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Preparing methods of Tadalafil intermediates

An intermediate, tryptophan methyl ester technology, which is applied in the field of preparation of drug tadalafil intermediates, can solve the problems of long duration of drug effect, etc., and achieves low dielectric constant, excellent solubility and low viscosity. Effect

Inactive Publication Date: 2016-07-13
GUANGZHOU PHARMACEUTICAL INDUSTRIAL RESEARCH INSTITUTE
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Problems solved by technology

[0007] 3. The drug effect lasts for a long time (up to 48 hours or more, but Viagra only has 4-6 hours)
[0016] Chinese patent 03818238.6 has no change in the preparation steps of Chinese patent 95192078.2, but some methods have been improved. From tryptophan as the starting material, D-tryptophan is obtained by using corrosive thionyl chloride in methanol. Methyl ester (Intermediate I), method unchanged

Method used

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  • Preparing methods of Tadalafil intermediates
  • Preparing methods of Tadalafil intermediates
  • Preparing methods of Tadalafil intermediates

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preparation example Construction

[0028] The preparation route of the preparation tadalafil intermediate I and II involved in the present invention:

[0029]

Embodiment 1

[0030] The preparation of embodiment 1 intermediate I

[0031] In a round bottom flask, add dimethyl diformate 75ml and 25ml methanol to form a mixed solvent, D-tryptophan 20.0g (98.0mmol), while stirring in the above solution, add phosphoric acid 10.0g (100mmol) and heat to reflux at 90°C After cooling for 12 hours, a solid precipitated out, washed with a small amount of dimethyl carbonate, and dried at 70°C to obtain 28 g of intermediate I phosphate, with a yield of 91%.

Embodiment 2

[0032] The preparation of embodiment 2 intermediate I

[0033] In a round bottom flask, add 100ml of dimethyl diformate and 20.0g (98.0mmol) of D-tryptophan. While stirring in the above solution, add methanolic hydrochloric acid solution (containing 4g of hydrogen chloride, 120mmol) and heat to reflux at 90°C for 6 hours After cooling, a solid was precipitated, washed with a small amount of dimethyl carbonate, and dried at 70°C to obtain 21 grams of intermediate I hydrochloride, with a yield of 90%.

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Abstract

The invention provides preparing methods of two Tadalafil intermediates shown as I and II in a solvent that is dimethyl carbonate. The intermediate I is prepared without the existence of thionyl chloride. High-purity stereoisomer that is the intermediate II can be prepared in the dimethyl carbonate solvent.

Description

technical field [0001] The invention belongs to medicine preparation technology, in particular to a preparation method of a drug tadalafil intermediate. Background technique [0002] Tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor originally developed by GlaxoSmithKline and subsequently transferred to ICOS, and later jointly developed by ICOS and Eli Lilly (Eli Lillv). The drug was first launched in the UK, Germany, Sweden in the European Union and Australia and New Zealand in Oceania, and was approved by the FDA in the United States in 2003. The trade name is Cialis, and it is also the third new drug for ED approved by the FDA. [0003] Tadalafil is a tetrahydro-β-carboline derivative, and its structure is different from that of sildenafil (Viagra) and vardenafil that have been marketed. It is also because of its special structure that tadalafil can highly selectively act on PDE5, but has little effect on other PDE isoenzymes such as PDE1, PDE2, PDF3, PDFA and PDE...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/20C07D471/04
Inventor 王玉平冯颂延
Owner GUANGZHOU PHARMACEUTICAL INDUSTRIAL RESEARCH INSTITUTE
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