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Method for synthesizing tadalafil

A technology for tadalafil and compounds, applied in the field of preparation of tadalafil, can solve the problems of controlled starting materials, complex preparation process, difficult industrial production, etc., achieving short synthesis steps, simple process operation, and short production cycle Effect

Active Publication Date: 2019-07-05
WATERSTONE PHARMA WUHAN
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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 disadvantages such as complex preparation process, low synthesis efficiency, controlled starting materials, and difficulty in industrialized production.
Therefore, the method for preparing tadalafil still needs to be improved at present

Method used

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  • Method for synthesizing tadalafil
  • Method for synthesizing tadalafil
  • Method for synthesizing tadalafil

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Weigh 200g of compound of formula 1 (1.02mol) and 204.2g of compound of formula 2 (1.0mol) into a 2L three-neck flask, stir, add 1500mL of toluene and 228g of trifluoroacetic acid (2.0mol), and heat to 110°C. React until the compound of formula 2 is less than 1.0%, lower the temperature to 10 degrees Celsius, filter with suction, and dry under reduced pressure at 60 degrees Celsius to obtain 286g of compound 3. The molar yield relative to the compound of formula 2 is 85%, and the purity is 98.5%. 1H NMR (600 MHz, [D6]DMSO): δ = 3.13 (m,1H), 3.37 (dd, J =12.0, 4.4 Hz, 1 H), 4.56 (dd, J = 11.7, 4.7 Hz,1 H), 5.83 (s, 1 H), 6.08 (m,2 H), 6.96 (s, 1 H), 7.03–7.05 (m, 3H), 7.12 (t, J = 7.3 Hz, 1 H), 7.29 (d, J = 8.2 Hz, 1 H), 7.54 (d, J = 7.9 Hz, 1 H) , 10.12 (br, 2 H), 10.80 (s, 1 H). MS(m / z):335.1[M-H] - .

Embodiment 2

[0031] Put 200g of the compound of formula 3 (0.59mol) in a 3L three-necked flask, add 2000mL of dichloromethane and 137.3g of triethylamine (1.36mol), protect with nitrogen after replacing the air, keep stirring, cool down to 0 degrees Celsius, and control Add 146g of chloroacetyl chloride when the temperature of the system does not exceed 10 degrees Celsius. After reacting for 1 hour, add 500g of water slowly, separate layers, wash the dichloromethane phase with 500g of water once, concentrate to dryness under reduced pressure, add 1000g of absolute ethanol, and stir for 4 hour, suction filtration, and drying under reduced pressure at 60°C to obtain 219g of the compound of formula 4, with a molar yield of 90% and a purity of 99.0%.

[0032] 1H NMR (400 MHz, [D6]DMSO): δ = 2.96-3.02 (m,1H), 3.40-3.46 (m,2H),4.39 (d, J = 14 Hz,1 H) , 4.81 (d, J = 14 Hz,1 H), 5.04 (d, J = 6.4 Hz,1 H) ,5.94 (d, J = 11.2 Hz,1 H),6.59-6.75 (m, 3 H),6.99–7.08 (m, 2H), 7.25 (d, J =7.6 Hz, 1 H)...

Embodiment 3

[0034] Put 100g of the compound of formula 4 (0.24mol) in a 1L three-necked flask, add 400mL of tetrahydrofuran and 75.2g of 40% aqueous methylamine (0.97mol), stir, heat up to 50 degrees Celsius, react until the compound of formula 4 disappears, add 500ml of Water alcohol, cooled to 0 degrees Celsius, suction filtered, dried under reduced pressure at 60 degrees Celsius to obtain 85 g of tadalafil, molar yield: 91%, purity 99.9%. 1HNMR (CDCl3): see attached figure 2 ; MS(m / z): 390.1[M+H] + .

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Abstract

The invention discloses a method for synthesizing tadalafil. Tadalafil is synthesized from D-tryptophan and a compound of formula 1. The method for preparing tadalafil of the invention can effectivelyprepare tadalafil. In addition, the starting material piperonyl dimethyl acetal of the preparation method is easy to obtain as a non-controlled material, the procurement and management are not restricted, the use of the controlled material piperonyl is effectively avoided, the management and procurement are convenient, the process steps are short, the production cost is greatly reduced, and the preparation method is more suitable for large-scale and industrial 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 following formula, [0003] [0004] Tadalafil, developed by Lilly Pharmaceuticals in the United States, is a selective, reversible inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase 5 (PDE5). When sexual stimulation leads to local release of nitric oxide, PDE5 is stimulated. Inhibition by tadalafil increases cGMP levels in the corpus cavernosum of the penis, which leads to relaxation of smooth muscle and blood flow into the penile tissues, resulting in an erection. It was launched in Europe in February 2003 and in the United States in December 2003. It is the third n...

Claims

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Application Information

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IPC IPC(8): C07D471/22
CPCC07D471/22Y02P20/55
Inventor 胡名龙孟源鄢宁
Owner WATERSTONE PHARMA WUHAN
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