Synthesis method of ATP competitive small-molecule AKT inhibitor A443654

A synthetic method and small molecule technology, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of low total yield, high toxicity, and low economic efficiency, and achieve the effect of shortening the reaction time and increasing the yield

Active Publication Date: 2015-05-13
SHANGHAI HAOYUAN MEDCHEMEXPRESS CO LTD +1
View PDF5 Cites 0 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this synthetic route is the use of highly toxic hexamethylditin reagent, and the preparation of tin reagent intermediate 5A has a long reaction time and low yield
The whole route has low economy, low total yield, high process cost, unfriendly environment, and is not conducive to industrial scale-up
[0007] In view of the shortcomings of the existing synthetic method for preparing the compound 6, such as complex reaction steps, high process cost, and low overall yield, it is necessary to develop a new route that is more economical, efficient, environmentally friendly, and simple to facilitate industrial production

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 ATP competitive small-molecule AKT inhibitor A443654
  • Synthesis method of ATP competitive small-molecule AKT inhibitor A443654
  • Synthesis method of ATP competitive small-molecule AKT inhibitor A443654

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Embodiment 1: the preparation of compound 2

[0055]

[0056] Compound 1 (50g, 237mmol, 1eq), 3,4-dihydropyran (60g, 713mmol, 3eq), pyridinium p-toluenesulfonate (3g, 11.8mmol, 0.05eq), chloroform (250ml , 5V), heated to reflux for 3 hours, and TLC detected that the reaction of raw materials was complete. The reaction system was lowered to room temperature, added saturated aqueous sodium bicarbonate (500ml), stirred for 5 minutes, allowed to stand, separated the organic phase, extracted the aqueous phase with chloroform (200ml) once more, combined the organic phases, and washed with saturated brine (500ml ) and water (500ml) were washed once each, dried over anhydrous sodium sulfate, and concentrated to give a black liquid (70g, Y=100%).

[0057] 1H NMR (CDCl 3 ,500MHz): δppm 7.72(s,1H),7.53(s,1H),7.29(s,1H),5.62(m,1H),4.10(m,1H),3.73(m,1H),2.63(s ,3H), 2.19(m,1H), 2.09(m,1H), 1.65(m,4H); ESI / MS: m / z=295(M+H)+.

Embodiment 2

[0058] Embodiment 2: the preparation of compound 3

[0059]

[0060] In the there-necked flask of 1L, add compound 2 (50g, 168.8mmol, 1eq), diboronic acid pinacol ester (45g, 177.3mmol, 1.05eq), potassium acetate (50g, 506.5mmol, 3eq) and DMSO (500ml), Stir for 15min under nitrogen protection, add Pd(dppf)Cl 2 (6.9g, 8.44mmol, 0.05eq), replaced with nitrogen, heated to 70°C, and reacted overnight. LCMS monitors that the reaction of the raw materials is complete, and the temperature is lowered to room temperature, water (500ml), ethyl acetate (500ml), and silica gel (50g) are added, stirred for 5 minutes, and then filtered. The organic phase was separated and the aqueous phase was extracted once more with ethyl acetate (500ml). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 57.1 g of a black liquid, Y=100%). It was directly used in the next reaction without purification.

[0061] 1H NMR(...

Embodiment 3

[0062] Embodiment 3: the preparation of compound 5

[0063]

[0064] In the 3L there-necked flask, add compound 4 (150g, 336mmol, 1eq), compound 3 (138g, 403.3mmol, 1.2eq), sodium carbonate (142.5g, 1344.3mmol, 4eq), dioxane (900ml, 6V), Water (600ml, 4V), add Pd(dppf)Cl under nitrogen protection 2 (8.2g, 10.1mmol, 0.03eq), replaced with nitrogen, and then warmed up to 75 for overnight reaction. LCMS monitored the complete reaction of the starting material. Add water (1.5L), ethyl acetate (1.5L), silica gel (150g), stir for 10min, filter, the filtrate separates the organic layer, and extract the aqueous phase with ethyl acetate (1.5L) once, combine the organic phases, organic The phase was washed once with saturated brine (1.5 L), dried over anhydrous sodium sulfate, and concentrated to obtain a black oily product (143.2 g, Y=73%).

[0065] 1H NMR (CD 3 OD,500MHz):δppm 8.45(s,1H),8.25(brs,1H),7.98(s,1H),7.61(m,4H),7.37(s,1H),7.16(s,1H),7.10( m,1H),7.00(m,1H),5.80(s,1H)...

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 synthesis method of an ATP competitive small-molecule AKT inhibitor A443654. According to the method, a compound 1 is used as a starting raw material, and the compound 6 (A-443654) is obtained through amino group protection, Suzuki reaction and protecting group removal. Usage of poisonous reagent hexamethylditin is avoided, the method is high in safety, environment-friendly, high in reaction yield and suitable for industrial large-scale production, the reaction time is shortened, and the process cost is reduced. The flow chart of the synthesis method is shown in the specification.

Description

Technical field: [0001] The invention relates to a method for preparing a compound, in particular to a method for synthesizing ATP competitive small molecule AKT inhibitor A443654. Background technique: [0002] The PI3K / AKT / mTOR signaling pathway is an important signal transduction pathway in cells, which affects cell metabolism, proliferation, transcription, survival and angiogenesis, and is closely related to the occurrence and development of various tumors, and is also associated with diabetes, related to cardiovascular disease. AKT, also known as protein kinase B (protein kinase B, PKB), is a serine / threonine protein kinase. PI3K / AKT signaling is activated in normal tissues, and when the pathway is overactivated, the overexpression of p-AKT may lead to tumor cell death by down-regulating the tumor suppressor protein p53, stimulating protein synthesis, and inhibiting apoptosis. Unlimited value-added. Therefore, inhibiting the activation of this pathway can promote the...

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): C07D401/14
CPCY02P20/55C07D401/14
Inventor 郑保富高强李硕梁杨成武周益南
Owner SHANGHAI HAOYUAN MEDCHEMEXPRESS 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