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Preparation method of tadalafil

A compound and solvent technology, applied in the field of medicine, can solve problems to be improved, and achieve the effects of short production cycle, mild reaction conditions and high purity

Active Publication Date: 2014-01-22
HUBEI BIO PHARMA IND TECHCAL INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Therefore, the method for preparing tadalafil still needs to be improved at present

Method used

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  • Preparation method of tadalafil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

Embodiment 2

[0044] Place 100g of compound 3 in a 2L three-necked flask, add 1000mL of dichloromethane, stir, and cool to 0 degrees Celsius. After compound 3 is dissolved, add 146g of diisopropylethylamine, slowly add 222g of compound 2, and keep it after adding. React at 0 degrees Celsius for 10 minutes, raise the temperature to 25 degrees Celsius, stir and react for 4 hours, stop the reaction, add dichloromethane and water, separate layers, and extract. The organic phase was washed three times with water, three times with saturated brine, dried, concentrated and added with 12N concentrated hydrochloric acid to make the product salted out, and filtered to obtain 220.2 g with a yield of 94%. 1 H NMR(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 to 0 degrees Celsius. After compound 3 is dissolved, add 108g of triethylamine, slowly add 222g of compound 2, and keep at 0 degrees Celsius after the addition. Reaction 10 Minutes, the temperature was raised to 25 degrees Celsius, the starting material was observed to disappear, the reaction was stopped, EA and water were added, layered, and extracted. The organic phase was washed three times with water, three times with saturated brine, dried, concentrated and added with 12N concentrated hydrochloric acid to make the product salted out, 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 preparation method of tadalafil. The method employs D-tryptophan as a starting material to synthesize tadalafil. The preparation method of tadalafil provided by the invention can effectively prepare tadalafil, and has high synthesis efficiency; and the prepared tadalafil has high purity. In addition, the preparation method has the advantages of easily available starting raw materials, simple process operation, mild reaction conditions, no special reaction equipment and no inseparable compound in the preparation process, thus the method is more suitable for large-scale industrialized production of tadalafil.

Description

Technical field [0001] The invention relates to the field of medical technology. Specifically, it relates to a method of preparing tadalafil. Background technique [0002] The chemical name of tadalafil (tadalafil, compound I) is (6R-12aR)-6-(1,3-benzodioxin-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 below, [0003] [0004] Tadanafil was developed by Lilly Pharmaceuticals 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 launched in the United States in December 2003. It is the third new drug approved by the FDA for ED. Although there are many methods for preparing tadalafil, there are disadvantages such as complex preparation process, low synthesis efficiency, low p...

Claims

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Application Information

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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
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