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

Preparation method of B cell lymphoma factor-2 inhibitor ABT-199

A technique for ABT-199, lymphoma

Inactive Publication Date: 2018-12-14
JIANGSU ZHONGBANG PHARMA
View PDF14 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among the starting materials of the reaction, compound 1 and compound 9 are raw materials that are difficult to purchase or synthesize, and this route is difficult to scale up production
In addition, the total yield of the whole route is too low (less than 10%), and anti-expensive palladium catalysts are used in the reaction of compound 3 and compound 4, and the total cost is relatively high
A large amount of potassium phosphate salt is used in the reaction of compound 8 and compound 9, and a large amount of phosphoric acid will be produced under the acidic condition of the system, which will cause great pollution to the environment

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 B cell lymphoma factor-2 inhibitor ABT-199
  • Preparation method of B cell lymphoma factor-2 inhibitor ABT-199
  • Preparation method of B cell lymphoma factor-2 inhibitor ABT-199

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Synthesis of Compound IV

[0057] Add 34.2g (0.20mol) compound II, 3.1g (8.4mmol) tetra-tert-butyl ammonium iodide (TBAI), 30.4g (0.22mol) potassium carbonate and 41.0g (0.22mol) compound III and 350mLDMSO in 1L reaction flask . After the addition, the system was heated to 100°C to react for about 5 hours. After cooling down to room temperature, the reaction was continued for 10 hours. Controlled by HPLC or TLC, the reaction of the raw materials was complete, and the reaction was stopped. After filtration, 300 mL of ethyl acetate and 83 mL of concentrated hydrochloric acid solution were added to the filtrate, stirred at room temperature for 1 h, and filtered to obtain 47.0 g of crude compound IV as a pale yellow solid. Directly used in the next step, HPLC: 97.8%, yield: 86.3%.

[0058] Synthesis of Compound V

[0059] Add 33.4g (0.46mol) of anhydrous DMF and 80mL of dichloromethane into a 500mL reaction flask, cool the system down to -5°C, and add 64.7g (0.42mol) of ...

Embodiment 2

[0068] Synthesis of Compound IV

[0069] Add 34.2g (0.20mol) compound II, 3.4g (10.5mmol) tetra-tert-butylammonium bromide (TBAB), 30.4g (0.22mol) potassium carbonate and 41.0g (0.22mol) compound III and 500mLTHF in 1L reaction flask . After the addition is complete, the system is heated to 30°C for about 5 hours, and the reaction is continued for 12 hours after cooling down to room temperature. The reaction is stopped when the reaction is completed by HPLC or TLC. After filtering, HCl gas was passed into the filtrate under stirring at room temperature until no solid was precipitated in the system. Filtration gave 44.2 g of the crude product of compound IV as a pale yellow solid. Directly used in the next step, HPLC: 97.8%, yield: 81.2%.

[0070] The synthesis of compound V is the same as in Example 1.

[0071] Synthesis of Compound VI

[0072] 30.0 g (0.12 mol) of compound V and 300 mL of xylene solution were added to a 2L reaction flask, and 40.8 g (0.15 mol) of compoun...

Embodiment 3

[0077] Synthesis of Compound IV

[0078] Add 34.2g (0.20mol) compound II, 2.9g (10.5mmol) tetra-tert-butyl ammonium chloride (TBAC), 30.4g (0.22mol) potassium carbonate and 41.0g (0.22mol) compound III and 500mL toluene. After the addition, the system was heated up to 80°C for about 5 hours, and continued to react for 10 hours after cooling down to room temperature. Controlled by HPLC or TLC, the reaction of the raw materials was complete, and the reaction was stopped. Filter, and the filtrate is spin-dried under reduced pressure. Add 200 mL of tetrahydrofuran into the system, and feed HBr gas into the filtrate with stirring at room temperature until no solid is precipitated in the system. After filtration, 49.2 g of crude yellow solid of compound IV was obtained. Directly used in the next step, HPLC: 97.6%, yield: 77.9%. The synthesis of compound V is the same as in Example 1.

[0079] Synthesis of Compound VI

[0080] 30.0 g (0.12 mol) of compound V and 300 mL of 1,4-d...

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 B cell lymphoma factor-2 inhibitor ABT-199, and belongs to the field of pharmaceutical synthesis. The method comprises the following steps: substituting a starting material methyl 4-fluorosalicylate that is compound II with tert-butyl-1-piperazinecarboxylate that is compound III in the presence of a phase transfer catalyst, then de-protecting underthe acidic condition to obtain a compound IV, performing reductive amination on the compound IV and a synthesized key intermediate compound V in the presence of a catalyst (sodium triacetoxyborohydride) to obtain an intermediate VI, substituting the intermediate VI with a raw material VII that is 5-bromo-azaindole, then directly hydrolyzing and acidifying the obtained esterified product to obtainan intermediate VIII, and finally amidating the intermediate VIII and a raw material compound IX to obtain a target product compound I. The raw materials are easy to purchase or synthesize, the synthesis steps are short, the total yield is more than or equal to 40%, the use of expensive or difficult-to-purchase raw materials is avoided, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, in particular to a preparation method of a B cell lymphoma factor-2 (BCL-2) inhibitor. Background technique [0002] ABT-199 (venetoclax) has the following structural formula: [0003] [0004] Molecular formula C 45 h 50 ClN 7 o 7 S, molecular weight 868.44, English trade name Venclexta, English drug name Venetoclax, Chinese drug name ABT-199, Chinese chemical name 4-[4-[[2-(4-chlorophenyl-4,4-dimethyl- 1-cyclohexyl-1-yl]methyl]-1-piperazinyl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino ]phenyl]sulfonate]-2-(1H-pyrrole[2,3-b]pyridine-5-oxyl)benzamide. [0005] Venclexta is a breakthrough cancer drug being developed by AbbVie in partnership with Roche. It is the first B-cell lymphoma factor-2 (BCL-2) inhibitor approved by the FDA, and has received 4 indications in the United States. Venclexta is an oral inhibitor of B-cell lymphoma factor-2 (BCL-2), which plays an imp...

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): C07D471/04A61P35/00
CPCA61P35/00C07D471/04
Inventor 黄双杨健吴小刚史凌云刘力萍
Owner JIANGSU ZHONGBANG 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