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Process for preparing N-methyladamantyl derivatives by a palladium catalysed coupling reaction followed by reductive amination

An alkyl-reaction technology, applied in the field of preparing N-methyladamantyl derivatives by palladium-catalyzed coupling reaction followed by reductive amination, can solve expensive, unfavorable large-scale commercial synthesis, air sensitivity, etc. question

Inactive Publication Date: 2009-08-19
ASTRAZENECA AB
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  • Abstract
  • Description
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  • Application Information

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Problems solved by technology

However, these complex catalysts are usually expensive, difficult to prepare and / or air-sensitive, which makes them unfavorable for large-scale commercial synthesis

Method used

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  • Process for preparing N-methyladamantyl derivatives by a palladium catalysed coupling reaction followed by reductive amination
  • Process for preparing N-methyladamantyl derivatives by a palladium catalysed coupling reaction followed by reductive amination
  • Process for preparing N-methyladamantyl derivatives by a palladium catalysed coupling reaction followed by reductive amination

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Embodiment Construction

[0035] The present invention will now be further explained by referring to the following exemplary embodiments.

[0036] Preparation of 2-chloro-5-iodo-N-(tricyclic [3.3.1.1 3，7 ]Dec-1-ylmethyl)-benzamide (Compound A)

[0037] In an inert atmosphere (N 2 ) Add 5-iodo-2-chlorobenzoic acid (40.00g, 141.6mmol) to a 500ml reaction vessel, and then add Bu 4 NCl (0.40 g, 0.01 equivalent, 1.42 mmol) and toluene (80 ml, 2 volumes). The suspension was heated to 70-75°C, and then thionyl chloride (12.40 ml, 1.2 equivalents, 169.94 mmol) was added dropwise over 30-60 minutes. The resulting suspension was heated at 70-75°C for about 3 hours. The reaction was monitored by HPLC (the sample was quenched with MeOH). Once it was over, the reaction mixture, now a clear solution of 5-iodo-2-chlorobenzoyl chloride, was cooled to 20-25°C.

[0038] Add 1-adamantane methylamine.HCl (28.56g, 1.0 equivalent, 141.62mmol), toluene (40ml, 1.0 volume) and 5M NaOH aqueous solution (84.96ml, 3.0 equivalen...

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Abstract

The application concerns a process for preparing 2-chloro-5- (3-amino) -N- (methyladamantyl) -benzamide derivatives. The first step of the process involves a palladium catalysed coupling reaction between an iodine containing compound and allyl alcohol with a tertiary amine as base. The second step involves a reductive amination on the formed aldehyde followed by subsequent transformation of the formed amine into a pharmaceutically acceptable salt.

Description

Technical field [0001] The present invention relates to methods for preparing compounds with pharmacological activity and intermediates for preparing compounds with pharmacological activity. Background technique [0002] P2X 7 Antagonists of receptors are involved in the treatment of inflammatory diseases, immune diseases and cardiovascular diseases. International patent application WO 01 / 44170 describes a series of P2X 7 Receptor antagonists and their preparation methods. One method described in WO 01 / 44170 uses 2-chloro-5-(3-oxopropyl)-N-(tricyclic [3.3.1.1 3，7 ]Dec-1-ylmethyl)-benzamide as an intermediate compound, the intermediate compound itself is through 2-chloro-5-iodo-N-(tricyclic [3.3.1.1 3，7 ]Dec-1-ylmethyl)-benzamide and allyl alcohol are prepared by reacting in the presence of sodium bicarbonate base in the Heck reaction catalyzed by palladium. [0003] Heck reaction is a palladium-catalyzed arylation reaction between allyl alcohol and aryl halide. The Heck reaction ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12
CPCC07C2103/74C07C231/12C07C2603/74C07C237/30C07C235/84C07C237/28
Inventor 戴维·恩尼斯阿格尼丝·福特乔尔·勒巴斯约翰·佩维
Owner ASTRAZENECA AB
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