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The method for preparing tadalafil

A technology for tadalafil and compounds, applied in the field of preparing tadalafil, can solve the problems of complex preparation process, difficult industrial production, low product purity, etc., and achieve the effects of simple process operation, short production cycle and high purity

Inactive Publication Date: 2015-11-25
HUBEI BIO PHARMA IND TECHCAL INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although there are many methods for preparing tadalafil at present, there are shortcomings such as complex preparation process, low synthesis efficiency, low product purity, and difficulty in industrialized production.
[0005] Therefore, the method for preparing tadalafil still needs to be improved at present

Method used

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  • The method for preparing tadalafil
  • The method for preparing tadalafil
  • The method for preparing tadalafil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Weigh 100g of compound 1 in a 2L three-neck flask, stir, add 1000mL of dichloromethane and 117g of SOCl 2, 5mL DMF was heated to 40 °C. After reacting for 1 hour, it was cooled and spin-dried to obtain 128 g of compound 3 with a crude yield of >99%. Melting point: 230-232 degrees Celsius (decomposition).

Embodiment 2

[0044] Put 100g of compound 3 in a 2L three-necked flask, add 1000mL of dichloromethane, stir, and cool down to 0 degrees Celsius. After compound 3 is dissolved, add 146g of diisopropylethylamine, slowly add 222g of compound 2, and keep React at 0°C for 10 minutes, increase the temperature to 25°C, stir for 4 hours, stop the reaction, add dichloromethane and water, separate layers, and extract. The organic phase was washed three times with water and three times with saturated brine, dried, concentrated and then added with 12N concentrated hydrochloric acid to precipitate the product as a salt, and filtered to obtain 220.2 g with a yield of 94%. 1 HNMR (CDCl 3 ):δ8.25(s,1H),7.47(d,J=7.6Hz,1H),7.29(m,2H),7.00-7.19(m,3H),5.65(d,J=8.3Hz,1H) ,4.95-5.07(m,3H),4.05(d,J=17.3Hz,1H),3.88(d,J=17.2Hz,1H),3.69(s,3H),3.09-3.16(m,2H), 2.86(s,1H); MS(m / z):326.1[M+H] + .

Embodiment 3

[0046] Put 100g of compound 3 in a 2L three-necked flask, add 1000mL of dichloromethane, stir, and cool down to 0 degrees Celsius. After compound 3 is dissolved, add 108g of triethylamine, slowly add 222g of compound 2, and keep it at 0 degrees Celsius to react for 10 Minutes, raise the temperature to 25 degrees Celsius, point the plate and observe the disappearance of the raw materials, stop the reaction, add EA and water, separate layers, and extract. The organic phase was washed three times with water and three times with saturated brine, dried, concentrated and then added with 12N concentrated hydrochloric acid to precipitate the product as a salt, and filtered to obtain compound 4 with a mass of 164 g and a yield of 70%.

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Abstract

The invention discloses a method for preparing tadalafil. The method uses D-tryptophan as a starting material to synthesize tadalafil. The method for preparing tadalafil of the present invention can effectively prepare tadalafil, and the synthesis efficiency is high, and the prepared tadalafil has high purity. In addition, the preparation method also has the advantages of easy-to-obtain starting materials, simple process operation, mild reaction conditions, no need for special reaction equipment, and no difficult-to-separate compounds in the preparation process, so it is more suitable for large-scale and industrialized production of tadalafil .

Description

technical field [0001] The invention relates to the technical field of medicine. Specifically, it relates to a method for preparing tadalafil. Background technique [0002] The chemical name of tadalafil (compound I) is (6R-12aR)-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7, 12,12a-hexahydropyrazino[1',2'-1,6]-pyrido[3,4-b]indole-1,4-dione, its chemical structure is shown in the figure below, [0003] [0004] Tadalafil was developed by Lilly Pharmaceutical Company in the United States. It relies on PDE-5 to increase the vasodilator effect of NO by inhibiting the decomposition of cGMP, so that ED patients can regain the ability of penile erection. It is mainly used to treat male erectile dysfunction. It was launched in Europe in February 2003 and in the United States in December 2003. It is the third new drug for ED approved by FDA. Although there are many methods for preparing tadalafil at present, there are disadvantages such as complex preparation process, low synthesi...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/14
CPCC07D471/14
Inventor 许勇李莉娥乐洋胡斌张绪文杨仲文王磊田华
Owner HUBEI BIO PHARMA IND TECHCAL INST