Synthesis method of pyrimidine heterocyclic ring-containing antitumor medicine molecule AZD6738

A technology of AZD6738 and compound, which is applied in the field of synthesis of pyrimidine-containing heterocyclic anti-tumor drug molecule AZD6738, can solve the problems of expensive raw materials and reactors, large investment in process production, etc., and achieve the effect of convenient purification and cost reduction

Pending Publication Date: 2020-09-11
JIANGSU JITRI MOLECULAR ENG INST CO LTD
View PDF8 Cites 2 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Org. Process Res. Dev. (2019, 23, 7, 1333-1342) recently reported the synthesis of AZD6738, using enzyme-catalyzed reaction technology to synthesize chiral sulfoxide intermediates, which is relatively innovative, but the use of The price of raw materials and reactors is relatively expensive, and the investment in process production is relatively large

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
  • Synthesis method of pyrimidine heterocyclic ring-containing antitumor medicine molecule AZD6738
  • Synthesis method of pyrimidine heterocyclic ring-containing antitumor medicine molecule AZD6738
  • Synthesis method of pyrimidine heterocyclic ring-containing antitumor medicine molecule AZD6738

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Embodiment 1 AZD6738 batch synthesis:

[0084] (1) The first step: the synthesis of compound 3:

[0085]

[0086]Compound 2, methyl 2,6-dichloropyrimidine-4-carboxylate (1000g) was dissolved in dichloromethane (5000 ml), compound 1 (480g) and TEA (900g) were added, the reaction solution was stirred at room temperature for 16h, LC-MS Tracking showed that the reaction was complete, and 1200mL of water was added to the reaction solution, separated and extracted, the aqueous phase was extracted with dichloromethane (4000mL*2), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo to obtain crude compound 3. Afterwards, it was purified by beating with a volume ratio of MTBE:EA=4:1 to obtain a light yellow solid powder (920 g, yield: 70%).

[0087] 1 H NMR (400 MHz, CDCl 3 ) δ 7.17 (s, 1H), 4.39 (s, 1H), 4.41 (d, J =13.2 Hz, 1H), 4.26-4.07 (m, 1H), 3.99 (s, 3H), 3.82 ...

Embodiment 2

[0120] Embodiment two: the fluid chemical synthesis method of AZD6738:

[0121] (1) In the first step, compound 1 ((R)-2-methylmorpholine, 48g) and triethylamine (90g) were dissolved in dichloromethane solution to form solution A of 250mL, and compound 2 ( 100g) was also dissolved in dichloromethane, and made into 250mL solution B. According to the set flow rate of 2.77mL / min, the two kinds of A and B dichloromethane solutions were respectively pumped into a T-shaped mixer. Then enter a coil reactor with a set temperature, the retention volume of the coil reactor is 250mL, the temperature is 36°C, and the retention time of the set material in the reactor is 45min. Inject water (300mL) through another pump at a rate of 5mL / min to quench the reaction solution coming out of the coil reactor, and then enter the membrane separator (Zaiput brand) to achieve liquid-liquid separation, and the water phase continues to enter the lower The first-stage liquid-liquid separator was pumped ...

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 belongs to the technical field of heterocyclic chemistry, particularly relates to a heterocyclic anti-tumor chemical medicine, and more particularly relates to a synthesis method of pyrimidine heterocyclic ring-containing antitumor medicine molecule AZD6738. A chiral ligand induced asymmetric oxidation method is used, chiral ligands are combined with cheap oxidizing agents (such as hydrogen peroxide) to oxidize dimethyl sulfide to prepare chiral sulfoxide, conversion of the chiral sulfoxide is efficiently achieved, a chiral sulfoxide compound 7 for the AZD6738 is prepared, and then the final product AZD6738 is prepared through an intermittent reaction. Besides, the AZD6738 is prepared by adopting a fluid chemical method, the total yield of total synthesis of the AZD6738 is remarkably improved compared with that of an intermittent reaction, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of heterocyclic chemistry, and specifically relates to a heterocyclic antitumor chemical drug, and more specifically to a synthesis method of a pyrimidine-containing heterocyclic antitumor drug molecule AZD6738. Background technique [0002] AZD6738, also known as (S)-Ceralasertib, is a drug that is undergoing phase I / II clinical trials for the treatment of solid tumors and hematological cancers developed by AstraZeneca in the United Kingdom. It is an effective and selective sulfoximine morpholine A pyrimidine ATR kinase inhibitor with excellent preclinical physicochemical and pharmacokinetic (PK) characteristics, IC50 is 2.578nM. [0003] The English name of AZD6738 is as follows: (S)-imino(methyl)(1-(6-((R)-3-methylmorpholino)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)pyrimidin -4-yl)cyclopropyl)-l6-sulfanone, its structural general formula is as shown in I formula: [0004] [0005] Type I [0006] Patents W...

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 Applications(China)
IPC IPC(8): C07D413/04B01J31/22C07C249/02C07C251/24
CPCB01J31/2234B01J2231/64B01J2531/56C07C249/02C07D413/04C07C251/24
Inventor 汪晓明李帅廖道红雷晓光
Owner JIANGSU JITRI MOLECULAR ENG INST 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