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Improved method for the manufacture of 3-[(1S)-1-imidazo[1,2-a]pyridin-6-ylethyl]-5-(1-methylpyrazol-4-yl)triazolo[4,5-b]pyrazine and polymorphic forms thereof

An imidazo, 2-a technology, applied in the directions of medical preparations containing active ingredients, pharmaceutical formulas, organic active ingredients, etc., can solve the problems of low chiral separation efficiency, generation of a large amount of chemical waste, loss and the like

Pending Publication Date: 2021-06-08
ASTRAZENECA AB +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although providing a reliable method for the production of safutinib, the synthetic route shown in Scheme 1 has a number of disadvantages, most notably the fact that the final step involves the conversion of 3-[1-imidazo[1,2- a]pyridin-6-ylethyl]-5-(1-methylpyrrol-3-yl)triazolo[4,5-b]pyrazine chiral resolution into its R and S enantiomers leading to About 50% loss of material produced during the entire synthesis
Chiral resolution at this point is inefficient and generates large amounts of chemical waste on an industrial scale, which is undesirable
Furthermore, this synthetic route does not provide many controlled cut-off points for purification (which would be desirable for industrial-scale manufacture) and also requires 5-bromo-3-(1-imidazo[1,2 - Chromatographic purification of a]pyridin-6-ylethyl)triazolo[4,5-b]pyrazine (this chromatographic purification would be impractical on an industrial scale)
[0008] In conclusion, while the synthetic route shown in Scheme 1 provides a means for the production of safutinib, there is clearly a need for a robust method that would be more suitable for the industrial scale production of this compound

Method used

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  • Improved method for the manufacture of 3-[(1S)-1-imidazo[1,2-a]pyridin-6-ylethyl]-5-(1-methylpyrazol-4-yl)triazolo[4,5-b]pyrazine and polymorphic forms thereof
  • Improved method for the manufacture of 3-[(1S)-1-imidazo[1,2-a]pyridin-6-ylethyl]-5-(1-methylpyrazol-4-yl)triazolo[4,5-b]pyrazine and polymorphic forms thereof
  • Improved method for the manufacture of 3-[(1S)-1-imidazo[1,2-a]pyridin-6-ylethyl]-5-(1-methylpyrazol-4-yl)triazolo[4,5-b]pyrazine and polymorphic forms thereof

Examples

Experimental program
Comparison scheme
Effect test

example

[0217] Various embodiments are illustrated by the following examples. The present invention should not be construed as being limited to these examples.

[0218] Abbreviations used:

[0219] CDI carbonyldiimidazole

[0220] DCM dichloromethane

[0221] DIPEA N,N-Diisopropylethylamine

[0222] DMSO Dimethyl Sulfoxide

[0223] ESI electrospray ionization

[0224] HPLC high performance liquid chromatography

[0225] HRMS High Resolution Mass Spectrometry

[0226] iPrOH isopropanol

[0227] mp melting point

[0228] NMP N-methyl-2-pyrrolidone

[0229] NMR nuclear magnetic resonance spectroscopy

[0230] Pd-132 Dichlorobis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(II)

[0231] PTFE Polytetrafluoroethylene

[0232] Q-ToF Quadrupole - Time of Flight

[0233] THF Tetrahydrofuran

[0234] use Draw, version 18.1 produces IUPAC names.

[0235] NMR data were collected using a Bruker Ultrashield AV3 400 MHz spectrometer equipped with a BBFO probe and running w...

example 1

[0239] Preparation of (1S)-1-imidazo[1,2-a]pyridin-6-ylethylamine (III)

[0240] Isopropylamine hydrochloride (379.8 g; 3.97 mol), sodium tetraborate decahydrate (31.22 g; 0.08 mol) and pyridoxal phosphate (0.7 g; 0.003 mol) were dissolved in water (2000 ml). The pH was adjusted to pH 10 using aqueous NaOH. ATA-436 enzyme (5.94 g) was charged to the reaction vessel. 1-(Imidazolo[1,2-a]pyridin-6-yl)ethanone (50 g; 0.30 mol) was charged to the reaction vessel as a solution in DMSO (500 ml). The reaction mixture was heated to 44°C-54°C for 72h.

[0241] After completion of the reaction, the mixture was cooled and the pH was adjusted to pH 12.0 to 12.5 with aqueous NaOH. diatomaceous earth (50 g) then nBuOH (625 ml) was charged to the reaction vessel and the contents were stirred for about 1 h. The mixture was filtered and washed with a mixture of water-DMSO-nBuOH (160ml-40ml-300ml). The filtrate was further diluted with nBuOH (325ml) and KCl (350g) was charged to the ves...

example 2

[0252] Preparation of 5-bromo-N3-[(1S)-1-imidazo[1,2-a]pyridin-6-ylethyl]pyrazine-2,3-diamine (V)

[0253](1S)-1-imidazo[1,2-a]pyridin-6-ylethylamine dihydrochloride (70 g, 0.281 mol) was suspended in DCM (263 mL), cooled to 10 °C, and aqueous 28 %NH 3 (76mL) and water (259mL). The reaction was stirred at 20 °C for 30 min to 1 h. The mixture was then allowed to settle, the organic phase was separated and retained, and the aqueous phase was extracted 4 times with a mixture of DCM-iPrOH (441ml-41mL). The resulting organic phases were combined and concentrated under vacuum to yield (1S)-1-imidazo[1,2-a]pyridin-6-ylethylamine.

[0254] NMP (89 mL), 3,5-dibromopyrazin-2-amine (91.02 g, 0.3599 mol) and DIPEA (96.1 mL, 0.551 mol) were added to (1S)-1-imidazo[1,2-a ] pyridin-6-ylethylamine, and the mixture was heated at 120 °C for 20-48h. After the reaction was complete, the mixture was cooled to 80°C, diluted with additional NMP (89 mL), and the temperature was maintained at 8...

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Abstract

This specification generally relates to an improved method for the manufacture of 3-[(lS)-l -imidazo[ 1,2-a]pyridin-6-ylethyl]-5-(l-methylpyrazol-4-yl)triazolo[4,5- bjpyrazine (I), or pharmaceutically acceptable salts thereof; polymorphic forms thereof; and intermediates useful in the manufacture of such compounds and salts thereof. Formula (I).

Description

technical field [0001] This description relates to a method for the manufacture of 3-[(1S)-1-imidazo[1,2-a]pyridin-6-ylethyl]-5-(1-methylpyrazol-4-yl)tri Improved processes for azolo[4,5-b]pyrazines, or pharmaceutically acceptable salts thereof; polymorphic forms thereof; and intermediates useful in the manufacture of such compounds and salts thereof. Background technique [0002] 3-[(1S)-1-imidazo[1,2-a]pyridin-6-ylethyl]-5-(1-methylpyrazol-4-yl)triazolo[4,5-b ] Pyrazine (also known as "Savolitinib", "AZD6094", "HMPL-504", or "volitinib") is a potent and selective small molecule c-Met kinase Inhibitor (Jia H. et al., J.Med.Chem. [Journal of Medicinal Chemistry] 2014; 57; 7577), which is currently used as a treatment for patients with non-small cell lung cancer (in combination with ostinib ( Oxnard GR, Ramalingam SS, Ahn M-J et al, J Clin Oncol [Journal of Clinical Oncology] 33, 2015 (suppl; abstract 2509)) and for patients with advanced or metastatic papillary renal cell ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D519/00
CPCC07D519/00C07D471/04C07D487/04A61K31/4985
Inventor A·R·特纳A·T·特纳G·P·豪厄尔M·A·Y·加尔K·R·穆尔霍兰N·K·阿林顿Z·田B·刘Q·龚W·于
Owner ASTRAZENECA AB