Method for synthesizing phosphodiesterase 5 inhibitor tadanafil

A synthetic method and diketone technology, applied in the field of medical engineering, can solve problems such as time-consuming and laborious, unfavorable synthetic process, and no specific conditions are specified, and achieve the effects of increasing yield, optimizing synthetic process, and simplifying separation methods

Inactive Publication Date: 2008-06-25
SHANGHAI JIAO TONG UNIV
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  • Abstract
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Problems solved by technology

However, there is no detailed report on the conditions for the conversion of the trans-configuration product to the cis-configuration
In the search, it was also found that in Lilly's patent US,6143746, it was briefly mentioned that acidic conditions can promote the conversion, but there is no description of the specific conditions for the conversion of trans isomers to cis isomers
[0006] At present, the separation method for the cis-trans configuration products of the Pickett-Spengler cyclization is based on the polarity difference of the cis-trans isomers. Column separation or recrystallization is used to separate the cis-trans isomers, which is time-consuming. Laborious and unfavorable for the enlarged synthesis process; such a separation method will inevitably affect the overall yield and process operation of tadalafil synthesis

Method used

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  • Method for synthesizing phosphodiesterase 5 inhibitor tadanafil
  • Method for synthesizing phosphodiesterase 5 inhibitor tadanafil
  • Method for synthesizing phosphodiesterase 5 inhibitor tadanafil

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Intermediate I (cis (1R,3R)-1-(3,4-dimethoxy-phenyl)-2,3,4,9-tetrahydro-1 hydrogen-β-carboline-3- Methyl formate and trans (1S,3R)-1-(3,4-dimethoxy-phenyl)-2,3,4,9-tetrahydro-1hydro-β-carboline-3- Synthesis of methyl formate)

[0028] Dissolve 0.04mol, 8.72g of D-tryptophan methyl ester, 0.042mol, 6.3g (1.05eq) of piperonal in 150ml of dichloromethane, cool down to 0°C with an ice-salt bath, and slowly add 5.7ml of trifluoroacetic acid dropwise . And stirred for 1h, rose to room temperature to continue the reaction for 24h. After the reaction is complete, add 30ml of saturated sodium bicarbonate and extract the layers with dichloromethane (50ml×3). The dichloromethane layers are combined, washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtered dichloromethane layer was concentrated to 1 / 2 volume, placed in a refrigerator to cool, and white crystals were precipitated, filtered under reduced pressure to ...

Embodiment 2

[0030]Intermediate II cis(1R,3R)-1-(3,4-dimethoxy-phenyl)-2,3,4,9-tetrahydro-1hydro-β-carboline-3-carboxylic acid Synthesis of methyl esters

[0031] Dissolve 9.7g of the intermediate I obtained in (1) in 150ml of mixed solvent of water and methanol, add hydrochloric acid to catalyze, stir to form a transparent solution, heat in a water bath to about 40-60°C and continue to react for 2-4 days, after the reaction is completed , was quenched with 30ml of saturated sodium bicarbonate, extracted with dichloromethane (50ml×3), the combined dichloromethane layers were washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtered dichloromethane layer was evaporated to dryness under reduced pressure to obtain a white solid with a yield of 98%, mp 152-154°C, [α] D 25 =+26.76° (c=0.1, CHCl 3 ); literature value: 24.4° (c=1.03, CHCl 3 ) This is intermediate II.

[0032] Through HPLC (high performance liquid phase) (Varion ...

Embodiment 3

[0037] Intermediate III (1R,3R)-1-(3,4-dimethoxy-phenyl)-2-chloroacetyl-2,3,4,9-tetrahydro-1hydro-β-carboline -Synthesis of methyl 3-carboxylate

[0038] Dissolve 3mmol, 1.05g of the intermediate II obtained in (2), 0.41g (1.2eq) of sodium bicarbonate in 50ml of chloroform at room temperature, cool down to 0°C in an ice bath, and slowly add 3.3mmol of chloroacetyl chloride dropwise under a nitrogen atmosphere , 0.264ml (1.1eq) (diluted in 10ml chloroform for use). After the dropwise addition was completed, the temperature was raised to 25° C. to continue the reaction for 1.5 h. After the reaction was complete, 50ml of water was added, and the aqueous layer was extracted with dichloromethane (20ml×3). The combined dichloromethane layers were washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. Concentrate the dichloromethane filtrate to 1 / 2, add 30ml of petroleum ether and oscillate gradually to see the precipitation of ...

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Abstract

The invention relates to a synthesis method for (6R, 12aR)-6-(1, 3-benzodioxane heterocyclas-5-base)-2-methyl-2, 3, 6, 7, 12, -12a-hexahydro pyrazinyl [1', 2':1, 6] pyridyl [3, 4-b] indole-1, 4-diketone in the technical field of the pharmaceutical engineering. With the D-methyl tryptophan and piperonal as raw materials, the cis-1, 3-disubstituted carboline intermediates are prepared and generated through the Pictet-Spengler cyclization and then the products called tadalafil are obtained through the acylation ammoniation of the 3-secondary amino group and the final MTX substitution and condensation close-loop. By adopting the acidic condition protic solvents in the invention, the trans-1, 3-disubstituted carboline intermediates generated through the Pictet-Spengler cyclization, which is a key step in the existing process, are converted into those with a cis-configuration, thus greatly enhancing the stereospecific configuration yield of the carboline intermediates so as to enhace the overal yield of the tadalafil with reaching the goal of optimizing and improving the synthesis process.

Description

technical field [0001] The present invention relates to a synthetic method of a compound in the technical field of medical engineering, in particular to a phosphodiesterase 5 inhibitor—(6R,12aR)-6-(1,3-benzodioxane-5- Base)-2-methyl-2,3,6,7,12,-12a-hexahydropyrazinyl[1',2':1,6]pyridyl[3,4-b]indole-1 , The synthetic method of 4-diketone (tadalafil). Background technique [0002] The incidence of male sexual dysfunction has shown an upward trend in the past ten years, and it is affecting the normal life of human beings more and more seriously. In 2003, the drug Tadalafil (Tadalafil trade name Cialis) for the treatment of sexual dysfunction was developed. (6R, 12aR)-6-(1,3-benzodioxan-5-yl)-2-methyl-2,3,6,7,12,-12a-hexahydropyrazinyl[1 ', 2': 1,6]pyridyl[3,4-b]indole-1,4-dione, namely tadalafil, started as a phosphodiesterase 5 (PDE5) inhibitory Compounds have entered people's research field of vision. Later, the researchers found that tadalafil had good anti-phosphodieste...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
Inventor 傅磊刘文陆张健存彭英丹陈尧
Owner SHANGHAI JIAO TONG UNIV
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