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Preparing method of phosphodiesterase 5 inhibitor tadalafil

A technology of phosphodiesterase and tadalafil, applied in the direction of organic chemistry, to achieve the effect of mild conditions and less volatilization of methylamine

Active Publication Date: 2014-08-13
湖北省医药工业研究院有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthetic route of WO2007110734 uses butyl lithium, the reaction conditions are harsh, and the yield is low

Method used

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  • Preparing method of phosphodiesterase 5 inhibitor tadalafil
  • Preparing method of phosphodiesterase 5 inhibitor tadalafil
  • Preparing method of phosphodiesterase 5 inhibitor tadalafil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] 1, 1R, 3R)-1,2,3,4-tetrahydro-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4-b]indole-3- Preparation of methyl carboxylate hydrochloride (compound IV):

[0045] D-tryptophan methyl ester hydrochloride (100 g, 0.39 mol), 20 ml of isopropanol, 1000 ml of acetonitrile, piperonal (65 g, 0.43 mol) were mixed and stirred to reflux for 11 to 13 hours, cooled to room temperature, filtered, Washed with isopropanol and dried to obtain 144.0 g (94.9%) of compound IV with an ee value of 99.6%, [α] D 20 =+82.0 0 (c1, CH 3 OH).

[0046] 2. (1R, 3R)-1,2,3,4-tetrahydro-2-chloroacetyl-1-(3,4-methylenedioxyphenyl)-9H-pyrido[3,4- b] Preparation of methyl indole-3-carboxylate (compound V):

[0047] Compound IV (48 g, 0.12 mol) was suspended in 1.0 liter of dichloromethane, added 50 ml of triethylamine, stirred for 30 minutes, cooled at 10°C, added dropwise with chloroacetyl chloride (14 ml, 0.18 mol), then stirred for 1.5 hours , 500 ml of 10wt% potassium carbonate solution was ad...

Embodiment 2

[0061] According to Example 1: in step 1, 1000 ml of isopropanol was used as the reaction solvent instead of the mixed solvent of isopropanol and acetonitrile to obtain compound IV with a yield of 89.5% and an ee value of 98.1%, [α] D 20 =+79.0 0 (c1, CH 3 OH).

Embodiment 3

[0063] According to Example 1, 1000 ml of acetonitrile was used as the reaction solvent in step 1 instead of the mixed solvent of isopropanol and acetonitrile to obtain compound IV with a yield of 91.0% and an ee value of 99.0%, [α] D 20 =+81.0 0 (c1, CH 3 OH).

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Abstract

The invention relates to a preparing method of a phosphodiesterase 5 inhibitor tadalafil. D-methyl tryptophanate hydrochloride is adopted as an initial raw material, and is subjected to cyclization with heliotropin, N-acylation, aminolysis-cyclization, and other reactions to obtain a tadalafil crude product. The tadalafil crude product is recrystallized to obtain a tadalafil finished product. The method has characteristics of mild reaction conditions, short reaction time, high yield, good product stability and convenience for industrial production.

Description

technical field [0001] The invention relates to a preparation method of a phosphodiesterase 5 inhibitor, more specifically, the invention relates to a preparation method of a phosphodiesterase 5 inhibitor tadalafil. Background technique [0002] There are 11 families of phosphodiesterases (PDEs) in the human body, and they have different biological functions in the body. Phosphodiesterase 5 (PDE5) is an enzyme present in corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidney, lung and brain, and PDE5 is specific in corpus cavernosum and vascular smooth muscle cells Express. Normal penile erection is caused by parasympathetic nerve excitation during sexual stimulation, which promotes the release of nitric oxide (NO) from non-adrenergic and non-cholinergic neurons, and activates guanylate cyclase in penile cavernous bodies and vascular smooth muscle cells. This enzyme metabolizes guanosine triphosphate (GTP) to cyclic guano...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/14
CPCC07D249/08
Inventor 吴国生章雁赵一朗凌飒梁璐肖志梅
Owner 湖北省医药工业研究院有限公司
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