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Process of synthesizing tadalafil

A technology of tadalafil and reaction mixture, applied in the field of tadalafil synthesis, which can solve the problems of unsafe reagents and expensive

Inactive Publication Date: 2008-02-20
TEVA PHARMA IND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The method of producing tadalafil in THF solution requires the use of expensive and unsafe reagents

Method used

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  • Process of synthesizing tadalafil
  • Process of synthesizing tadalafil
  • Process of synthesizing tadalafil

Examples

Experimental program
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Embodiment 1

[0045] Embodiment 1: Synthesis of tadalafil in acetonitrile

[0046] TDCl (5 g, 11.7 mmol), acetonitrile (125 ml) and methylamine (4 ml, 8M, 32 mmol, 33% EtOH) were combined to form a reaction mixture. The reaction mixture was stirred and heated in an autoclave at about 90°C for about 4 hours. The reaction mixture was cooled to room temperature and filtered. A solid was obtained which was dried (3.43 g; 75% yield). The solid was detected as tadalafil, and the purity was 100% as detected by HPLC.

Embodiment 2

[0047] Embodiment 2: synthesizing tadalafil in ethanol

[0048]TDCl (5 g, 11.7 mmol), ethanol (125 ml) and methylamine (4 ml, 8M, 32 mmol, 33% EtOH) were combined to form a reaction mixture. The reaction mixture was stirred and heated in an autoclave at about 78°C for about 5.5 hours. The reaction mixture was cooled to room temperature and filtered. A solid was obtained which was dried (3.3 g; 72% yield). The solid was detected as tadalafil, and the purity was 99.63% as detected by HPLC.

Embodiment 3

[0049] Embodiment 3: synthesizing tadalafil in toluene

[0050] TDCl (10 g, 23.4 mmol), toluene (200 ml) and methylamine (23 ml, 8M, 184 mmol, 33% EtOH) were combined to form a reaction mixture. The reaction mixture was stirred and heated in an autoclave at about 89°C for about 6 hours. The reaction mixture was cooled to room temperature and filtered. A solid was obtained which was slurried twice with methanol (25ml). The solid was then dried (7.8 g; 85.3% yield), which was detected as tadalafil with a purity of 100% by HPLC. The solid does not contain chloride ions.

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Abstract

The present invention provides tadalafil of high purity and processes of making such tadalafil by cyclization of TDCl in a solution.

Description

[0001] related application [0002] This application claims the benefit of the following applications: U.S. Provisional Application No. 60 / 656,664, filed February 25, 2005; U.S. Provisional Application No. 60 / 736,807, filed November 14, 2005; and U.S. Provisional Application No. 60 / 737,080. The contents of these applications are incorporated herein by reference. technical field [0003] The present invention relates to an improved synthetic method for the synthesis of tadalafil by cyclization of TDC1 in solution. Background technique [0004] Tadalafil, (6R-trans)-6-(1,3-benzodioxolan-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl -Pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione, which is a white crystal powder, and its general structure is as follows. (CAS#171596-29-5). Tadalafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase (PDE5). Inhibition of PDE5 increases the amount of cGMP, which leads to smooth muscle relaxati...

Claims

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Application Information

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IPC IPC(8): C07D471/14
CPCA61K9/14A61K31/498C07D405/04C07D471/14
Inventor B·-Z·多利奇基D·迪勒
Owner TEVA PHARMA IND LTD
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