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Process of purifying tadalafil

A tadalafil and solution technology, applied in organic chemistry, pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve problems such as increasing production costs of tadalafil

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

Such purification method increases the cost of producing tadalafil

Method used

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  • Process of purifying tadalafil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Example 1: Crystallization of Tadalafil in n-Butanol

[0033] In a 3 liter reactor equipped with a mechanical stirrer, condenser and thermometer, crude tadalafil (30 g dry basis) and butanol (2400 mL) were mixed to form a crude tadalafil solution. The solution was heated to 125°C and stirred at 100 rpm for about 1 hour to obtain a clear solution. The solution was cooled to 90°C and seeded. The mixture was stirred at about 90°C for 1 hour and then cooled to 10°C over 12 hours. The mixture was stirred for an additional 3 hours at about 10°C, filtered under vacuum, and washed with butanol (180 mL). Wet tadalamorph crystals were obtained (28.9 g, 99.5% by HPLC).

Embodiment 2

[0034] Example 2: Crystallization of Tadalafil in Acetone / Methanol

[0035]In a 1-liter reactor equipped with a mechanical stirrer, condenser, and thermometer, combine crude tadalafil (20 g of dry base), acetone (600 mL), and methanol (120 mL) to form a crude tadalafil solution . The solution was heated to 50°C and stirred at 100 rpm for about 1 hour to obtain a clear solution. The solution was then filtered and cooled to about 20°C and seeded. The mixture was stirred at about 20°C for 1 hour, then further cooled to 0°C over 3 hours. The mixture was stirred at 0 °C for an additional 1 h, then filtered under vacuum and washed with methanol (120 mL). Wet tadalamorph crystals were obtained (12.4 g, 100% by HPLC).

Embodiment 3

[0036] Example 3: Crystallization of Tadalafil in Acetone / Water

[0037] In a 1-liter reactor equipped with a mechanical stirrer, condenser, and thermometer, combine crude tadalafil (30 g of dry base), acetone (900 mL), and water (90 mL) to form a crude tadalafil solution . The solution was heated to 30°C and stirred at 200 rpm for about 1 hour to obtain a clear solution. The solution was then cooled to about 12°C and seeded. The mixture was stirred at about 12°C for 1 hour, then further cooled to -10°C over 12 hours. The mixture was stirred at -10°C for an additional 6 hours, then filtered under vacuum and washed with methanol (120 mL). Wet tadalamorph crystals were obtained (22.35 g, 99.7% by HPLC). According to the XRD analysis of the obtained substance, what is obtained is type I tadalafil.

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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 U.S. Provisional Application 60 / 656,664, filed February 25, 2005; U.S. Provisional Application 60 / 683,058, filed May 19, 2005; U.S. Provisional Application 60 / 736,807, filed November 14, 2005; and Priority to US Provisional Application 60 / 737,080, filed November 15, 2005, and US Provisional Application 60 / 677,514, filed May 3, 2005. The contents of these applications are hereby incorporated by reference. technical field [0003] The present invention relates to a method of purifying tadalafil by crystallization. Background technique [0004] Tadalafil, (6R-trans)-6-(1,3-benzodioxol-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 has the structural formula shown below, is a white crystalline powder . (CAS#171596-29-5). Tadalafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase PDE5. Inhibiting...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14
CPCA61K9/14A61K31/498C07D405/04C07D471/14
Inventor I·奥尔南
Owner TEVA PHARMA IND LTD
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