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Methods for the production of sildenafil base and citrate salt

A technology for sildenafil and sildenafil citrate, which is applied in the field of preparing sildenafil base and its citrate, can solve problems such as difficulty in removing by-products, complicated purification, and economic limitations

Inactive Publication Date: 2007-03-07
TEVA PHARMA IND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this method uses an excess of cyclic amine, which may be economically restrictive depending on the cyclic amine used
Also, because the protonated amine compound is similar to the final product, purification is complicated, i.e. removal of by-products from the reaction mixture is difficult

Method used

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  • Methods for the production of sildenafil base and citrate salt

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Embodiment 1: unconventional preparation of sildena

[0052] In a three-necked flask, benzenesulfonyl chloride-3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo(4,3-d )pyrimidin-5-yl)-4-ethoxyphenyl) (5g, 12.2mmol) was mixed with acetone (100ml) followed by the addition of 47% aqueous NaOH (0.487g, 10mmol). N-methylpiperazine (1.34 g, 11 mmol) was added dropwise. The reaction mixture was stirred for 45 min, then cooled to 0 °C and filtered. The precipitate was washed twice with water, and dried at 50° C. and a vacuum of 10 mmHg to obtain sildenafil with a yield of 88.8%.

Embodiment 2-13

[0054] Table 1. The yields of sildenafil synthesized using various solvents

Embodiment 14

[0055] Embodiment 14: the synthesis of sildenafil citrate

[0056] In a three-necked flask, sildenafil (5 g, 10 mmol) was dissolved in acetone (40 ml) at 50°C. In a separate vessel, citric acid (2 g, 10 mmol) was dissolved in acetone (15 ml). Both solutions were filtered. When the citric acid solution was added dropwise to the sildenafil solution, a white precipitate appeared immediately. Thereafter the reaction mixture was heated, maintained at the reflux temperature of the solvent for 1 hour, then cooled at room temperature for 3 hours. The precipitate was collected by filtration and dried at 50° C. and a vacuum of 10 mmHg to obtain sildenafil citrate with a yield of 95.5%.

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Abstract

Provided are processes for the preparation of sildenafil base and the citrate salt sildenafil. Also provided are sildenafil citrate water adduct and a method of preparing pharmaceutical compositions comprising combining the sildenafil citrate and / or sildenafil citrate water adduct with at least one pharmaceutically-acceptable excipient.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Patent Provisional Application 60 / 534,527, filed January 5, 2004, U.S. Patent Provisional Application 60 / 547,232, filed February 23, 2004, and U.S. Patent Provisional Application 60 / 549,268, filed March 1, 2004 interests, the contents of which are incorporated herein by reference in their entirety. field of invention [0003] The invention includes methods for preparing sildenafil and sildenafil citrate. The present invention also includes sildenafil citrate water adduct, and a method for preparing a pharmaceutical composition, comprising mixing sildenafil citrate and / or sildenafil citrate water adduct with at least one medicinal Mix with excipients. Background of the invention [0004] Sildenafil citrate is a cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) selective inhibitor commercially developed by ...

Claims

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Application Information

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IPC IPC(8): A61K31/519A61P15/10C07D487/04
Inventor V·布劳德J·阿伦希姆S·夏巴特
Owner TEVA PHARMA IND LTD
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