Sunday, 30 November 2014

New patent on Avanafil WO-2014187273

Avanafil ball-and-stick.png

WO 2014187273

Avanafil preparation method
Suzhou Lixin Pharmaceutical Co Ltd; Suzhou Mingyue Medical Technology Co Ltd;  

Novel process for the synthesis of avanafil comprises reacting cytosine with 3-chlorine-4-Methoxybenzyl halogen, N-(2-methylpyrimidine) methanamide and S-hydroxymethyl pyrrolidine. Useful for treating erectile dysfunction.


[en] Disclosed is a method for preparing avanafil (I) by using cytosine as the starting material. The preparation steps comprise: using cytosine as the raw material, and enabling the cytosine to react with side chain 3-chlorine-4-Methoxybenzyl halogen, N-(2-methylpyrimidine) methanamide, and S-hydroxymethyl pyrrolidine, to prepare the target product avanafil (I). For the preparation method, the raw material is easily obtained, and the process is simple, economical, and environmentally friendly, so the method meets the requirement of industrial boost.
[fr] Procédé de préparation d'avanafil (I) utilisant de la cytosine comme matière de départ. Les étapes de préparation de ce procédé consistent à utiliser de la cytosine en tant que matière de départ, et à laisser la cytosine réagir avec un halogène 3-chloro-4-méthoxybenzyle à chaîne latérale, du N-(2-méthylpyrimidine)méthanamide, et de la S-hydroxyméthyle pyrrolidine, pour préparer le produit cible : l'avanafil (I). Pour le procédé de préparation, la matière de départ est facilement obtenue, et le procédé est simple, économique et respectueux de l'environnement, de sorte que le procédé satisfait aux exigences de la croissance industrielle rapide.
[zh] 本发明揭示了一种以胞嘧啶(Cytosine)为起始原料制备阿伐那非(Avanafil,I)的方法,其制备步骤包括以胞嘧啶为原料,经与侧链3-氯 -4-甲氧基苄卤素、N-(2-甲基嘧啶)甲酰胺和S-羟甲基吡咯烷反应,制得目标产物阿伐那非(I)。该制备方法原料易得、工艺简洁、经济环保,适合工 业化放大的要求。
[zh] 阿伐那非的制备方法
Application Number
Publication Number
Application Date
May 16, 2014
Publication Date
November 27, 2014
XU Xuenong
XU Xuenong
C07D 403/14

Crash course on patents

Saturday, 29 November 2014

What is Intellectual Property?

Intellectual property (IP) rights are legally recognized exclusive rights to creations of the mind.[ Under intellectual property laws, owners are granted certain exclusive rights to a variety of intangible assets, such as musical, literary, and artistic works; discoveries and inventions; and words, phrases, symols, and designs. Common types of intellectual property rights include copyright,trademarkspatentsindustrial design rightstrade dress, and in some jurisdictions trade secrets.
Although many of the legal principles governing intellectual property rights have evolved over centuries, it was not until the 19th century that the term intellectual property began to be used, and not until the late 20th century that it became commonplace in the majority of the world. The British Statute of Anne (1710) and the Statute of Monopolies (1624) are now seen as the origins ofcopyright and patent law respectively.
Generally speaking, “intellectual property” is probably best thought of (at least form a conceptual standpoint) as creations of the mind that are given the legal rights often associated with real or personal property. The rights that are obtained by the creator are a function of statutory law (i.e., law created by the legislature). These statutes may be federal or state laws, or in some instance both federal and state law govern various aspect of a single type of intellectual property.
The term intellectual property itself is now commonly used to refer to the bundle of rights conferred by each of the following fields of law: (1) patent law; (2) copyright law; (3) trade secret law; (4) the right of publicity; and (5) trademark and unfair competition law. Some people confuse these areas of intellectual property law, and although there may be some similarities among these kinds of intellectual property protection, they are different and serve different purposes.

What is a Patent?
Whenever you think patent you should think  invention. Thus, a patent is the grant of a property right to an inventor. Patents only exist once they have been granted, and in the United States patents are issued by the U.S. Patent and Trademark Office, which is a non-commercial federal entity and one of 14 bureaus in the Department of Commerce. Before going any further it is worth pointing out that ideas are not patentable, although every invention starts out with an idea. Still, in order to be in a position where you can obtain a patent your idea must have matured into an invention. 
There are three very different kinds of patent in the United States: (1) a utility patent, which covers the functional aspects of products and processes; (2) a design patent, which covers the ornamental design of useful objects; and (3) a plant patent, which covers a new variety of living plant.
Each type of patent confers “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States or “importing” the invention into the United States. It is important to note, however, that patents do not protect ideas, but rather protect only tangible or identifiable structures and methods.

Typically when someone refers generically to “a patent” they are talking about a utility patent. In order to obtain a utility patent it is necessary to file a non-provisional patent application and go through an examination process where a patent examiner will review the application to determine what, if any, claims can be allowed. Many are probably also familiar with aprovisional patent application, which can be used to establish priority and give the applicant “patent pending” status. A provisional patent application will never mature into a patent though. It is always necessary to file a non provisional patent application to obtain a patent.
Patent claims define the exclusive rights granted by the government. If it is not in a patent claim you do not have rights associated with it. If the claims are too detailed they can be easy to get around and not commercially useful. There is a lot that goes into any patent application, both from a technical and strategic standpoint.
Generally speaking the patent term for utility patents is now 20 years from the date on which the application for the patent was filed in the United States. Under some circumstances it is possible to obtain a 5 year extension to the patent grant, but this is rare, unless your invention relates to a pharmaceutical composition. It is also possible to obtain extension of patent term due to USPTO delay. Design patents, unlike utility patents, have a 14 year term from date of issuance.  Historically, design patents were quite weak, but as the result of an important decision from the United States Court of Appeals for the Federal Circuit in the Fall of 2008, design patents are now much stronger and should be considered an important part of a patent portfolio when your invention relates to a product.

What is a Copyright?
Copyright is a form of protection provided to the authors of “original works of authorship” including literary, dramatic, musical, artistic, and certain other intellectual works, both published and unpublished. Copyright law generally gives the owner of a copyright the exclusive right to reproduce the copyrighted work, to prepare derivative works, to distribute copies or phonorecords of the copyrighted work, to perform the copyrighted work publicly, or to display the copyrighted work publicly.
The copyright protects the form of expression rather than the subject matter of the writing. For example, a description of a machine could be copyrighted, but this would only prevent others from copying the description; it would not prevent others from writing a description of their own or from making and using the machine. In order to prevent the making and using of the machine one would have to seen patent protection. Copyrights are registered by the Copyright Office, which is a part of the Library of Congress.
Copyright protection does not and cannot exist for an idea, procedure, process, system, method of operation, concept, principle, or discovery, regardless of the form in which it is described or embodied. This is true because a copyright protects only the form of expression rather than the subject matter of the writing. It is simply not the function of the copyright laws to protect anything other than original expression. Ideas are not protected by copyright law because protecting an idea would take the idea out of the public domain and would prevent others from using the idea to create their own independent and original works of authorship.
What is a Trade Secret?
A trade secret is any valuable business information that is that is not generally known and is subject to reasonable efforts to preserve confidentiality. A trade secret will be protected from misappropriation from exploitation (through state law) by those who either obtain access through improper means or who breach a promise to keep the information confidential.
Trade secret misappropriation is really a type of unfair competition. Remedies for infringement of a trade secret include damages, profits, reasonable royalties, and an injunction. Some statutes also provide for enhanced damages and attorneys fees in certain circumstances.

Trade secrets are a very important part of any intellectual property portfolio. It is not at all an overstatement to say that virtually every business has trade secrets worth protection, regardless of whether the business is run as a sole proprietorship, a small business or Fortune 500 company. This is true because any business information that is valuable as a result of being kept secret qualifies for treatment as a trade secret.  Nevertheless, it may be better to say that every business has assets that could and should be protected as trade secrets, but the truth is that many companies, even large companies, fail to do so properly.  The failure to treat information as a trade secret means you have no asset at all, and no remedy if the information is taken or stolen by others.  Thus, appreciating what can be a trade secret and how to take steps to protect a trade secret are vital for inventors and businesses alike. 
What is a Trademark?
Generally speaking a trademark is a word, name, symbol or device which is used in trade with goods to indicate the source of the goods and to distinguish them from the goods of others. A service mark is the same as a trademark except that it identifies and distinguishes the source of a service rather than a product. The terms “trademark” and “mark” are commonly used to refer to both trademarks and service marks.
A trademark is a significant asset.  A trademark not only becomes your company seal, but it is how consumers will relate to your goods or services.  If you have high quality goods and services for a reasonable price then customers will associate your company with positive feelings and memories, so the next time they see your trademark they will conjure up in their minds a whole host of positives.  This conjuring up of positive feelings, emotions and memories of satisfaction can be powerful. 
Trademark rights may be used to prevent others from using a confusingly similar mark, but not to prevent others from making the same goods or from selling the same goods or services under a clearly different mark. Trademarks which are used in interstate or foreign commerce may be registered with the Patent and Trademark Office.
Filing a trademark application is an excellent step to take to protect your name, slogan or logo. It is, however, important to understand that not all trademarks are created equal. While every state allows you to obtain a trademark registration, federal trademark registration provides the greatest rights. This is because when you obtain a United States federal trademark your rights will exist throughout the country, and not in just one particular state or geographic locality.
The first step to acquiring federal trademark rights requires that you either (1) start using the slogan, name or logo in commerce (i.e., some kind of commercial use) and then subsequently file a trademark application; or (2) file an intent to use application which will lock in your filing date but which does not require immediate use. 

What is Trade Dress Protection?
Trade dress is the totality of elements in which a product or service is packaged or presented. These elements combine to create the whole visual image presented to customers and are capable of acquiring exclusive legal rights as a type of trademark or identifying symbol of origin. Because trade dress includes all factors making up the total image under which a product or service is presented to customers, it potentially covers almost all aspects of appearance. Things that have been held protectable under the category of trade dress include: (1) the shape and appearance of a product; (2) the shape and appearance of a container; (3) the cover of a book or magazine; (4) the layout and appearance of a business establishment such as a restaurant; (5) the theme and look of a line of greeting cards; and (6) the recognizable shape of an automobile.
What is the Right of Publicity?
The “right of publicity” is the inherent right of every human being to control the commercial use of his or her identity. Please note these carefully chosen words. It is the right of “every human being,” not the right of every person. In many contexts we could substitute the phrase “every human being” with the word “person,” but it is important to remember that the right of publicity is an individual right. When the word “person” is used in the law we most often define “person” to include corporations or other similar entities. This is not the case with the right of publicity. The right of publicity does not protect the persona of a corporation, partnership, institution or other similar entities; it protects only the human identity.
Infringement of the right of publicity can be triggered by any unauthorized use in which the plaintiff is “identifiable.” A plaintiff is identifiable by name, nickname, stage name, pen name, picture, photograph, voice (particularly a distinctive voice) or any object closely identified with a person. An unpermitted commercial use where the plaintiff is identifiable triggers a prima facie case of infringement of the right of publicity.

Sunday, 23 November 2014

New patent on tadalafil



 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.
External Links: SIPO, Espacenet

view pdf on google drive...........

 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%.