that the reaction system is acidified under the condition that the pH is 2, and then at 5 Stir at ℃ for 15 min, rise to room temperature and continue to stir for 30 min before filtering. The obtained filter cake is beaten with methanol at a stirring speed of 60 rpm for 1 h...

Embodiment 3

[0072] (1) Add 20.0 g of the compound shown in formula I (R is benzyl, 0.061 mol), 12.30 g of lithium isopropoxide (0.186 mol) and 60 mL of tetrahydrofuran to the three-necked reaction flask in sequence, and use nitrogen to degas the reaction system. The air in the mixture was replaced three times, and 19.64 g of the compound of formula II (0.122 mol) was added to the reaction system at one time, and then the system was heated to 60° C. for 12 hours until the compound I was monitored by HPLC, and the reaction was stopped to generate the intermediate compound of formula III;

[0073] (2) The reaction system is cooled to 0° C., and 80 mL of dilute hydrochloric acid with a mass percentage concentration of 10% is added dropwise under stirring under heat preservation, so that the reaction system is acidified at a pH of 3, and then acidified at 5 Stir at ℃ for 15 min, rise to room temperature and continue stirring for 30 min before filtering. The obtained filter cake is beaten with m...

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 preparation method of a rivaroxaban intermediate, comprising the following steps: (1) reacting a compound of the following formula I with a compound of the following formula II in the presence of an organolithium salt or an organolithium salt and an inorganic lithium salt, Obtain the compound of the following formula III; (2) carry out the acidification reaction of the compound of the formula III in the presence of inorganic acid HX to obtain the rivaroxaban intermediate shown in the following formula IV; wherein, R in the compound of the formula I is selected from methyl, isopropyl, n-butyl, phenyl or benzyl, and the inorganic acid HX is selected from hydrochloric acid or sulfuric acid. The preparation method of the invention is easy to operate, has high yield, and is convenient for industrialized production and quality control of finished medicine.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a rivaroxaban intermediate 4-[4-[(5S)-5-(aminomethyl)-2-oxo-3-oxazolidinyl]phenyl] -The preparation method of 3-morpholinone mineral acid salt. Background technique [0002] Rivaroxaban, 5-Chloro-N-[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinone)phenyl]-1,3-oxazolidine -5-yl]-2-thiophene carboxamide is a coagulation factor Xa inhibitor used for the prevention and treatment of thrombotic diseases. [0003] [0004] The preparation method of rivaroxaban has many reports, and one of the key intermediates is 4-[4-[(5S)-5-(aminomethyl)-2-oxo-3-oxazolidinyl]phenyl ]-3-morpholinone or its salt, the structural formula is as follows: [0005] [0006] J.Med.Chem., 2005, 48, 5900 and US Patent Document 7,576,111 reported a linear synthesis method of rivaroxaban, the route is shown below. The route of this method is long, the utilization rate of the phthalimide atom of the protecting gro...

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): C07D403/10
CPCC07D403/10
Inventor 李洪明褚长虎梁朝吴小澍江俊邱志海朱灿
Owner SHANGHAI HISOAR PHARMA TECH & DEV CO LTD
Features
  • R&D
  • Intellectual Property
  • Life Sciences
  • Materials
  • Tech Scout
Why Patsnap Eureka
  • Unparalleled Data Quality
  • Higher Quality Content
  • 60% Fewer Hallucinations
Social media
Patsnap Eureka Blog
Learn More

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

© 2025 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com