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A process for the preparation of 3-phenyl/heteroaryl-6-phenoxy-8-alkylamino-imidazo[1,2-b]pyridazine derivatives

A technology of heteroaryl and alkyl, applied in the field of intermediate compounds for the preparation of said compounds, can solve the problems of increasing the total yield and undesirable by-products

Inactive Publication Date: 2017-05-31
BAYER PHARMA AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Hydroxyl compound R in step 3 of the scheme 1 The introduction of -OH must be carried out under relatively harsh reaction conditions - leading to undesired by-products and thus to an overall yield that must be increased

Method used

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  • A process for the preparation of 3-phenyl/heteroaryl-6-phenoxy-8-alkylamino-imidazo[1,2-b]pyridazine derivatives
  • A process for the preparation of 3-phenyl/heteroaryl-6-phenoxy-8-alkylamino-imidazo[1,2-b]pyridazine derivatives
  • A process for the preparation of 3-phenyl/heteroaryl-6-phenoxy-8-alkylamino-imidazo[1,2-b]pyridazine derivatives

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preparation example Construction

[0196] In another preferred embodiment, the present invention relates to N-cyclopropyl-4-{6-(2,3-difluoro-4-methoxyphenoxy)-8-[(3,3,3 -trifluoropropyl) amino] imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide preparation method, said method comprising the steps of:

[0197] (a) make 8-bromo-6-chloro-3-iodoimidazo[1,2-b]pyridazine or 6,8-dibromo-3-iodoimidazo[1,2-b]pyridazine with 2 , 3-difluoro-4-methoxyphenol reaction; resulting in 6,8-bis(2,3-difluoro-4-methoxyphenoxy)-3-iodoimidazo[1,2- b] pyridazine;

[0198] (b) 6,8-bis(2,3-difluoro-4-methoxyphenoxy)-3-iodoimidazo[1,2-b]pyridazine and [4-(cyclopropylamino Formyl)-3-methylphenyl]boronic acid reaction; thus giving 4-[6,8-bis(2,3-difluoro-4-methoxyphenoxy)imidazo[1,2-b ]pyridazin-3-yl]-N-cyclopropyl-2-methylbenzamide;

[0199] (c) Make 4-[6,8-bis(2,3-difluoro-4-methoxyphenoxy)imidazo[1,2-b]pyridazin-3-yl]-N-cyclopropane N-cyclopropyl-4-{6-(2,3-difluoro-4-methyl oxyphenoxy)-8-[(3,3,3-trifluoropropyl)amino]imidazo[1,2-b]py...

Embodiment 1

[0253] 6,8-bis(2,3-difluoro-4-methoxyphenoxy)-3-iodoimidazo[1,2-b]pyridazine

[0254]

[0255] 1.00 kg 6,8-dibromo-3-iodoimidazo[1,2-b]pyridazine (2.48 mol), 0.87 kg 2,3-difluoro-4-methoxyphenol (5.46 mol) and 2.43 kg cesium carbonate (7.45 mol) was stirred in 5.0 L NMP and heated to 70 °C. After 4 h at 70 °C, the reaction mixture was cooled to 50-60 °C and 5.0 L of THF was added. 20.0 L of water was heated to 55°C and added to the suspension within 12 min. After dissolution of the inorganic salts, the product precipitates out of a clear solution. The temperature was raised to approximately 87°C and approximately 4 L of solvent (mainly THF) was removed by distillation. The mixture was cooled to 20-22 °C within 2 h and stirred at this temperature for 14 h. The product was isolated by suction filtration, washed twice with water (2.0 L each), and dried in vacuo at 40 °C for 20 h to constant mass. This gave 1.38 kg (99%) of the title compound as a light gray solid.

[025...

Embodiment 2

[0259] 6,8-bis(2,3-difluoro-4-methoxyphenoxy)-3-iodoimidazo[1,2-b]pyridazine

[0260]

[0261] 10.0 g 6-chloro-8-bromo-3-iodoimidazo[1,2-b]pyridazine (27.9 mmol), 9.83 g 2,3-difluoro-4-methoxyphenol (61.4 mmol) and 11.6 g potassium carbonate (83.7 mmol) was stirred in 50 mL DMSO and heated to 100°C. After 5 h at 100 °C, the reaction mixture was cooled to 50 °C and 50 mL THF was added. 200 mL of water was slowly added to the suspension at 50 °C. After dissolution of the inorganic salts, the product precipitates from a clear solution. The mixture was heated with a jacket temperature of 100°C until an internal temperature of approximately 87°C was reached and 38 mL of solvent (mainly THF) had been removed by distillation. The mixture was cooled to 20 °C and stirred at this temperature for 3 h. The product was isolated by suction filtration, rinsed 3 times with water (5 mL each), and dried in vacuo at 50° C. overnight. 15.6 g (99.6%) of the title compound were obtained in ...

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Abstract

A process for the preparation of 3-phenyl / heteroaryl-6-phenoxy-8-alkylamino-imidazo[1,2-b]pyridazine derivatives and intermediates of this process. A crystalline form of N-cyclopropyl-4-{6-(2,3-difluor-4-methoxyphenoxy)-8-[(3,3,3-trifluorpropyl)amino]imidazo[1,2-b]pyridazin-3-yl}-2-methylbenzamide. The compounds are inhibitors of the Mps-1 kinase (Monopolar Spindle 1 kinase; also known as Tyrosine Threonine Kinase, TTK).

Description

[0001] The present invention relates to a process for the preparation of substituted imidazopyridazine compounds of general formula (I) as described and defined herein, and to intermediate compounds useful in the preparation of said compounds. [0002] Background of the invention [0003] The present invention relates to a process for the preparation of substituted imidazopyridazine compounds that inhibit Mps-1 (monopolar spindle 1) kinase (also known as tyrosine threonine kinase, TTK). [0004] It has been found that imidazopyridazine derivatives potently inhibit Mps-1 kinase. Imidazopyridazine derivatives and methods for their preparation are disclosed eg in EP2460805A1 and WO2012 / 032031A1. [0005] Many of the compounds disclosed in WO2012 / 032031A1 were prepared according to the following scheme (see eg Examples 253, 254, 256, 257, 258, 259, 260 and 262): [0006] [0007] where R 1 and R 2 is an optionally substituted phenyl-group, R 3 is an optionally substituted al...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04A61P35/00A61P43/00C07B41/02
Inventor H.保尔森U.明斯特N.吉蒙德
Owner BAYER PHARMA AG