Archive | June, 2018

The Benefits of Educational Videos for Kids

30 Jun

Every child learns best in a different way. One of the ways children can easily learn is through watching videos. This is why some websites that offer educational resources for parents and teachers to use with children offer educational Kids videos to help them understand various concepts. These videos provide children with many advantages over simply writing the instructions out and possibly even using pictures to follow along.

If you have ever seen a child watching cartoons or another show of interest to him, you see how mesmerized he is by the action on the screen. When you can make use of educational videos to supplement what he is learning, he will be interested in watching them to find out what happens next. As long as the videos are well done in a way that attracts children, it can be a useful tool to help in their education.

Especially in the area of science, it is important for children to be able to actually see what happens during an experiment. Not everyone can perform the experiments in their homes or classrooms due to restricted space, safety issues or lack of materials. Science educational videos for kids can show them what happens through the course of the experiment without having to physically perform the experiment.

Students listen to their teacher talk all day and often aren’t interested in getting this type of information from parents either. This can make learning ineffective over time, which is why parents and teachers often strive to use a variety of methods to teach students. When they learn new concepts through videos, though, they will be learning them from someone with whom they aren’t in contact on a regular basis. Changing things up will ensure students remain interested so they don’t miss out on learning anything important.

Related Post: Did You Know Video Games Can Help Your Kids?

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DAV NETWORK Project Review: A Decentralized Ecosystem for Autonomous Transportation

25 Jun

DAV Network aims to create a decentralized, highly-secured, and highly-scalable ecosystem that brings all the participants in the transportation industry together. The project’s target is the future autonomous vehicles market but they have use cases that will impact the current system in place.

DAV Network ICO Review Highlights

ICO Platform Ethereum
Rating 3.8/5
Grade B+
Industry Transportation
Price 1 DAV = 0.0001 ETH
Bonus ______
Soft Cap ______
Hard Cap 63,123 ETH
Total Number of Tokens (Available for sale) 1.8 billion DAV (777 million DAV)
Website URL DAV Network Official Website
Whitepaper URL DAV Network Whitepaper
Social media accounts URL DAV Network Telegram
DAV Network Twitter
DAV Network Reddit

 

Let’s decrypt DAV Network Use Case

What problem is DAV Network Addressing?

The transportation industry is going through its “biggest revolution since the invention of Henry Ford’s assembly line in 1908” ( DAV Network Whitepaper, 2017). Uber, Lyft, and other ridesharing companies are disrupting the industry and redefining how people are transported. Another consequence of this advancement in technology in the transportation industry, however, is the emergence of autonomous vehicles, and in a matter of years, self-driving vehicles would have populated the market considerably.

When this happens, the current closed-platform model that ridesharing companies current adopt would no longer be very effective. A decentralized ecosystem that allows the different participants in the transportation industry—consumers, businesses, hardware companies, software developers, insurance providers, maintenance workers, and arbitrators—benefit from/contribute to the growth of the network is urgently needed.

DAV Network Value Proposition

Decentralized Autonomous Vehicle (DAV) Network aims to develop a highly-scalable and open-source ecosystem where all contributors can operate without a central authority. Using the DAV Network, users may order for a drone, send it to deliver an item to a specific address, and pay for the service using DAV tokens. This will be particularly useful for delivery companies; last-mile delivery accounts for 55% of delivery costs today. Taking a delivery truck to an area and having drones deliver parcels from house-to-house is more cost-efficient than driving the filled truck to every house.

In the future, when autonomous vehicles have populated the market, individuals may order for driverless rides and pay using DAV. Owners of these vehicles may make them available and earn tokens too. Maintenance workers may earn DAV for looking after and running checks on the vehicles in the ecosystem, and hardware and software companies may also earn DAV for making their products and services available to consumers in the ecosystem.

DAV Network Leadership Team

Founder and CEO, Naom Copel, is a veteran strategist and expert in blockchain technology, cryptocurrencies, and encryption. In 2003, Copel developed the first smartphone encryption system in the world; it was distributed to almost 50 countries. Co-founder and CCO, John Frazer was External Relations Lead for the Ethereum Foundation and a senior member of the Devcon3 team. Co-founder and CMO, Joe Lopardo worked with reputable companies like Google, Oracle, SAP, and Salesforce as a brand developer and marketing strategist.

They are joined on the team by other well-qualified personnel and an advisory board that includes a former executive at GM, an astronaut from NASA and many more prominent names. ( DAV Network website, 2018).

DAV Network Target Market

The emergence of autonomous vehicles is expected to kick-start the “Passenger Economy”, and according to a report by Intel, this economy will be worth $800 billion in 2035 and in excess of $7 trillion by 2050.

DAV Network aims to be a significant part of this economy and if they succeed in securing even a portion of the market share, any investment now will definitely yield significant returns. The project sold $20 million worth of DAV during their presale.

DAV Network Roadmap

According to their website, the DAV network was launched in May 2018 and their drone charging service was launched in the same month. May 2018 also saw the first autonomously-completed vehicle charging on the network.

DAV token sale commenced on the 11th of June 2018 and it should go on till the 25th of June or when all tokens have been sold. DAV network’s decentralized non-autonomous ride hailing network should be released in Q4 2018.

DAV Network SWOT Analysis

DAV Network Strengths

  • A strong team with a large community of open source contributors.
  • Well-connected advisors with ties to IBM, GM, NASA, UPS, SAP etc.
  • The Passenger Economy is an emerging market that holds ample potential.

DAV Network Weaknesses

  • Long developmental roadmap.
  • Given current market conditions, $38 million is a considerably high hard cap.

DAV Network Opportunities

  • A Network has been launched and they have working prototypes.
  • The project raised $20 million during their presale.

DAV Network Threats

  • Their use case piths them against more recognizable companies like IOTA and IoT Chain.
  • Mass adoption may not happen until autonomous vehicles populate the market; there is no timeline for this at the moment.

In conclusion, DAV Network has many good parts—the team, their advisors, prototypes, future potential etc. They also have the public’s sentiment on their side despite the fact that their most important features may not be launched soon. Because of this, DAV Network may be one of the few projects whose tokens hold both present and future promise. As always, however, prospective investors are advised to keep their eyes open for future updates and information.

Related Post: : DAV NETWORK Project Review: A Decentralized Ecosystem for Autonomous Transportation

Why You Want Snow Algae In Your Face Cream

18 Jun

What Is Snow Algae?

Cream with snow algae is found at the coldest of mountain tops, such as the Alps or even coastal polar regions. During the summer it remains a hearty green, however when winter comes, it turns bright red.

It’s able to turn red in order to protect itself from the harsh UV exposure of the sun. The red pigment it produces is able to defer the sun’s radiation.

As it is found at the highest mountain peaks, this plant has to be very sturdy to thrive in such a harsh environment.

How Does It Benefit You?

Snow Algae’s ability to increase your longevity and revitalise aged skin works in two ways:

  1.  It activates an enzyme called AMPK (adenosine monophosphate-activated protein)

This energy enzyme focuses mainly on repair and protection when it is activated. It also is able to help skin cells resist stress, slowing down the raging process.

As you get older, your body finds it harder to activate AMPK by itself and will need the external support.

  1.   It activates an essential longevity gene

The gene is named after the Greek Goddess, Clotho, who was responsible for spinning the fate of human life. It was given the name after scientists discovered it in 1997 and established that an over expression of this gene could extend a human life by 30%.

Related Post: Natural Face Cream Ingredients That Work Wonders on Your Skin

Obtenga un plan de hospedaje web asequible

13 Jun

El hospedaje web en méxico es un servicio que permite a una organización o individuo publicar su propio sitio web en Internet. El proveedor del servicio está destinado a proporcionar las tecnologías y servicios necesarios para permitir la visibilidad del sitio web o la página web en Internet. Los sitios web están alojados o toda la información requerida por los sitios web se almacena en computadoras especiales llamadas servidores. Casi todas las casas de negocios en el mercado poseen un sitio web propio en estos días. Sin embargo, debido a los rápidos avances tecnológicos, desarrollar y mantener un servidor web por sí mismos se está convirtiendo en una molestia para las empresas. Por lo tanto, muchas de las principales empresas corporativas subcontratan sus servicios a un tercero confiable que puede proporcionarles planes de alojamiento web asequibles. La mayoría de las empresas lo obligan a tener su propio dominio para alojar un sitio web con ellos. Sin embargo, si no posee un dominio, estas compañías lo ayudarán a comprar uno para usted.

Existen diferentes tipos de planes de alojamiento disponibles para lanzar un sitio web. Antes de registrarse con un proveedor de servicios, es importante comprender qué tipo de servicio necesita su sitio web, el tipo de servidor que usted o su empresa necesita, el presupuesto y el tipo de planes que ofrece la compañía. Echemos un vistazo a algunos planes de alojamiento web asequibles de varias compañías,

  • Desarrolladores de sitios web: este tipo de servicio atiende las necesidades de los principiantes que necesitan alojar un sitio web pero carecen de las habilidades técnicas para construir un sitio web por su cuenta. Proporcionan una interfaz en línea basada en navegador a través de la cual puede iniciar su propio sitio web sin ninguna configuración adicional. Este tipo de alojamiento web es el tipo más básico sin muchas dificultades técnicas.
  • Alojamiento compartido: en un entorno de alojamiento compartido, usted y otros propietarios de sitios web comparten un servidor. Esto incluye compartir el servidor físico y las aplicaciones de software dentro del servidor. Los servicios compartidos son los más asequibles porque el costo de operar el servidor se comparte entre usted y los otros propietarios.
  • Alojamiento dedicado: en este entorno de servidor, usted es propietario de un servidor web completo. Esto mejora su servidor para que funcione de forma más rápida y eficiente, ya que todos sus recursos de servidor están dedicados a servir solo a su sitio web. Sin embargo, este tipo de servidores es bastante costoso y el costo de diseño y mantenimiento debe ser el único que nace de una entidad. Por lo tanto, estos tipos de servidores son adecuados para entidades grandes y bien establecidas y no son para pequeñas empresas o nuevas empresas.

Related Post: Cosas a considerar antes de comprar un servicio de hospedaje web

What is S4 Andarine?

13 Jun

As mentioned in the introduction, this is a SARM. This type of supplement works by attaching to an AR or androgen receptor and changing the way that it reacts. Let’s break down the nature of an androgen receptor here to give you an idea of why this matters so much. The androgen receptor in the body reacts to certain chemicals and makes it easier for you to work out.

There are three different types of chemicals that this receptor can interact act with the inside of the body. The first of these kinds is an AR antagonist. These chemicals are typically human-made and work by blocking the AR receptor from operating. There are a few reasons a person may use an AR receptor. For example, they are often used to treat certain types of cancer and to help men who are androgen-dependent.

The second type of chemical that can work on an androgen receptor is an AR agonist. This kind of chemical will bond with the receptor, detach, and re-bind to it several times. It causes the receptor to activate and increases its effectiveness. Natural types of AR agonists include testosterone. Human-made versions help supplement the body’s natural supply and work to propel the AR receptor to a higher level.

However, a like Andarine or S4 is neither of these chemicals. It is instead a third chemical known as an AR modulator. This item attaches to an AR and changes its structure in a variety of different ways. The ways that it changes the AR changes depending on how it has been designed. They are typically intended to increase the effectiveness of testosterone and other AR chemicals.

Related Post: A Scientific Study Finds Positive Results With Andarine S4

What Is Drug Rivaroxaban powder(Xarelto) Use For

12 Jun

Content

  1. Whatis Rivaroxabanpowder? Rivaroxaban reviews ………………………………………………………….. 1

What is Rivaroxaban powder: ……………………………………………………………………………………… 1

Rivaroxaban powder usage: ………………………………………………………………………………………… 2

Rivaroxaban metabolism: ……………………………………………………………………………………………. 2

  1. Rivaroxabanmechanism of action…………………………………………………………………………………… 3
  2. Rivaroxabanhalf life……………………………………………………………………………………………………….3
  3. Whatis thedrug Rivaroxaban used for?…………………………………………………………………………… 3
  4. Rivaroxabandosage………………………………………………………………………………………………………. 3

How to use Rivaroxaban? ……………………………………………………………………………………………. 3

Rivaroxaban(Xarelto)   Overdose …………………………………………………………………………………. 4

Rivaroxaban(Xarelto)   Missed Dose …………………………………………………………………………….. 5

  1. Canyoudrink alcohol while taking Rivaroxaban?………………………………………………………………. 5
  2. Whatmedications shouldnot be taken with Xarelto(Rivaroxaban powder)?…………………………6
  3. Howlong does ittake for Rivaroxaban to get out of your body? …………………………………………. 6
  4. Whatfoods to avoidwhile on Xarelto(Rivaroxaban powder)………………………………………………. 7
  5. CanIjust stop taking Rivaroxaban? ……………………………………………………………………………….. 7
  6. Whatarethe side effects of Rivaroxaban? ……………………………………………………………………… 8
  7. Whatis the costof Rivaroxaban(rivaroxaban cost)? ………………………………………………………… 9
  8. Buy Rivaroxabanpowderfrom AASraw with the best price ………………………………………………. 9
  9. 1.Whatis Rivaroxaban powder? Rivaroxaban reviews

What  is  Rivaroxaban  powder:

Rivaroxaban powder/Xarelto powder, brand name is Xarelto, and others. It is a morpholine and thiophene derivative that functions as a FACTOR XA INHIBITOR and is used in the treatment and prevention of DEEP-VEIN THROMBOSIS and PULMONARY EMBOLISM. It is also used for the prevention of STROKE and systemic embolization in patients with non-valvular ATRIAL FIBRILLATION, and for the prevention of atherothrombotic events in patients after an ACUTE CORONARY SYNDROME.

Rivaroxaban powder/Xarelto powder is an anticoagulant which binds directly to factor Xa. Thereafter, it effectively blocks the amplification of the coagulation cascade, preventing the formation of thrombus. Rivaroxaban is a unqiue anticoagulant for two reasons. First of all, it is does not involve antithrombin III (ATIII) to exert its anticoagulant effects. Secondly, it is an oral agent whereas the widely used unfractionated heparin and low molecular weight heparins are for parenteral use only. Although the activated partial thromboplastin time (aPTT) and HepTest (a test developed to assay low molecular weight heparins) are prolonged in a dose-dependant manner, neither test is recommended for the assessment of the pharmacodynamic effects of rivaroxaban. Anti-Xa activity and inhibition of anti-Xa activity monitoring

is also not recommended despite being influenced by rivaroxaban.

Rivaroxaban  powder  usage:

Following oral administration, rivaroxaban powder is rapidly absorbed and reaches peak plasma concentration in 2-4 hours. Bioavailability of the 10 mg dose is >80%. However, the 15-20 mg dose have a lower bioavailability if taken in the fasted state and consequently should be taken with food.

Rivaroxaban metabolism:

Approximately two-thirds of rivaroxaban is excreted into urine (via active tubular secretion in which approximately 36% as unchanged drug and 30% as inactive metabolism). The remaining third of the administered dose is excreted via feces in which 7% is in the form of unchanged drug and 21% as inactive metabolites.

  1. 2.Rivaroxabanmechanism of action

Rivaroxaban (Xarelto) is an oral anticoagulant (blood thinner) that is used to prevent and treat blood clots. Blood clots formed in the heart are dangerous since they can travel to the brain and cause a stroke. Similarly, blood clots formed in the legs or

lungs can be equally life threatening if not treated. Rivaroxaban(Xarelto) is a selective inhibitor of factor Xa, an enzyme necessary to form blood clots. It reduces the ability of blood to clot. The FDA approved Xarelto in July, 2011.

  1. 3.Rivaroxabanhalf life

The terminal rivaroxaban half life is 5-9 hours in adults and 11-13 hours in the elderly.

  1. Whatis the drug Rivaroxaban used for?

-reduce the risk of stroke and blood clots in patients with atrial fibrillation not due to a heart valve problem,

-treat and reduce the risk of deep vein thrombosis (DVT, blood clots in the veins of the legs) and pulmonary embolism (PE, blood clots in the lungs)

-reduce the risk of blood clots in the legs and lungs of patients who have just had hip or knee replacement surgery.

  1. Rivaroxabandosage

How to  use  Rivaroxaban?

Rivaroxaban(Xarelto) is available in 10, 15, and 20 milligram (mg)

tablets(rivaroxaban 20mg)that you take by mouth.

For treating DVT or PE, the typical dose is 15 mg twice daily with food for the first 21 days. After that, people usually take 20 mg(rivaroxaban 20mg) once a day for the remainder of their treatment.

For nonvalvular atrial fibrillation, the typical starting rivaroxaban dose is either 15 or 20 mg (ravaroxaban dosing)once in the evening, with a meal.

To prevent DVT or PE, people usually take 10 mg of rivaroxaban dose once a day, with or without food.

After hip or knee replacement surgery, the usual recommendation is to start treatment at least 6 to 10 hours after surgery. People who’ve had a hip replacement generally are prescribed 10 mg of the rivaroxaban dosage for 35 days.

If you’ve had a knee replacement procedure, you can take rivaroxaban dosing for 12 days following surgery.

Be sure to take Rivaroxaban(Xarelto) to at about the same time each day.

If you have difficulty swallowing the tablets, you can crush them and mix them with applesauce. Eat the mixture right away, followed by additional food.

Rivaroxaban(Xarelto)  Overdose

If you take too much Rivaroxaban(Xarelto) , you could bleed internally, or hemorrhage.

Symptoms of an overdose may include: Abnormal bleeding or bruising

Bloody or black stools

Blood in urine

Coughing up blood or vomiting blood

If you or someone else has symptoms of an overdose, call your doctor right away or go to the nearest emergency room. If someone taking Xarelto collapses or isn’t breathing, call 911.

Rivaroxaban(Xarelto)  Missed  Dose

Be sure to take the drug as prescribed by your doctor, even if you feel well. Don’t stop taking Rivaroxaban(Xarelto)   without talking to your doctor first because you’re at greater risk of stroke after you stop taking this medication.

If you’re supposed to take Rivaroxaban(Xarelto)  once a day but miss a dose, take the missed dose as soon as you remember that day. Go back to your normal treatment schedule the next day.

If you take Rivaroxaban(Xarelto)  twice a day, take the missed dose as soon as you remember it on the same day. You can take even two doses of the medication at the same time to make up for the missed dose.

The next day, stick to your usual dosing schedule.

  1. 6.Canyou drink alcohol while taking Rivaroxaban?

Daily use of alcohol while using Rivaroxaban will increase your risk for stomach bleeding. Limit alcoholic beverages. Ask your doctor or pharmacist about how much alcohol you may safely drink. Rivaroxaban can cause bleeding.

  1. What medications should not  be  taken  with Xarelto(Rivaroxa ban powder)?

Rivaroxaban contraindications, what medications should not be taken with Xarelto(Rivaroxaban anticoagulant)?

The CYP3A4 liver enzymes and P-glycoprotein (P-gp) drug transporter systems are primarily responsible for metabolizing and removing Rivaroxaban to from the body. Taking Xarelto with medicines that alter the activity of both the CYP3A4 enzymes and P-gp drug transporters may affect blood levels of Rivaroxaban. Rivaroxaban should not be taken with:

-ketoconazole (Nizoral),

-ritonavir (Norvir),

-clarithromycin (Biaxin),

-erythromycin (Ery-Tabs),

-fluconazole (Diflucan),

-carbamazepine (Tegretol),

-phenytoin (Dilantin),

-rifampin (Rimactane), or,

-St. John’s Wort.

Rivaroxaban anticoagulant to should not be used with other blood thinners due to the increased risk of bleeding.

  1. 8.Howlong does it  take for Rivaroxaban to get out of your bo dy?

As warfarin’s blood thinning effect sticks around for several days after it has been stopped, discontinuation 5- 7 days before surgeries is typically needed. Rivaroxaban, on the other hand, is relatively quickly out of the system. Discontinuation 24 to 36 hours before surgeries is typically enough.

  1. Whatfoods to avoid while on Xarelto(Rivaroxaban powder)

Rivaroxaban has no known dietary restrictions. Rivaroxaban doesn’t interact with vitamin K like warfarin does. So you can enjoy healthy options like leafy green vegetables and other foods rich in vitamin K whenever you like, without having to worry about them changing the way Rivaroxaban works.

  1. 10.CanI just stop taking Rivaroxaban?

You are at risk of stroke from AFib even if you don’t feel symptoms. Don’t stop taking Rivaroxaban(Xarelto) unless your doctor tells you to. Stopping Rivaroxaban(Xarelto) increases your risk of having a stroke. If you have to stop taking

Rivaroxaban(Xarelto), your doctor may prescribe another blood thinner to help prevent blood clots from forming.

  1. 11.Whatare the side effects of Rivaroxaban?

Along with its needed effects, a medicine may cause some unwanted Rivaroxaban side effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following Rivaroxaban side effects occur:

More common

-Back pain

-bleeding gums

-bloody stools

-bowel or bladder dysfunction

-burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings

-coughing up blood

-difficulty with breathing or swallowing

-dizziness

-headache

-increased menstrual flow or vaginal bleeding

-leg weakness

-nosebleeds

-numbness

-paralysis

-prolonged bleeding from cuts

-red or black, tarry stools

-red or dark brown urine

-vomiting of blood or material that looks like coffee grounds

Less common

-Fainting

-pain in the arms or legs

-wound secretion

  1. 12.Whatis the cost of Rivaroxaban(rivaroxaban cost)?

At a monthly cost of approximately $255 for a 20-mg daily dosage, rivaroxaban cost is significantly more expensive than warfarin (approximately $6 for a 30-day supply of 1-, 2-, 2.5-, or 5-mg tablets; and between $6 and $7 for a 30-day supply of 7.5- or

  • mg tablets), and roughly the samepriceas dabigatran (approximately $255 for a one-month supply of 150 mg twice daily).
  1. BuyRivaroxaban powder from AASraw with the best price

Rivaroxaban is a new and leading drug, the rivaroxaban cost of course expensive than normal products. AASraw is a professional manufacturer that provide high quality

raw powder, include steroids raw powder, sex hormone material, fat loss material…etc. AASraw have professional lab and cooperate with famous university lab, famous hospital, can guarantee high quality. And can provide bulk order with factory price. Buy Rivaroxaban powder from AASraw with the best price.

Related Post: What Is Drug Rivaroxaban powder(Xarelto) Use For

Crizotinib powder 877399-52-5 is an anti-cancer agent acting

12 Jun

1.What is Crizotinib?

Crizotinib(trade name Xalkori, Pfizer) is an anti-cancer drug acting as an ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) inhibitor, approved for treatment of some non-small cell lung carcinoma (NSCLC) in the US and some other countries, and undergoing clinical trials testing its safety and efficacy in anaplastic large cell lymphoma, neuroblastoma, and other advanced solid tumors in both adults and children.

Crizotinib is an anti-cancer agent acting as anaplastic lymphoma kinase inhibitor and recently approved for treatment of non-small cell lung carcinoma.The retrosynthetic analysis of this molecule clearly takes our eyes to two major building blocks, as described in Scheme 1, being the racemic 1-(2,6-dichloro-3-fluorophenyl)ethanol a very interesting target for biotransformations. Indeed, some research groups have already reported their results on biocatalytic or biotransformation approaches for arriving on the desired intermediate.

2.How does Crizotinib works?

Crizotinib has an aminopyridine structure, and functions as a protein kinase inhibitor by competitive binding within the ATP-binding pocket of target kinases. About 4% of patients with non-small cell lung carcinoma have a chromosomal rearrangement that generates a fusion gene between EML4 (‘echinoderm microtubule-associated protein-like 4’) and ALK (‘anaplastic lymphoma kinase’), which results in constitutive kinase activity that

contributes to carcinogenesis and seems to drive the malignant phenotype.The kinase activity of the fusion protein is inhibited by crizotinib. Patients with this gene fusion are typically younger non-smokers who do not have mutations in either the epidermal growth factor receptor gene (EGFR) or in the K-Ras gene. The number of new cases of

ALK-fusion NSLC is about 9,000 per year in the U.S. and about 45,000 worldwide.

ALK mutations are thought to be important in driving the malignant phenotype in about

15% of cases of neuroblastoma, a rare form of peripheral nervous system cancer that occurs almost exclusively in very young children.

Crizotinib inhibits the c-Met/Hepatocyte growth factor receptor (HGFR) tyrosine kinase, which is involved in the oncogenesis of a number of other histological forms of malignant neoplasms.

Crizotinib is currently thought to exert its effects through modulation of the growth, migration, and invasion of malignant cells. Other studies suggest that crizotinib might also act via inhibition of angiogenesis in malignant tumors.

In order to get chiral 1-phenylethanol derivative, Liang and co-workers have used several microorganism for efficient reduction the ketone towards intermediate. Other groups tried to increase the efficiency and selectivity towards the chiral intermediate by using similar approaches. A fit-for-purpose route published by Koning and co-workers from Pfizer revels the strategy for producing the racemic alcohol by traditional NaBH4 reduction, followed by acetylation, resolution mediated by PLE and Mitsunobu inversion towards the required enantiomer.

Lipases are always the first option when thinking about obtaining highly enantiomeric pure chiral alcohols by kinetic resolutions or dynamic kinetic resolution (DKR) methods. Furthermore, lipases can be combined with racemization catalysts, namely palladium, iridium, vanadium or ruthenium complexes complexes. Unfortunately, to the best of our knowledge, no reports of lipases used on the kinetic or DKR of

1-(2,6-dichloro-3-fluorophenyl)ethanol were found.

In our continuous effort towards the development of biocatalytic protocols for the synthesis of intermediates for API synthesis, herein, we report our studies on the kinetic and DKR of 1-(2,6-dichloro-3-fluorophenyl)ethanol, an important intermediate on Crizotinib synthesis.

3.Crizotinib Materials and methods

Name:     Crizotinib powder

CAS:    87739952-5

Molecular Formula:    C21H22Cl2FN5O

 

Molecular Weight:    450.343

Melt Point:    197-203°C Storage Temp:    RT

Color:    white to pale-yellow powder

1-(2,6-Dichloro-3-fluoro-phenyl)-ethanol and isopropenyl acetate purchased from

Sigma-Aldrich. Candida antarctica lipase B (CAL B) purchased from Novozymes. All other materials were at least reagent-grade.

  • Kinetic resolution reactions

The reaction mixture was composed by a 3 mL solution of 0.048 mmol

1-(2,6-dichloro-3-fluoro-phenyl)-ethanol, 0.096 mmol acyl donor and 60 mg of enzyme (20% w/v) in solvent. The screening reactions were performed in silicon carbide plates at temperatures of 60–80 °C, under magnetic stirring to obtain

1-(2,6-dichloro-3-fluorophenyl)ethyl acetate (1H NMR (300 MHz, CDCl3) δ 7.26 (dd, J =

8.3, 5.6 Hz, 5H), 7.03 (t, J = 8.5 Hz, 3H), 6.39 (q, J = 7.1 Hz, 3H), 2.09 (s, 3H), 1.66 (d, J =

6.9 Hz, 3H). In order to screen the influence of the different reaction medium’s components, enzymes, solvent, acyl donor and temperature were evaluated. A 20 μL aliquot was transferred to a new vial and 980 μL of ethyl acetate was added and analyzed in the GC-FID.

  • Dynamic kinetic resolution (DKR) reactions in continuous flow

Continuous flow experiments were performed using an Asia Flow System (Syrris) which included a syringe pump, a heater and a glass column. The glass column was packed with immobilized CAL B and VOSO4.XH2O alternately. A 10 mL-packed-bed reactor with 4 layers of enzyme (each layer containing 500 mg of the catalyst) and 3 layers of VOSO4.XH2O (each layer containing 500 mg of the catalyst) separated by thin cotton layers was obtained. The bed-packed reactor was heated at 80 °C and perfused with isooctane at a flow rate of 1.0 mL.min?1. Continuous flow reactions were carried out by pumping a isooctane solution (15 mL) of 1-(2,6-dichloro-3-fluoro-phenyl)-ethanol (0.1 M) and vinyl acetate as acyl donor (0.1 M) through the bed-packed reactor at flow rates of 0.1,

0.5 and 1.0 mL.min?1, which correspond to residence times of 100, 50 and 10 min, respectively. Due to the long reaction time in batch, the solution was recycled in the continuous flow to optimize the conversion results. Aliquots of 20 μL were collected from the output of the reactor after pumping the reactional solution for two times the residence time and after 21 h. Afterwards, the aliquots were diluted with ethyl acetate to 1.0 mL solution and analyzed by GC-FID.

  • Chromatography analysis

Kinetic Resolution and Dynamic Kinetic Resolution

1-(2,6-Dichloro-3-fluorophenyl)-ethanol GC-FID: (Shimadzu CG2010 – chiral capillary column Gamadex – 225) 8 μL samples were injected at 117 °C. The oven was heated at

2 °C/min to 150 °C then maintained for 5 min and at 30 °C/min to 200 °C and then maintained for 1 min, with a 3.0 mL/min flow, and a Split injection mode (Ratio: 20:1).

  • Results and discussions

Based on our previous experience on kinetic resolutions of sec-phenylethanol derivatives, we have learned along these years that ortho-substituted aryl alcohols are less reactive for the kinetic resolution. Since 1-(2,6-dichloro-3-fluorophenyl)ethanol (2) contains substituents on both ortho positions, we were expecting long reaction times for this transformation. We have started by screening the influence of acyl donor on the reaction outcome when using commercial immobilized CAL B (N435) at 60 °C and cyclohexane as solvent for 10 days (Table 1).

Acyl donor evaluation for kinetic resolution of 1-(2,6-dichloro-3-fluorophenyl)ethanol (2)

mediated by immobilized CAL-B.

Entry    Acyl Donor (1 eq)    Conv. (%)    e.e.prod (%)    E

1    Isopropenyl acetate    44    99    >200

2    Ethyl acetate    32    99    >200

3    Vinyl acetate    26    95    54

Reaction conditions: 1-(2,6-dichloro-3-fluorophenyl)-ethanol (2) (0.048 mmol, 10mg), isopropenyl acetate or vinyl acetate or ethyl acetate (1eqv) as acyl donor, and 60mg (20%w/v) of CAL B Novozym 435 (N435) in cyclohexane (3 mL) for 10 days at 60 °C, measured by GC-FID method and enantioselectivity was measured based on

  • -1-(2,6-dichloro-3-fluorophenyl)ethanoland the corresponding ester retention times.
  1. Approvals andindications for Crizotinib

On August 26, 2011, the U.S. Food and Drug Administration approved crizotinib (Xalkori) to treat certain late-stage (locally advanced or metastatic) non-small cell lung cancers that express the abnormal anaplastic lymphoma kinase (ALK) gene. Approval required a companion molecular test for the EML4-ALK fusion. In March 2016, the U.S. Food and Drug Administration approved crizotinib in ROS1-positive non-small cell lung cancer.

As expected, isopropenyl acetate lead to the best results on the kinetic resolution of

1-(2,6-dichloro-3-fluorophenyl)ethanol (2), arriving on the desired acetylated

R-enantiomer in good conversions and high selectivity (Table 1, entry 1). Vinyl acetate was probably too reactive under the designed reaction conditions, leading to a decrease of enantiomeric ratio. A blank experiment was performed in order to evaluate the uncatalyzed reaction and small amounts of acetylated alcohol could be obtained (<10%). Regarding ethyl acetate, surprisingly, it presented interesting selectivity with moderate conversion (Table 1, entries 3 and 2 respectively). Despite the fact that Table 1 present

the results for the kinetic resolution after 10 days, the reactions were monitored in the first

3 days every 12 h and after the 3rd day, every 24 h. What could be seen is the conversion improvement along the days until 10 days of reaction. Further reaction time has also been evaluated (12 days) but no improvement on conversion was observed.

In order to try to reduce the reaction time, one of the strategies was to evaluate the effect of higher proportions of acyl donor but unfortunately with values higher then two equivalents the enantiomeric ratio dropped from >200 to 31, showing that the chemical esterification is taking place. Another attempt was to screen other lipases but no better results were found when compared to the commercial immobilized CAL B (N435) (Table S1 – Supporting information).

In order to try to reduce the long reaction time obtained for this specific substrate, different temperatures and solvents were evaluated.

Solvent screening for kinetic resolution of 1-(2,6-dichloro-3-fluorophenyl)ethanol, using isopropenyl acetate mediated by immobilized CAL B.

Entry    T (°C)    Solvent    Time (Days)    Conv. (%)    e.e.prod (%)    E

1    60    ACN    5    2    99    >200

2    60    Acetone    5    n.d.    n.d.    n.d.

3    60    MTBE    5    n.d.    n.d.    n.d.

4    60    Toluene    5    11    99    >200

5    60    Hexane    6    n.d.    n.d.    n.d.

6    60    Heptane    6    44    99    >200

7    60    Isooctane    6    39    99    >200

8    70    Isooctane    5    45    99    >200

9    75    Isooctane    5    40    99    >200

10    80    Isooctane    5    44    99    >200

Reaction conditions: 1-(2,6-dichloro-3-fluorophenyl)ethanol (2) (0.048 mmol, 10mg), isopropenyl acetate (2eqv) as acyl donor, and 60mg (20%w/w) Novozym 435 in different solvents (3 mL, ACN – acetonitrile, MTBE – methyl ter-butyl ether), measured by GC-FID method and enantioselectivity was measured based on

(S)-1-(2,6-dichloro-3-fluorophenyl)ethanol and the corresponding ester retention times.

As observed on Table 2, among all solvents evaluated for the desired resolution, isooctane presented the best results in terms of reaction time. Under the conditions studied, at 70 °C, isooctane could lead to 45% of conversion (42% yield) after 5 days, a

50% reduction on reaction time (Table 2, entry 7). Other solvents as acetone, MTBE, acetonitrile (ACN), toluene and hexane, have failed or lead to very poor conversions. At higher temperatures, no improvement on reaction conversion could be observed. An exception is heptane, which could lead to similar results to isooctane, but the later can lead us to a better stability for the immobilized enzyme.

Despite the good results obtained under kinetic resolution conditions, 50% of the product is waste or need to be racemized in order to be used again in another campaign.

Based on the results obtained for the kinetic resolution of

1-(2,6-dichloro-3-fluorophenyl)ethanol (2), we decided to move forward in order to develop a method for the DKR which should deliver the desired acetylated R-enantiomer of 1-(2,6-dichloro-3-fluorophenyl)ethanol (2) as main product. This strategy is based on the fact that after DKR, a simple hydrolysis leads to the desired enantiomer, which can be coupled with the side chain through standard nucleophilic aromatic substitution procedure. Two different racemization catalysts were tested for this purpose, vanadyl sulfate19–25 and Shvo’s ruthenium catalyst.26–30.

The reactions were carried out at 70 °C, using isopropenyl acetate as acyl donor and the conversion analyzed by GC-FID daily during 5 days. It is important to note that short chain acyl donors are not the best choice for DKR mediated by vanadium catalysts, as already reported by other groups.20,22 Despite that, we decided to keep isopropenyl acetate since we already know that the kinetic resolution should be the rate limiting step of our process and a long chain acyl donor, as vinyl decanoate, could increase even more the reaction time.31 The results obtained for the dynamic kinetic resolution are presented on Table 3.

DKR of 1-(2,6-dichloro-3-fluorophenyl)ethanol (2) mediated by immobilized CAL-B and different racemization catalysts under batch conditions.

Entry    Racemization Catalyst    Conv. (%)    e.e.prod (%)    Selectivity (%)

1    VOSO4    30    98    >99

2    Shvo    35    92    >99

Reaction conditions:1-(2,6-dichloro-3-fluoro-phenyl)-ethanol (0,1 M), isopropenyl acetate (0,1 M) as acyl donor, in isooctane (15 mL) were carried by mixing all reagents and catalysts on a batch reactor. Determined by GC-FID and enantioselectivity was measured based on (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol and the corresponding ester retention times.

5.Clinical trials for Crizotinib

Crizotinib caused tumors to shrink or stabilize in 90% of 82 patients carrying the ALK fusion gene. Tumors shrank at least 30% in 57% of people treated. Most had adenocarcinoma, and had never smoked or were former smokers. They had undergone treatment with an average of three other drugs prior to receiving crizotinib, and only 10% were expected to respond to standard therapy. They were given 250 mg crizotinib twice daily for a median duration of six months. Approximately 50% of these patients suffered at least one side effect, such as nausea, vomiting, or diarrhea. Some responses to crizotinib have lasted up to 15 months.

A phase 3 trial, PROFILE 1007, compares crizotinib to standard second line chemotherapy (pemetrexed or taxotere) in the treatment of ALK-positive NSCLC. Additionally, a phase 2 trial, PROFILE 1005, studies patients meeting similar criteria who have received more than one line of prior chemotherapy.

Crizotinib is also being tested in clinical trials of advanced disseminated anaplastic large-cell lymphoma, and neuroblastoma.

In February 2016 the J-ALEX phase III study comparing alectinib with crizotinib ALK-positive metastatic NSCLC was terminated early because an interim analysis showed that progression-free survival was longer with alectinib. These results were confirmed in a 2017 analysis.

As can be observed on Table 3, the racemization protocol performed with Shvo or vanadyl sulphate catalyst, lead to moderate conversions towards the desired chiral alcohol. It is important to note that under the reaction conditions studied, Shvo’s catalyst did not performed better then VOSO4, even presenting a decreasing on enantiomeric excess of the product, showing that VOSO4 could be an interesting and cheaper alternative for further improvements.19–25,32–34 Following our recent studies on the use of VOSO4 for DKR under continuous-flow conditions 31 we applied the reactions conditions already optimized for sec-phenylethanol to our substrate 1-(2,6-dichloro-3-fluorophenyl)ethanol. In this way, the reaction was performed in closed loop system due to the high reaction time needed for the kinetic resolution step. Although we did not observe any incompatibility between CAL B and VOSO4,19–25,32–34 as previously reported by other authors, a continuous flow packed-bed reactor was designed so that four layers of the immobilized enzyme and three layers of VOSO4 were alternately disposed along a glass column and physically separated by a thin cotton layer. The results obtained under different reaction times and flow rates are presented below (Table 4).

Continuous-flow DKR of 1-(2,6-dichloro-3-fluorophenyl)ethanol.

Entry    Flow Rate (mL.min?1)    Reaction Time (days)    Conv. (%)    e.e.prod (%)

1    1.0    1    28    98

2    3    38    98

3    5    44    98

4    0.5    1    32    98

5    3    47    96

6    5    57    96

7    0.1    1    33    88

8    3    47    84

9    5    47    82

Reaction conditions:1-(2,6-dichloro-3-fluoro-phenyl)-ethanol (2) (0,1 M), isopropenyl acetate (0,1 M) as acyl donor, in isooctane (15 mL) were carried out by pumping through the bed-packed reactor at different flow rates. The glass column was packed with immobilized N435 and VOSO4.XH2O alternately so that a 10 mL-packed-bed reactor with 4 layers of enzyme (each layer containing 500 mg of the catalyst) and 3 layers of VOSO4.XH2O (each layer containing 500 mg of the catalyst) separated by thin cotton layers. The bed-packed reactor was heated at 80 °C. Determined by GC-FID and enantioselectivity measured based on (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol and the corresponding ester retention times.

The results presented on Table 4 show that under continuous-flow conditions the DKR mediated by Novozyme 435 and VOSO4, is more efficient in terms of conversion and reaction time when compared to the batch set-up, as observed in entry 6 (Table 4). No further improvement on reaction conversion could be observed increasing the reaction time, which seems to be a limitation in this specific case. Increasing the residence time by using low flow rates do not lead to better conversion and a small decrease on enantiomeric excess of the product could be observed (entries 7–9, Table 4). At 0.5 mL.min?1 a significant improve on reaction conversion could be obtained when compared to the batch process, it is important to note that despite the reaction has been performed for 5 days, the actual time of contact between reagents and catalysts is much less since it works on a closed loop system. Another advantage of DKR is the fact that the remaining starting material is racemic been able to be re-used in a different campaign without any further purification.

6.The Conclusion of Crizotinib

In conclusion we have developed different approaches towards production of chiral

  • (2,6-dichloro-3-fluorophenyl)ethanol(2),an important intermediate for Crizotinib (1) synthesis. Kinetic resolution was accomplished with very good conversions and high selectivity while dynamic kinetic resolution, also under batch conditions afforded poor results of conversions with good enenatiomeric excess of the produc Further improvement was obtained translating the dynamic kinetic resolution to a continuous-flow protocol where conversion could be improved with still good selectivity.

7.Where to  Buy Crizotinib powder?

AASraw is one of legit resource for Choosing, if more info. need to know, please  contact us.

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