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Processes for producing phenyl-6-(1-(phenyl)ureido)nicotinamides)

A nitro and aryl technology, applied in the field of compound preparation, can solve the problems of IL-1β and TNFα block, and achieve the effects of reducing the number of reactions, mild reaction conditions and rapid production

Inactive Publication Date: 2012-02-08
VERTEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Inhibition of p38 kinase results in blockade of IL-1β and TNFα production

Method used

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  • Processes for producing phenyl-6-(1-(phenyl)ureido)nicotinamides)
  • Processes for producing phenyl-6-(1-(phenyl)ureido)nicotinamides)
  • Processes for producing phenyl-6-(1-(phenyl)ureido)nicotinamides)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0202] Example 1: Preparation of ethyl 6-chloro-2-(2,4-difluorophenyl)nicotinate (5)

[0203]

[0204] Preparation of ethyl 2-(2,4-difluorophenyl)nicotinate (3)

[0205]

[0206] Add Pd(Ph 3 ) 4 (5.0g, 4.33mmol, 0.005eq), sodium carbonate (92.6g, 874mmol, 1.3eq), ethyl 2-chloronicotinate 1 (126.0g, 678mol, 1.0eq), 2,4-difluorophenylboronic acid 2 (125 g, 791 mmol, 1.2 eq), then 0.5 L of toluene and 125 mL of denatured EtOH were added. The reaction system was stirred vigorously under N 2 Heat to 82° C. overnight under atmosphere (reaction complete by HPLC and TLC). The reaction system was cooled to room temperature, The mixture was pad filtered and the solvent was removed in vacuo at 55°C. The residue was dissolved in EtOAc, washed, dried (MgSO 4 ), and then pass Filter and concentrate. The product was obtained as a yellow solid.

[0207] Preparation of 2-(2,4-difluorophenyl)-3-(ethoxycarbonyl)pyridine 1-oxide (4)

[0208]

[0209] To a nitrogen purged 12 ...

Embodiment 2

[0213] Embodiment 2: Preparation of tert-butyl 2,6-difluorophenylcarbamate (7)

[0214]

[0215] Mix 2,6-difluoroaniline 6 (4.5 mL, 42 mmol, 1.0 equiv) and Boc anhydride (11.1 g, 51 mmol, 1.2 equiv) in THF and add 1 M sodium hexamethyldisilazane to the mixture at room temperature (100 mL, 100 mmol, 2.3 equiv (reaction complete by HPLC). Then 50 mL of brine was added, the solution was concentrated and extracted with EtOAc (2×100 mL). ) to wash the combined organic layers. Then with MgSO 4 The resulting solution was dried, filtered and concentrated to give the title compound 7 as an orange solid which was used in the next step without further purification. 1 H NMR (500.0MHz, CDCl 3 ) 7.18-7.13 (m, 1H), 6.96-6.91 (m, 2H), 6.06 (s, 1H) and 1.52 (s, 9H) ppm

Embodiment 3

[0216] Example 3: Preparation of ethyl 6-(tert-butoxycarbonyl(2,6-difluorophenyl)amino)-2-(2,4-difluorophenyl)nicotinate (8)

[0217]

[0218] A mixture of compound 5 (100.82 g, 0.33 mol, 1.0 eq), compound 7 (101.05 g, 0.44 mol, 1.30 eq) and cesium carbonate (177.12 g, 0.54 mol, 1.60 eq) was suspended in DMSO (250 mL, 2.5 vol ), vigorously stirred at 55-60° C. for 48 h (reaction complete by HPLC). The mixture was cooled to 20-30°C and the base was quenched by cautiously slow addition of 1N HCl(aq) solution (540 mL, 1.60 eq), keeping the internal temperature below 30°C. On cooling, a precipitate formed which was filtered and washed with water (2 x 250 mL, 2 x 2.5 vol). The precipitate was then suspended in absolute ethanol (1000 mL, 10 volumes) and heated to reflux. Reflux was maintained for 30-60 minutes and water (200 mL, 2 volumes) was added to the mixture. The resulting mixture was then reheated to reflux and maintained at reflux for 30 minutes at which time the suspe...

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Abstract

The present invention relates to processes for the preparation of compounds useful as inhibitors of p38 kinase. The processes of the present invention are amenable for large scale preparation and produce stable phenyl-6-(l-(phenyl)ureido)nicotinamides in high purity and yields.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application Serial No. US 61 / 152,653, filed February 13, 2009. The entire contents of U.S. Provisional Application Serial No. US 61 / 152,653 are incorporated herein by reference in its entirety. [0003] Technical Field of the Invention [0004] The present invention relates to processes for the preparation of compounds useful as p38 kinase inhibitors. The method of the present invention is suitable for large-scale preparation and production of stable phenyl-6-(1-(phenyl)ureido)nicotinamides with high purity and yield. Background of the invention [0005] Protein kinases are involved in various cellular responses to extracellular signals. A family of mitogen-activated protein kinases (MAPKs) has recently been discovered. Members of this family are Ser / Thr kinases that activate their substrates by phosphorylation [B. Stein et al., Ann. Rep. Med. Chem., 31, pp. 289-98 (...

Claims

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Application Information

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IPC IPC(8): C07D213/80C07D213/803A61K31/4418A61P37/06A61P29/00
CPCC07D213/80C07D213/803A61P29/00A61P37/06C07D213/72A61K31/4418
Inventor S·罗伊珀A·R·鲁克T·A·马丁诺特B·纽伯特-兰吉尔M·P·瑞恩J·R·史努尼安
Owner VERTEX PHARMA INC
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