Preparation method of 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1h)-pyridone

A ‐morpholinyl and ‐piperidinyl technology, applied to the synthesis intermediate of apixaban, the preparation of 5,6‐dihydro‐3‐‐1‐[4‐phenyl]‐2‐pyridone It can solve the problems of complex reaction operation, harsh reaction conditions, and low total yield, and achieve the effect of reasonable synthesis route, simple reaction operation, and simplified synthesis

Active Publication Date: 2016-01-20
SHANGHAI SHYNDEC PHARMA CO LTD
View PDF6 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route avoids the Ullmann reaction in the patent WO20003049681, the reaction conditions are relatively mild, and the applicability is strong; but the design of this route is not rational, mainly because the enamine structure in compound 11 is sensitive to acid, and its amide structure is sensitive to strong Alkali tolerance is not high, so the subsequent steps of the reaction need to be carried out in neutral to weakly alkaline, so that the reaction conditions become harsh; at the same time, in the process of preparing compound 12 from compound 11, basic sulfide is used to react with nitrate The reduction of the base is not thorough enough, which has a destructive effect on the amide bond, resulting in more by-products in this step reaction, which is not conducive to the separation and purification of related intermediates, and related impurities may be brought into the final product with subsequent reactions, reducing the purity of the final product
This fatal flaw severely limits the practical application of this route
[0015] Through the analysis of the above three routes, apixaban intermediate -5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl) was synthesized The existing technology of phenyl]-2(1H)-pyridone (5) has the following disadvantages: unreasonable synthetic route, many reaction by-products, low overall yield and complicated reaction operation or harsh conditions

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
  • Preparation method of 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1h)-pyridone
  • Preparation method of 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1h)-pyridone
  • Preparation method of 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1h)-pyridone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Embodiment 1. Preparation of compound 9

[0040]

[0041] Under stirring, put 13.8g (0.1mol) of p-nitroaniline into 55.2mL of tetrahydrofuran, add 11.85g (0.15mol) of pyridine and 1.38g (10%, W / W) of DMAP, and add dropwise at a temperature of 0°C-10°C 5‐Bromovaleryl chloride 23.94 (0.12mol), dripped within 1 hour, TLC detected that the raw material p-nitroaniline disappeared, and a large number of white crystals precipitated, filtered and washed the filter cake with 13.8mL tetrahydrofuran, poured into the filtrate at 0°C‐10°C Slowly add 0.93 g of potassium hydroxide (content 90%, 0.15 mol), and complete the addition within 1 hour, and continue the reaction until the end of the reaction observed by TLC. 5 mL (0.05 mol) of concentrated hydrochloric acid was added dropwise to pH=5‐6, the reaction solution was evaporated to dryness under reduced pressure, filtered, the filter cake was washed with tetrahydrofuran, and dried to obtain 21.30 g (yield 96.82%) of the target c...

Embodiment 2

[0044] Embodiment 2. Preparation of compound 10

[0045]

[0046] Dissolve 22g (0.1mol) of compound 9 in 110mL of chloroform under stirring, add 62.5g (0.3mol) of phosphorus pentachloride in batches at a temperature below 40°C within 30 minutes, then raise the temperature to reflux, and keep warm until the end of the reaction is observed by TLC . The reaction solution was cooled to room temperature, slowly poured into 110g of ice water, separated, the organic layer was washed twice with 110g of water, sodium bicarbonate was added to adjust the pH to 6-7 during the last washing, separated, the organic layer was evaporated to dryness under reduced pressure, A light yellow solid was obtained, which was dried to obtain 25.51 g (88.58% yield) of compound 10.

[0047] EI‐MS (M / Z): 288.0

[0048] 1 HNMR (400Hz, CDCl 3 , ppm) δ: 8.37(d, J=8.84Hz, 2H), 7.69(d, J=8.84Hz, 2H), 3.90(t, J=7.93Hz, 2H), 2.98‐3.06(m, 2H), 2.21 (m, 2H)

Embodiment 3

[0049] Embodiment 3. Preparation of compound 13

[0050]

[0051] Put 28.8g (0.1mol) of compound 10 into 230mL of methanol under stirring, add 90.26g (0.4mol) of SnCl at room temperature 2 2H 2 O, the temperature is raised to reflux, and the insulation reaction is completed until TLC observes the reaction, slowly adds 31.8g (0.3mol) Na 2 CO 3 solid, followed by the addition of 8.4 g (0.1 mol) NaHCO 3 The solid was filtered with suction, and the filter cake was slurried with 115 mL, filtered with suction, and the combined filtrates were evaporated to dryness under reduced pressure to obtain a white solid, which was recrystallized from dichloromethane to obtain 19.09 g (yield 74%) of compound 13.

[0052] EI‐MS (M / Z): 258.0

[0053] 1 HNMR (400Hz, CDCl 3 , ppm) δ: 6.93(m, 2H), 6.74(m, 2H), 3.60(t, J=6.2Hz, 2H), 3.47(brs, 2H), 2.85(m, 2H), 2.06(m, 2H )

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 provides a preparation method of 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxy-1-piperidyl) phenyl]-2(1H)-pyridine. The preparation method comprises the following steps: step (1) reducing N-(4-nitrobenzophenone)-3,3-dichloro-2-oxy piperidine (10) which is used as an initial raw material by utilizing a reducing agent to obtain a compound 13; step (2) acylating the compound 13 and 5-bromine valeryl chloride in the presence of catalyst and acid-binding agent to obtain a compound 14; step (3) facilitating the reaction of the compound 14 in the presence of cyclic condensation agent to obtain a compound 15; step (4) facilitating the reaction of the compound 15 and morpholine in the presence of alkali to obtain a compound 5, wherein the reaction route is as follows. Compared with the prior art, the preparation method has the advantages that the limitation of enamine structure on the synthesized pyridone ring can be avoided, the synthesis of the pyridone ring can be simplified, and the synthesizing route is more reasonable; fewer reaction side products are produced, easiness in purification is realized, the total yield is high, and simplicity in reaction operation is realized; the preparation method is very suitable for the industrialized production.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis, in particular to a synthetic intermediate 5,6-dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl) of apixaban ) phenyl]-2 (1H)-pyridone preparation method. Background technique [0002] Apixaban (1), English name is Apixaban, chemical name l‐(4‐methoxyphenyl)‐7‐oxo‐6‐[4‐(2‐oxopiperidin‐1‐yl)benzene base]‐4,5,6,7‐tetrahydro‐1H‐pyrazolo[3,4‐c]pyridine‐3‐carboxamide, the CAS number is 503612‐47‐3, and has the following molecular structure. [0003] [0004] Many publications include patents WO03026652 (A1), WO03049681 (A2), CN101967145A, WO2012168364 (A1) and documents BradDM, ScottBT, ShiangYC, etal.JLabelCompdRadiopharm, 2010, 53(5-6): 355-367, etc. The core reaction in the process of preparing apixaban is the reaction of compound 2 and compound 3 derivatives to construct compound 4 with a pyrazole ring, see the following reaction formula: [0005] [0006] In the structure of com...

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): C07D211/86
CPCC07D211/86
Inventor 侯建刘超王国平郭璠
Owner SHANGHAI SHYNDEC PHARMA 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