Hebei youze Biotechnology Co.,Ltd(expird)
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CAS NO.171596-29-5
high purity(1-15)Kilogramhigh purity(15-30)Kilogram
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Our Company
Hebei Youze Biological Technology Co., Ltd. has a registered capital of 1 million yuan and is one of the most dynamic foreign trade companies in the Chinese market. We have a pharmaceutical raw material production plant and a reagent R&D center. We now have the most complete product line. In addition, we have developed and produced tens of thousands of reagents. We also have the business of custom synthesis of various organic compounds as a supplement. We can synthesize almost all chemicals. Our goal is to survive by quality and develop by credit.
In the past two years, our products have spread over more than 30 countries in the world, Europe, South America, North America, Southeast Asia and Africa. We work with friends all over the world to develop the best quality products, the most reasonable prices and safe and effective transportation. Product can be ordered from milligrams to tons. Meet the purchase of new and old customers. We will not let you down.
Quick Details
Technical field
The invention belongs to the field of medical technology, and specifically relates to a production process of tadalafil bulk medicine.
Background technique
Tadalafil (tadalafil), chemical name: (6R-12aR)-6-(1,3-benzodioxan-5-yl)-2-methyl-2,3,6,7,12, 12a-hexahydropyrazino[1',2'-1,6]-pyrido[3,4-b]indole-1,4-dione; molecular weight: 389.41; molecular formula: C22H19N3O4. Tadalafil is a phosphodiesterase 5 inhibitor, originally developed by GlaxoSmithKline (GSK), and then transferred to ICOS, and then jointly developed by ICOS and EliLillv. Approved by the FDA in 2003, it was marketed in the United States as a treatment for male erectile dysfunction (MED). It was later discovered that another clinical application of the drug was to treat pulmonary hypertension. Compared with similar drugs, it has the advantages of high selectivity, long half-life, and greater autonomy for patients. However, the cost of the existing production process of tadalafil products is relatively high, especially the production process of the bulk drug is complicated, the purification is difficult, and the comprehensive yield is low, resulting in high market prices.
Summary of the invention
In order to overcome the shortcomings of the prior art, the present invention provides a production process of tadalafil bulk drug. The tadalafil bulk drug produced by this process has good economics, low production cost, stable quality, high purity, and high yield. Higher characteristics. The production process of the tadalafil bulk drug includes the following steps:
A1: Methanol and D-tryptophan undergo an esterification reaction to obtain Intermediate I;
A2: Intermediate Ⅰ undergoes condensation reaction with piperonal to obtain intermediate Ⅱ;
A3: Intermediate II undergoes acylation with chloroacetyl chloride to obtain Intermediate III;
A4: Intermediate III undergoes a cyclization reaction with monomethylamine to obtain tadalafil crude drug.
Further, in the above-mentioned production process of tadalafil bulk drug, in step A1, thionyl chloride is used as a catalyst and a dehydrating agent. Thionyl chloride has a dehydration effect and can also participate in and accelerate the esterification reaction.
Further, in the production process of the above-mentioned tadalafil bulk drug, step A1 is: by weight, 50.0 parts of methanol and 12.0 parts of D-tryptophan are put into the reaction kettle, the temperature is lowered to 10-20°C, and chlorine is added dropwise. 16 parts of sulfoxide; After the addition, the temperature is raised to 40～45°C, and the reaction is stirred for 2 hours; after the reaction is completed, the methanol is evaporated by concentration under reduced pressure, and then 50.0 parts of ethyl acetate is put into the reactor, and the slurry is beaten at room temperature for 1 hour. After filtering and drying, intermediate I is obtained.
Further, in the above-mentioned production process of tadalafil bulk drug, in step A2, isopropanol is used as a solvent.
Further, in the above-mentioned production process of tadalafil bulk drug, step A2 is: by weight, 100 parts of isopropanol and 12 parts of intermediate I are put into the reactor, and then 10 parts of piperonal are added, and heated to React at 70-80°C for 10 hours, cool to 10-20°C after the completion of the reaction, stir for 2 hours and then filter by shaking. After the filter cake is dried, Intermediate II is obtained.
Further, in the above-mentioned production process of tadalafil bulk drug, in step A3, triethylamine is used as an acid binding agent.
Further, in the above-mentioned production process of tadalafil bulk drug, step A3 is: by weight, put 80 parts of chloroform and 16 parts of intermediate II into the reactor, add 12 parts of triethylamine, and then control the temperature to 20~ Add 6.5 parts of chloroacetyl chloride dropwise at 30°C, continue the reaction for 2 hours after dropping, and then concentrate under reduced pressure to recover the chloroform, and add 50 parts of ethanol to the concentrated residue to be slurried for 1 hour, put in a centrifuge and filter, and dried to obtain Intermediate III.
Further, in the above-mentioned production process of tadalafil bulk drug, in step A4, methylene chloride is used as a solvent.
Further, in the production process of the above-mentioned tadalafil bulk drug, step A4 is: by weight, 100 parts of dichloromethane and 17 parts of intermediate III are put into the reactor, and then monomethylamine gas 5 is introduced under stirring. After the reaction is completed for 2 hours, the dichloromethane is concentrated to dryness after the reaction is completed, 50 parts of methanol are added to make a slurry for 1 hour, and then placed in a centrifuge to filter and dried to obtain the tadalafil crude drug.
Beneficial effects: The present invention provides a production process for tadalafil bulk drug, which reasonably selects the reaction path, and at the same time deeply optimizes the process details of each reaction step, so that the product of each reaction step can reach a very high Purity and yield, the prepared tadalafil bulk drug has low cost and good stability, which improves the economy of the entire reaction path and reduces production costs.
Description of the drawings
Figure 1 is a synthetic route diagram of the tadalafil bulk drug of the present invention.
detailed description
Example 1
A production process of tadalafil API, as shown in Figure 1, includes the following steps:
A1: Methanol and D-tryptophan undergo an esterification reaction to obtain Intermediate I;
A2: Intermediate Ⅰ undergoes condensation reaction with piperonal to obtain intermediate Ⅱ;
A3: Intermediate II undergoes acylation with chloroacetyl chloride to obtain Intermediate III;
A4: Intermediate III undergoes a cyclization reaction with monomethylamine to obtain tadalafil crude drug.
In this embodiment, step A1 is: put 50.0 kg of methanol and 12.0 kg of D-tryptophan into the reaction kettle, drop the temperature to 10-20°C and then add 16 kg of thionyl chloride; after the addition, heat up to 40- The reaction was stirred at 45°C for 2 hours; after the reaction, methanol was evaporated by concentration under reduced pressure. After the evaporation, 50.0 kg of ethyl acetate was put into the reactor, and the slurry was beaten at room temperature for 1 hour, and then filtered by shaking. After drying, 12 kg of intermediate I was obtained, purity: 99.2% , Yield: 93.6%.
In this embodiment, step A2 is to put 100kg of isopropanol and 12kg of Intermediate I into the reaction kettle, then add 10kg of piperonal, heat to 70～80℃ for 10 hours, and cool to 10～20℃ after the reaction. After stirring for 2 hours, it was shaken and filtered. After the filter cake was dried, 16kg of Intermediate II was obtained, purity: 99.5%, yield: 83.0%.
In this example, step A3 is: put 80kg of chloroform and 16kg of intermediate II into the reaction kettle, add 12kg of triethylamine, and then add 6.5kg of chloroacetyl chloride dropwise at 20-30°C, and continue the reaction for 2 hours after the drop. , And then concentrated under reduced pressure to recover chloroform, add 50kg of ethanol to the concentrated residue for 1 hour, put it in a centrifuge to filter and dry to obtain Intermediate III 17kg, purity: 99.3%, yield: 87.2%
In this embodiment, step A4 is: put 100kg of dichloromethane and 17kg of Intermediate III into the reactor, then pass 5kg of monomethylamine gas under stirring, complete the reaction for 2 hours, and concentrate the dichloromethane to Dry, add 50kg of methanol to beat for 1 hour, put it in a centrifuge to filter, and dry to get 14.5kg of tadalafil, purity: 99.9%, yield 93.5%.
It can be seen that the tadalafil crude drug prepared in this example has high purity and high yield, and each intermediate product can also achieve high purity and yield. The entire synthesis process is simple and compact, indicating that the production process provided by the present invention has Higher rationality and economy.
The above are only the preferred embodiments of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements can be made, and these improvements should also be regarded as the present invention. The scope of protection of the invention.