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Method for preparing substituted triazolopyridines

A technology of alkyl and compound, which is applied in the field of intermediate compounds for the preparation of said compounds, and can solve the problems of undisclosed preparation of compounds, undisclosed, etc.

Inactive Publication Date: 2015-05-06
BAYER PHARMA AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] However, the aforementioned prior art neither discloses triazolopyridine compounds of general formula (I) as described and defined herein, and referred to herein as "compounds of the invention", nor does it disclose and defined methods for the preparation of said compounds

Method used

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  • Method for preparing substituted triazolopyridines
  • Method for preparing substituted triazolopyridines
  • Method for preparing substituted triazolopyridines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 0101

[0894] (2R)-2-(4-fluorophenyl)-N-[4-(2-{[2-methoxy-4-(methylsulfonyl)phenyl]amino}[1,2,4]tri Azolo[1,5-a]pyridin-6-yl)phenyl]propionamide

[0895]

[0896] Route 1

[0897] To a stirred suspension of Int08.011 (6.0 g) in DMF (48 mL) and dichloromethane (96 mL) was added sodium bicarbonate (3.69 g), (2R)-2-(4-fluorophenyl)propanoic acid ( 2.71 g) and HATU (8.36 g). The mixture was stirred at room temperature for 4 h. Water was added, and the mixture was stirred for 30 minutes. A half-saturated solution of sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuo. Silica gel chromatography gave a solid which was triturated with ethyl acetate to afford 7.44 g of the title compound.

[0898] 1 H-NMR (400MHz, DMSO-d 6 ):δ[ppm]=1.40(d,3H),3.16(s,3H),3.84(q,1H),3.96(s,3H),7.09-7.18(m,2H),7.36-7.44(m, 3H),7.51(dd,1H),7.63-7...

Embodiment 0102

[0918] (2R)-N-[4-(2-{[2-Ethoxy-4-(methylsulfonyl)phenyl]amino}[1,2,4]triazolo[1,5-a]pyridine -6-yl)phenyl]-2-(4-fluorophenyl)propionamide

[0919]

[0920] 180 mg of the enantiomers of racemate 01.02.r were separated using chiral HPLC. Column: Chiralpak IA 5 μ 250x30; Flow rate: 20,0 mL / min; Solvent: A: Ethanol with 0.1% formic acid; Solvent: 100% A. Retention time of the title compound: 37.2-49.1 min (peak 2). Obtained: 74mg.

[0921] 1 H-NMR (300MHz, DMSO-d 6 ):δ[ppm]=1.35-1.49(m,6H),3.15(s,3H),3.84(q,1H),4.22(q,2H),7.07-7.19(m,2H),7.36-7.44( m,3H),7.50(dd,1H),7.61-7.78(m,5H),7.93(dd,1H),8.44-8.54(m,2H),9.10(d,1H),10.19(s,1H) .

[0922] [α] D 20 : -72.7° (in DMSO).

[0923] Column: Chiralpak IA 5 μl 50x4.6; Flow rate: 1,00 mL / min; Solvent: A: Ethanol with 0.1% formic acid; Solvent: 100% A. Running time: 30min. Retention time: 14.3min; UV254nm; Enantiomer ratio: 99%.

Embodiment 0103

[0925] (2R)-2-(4-fluorophenyl)-N-[4-(2-{[4-(methylsulfonyl)-2-(2,2,2-trifluoroethoxy)phenyl] Amino}[1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl]propionamide

[0926]

[0927] Route 1

[0928] To a stirred suspension of Int08.021 (5.6 g) in DMF (45 mL) and dichloromethane (90 mL) was added sodium bicarbonate (1.97 g), (2R)-2-(4-fluorophenyl)propanoic acid ( 2.17g) and HATU (6.69g). The mixture was stirred at room temperature for 4 h. Water was added, and the mixture was stirred for 30 minutes. A half-saturated solution of sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuo. Chromatography of the amino phase on silica gel gave a solid which was triturated with a mixture of ethyl acetate and cyclohexane to afford 6.60 g of the title compound.

[0929] 1 H-NMR (300MHz, DMSO-d 6 ):δ[ppm]=1.39(d,3H),3.17(s,3H),3.83(q,1H...

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Abstract

The present invention relates to methods of preparing substituted triazolopyridine compounds of general formula (I) as described and defined herein, as well as to intermediate compounds useful in the preparation of said compounds.

Description

[0001] The present invention relates to processes for the preparation of substituted triazolopyridine compounds of general formula (I) as described and defined herein and to intermediate compounds useful in the preparation of said compounds. Background of the invention [0002] The present invention relates to a process for the preparation of specifically substituted triazolopyridine compounds that inhibit the Mps-1 (monopolar spindle 1) kinase (also known as tyrosine threonine kinase, TTK). Mps-1 is a dual-specificity Ser / Thr kinase that plays an important role in the activation of the mitotic checkpoint (also called spindle checkpoint, spindle assembly checkpoint), thereby ensuring proper chromosome segregation during mitosis [Abrieu A et al., Cell, 2001, 106, 83-93]. Every dividing cell needs to ensure that the duplicated chromosomes are divided equally between the two daughter cells. After entering mitosis, the chromosomes join at their kinetochores to the microtubules of...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61P35/00
CPCC07D471/04A61P35/00
Inventor V·舒尔策F-J·迈斯
Owner BAYER PHARMA AG