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Preparation method of raw-material compound for preparing important impurity of Tadalafil

A technology for tadalafil and compounds is applied in the field of preparation of raw material compounds, which can solve the problems of complex preparation methods and low yields, and achieve the effects of simple conditions, improved yields and fewer steps.

Active Publication Date: 2020-03-06
ZHUZHOU QIANJIN PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The object of the present invention is to provide a new preparation method for the shortcomings and shortcomings of the relatively complicated preparation method of the preparation raw materials of tadalafil-related impurities F and G and low yield

Method used

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  • Preparation method of raw-material compound for preparing important impurity of Tadalafil
  • Preparation method of raw-material compound for preparing important impurity of Tadalafil
  • Preparation method of raw-material compound for preparing important impurity of Tadalafil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] 1. Preparation of Compound II

[0036] Dissolve D-glutamic acid dimethyl ester hydrochloride (12.08g, 57.08mmol, 1.00eq) and piperonal (10.28g, 68.50mmol, 1.20eq) in absolute ethanol (60mL), slowly add concentrated hydrochloric acid dropwise Adjust the Ph to 3-4, stir the reaction at 45°C for 4-6h, monitor the reaction with a TLC plate, after the reaction is over, let it stand and precipitate to obtain the crude product, add 20mL ethanol solution to the crude compound, heat to dissolve, and quickly add to 100mL In deionized water, stand at 0-2°C for 1 hour, filter to obtain a solid, repeat this method for recrystallization with ethanol 2-3 times, and vacuum-dry the obtained solid at room temperature to obtain the final product shown in Formula II Mannich Base (13.82 g, 70.44% yield, HPLC: 97.67%), ESI (m / z) [M+H-HCl] + : 308.1144.

[0037] 2. Preparation of Compound III

[0038] Mannich base (13.82g, 40.19mmol, 1.00eq), sarcosine (4.30g, 48.23mmol, 1.20eq), triethyla...

Embodiment 2

[0041] Conditions in the preparation process of embodiment 2 compound Ⅱ are explored

[0042] During the preparation of compound II, the influence of various reaction conditions on the product yield is shown in Table 1.

[0043] The influence of table 1 reaction system pH and temperature on reaction

[0044] serial number pH temperature(℃) Yield (%) 1 1 45 7.86 2 2 45 61.71 3 3 45 64.18 4 5 45 60.54 5 6 45 -- 6 4 25 10.23 7 4 35 40.32 Example 1 4 45 70.44 8 4 55 68.71 9 4 65 40.90

[0045] As can be seen from the results in Table 1, the difference in reaction system pH has a greater impact on the yield of product. When the pH of the reaction system is too low or too high, the reaction product cannot be obtained or the yield of the reaction product is extremely low; only When the pH of the reaction system is in the range of 2-5, the yield of the product is better, exceeding 60%, and when ...

Embodiment 3

[0048] During the preparation of compound I, the influence of the oxidation system on the product yield is shown in Table 2.

[0049] Table 2 The influence of different oxidation systems on the reaction

[0050] serial number oxidation system Reaction temperature (°C) Yield (%) 1 tert-butyl hydroperoxide / acid 30 40.37 2 Potassium permanganate / acid 30 34.15 3 Sodium hypochlorite / acid 30 38.40 4 Chromium Trioxide / Acid 30 30.79 5 hydrogen peroxide / acid 30 41.53 6 Hydrogen Peroxide / Copper Disalicylaldehyde Ethylenediamine 30 52.96 7 Hydrogen Peroxide / Copper Disalicylaldehyde Ethylenediamine 40 58.27 8 Hydrogen Peroxide / Copper Disalicylaldehyde Ethylenediamine 50 67.97 9 Hydrogen Peroxide / Copper Disalicylaldehyde Ethylenediamine 60 70.98 10 Hydrogen Peroxide / Copper Disalicylaldehyde Ethylenediamine 70 75.12 Example 1 Hydrogen Peroxide / Copper Disalicylaldehyde Ethylenediamine 8...

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Abstract

The invention discloses a preparation method of a raw-material compound for preparing an important impurity of Tadalafil. The raw-material compound has a structural formula shown as formula I. The preparation method of the raw-material compound comprises the following steps: S1, taking D-glutamic acid dimethyl ester hydrochloride and piperonyl aldehyde as raw materials, and carrying out heated reaction under acid conditions at a pH value of 1-5 so as to produce Mannich base of formula II; S2, allowing amidation reaction and amination reaction between the Mannich base of formula II so as to produce a compound of formula III; and S3, causing heated reflux reaction on the compound of formula III in the presence of a catalyst and an oxidant, thereby producing the raw-material compound of formula I. The preparation method of the raw-material compound for preparing the important impurity of Tadalafil is relatively few in steps that the target product, namely the raw-material compound, can beprepared by the three-step reactions; and moreover, the reactions in all steps are relatively high in yield that the yield of each step is higher than 68%. Compared with existing preparation methods,the preparation method of the raw-material compound for preparing the important impurity of Tadalafil has the advantages of being quick, simple and high in yield; and thus, the preparation method isactually convenient for large-scale high-yield production in factories.

Description

technical field [0001] The invention relates to the technical field of synthesizing compounds related to important impurities of tadalafil, and more specifically, to a method for preparing raw material compounds of important impurities of tadalafil. 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...

Claims

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Application Information

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IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 杨丽芳刘舞扬袁红波王雪姣金秉德
Owner ZHUZHOU QIANJIN PHARMA
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