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A kind of preparation method of tadalafil impurity g

A technology for tadalafil and impurities, which is applied in the field of drug impurity synthesis, can solve problems such as low conversion rate, unreported purification method, yield, and only purity, and achieve high conversion rate, obvious advantages of finished products, and experimental conditions mild effect

Active Publication Date: 2020-09-29
ZHUZHOU QIANJIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The method first passes through specific oxidation conditions, first reacts with Oxone (potassium hydrogen persulfate compound salt) and the substrate under ice bath, and then processes the reaction solution with mCPBA, the conversion rate is low, and the purification method adopts column chromatography to obtain impurity H , but its purity is only about 80%; impurity H is condensed by adol under strong alkali conditions, and then dehydrated to obtain impurity G
At the same time, the literature does not report the method of purification and the yield situation

Method used

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  • A kind of preparation method of tadalafil impurity g
  • A kind of preparation method of tadalafil impurity g
  • A kind of preparation method of tadalafil impurity g

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] The structure of tadalafil impurity G is shown below:

[0057]

[0058] The specific process of impurity G preparation is:

[0059]

[0060] S1. Preparation of Compound 7

[0061] Dissolve compound 6 (12.00g, 31.07mmol, 1.00eq) in 30mL of ethyl acetate, add 10% ammonia / ethanol solution (34mL, 5.00eq), stir at room temperature for 2-3h, monitor the end point of the reaction by TLC, and wait for the reaction to complete Finally, concentrate under reduced pressure to remove the solvent, add 30mL of methanol, heat to about 40°C, fully dissolve, add L+(-) tartaric acid (5.13g, 34.18mmol, 1.10eq), stir for 1h, cool to 10-20°C, there is a solid Precipitate, continue to cool down to minus 10°C, a large amount of solid precipitates, filter to obtain a white solid, dissolve the white solid in 20mL of water, add sodium carbonate to adjust pH = 6-7, add 30*2mL ethyl acetate for extraction, combine the organic phase, Dry over anhydrous sodium sulfate, and concentrate the fil...

Embodiment 2

[0077] The preparation of embodiment 2 compound 6

[0078] The specific preparation process of compound 6 is as follows:

[0079]

[0080] (1). Preparation of compound 4

[0081] Under nitrogen protection, compound 3 (11.2g, 50mmol, 1.00eq), dimethyl malonate (9.24g, 70mmol, 1.40eq), Pd(dba) 3 (0.92g, 1.0mmol, 0.02eq), cesium carbonate (32.58g, 1.0mmol, 2.00eq), tri-tert-butylphosphine (0.61g, 3.0mmol, 0.06eq) dissolved in ethylene glycol dimethyl ether (100mL) , stirred and reacted at 140°C for 36 hours, LC-MS monitored the reaction end point, after the reaction was completed, the organic phase was extracted with 200mL ethyl acetate, washed with 200*2mL water, dried with anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure After column chromatography (eluent: ethyl acetate:petroleum ether=1:5) to obtain yellow solid compound 4 (8.61g, 79.2%, HPLC: 98.53%); ESI: m / z [M +H] + 218.20.

[0082] The results of the influence of temperature and ...

Embodiment 3

[0089] The preparation of embodiment 3 compound 3

[0090] The specific preparation process of compound 3 is as follows:

[0091]

[0092] (1) Preparation of compound 1

[0093] Aniline (9.31g, 100mmol, 1.00eq) and methyl propiolate (8.41g, 100mmol, 1.00eq) were dissolved in absolute ethanol (100ml), stirred at 80°C for 12-15h, and monitored by TLC at the end of the reaction. After the reaction was completed, it was concentrated under reduced pressure to obtain a pale yellow oily substance which was the target product compound 1, and the next reaction was directly carried out without purification. (HPLC: 97.36%); ESI: m / z [M+H] + 178.20.

[0094] (2) Preparation of Compound 2

[0095] Mix the compound 1 obtained in the previous step with 40mL polyphosphoric acid (PPA), stir and react at 100°C for 1-2h, monitor the end point of the reaction by TLC, after the reaction is completed, pour the reaction solution into 200mL of ice water, adjust the pH with sodium carbonate =5...

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PUM

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Abstract

The invention discloses a preparation method of a tadalafil impurity G. The preparation method comprises following steps: step one, reacting a compound (6) with an ammonification reagent, and splitting to obtain a compound (7); step two, carrying out Pictet-Spengler reactions between the compound (7) and heliotropin to obtain a compound (8); step three, making the compound (8) carry out acylationreactions to obtain a compound (9); and step four, carrying out cyclization reactions between the compound (9) and methyl amine to obtain a compound (10), and removing the protective group to obtain the impurity G; wherein the structures of the compounds (6, 7, 8, 9, 10) and the impurity G are shown in the description. The adopted raw materials are cheap and easily available, during the whole preparation process, basically no expensive material or reagent is used, and the cost advantage is obvious. The operation of each step of the preparation method is simple. The experiment conditions are mild, no severe experiment condition is required, and the post treatment is simple. The conversion rate of each step is high, and the yields are high and are almost 80% or more. The purity of each stepis high and can reach 95% or more. The preparation method is suitable for large scale production.

Description

technical field [0001] The present invention relates to the technical field of drug impurity synthesis, and more specifically, to a preparation method of tadalafil impurity G. Background technique [0002] Tadalafil is a selective reversible inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase V (PDE5), jointly developed by ICOS and Eli Lilly and Company, and approved by the FDA in 2003 for marketing in the United States. As a drug for the treatment of erectile dysfunction (ED) in men. Tadalafil has a rapid onset of action and a long duration of drug effect. It is the only drug among the four anti-ED drugs that is not affected by high-fat diet and alcohol intake. In addition to ED indications, tadalafil has also been approved for pulmonary arterial hypertension (PAH) and benign prostatic hyperplasia (BPH). In 2013, the global sales of tadalafil reached 2.16 billion US dollars, which is a typical blockbuster drug. It was approved to be listed in my countr...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/14
CPCC07D471/14Y02P20/55
Inventor 周泽银宿亮徐彬滨曾航日郭伟钟超泽
Owner ZHUZHOU QIANJIN PHARMA