Processes for the preparation of N-heteroaryl-N-aryl-amines by reacting an N-aryl carbamic acid ester with a halo-heteroaryl and analogous processes

A technology of diarylamine and aryl, applied in the field of simple synthesis of diarylamine and its analogs, can solve the problems of limited palladium catalytic range, low yield and the like, and achieve easy large-scale preparation, high yield, The effect of simple reaction conditions

Inactive Publication Date: 2006-04-19
VERTEX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, when using monoaryl amines, the problem of adding an aryl halide partner to the amine in excess has traditionally resulted in low yields and problems with impurities
For this reason, monoamines are not commonly employed substrates for this transformation, which limits the scope of palladium-catalyzed coupling reactions.

Method used

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  • Processes for the preparation of N-heteroaryl-N-aryl-amines by reacting an N-aryl carbamic acid ester with a halo-heteroaryl and analogous processes
  • Processes for the preparation of N-heteroaryl-N-aryl-amines by reacting an N-aryl carbamic acid ester with a halo-heteroaryl and analogous processes
  • Processes for the preparation of N-heteroaryl-N-aryl-amines by reacting an N-aryl carbamic acid ester with a halo-heteroaryl and analogous processes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0209]

[0210] 2-Chloro-nicotinic acid methyl ester (52): 52 was prepared according to the method of Synth.Comm.26(12), 2257-2272(1996). To the nitrogen purged flask was added 2-chloro-nicotinic acid (1000.0 g, 6.0 mol, 1.0 eq) followed by 9 L of dichloromethane. To this was added thionyl chloride (1.4 L, 19.7 mol, 3.2 eq) and the reaction was heated to 4OC with vigorous stirring under nitrogen overnight. The acid chloride solution was cooled in an ice bath, and methanol (3 L, 74 mol, 12 equiv) was slowly added while maintaining the temperature at 20°C. The rate-limiting parameter is the vigorous evolution of large amounts of HCl gas. After adding, HPLC analysis [T ret Raw material = 7.5 minutes, T ret 52 = 11 minutes] shows that product has been formed immediately. Volatiles were removed in vacuo with EtOAc from 10% Na 2 CO 3 Extraction residue. The combined organic layers were dried (MgSO 4 ), filtered, and concentrated to a pale yellow oil.

Embodiment 2

[0212]

[0213] 2-(4-Fluoro-phenyl)-nicotinic acid methyl ester (54): Add Pd(Ph 3 ) 4 (1.84g, 1.6mmol, 0.005eq), sodium carbonate (42.8g, 404mmol, 1.3eq), 52 (55.5g, 320.6mmol, 1.0eq), p-fluorophenylboronic acid (53.8g, 384.7mmol, 1.2eq ), followed by 1.3 L of denatured EtOH. The reactants were heated to 78°C while under N 2 Stir vigorously overnight. HPLC analysis of the reaction mixture [T ret 52 = 10 minutes, T ret 54 = 12 min] shows complete consumption of starting material, resulting in a post-eluting peak. The reaction was cooled to room temperature and the solvent was removed under vacuum. The residue was dissolved in EtOAc, washed, dried (MgSO 4 ), filtered through celite, and concentrated to give 54 as a pale yellow solid.

Embodiment 3

[0215]

[0216] 2-(4-Fluoro-phenyl)-1-oxo-nicotinic acid methyl ester (55): To a nitrogen purged flask was added urea hydroperoxide (86.9 g, 924 mmol, 4.0 equiv), diaryl Pyridine 54 (53.4 g, 231 mmol, 1.0 equiv) and 530 mL of acetic acid. Heat the pale yellow homogeneous solution to 70-75 °C while stirring vigorously under nitrogen until HPLC analysis [T ret 54 = 12 minutes, T ret 55 = 10 minutes] showed >97% complete. The reaction was cooled to room temperature and the contents were slowly poured onto 500 g of ice. To the vigorously stirred ice-like mixture was slowly added 6N NaOH to pH 7 while maintaining the temperature at 30 °C. Add EtOAc and NaHCO 3 (solid) until an aqueous pH of 8-9 is reached and the solid dissolves. The layers were separated and the aqueous layer was back extracted with EtOAc. Combine the organic layers and wash with 5% NaHCO 3 Wash, then test for the presence of oxidizing agents with peroxide paper. If the organic layer is positive for per...

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Abstract

The present invention relates to processes for producing a diaryl amine compound of the formula (I); or a salt thereof, said process comprising the step of coupling a compound of formula (II) with an amine of formula (III) in the presence of an alkali metal salt or a transition metal catalyst, wherein: Ar1 and Ar2 are independently Q; wherein each Q is an aryl or heteroaryl ring system optionally fused to a saturated or unsaturated 5-8 membered ring having 0-4 heteroatoms; wherein Q is optionally substituted as defined in claim 1, wherein: X is a leaving group; and Y is -C(O)-O-Z; and Z is selected from C1-C6 aliphatic, benzyl, Fmoc, -SO2R' and Q, provided that Q is not substituted with X or alkyne; wherein R' is as defined in claim 1.

Description

technical field [0001] The present invention relates to the simple synthesis method of diarylamine and its analog. The yield and purity of diarylamine produced by the method of the invention are high. The invention also relates to intermediates useful in the process of the invention. The invention also relates to the diarylamines produced by the process of the invention. Background technique [0002] Protein kinases are involved in a variety of cellular responses to extracellular signals. Recently, the mitogen-activated protein kinase (MAPK) family has been discovered. Members of this family are Ser / Thr kinases, which activate their substrates by phosphorylation [B. Stein et al., Ann. Rep. Med. Chem., 31, pp. 289-98 (1996)]. MAPKs themselves are activated by a variety of signals, including growth factors, cytokines, UV radiation, and stress-response inducers. [0003] One MAPK of particular interest is p38. p38, also known as cytokine suppressive anti-inflammatory drug...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/80C07D213/79C07D213/75C07C273/18C07C275/42C07C275/30
Inventor J·R·史努尼安P-A·奥利弗-沙菲尔
Owner VERTEX PHARMA INC
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