Sunday, 23 November 2014

New patent on tadalafil

 


WO-2014183730

 20-Nov-2014         WO-2014183730 -A2
 07-Aug-2013         CN-103232451-A

Method of preparing tadalafil
  Zhang, Mei; Zhao, Jinzhao; Peng, Xuedong; Wang, Long
Zhangjiagang Weisheng Biological Medical Co Ltd

Process for the preparation of tadalafil. Appears to be a new area of interest to the applicant and the inventors on this API. Lilly ICOS (the joint venture between ICOS and Eli Lilly) and United Therapeutics have developed and launched tadalafil, an orally active phosphodiesterase-5 inhibitor. Family members of the product case, WO9519978, have SPC protection in EU states until 2019. 


http://www.google.com/patents/CN103232451A?cl=en
External Links: SIPO, Espacenet

view pdf on google drive........... https://drive.google.com/viewerng/viewer?url=patentimages.storage.googleapis.com/pdfs/eb402079c77fe79b5c84/CN103232451A.pdf






 The invention relates to a preparation method of tadalafil. A product is obtained through condensation and cyclization, chloromethylation and aminolysis cyclization reaction based on D-tryptophan methyl ester hydrochloride and heliotropin as starting preparation materials. The simple preparation process is characterized in that condensation and cyclization are used for solving an isomer problem caused by Pictet-Spengler reaction by using isopropanol or nitromethane as a solvent; the yield of ethyl acetate in the aminolysis cyclization reaction is obviously improved; the aminolysis cyclization route includes three preparation steps, wherein the reaction yield of each step is high, the relevant impurities are easy to separate, the reaction conditions are simple, the production period is shorter, and toxic and highly corrosive reagents are not used, and therefore, the simple preparation process is safe and environment-friendly and easy to industrially produce, so that the high-purity qualified products are obtained.


According to the invention the lower alcohol [0022] the present invention include: methanol, ethanol, isopropanol and the like.
[0023] advantages of the present invention, the process is as follows:
[0024] (I) Preparation of a total of three-step synthesis of tadalafil, the route was shortened, shortening the production cycle, improve process efficiency.
[0025] (2) three-step reaction conditions are not harsh, easy to implement, easy to operate ,, no high temperature and pressure, waste recycling and easy to apply.
[0026] (3) The process route is simple, avoid the loss of the tedious process.
[0027] (4) the absence of high yield and high purity catalyzed direct preparation of cis tetrahydrocarbazol Lynn intermediate.
[0028] (5) chloroacetyl intermediate was used without purification in the next step involved in the reaction.
[0029] (6) Preparation of tadalafil after treatment, lower alcohol products tadalafil insoluble and soluble impurities related to its characteristics, without recrystallization, qualified directly to obtain high purity products, significantly increase the yield, reduce costs.
[0030] The process of the invention the total yield of up to about 70%, more than 98% purity, created from a D- tryptophan methyl ester hydrochloride to tadalafil complete the process, the process is simple, low cost, safety environmental protection, in line with industrial production standards. Brief Description
[0031] Figure 1 is that the chemical structural formula of his non.
[0032] FIG. 2 of the present invention tadalafil preparation route.
Specific embodiments
[0033] The following embodiments of the present invention will be described in detail: In this aspect of the embodiment of the present invention is implemented under the premise given in detail embodiments and processes, but the protection scope of the present invention is not limited to the following embodiments cases.
[0034] Example 1
Preparation [0035] cis tetrahydrocarbazol Lynn intermediates
[0036] D- tryptophan methyl ester hydrochloride 20g, piperonal 10.2~12.2ml, 160~200ml in isopropanol with a reflux apparatus and a thermometer, 250ml three flask, the reaction was heated to reflux with stirring 9~10h, the reaction end, followed by stirring under cooling to room temperature, filtered and the filter cake dried and dried to give a pale yellow cis-tetrahydrocarbazole Lin intermediate molar yield of 94~96%.
[0037] Example 2
Preparation [0038] cis tetrahydrocarbazol Lynn intermediates
[0039] D- tryptophan methyl ester hydrochloride 20g, piperonal 10.2~12.2ml, nitromethane 160~200ml on having a reflux device and a thermometer 250ml three-necked flask, the reaction was heated to reflux with stirring 9~10h, the reaction the mixture was stirred under cooling to room temperature, filtered, the filter cake dried and drying to give a pale yellow cis-tetrahydrocarbazole Lin intermediate molar yield of 90~92%.
[0040] Example 3
Preparation [0041] Chloro-acetyl intermediates
[0042] acetate 160~200ml, potassium 33~43g equipped with a thermometer in 250ml three-necked flask and stirred for about 30min, the input-step reaction of cis tetrahydrocarbazol Lynn intermediate ice bath temperature below 3 ~5 ° C, the 5 to 6-fold diluted with ethyl acetate was slowly added dropwise chloroacetyl chloride (8.8~10.6ml), after the reaction was continued I~1.5h, then warmed to room temperature for about 1.5h, the reaction was complete, water was added to about 400ml, extraction, the organic phase was concentrated under reduced pressure to a yellow-brown solid in powder, the molar yield of 78~80%.
[0043] Example 4
Preparation [0044] Chloro-acetyl intermediates
[0045] acetate 160~200ml, sodium bicarbonate 20~26g equipped with a thermometer in 250ml three-necked flask and stirred for about 30min, the input-step reaction of cis tetrahydrocarbazol Lynn intermediate ice bath temperature is below 3~5 ° C, the 5 to 6-fold diluted with ethyl acetate was slowly added dropwise chloroacetyl chloride (8.8~10.6ml), after the reaction was continued I~1.5h, then warmed to room temperature for about 1.5h, the reaction was complete, water was added about 400ml, extraction, the organic phase was concentrated under reduced pressure brownish yellow powder solid, molar yield 76~79%.
[0046] Example 5
[0047] Preparation of tadalafil
[0048] in the above Step was added directly chloroacetyl intermediate tetrahydrofuran 100~120ml, aqueous methylamine 18.5~23.1ml, the reaction was heated to reflux for about 12h, the reaction was concentrated under reduced pressure dark yellow solid, add methanol to about 200ml, stirred vigorously I~
1.5h cleaning, filtration, namely high purity qualified tadalafil, this step molar yield 92~95%.
[0049] Example 6
[0050] Preparation of tadalafil [0051] on chloroacetyl intermediate step directly into DMFlOO~120ml, methylamine solution 18.5~23.1ml, stirred at room temperature for about 24h, the reaction was extracted with dichloromethane, the organic phase was concentrated to dryness brown solid, plus methanol and about 200ml, stirred vigorously I~1.5h cleaning, filtration, namely high purity qualified tadalafil, this step molar yield 90~93%.

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