text:
If you haven't already heard, Search Ads will be one of the latest features in the most recent iOS update and will allow you to pay for ads to appear on top of search results in the app store.
"Meaning you can put the right app in front of the right users at the right time"
Why use Search Ads
We all know that keeping your app at the top of search results takes work and that's for those of you who can get your apps to the top to begin with. There are a countless number of you struggling just to get your apps noticed full stop.
Currently 65% of iOS app downloads come from direct searches on the App Store, which means those of you whose apps don't feature near the top have a hard time competing. With the launch of iOS 10 you will be able to buy visibility through Search Ads.
How it will work
Once you have created an ad, Apple will automatically match it to relevant searches so you won't need to choose keywords. This move could also be a risky one though, as you won't have control over exactly which users your ad will target.
For more control it is advisable to decide whether you want to use your ad to acquire new customers or target existing ones and then choose your own keywords along with other targeting options such as age, gender, device type and location. You can also choose specific times and days when you want your ad to be shown.
Regarding budget, there is no minimum spend and pricing is on an auction basis. You bid the maximum amount you are willing to pay for a customer to click on your ad and the final charge will be based on the amount your nearest competitor is willing to pay for their ad. It is important to know how much a new customer is worth and estimate a conversion rate, as this will help you work out your initial maximum cost.
One thing to remember is, if the ad is not relevant to what the user is looking for it will not show up, no matter how much you pay.
Sounds simple enough but we are unlikely to ever fully understand how Search Ads will work, as with a lot of features Apple are always careful to keep some things to themselves. Which means getting the best results for your money will take expert knowledge.
The main take away is ensuring your Paid Search terms work together with Organic Search terms. This will be the overall deciding factor in being visible inside the app store.
We have been predicting Search Ads in the app store for some time, which is why our ASO strategy is designed to work in harmony with Search Ads and maximise the efficiency of your ad spend.
Redbox lifts the lid on best-practice Apple Search Ads with new video podcast, AdBites.
Far from being yet another video podcast, AdBites is broadcast live every fortnight and invites viewers to participate by raising their own questions about Apple Search Ads to Samuel Chorlton, Redbox CTO and his guest, via a live Q&A.
Redbox Mobile Adds New Key Features and Ad Placements to Apple Search Ads Platform, Astra.
Redbox Mobile, Apple Search Ads Partner and award-winning app store performance specialist, has added some significant new features to its innovative Apple Search Ads campaign management platform, Astra.
Promoting Gaming Apps in Apple Search Ads
Redbox Account Manager Jemima Wildi shares her thoughts and knowledge about successfully managing Apple Search Ads campaigns for gaming apps.


text:
Bars sue Arizona Gov. Ducey over executive order that forces them to close
By Bailey Miller
Coronavirus in Arizona
Arizona bars sue Gov. Ducey over order that closed down bars during COVID-19 pandemic
The bars say the governor's executive order was not constitutional
PHOENIX - Another group of business owners is fighting to reopen, as 26 bars across the state are filing a lawsuit against Governor Doug Ducey, claiming an executive order forcing them to close is unconstitutional.
The bars are located in, among other places, Chandler, Phoenix, Prescott, and Sedona, and the bars are demanding a reopening.
The conversation started around July 4, because that is a busy holiday for them and many are struggling to survive.
ASU law professor argues that bars can be as sanitary as restaurants
Illan Wurman, an associate professor at Arizona State University's law school, is representing the businesses. Wurman argues the executive order to shut down bars is unconstitutional, because legislative powers of the state are given to the Governor without guidance. He also adds it is not fair that other businesses have remained open.
"Restaurants can be open at 50% capacity and meeting sanitary measures, then bars can meet those measures too," said Wurman.
Wurman says he is confident in his filing with the Supreme Court, adding it's a violation of the Immunities Clause, arguing that bars can and will be as sanitary as restaurants with bars inside.
"To say that bars -- not a single bar -- can meet the same sanitary standard and safety requirements as other restaurants that have bars in them is crazy," said Wurman. "If the governor wants to make that argument in court, be my guest. Qe will mop the floor with that argument."
Constitutional lawyer weighs in on lawsuit
Dan Barr, who works as a constitutional lawyer, says lawsuits similar to this one have been happening across the country during the pandemic, and says the plaintiffs will all lose for a reason.
"Governors, state and local officials have tremendous amount of power and discretion in public health, and courts are reluctant to second-guess governors and local health officials," said Barr.
Governor's Office responds
In a statement, officials with the office of Governor Doug Ducey said:
"We're making reasonable and responsible decisions in the best interest of public health. We're following the law and the constitution."
Tune in to FOX 10 Phoenix for the latest news
Download FOX 10 apps for local breaking news and weather

redpajama_set_name: RedPajamaCommonCrawl


text:
Major Horse Races
One of the most famous and prestigious horse races in the world, the history of the Kentucky Derby stretches back to 1875, when Aristides crossed the finish line as the winner of the very first Derby. Known as the Run for the Roses – due to the fact the winner is draped in a carpet of the flowers – and also as "the most exciting two minutes in sports", the Derby is held every year on the first Saturday in May under the Twin Spires of Churchill Downs in Louisville, Kentucky. The Derby is run at the "American classic" distance of 1 1/4 miles on the dirt track. It currently offers a total winning purse of $2 million, with $1.4 million going to the winner.
2022 Kentucky Derby Free Picks here
Complete List of Kentucky Derby Winners by Year
Restricted to three-year-old horses, the Derby signifies the very basic idea behind the history of racing – who has the fastest young horse in their barn? It also carries major significance as the first leg of the American Triple Crown series. Obviously, only one horse can win the Derby, and then that horse is the only one with a shot at sweeping both the Preakness and Belmont Stakes, achieving legendary status as a Triple Crown winner. Since recognition of the Triple Crown started with the first running of the Derby (the Preakness first ran two years earlier, and the Belmont debuted in 1867) only 12 horses have managed the feat. [+]
Following in the hoof-steps of Aristides, some of the most famous horses in American racing have been Derby Champions, including Whirlaway (1941) and Assault (1946) who share the record for largest margin of victory at eight lengths. The great Secretariat still holds the race record of 1:59.4 that he set in winning the 1973 Derby, with only one other horse – Monarchos in 2001 – ever cracking the two-minute barrier.
Other notable horses that have won the Derby include the Canadian-bred Northern Dancer (1964) who would go on to be recognized as one of the greatest sires in the world, with several of his offspring also winning the Derby. The first filly to win the Derby was Regret in 1915 (interestingly, a different filly, Rhine Maiden, would win the Preakness that year) and since then only two other fillies have won, Genuine Risk (1980) and Winning Colors (1988). The biggest longshot to ever win the Derby was Donerail, who went off at 91-1 in 1913, while Dancer's Image remains the only Derby winner ever disqualified, with the win awarded to Kauai King, who remains the only Maryland-bred horse to win the race.
Kentucky Derby Betting Odds
Over the past three years, the Kentucky Derby win has paid $9.20 on a $2 bet - a nice return, but nothing to write home about. That same $2 put on a a winning exacta, however, has paid an average of $464.40, including a whopping $981 in 2013 when 5-1 favorite Orb combined with 35-1 Golden Soul to top the ticket. Such is the nature of betting the Derby, where smart handicapping leads to big exotic payouts, especially when the wager is placed with Bovada, our #1 recommended online racebook.
* REMINDER! - you must be of legal age in your state or province to legally wager on thoroughbred or harness horse racing. Please bet responsibly!
2016 Kentucky Derby Contenders
With the Saturday, April 16 running of the Arkansas Derby and Lexington Stakes, the prep races on the road to the Kentucky Derby have been completed, and the Top 20 contenders based on points accumulated over the past nine months have been set. While the official entries are still to be determined, and injury or other factors may still come into play in setting the final field, for now it can be assumed that the horses on the following list will go to the gate to make the Run for the Roses on May 7 at historic Churchill Downs.
Entries by PP with ML Odds
1) Trojan Nation (50-1) Still a maiden after six career starts, finished second in the Wood at 81-1 and will likely be higher odds than that when the gate opens.
2) Suddenbreakingnews (20-1) Late stretch runner doesn't have the best style to win the Derby but there's some talent here to get onto the ticket if there's a late pace meltdown.
3) Creator (10-1) Broke his maiden in sixth attempt in the Arkansas Derby at 11-1, coming from last to first. Not a style that typically wins in the Derby, but a move forward from that effort might put him in the mix.
4) Mo Tom (20-1) Drew into the field with the withdrawl of Cupid, could only a manage a 3rd and 4th last two efforts in Louisiana.
5) Gun Runner (10-1) A winner of 4 of 5 lifetime, with both Derby points wins coming back-to-back at Fair Grounds in the Risen Star Stakes and Louisiana Derby.
6) My Man Sam (20-1) The best of the rest behind Brody's Cause in the Blue Grass, made a solid rally to get up for second but the time wasn't fast and there are others here with the same style who appear to be better.
7) Oscar Nominated (50-1) Spiral Stakes win over the Turfway synthetic puts him in the field, but there's nothing in his past form to suggest he can compete with the best here.
8) Lani (30-1) Japan-based runner gets in from a win over the synthetic track in the UAE Derby. No UAE runner has threatened in the Derby yet, and it would be a shocker if he is the first.
9) Destin (15-1) Both stakes wins have come at Tampa Bay, and he'll go into the Derby after 8 weeks off, which is not a likely combination for success against these.
10) Whitmore (20-1) Of the long shots to come from behind, he might be the most intriguing. Has run very well without actually winning any of his preps, distance is a question, but could be an exotics bomber.
11) Exaggerator (8-1) Has been inconsistent in the preps, but spotted the first flight more than 10 lengths in the Santa Anita Derby before hitting the gas into the far turn and blowing by them all to win going away.
12) Tom's Ready (30-1) Ran in all three of the Louisiana preps, going 2-7-2 in those. He's game, but like Oscar Nominated he simply doesn't have the form that suggests he's a threat.
13) Nyquist (3-1) Undefeated lifetime (7/7) including the 2015 Breeders' Cup Juvenile, he crushed a good field in his final prep, the Florida Derby, and will likely be the post time favorite on Derby Day.
14) Mohaymen (10-1) The East-coast favorite following five straight wins to start his career, his final prep in the Florida Derby was a step back, where Nyquist made him look ordinary. Needs a bounce-back.
15) Outwork (15-1) Made the field with a victory in the slowest Wood Memorial in history, and had to dig in hard right to the wire to hold off a 81-1 longshot that has yet to win a race.
16) Shagaf (20-1) Created some buzz with three straight wins to start his career, including the Gotham Stakes, but his fifth-place finish in an extremely slow Wood Memorial doesn't offer much hope.
17) Mor Spirit (12-1) A big, grind-it-out type colt has been first or second in all six lifetime starts, so getting onto the exotics would not be a surprise, but may be just a step behind the best in the field.
18) Majesto (30-1) Ran second in the Florida Derby coming off a maiden win in his fifth lifetime start, but that was by default as much as anything else.
19) Brody's Cause (12-1) A bit of a wise guy pick at the start of 2016, ran 7th in his season debut in the Tampa Bay Derby, and then booked his Derby ticket with a Blue Grass win over an arguably weak field.
20) Danzing Candy (15-1) Stepped up from the allowance ranks to win the San Felipe Stakes over Mor Spirit and Exaggerator, followed by a poor showing to finish 4th in the SA Derby. PP draw was a disaster.
AdvantageWagering Picks:
1) Nyquist
2) Exaggerator
3) Suddenbreakingnews
4) Mor Spirit
Useful Pages on AdvantageWagering.com
The Kentucky Derby, Breeders' Cup Classic, the Queen's Plate and more, everything you need to know about the most important races all year around in North America.
Top Race Tracks
Racing dates, post times and contact information for more than 75 tracks throughout the United States and Canada.
Here's what we have to say about the most popular racebooks so you can find the online betting platform that fits your wagering strategy.
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text:
Q: Could not access type BSONElement in package reactivemongo.bson.package Hi I am trying to compile a play framework application which uses the reactivemongo driver.
The ./activator compile works great on my dev machine but gives me the following error on a remote ubuntu box. The build.sbt is exactly the same in both machines.
summer@nights:/var/jenkins/workspace/myApp$ ./activator compile
    [info] Loading project definition from /home/summer/.sbt/0.13/staging/38ee4fc38fad7d5824e0/myApp/project
    [info] Set current project to myApp (in build file:/var/jenkins/workspace/myApp/)
    [info] Compiling 8 Scala sources and 1 Java source to /home/summer/.sbt/0.13/staging/38ee4fc38fad7d5824e0/myApp/target/scala-2.11/classes...
    [error] missing or invalid dependency detected while loading class file 'LowerImplicitBSONHandlers.class'.
    [error] Could not access type BSONElement in package reactivemongo.bson.package,
    [error] because it (or its dependencies) are missing. Check your build definition for
    [error] missing or conflicting dependencies. (Re-run with `-Ylog-classpath` to see the problematic classpath.)
    [error] A full rebuild may help if 'LowerImplicitBSONHandlers.class' was compiled against an incompatible version of reactivemongo.bson.package.
    [error] one error found
    [error] (compile:compileIncremental) Compilation failed
    [error] Total time: 16 s, completed Oct 7, 2016 10:19:29 AM

redpajama_set_name: RedPajamaStackExchange


My bike helmet was quickly crushed by oncoming traffic. I managed to retrieve a yoga mat and one of Cindy's sandals. It was a scary experience to say the least and I still don't know what happened exactly.
I relocked the case and threw a ratchet strap over it as an extra precaution and we were back on the road.
Because we left late after a dreadful day in storage, we only managed to make it to Lone Pine. We stayed at the hotel that was our home for several weeks while we were shooting GI Jane oh so many years ago. So that was a hoot.
And then there was the stop at Manzanar. OK, so the journey was more than nothing.
But the beauty that is Mammoth and the Sierras, trumps our quick jaunt.
Hiking is, at its essence, about the journey, even though one often has a goal in mind, as in a peak to summit, a hill to climb. It is one of the big draws to Mammoth. And yet it took us a couple of days of decompressing before we actually got out and onto the trails.
Even then it wasn't without a certain amount of drama.
We left the house not knowing where we were going. We arrived at Tamarack where we had skied cross-country the last time we were in Mammoth. It was winter then and Tamarack was quiet and peaceful.
It was anything but that in summer at the height of the tourist season on a weekend. After a enlivened discussion, Cindy agreed that we could find a better hike than walking around and through the Tamarack campground. As it turned out finding a trail-head when you haven't done any research prior to jumping in the car and just going, was not as easy as we thought.
And even though I showed Cindy 3 rain jackets when we were going through storage a few days before, two of which we had just purchased in Vail because we didn't have our coats with us on that day, I had once again forgotten to bring them, so now I was lucky to have Cindy's because she thought to bring an extra one.
We did have the foresight to pick-up and actually remember to bring a map. So we did finally find and arrive at a trail that was appropriate in difficulty and in length.
Driving around we began to realize how much of the Mammoth Lakes area we hadn't yet seen and how much more was left to explore.
Among a variety of other things that I am doing in preparation for Burning Man is getting more familiar with my Go-Pro camera and the many mounts and accessories.
Today I wore my Go-Pro on the wrist attachment with the LED screen back.
It was a bit unwieldy, but after I got used to the weight, it was nice to be able to see what I was shooting and the wrist mount was a good way to keep the Go-Pro literally close at hand.
I have a knack for getting lost.
Some of my greatest experiences have come as a result of being off-course.
So when I told Cindy and Skye to go on ahead of me, that I'd catch up and then I proceeded to take the wrong turn and end up going downhill when I should have been going uphill, I didn't worry, I just went the way I thought would ultimately reunite us.
Cool, except Cindy wasn't sure about the trail she was on. Skye was and had we not had cell phones, they would have carried on and met up with me.
But we do have cell phones.
When Cindy called me, I was pretty lost.
I saw a lake below me and was pretty sure it was Lake George but I still didn't know if the trail was going to lead me all the way there and then if I could find another trail to link me back to the trail we had originally taken.
I was pretty sure that all that would be the case but I wasn't certain.
I ended up running through some paths that were little more than game trails and then back up the hill to meet with them. Skye led the way back to prove to her mom that she really did know the way back.
To quote Tolkien, "Not all who wander are lost"
But sometimes they are, which isn't necessarily a bad thing.


text:
Chennai Super Kings Vs Royal Challengers Bangalore 16th Match at Chennai- Apr 13, 2013
Cricket News sort by Chennai Super Kings Vs Royal Challengers Bangalore 16th Match at Chennai- Apr 13, 2013
CSK Vs RCB: Jadeja was amazingly calm under pressure
Published on :Apr 14, 2013 14:37
Till now, Ravindra Jadeja was jokingly referred to as Sir Ravindra Jadeja in social networking cycles. But, after his excellent cameo under pressure against Royal Challengers Bangalore at Chepauk on Saturday
Tags: Indian Premier League - 2013, Chennai Super Kings Vs Royal Challengers Bangalore 16th Match at Chennai- Apr 13, 2013, Ravindrasinh Anirudhsinh Jadeja
Jadeja blinder helps CSK clinch a thriller from RCB
The legend of tonight's game goes that when Sir Ravindra Jadeja got caught at thirdman with two runs needed to win off the last ball in an IPL match, it wasn't given out but declared as a noball with the bowler RP Singh overstepping the crease.
Tags: Indian Premier League - 2013, Chennai Super Kings Vs Royal Challengers Bangalore 16th Match at Chennai- Apr 13, 2013, Ravindrasinh Anirudhsinh Jadeja, Virat Kohli, Abraham Benjamin de Villiers
IPL 2013: CSK Vs RCB 16th Match Live Scorecard, Apr 13, 2013
IPL 2013 Live Scores: Chennai Super Kings vs Royal Challengers Bangalore, 16th Match Live Scorecard at Chennai, 13 Apr, 2013. Match start at 20:00 local time (14:30 GMT).
Tags: Indian Premier League - 2013, IPL 2013, Chennai Super Kings Vs Royal Challengers Bangalore 16th Match at Chennai- Apr 13, 2013, Chennai Super Kings, Royal Challengers Bangalore


text:
package io.flow.lint.linters

import io.apibuilder.spec.v0.models._
import io.flow.lint.Linter

/**
  *  All subtypes of the beacon event must have an attributes field
  */
case object BeaconEventsMustHaveAttributes extends Linter with Helpers {

  private[this] val AttributesType = "beacon_attributes"

  override def validate(service: Service): Seq[String] = {
    service.unions.find(_.name == "event") match {
      case None => Nil
      case Some(u) => {
        val typeNames = u.types.map(_.`type`).toSet
        service.models.filter { m => typeNames.contains(m.name) }.flatMap(validateModel)
      }
    }
  }

  def validateModel(model: Model): Seq[String] = {
    model.fields.find(_.name == "attributes") match {
      case None => {
        Seq(error(model, s"Must have a field named 'attributes' of type '$AttributesType'"))
      }
      case Some(f) => {
        validateField(model, f)
      }
    }
  }

  def validateField(model: Model, field: Field): Seq[String] = {
    val requiredErrors = if (field.required) {
      Seq("not be required")
    } else {
      Nil
    }

    val typeErrors = if (field.`type` == AttributesType) {
      Nil
    } else {
      Seq(s"have type '$AttributesType' and not '${field.`type`}'")
    }

    (requiredErrors ++ typeErrors).toList match {
      case Nil => Nil
      case errors => {
        Seq(error(model, field, "Must " + errors.mkString(" and ")))
      }
    }
  }

}

redpajama_set_name: RedPajamaGithub


text:
What is 'USB Type C' and 'USB 3.1 Gen 1'?
Apple's decision to include just one single USB Type C port on the new MacBook that will handle both power and connectivity has caused a fair bit of confusion. How can a single port take over the function of the myriad of ports that are usually present on a MacBook?
By Adrian Kingsley-Hughes for Hardware 2.0 | March 16, 2015 -- 15:35 GMT (08:35 PDT) | Topic: Hardware
The port that has replaced the standard offering of USB, Thunderbolt, DisplayPort, and even the MagSafe is a port called USB Type C. The USB Type C connector differs dramatically from the regular USB port that we're accustomed to. First off, it's physically different. It's smaller and the connector is reversible, so it's not as annoying to use as the regular USB ports of old.
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Now, what's interesting about USB Type C is that unlike the MagSafe or Lightning ports you find on other Apple products, it's not proprietary. It is, in fact, part of the USB-IF spec that's been in the works since the end of 2013 and forms part of the USB 3.1 specification. The new MacBook isn't even the first device to feature a USB Type C port, but it was the first to use it so comprehensively, at least until Google unveiled the new Chromebook Pixel a few days later.
The port isn't physically backward-compatible with existing USB ports, but the USB 3.1 standard it is built on is, so all that's needed is an adapter to make the conversion.
USB Type C is the port, and if you look closely at the specifications, you'll find that Apple claim that the port can do a lot:
USB 3.1 Gen 1 (up to 5 Gbps)
Native DisplayPort 1.2 video output
VGA output using USB-C VGA Multiport Adapter (sold separately)
HDMI video output using USB-C Digital AV Multiport Adapter (sold separately)
Which brings us to the next point of confusion - what is USB 3.1 Gen 1?
USB 3.1 Gen 1 is essentially what USB 3.0 was before it was updated to USB 3.1 (or, more specifically, USB 3.1 Gen 2). While the updated Gen 2 offers speeds up to 10 Gbps, Gen 1 peaks at 5 Gbps (which is still a huge improvement over USB 2.0 which maxed out at 480Mbps).
Other than that, USB 3.0 and USB 3.1 are the same thing.
USB-IF
Apple could have undoubtedly made things clearer by saying the connector was USB 3.0, but that doesn't sound as cool at USB 3.1 Gen 1 I guess.
Finally, here are my thoughts on some questions I've been asked:
Is Apple going to replace every port with USB Type C? I doubt it, given that Thunderbolt 2 has four times the data carrying capacity.
Will Apple replace the Lightning port on iOS devices with USB Type C? I wouldn't think so, given that the port is taller than the Lightning port Apple uses, which would result in thicker devices.
Are using dongles going to be a pain? If you use them a lot, maybe, but if that's your usage, then maybe the new MacBook isn't the right device for you.
Apple has all the tech pieces in place to build a MacBook tablet
LaCie unveils USB-C external drive for the new MacBook
Apple Watch: Answers to questions such as battery life and waterproofing
Apple Watch: Official battery life data
Innovation PCs Servers Storage Networking Data Centers
More from Adrian Kingsley-Hughes
Best Prime Day deals 2019: Small business servers
IT Priorities
Best Prime Day deals 2019: IT technician and DIY repair tools
Sales are slow at present but it may only take four years for 5G to become the new standard.
Xiaomi takes the lead as Indian smart TV market share rises to 39%
Meanwhile, Huawei announced it will be releasing smart display products next month via its Honor brand.
Korean researchers develop ternary semiconductor tech
Future semiconductors may perform logic with 0, 1, or 2 instead of the current binary system of 0 and 1 with the new technology.
The best of the Prime Day small business server deals on Amazon.
The best of the Prime Day IT and DIY repair tool deals for business on Amazon.


Looking for the best Mercedes-Benz 280SL aftermarket replacement parts? Replacing worn and broken parts on your Mercedes-Benz 280SL? Check out our online catalog to find the best selection of aftermarket Mercedes-Benz 280SL parts as well as real user reviews on Mercedes-Benz 280SL replacement parts. Make an informed decision about every component you add to your 280SL.
At Advance Auto, we've got you covered when it comes to getting your Mercedes-Benz 280SL in tip top condition. We've got over 453 Mercedes-Benz 280SL parts to choose from in popular categories like Electronics & Navigation, Tools, Fluids & Garage and Air, Fuel, Emission & Exhaust parts. If you're looking for the best prices, try searching our Mercedes-Benz 280SL parts catalog to compare OEM and aftermarket parts for your Mercedes-Benz 280SL.
Whether you need Mercedes-Benz 280SL body parts, interior components, or custom Mercedes-Benz 280SL parts you can find them online at Advance Auto. Want to order your Accessories, Body & Wipers parts online? Or maybe you need your Mercedes-Benz Cooling & Heating parts same day? No problem, you can pick up discount 280SL parts in person at locations across the country, or have them delivered to straight to your door after ordering online. Finding a great deal on new and used Mercedes-Benz 280SL parts has never been easier.


"The Troopship Serapis off Bombay, Circa 1870"
Measuring 360 feet in length and weighing 6,211 tons, Serapis was one of five Indian government troopships which had been ordered in 1863 to bolster the policing of Britain's ever expanding overseas empire during the reign of Queen Victoria.
The Serapis was identical in both tonnage and design to her sister ships Malabar, Crocodile, Jumna and Euphrates. She was launched on 2 September 1866 from the Thames Shipbuilding Company's yard at Blackwall , entering service as soon as she was completed.
All five troopships were fast, handsome vessels which provided accommodation far superior to any previous forms of such transport. Jumna was to suffer recurrent engine trouble, but that apart, the new ships proved extremely popular with all remaining in service until they were withdrawn in 1894; when they were either relegated to depot duties or broken up.
Serapis was to achieve her moment of glory in 1875, when the Prince of Wales (later Edward VII) chose to visit India and Serapis was chosen as the most suitable vessel to accommodate him and his entourage. Traversing Europe by special train, the royal party boarded Serapis at Brindisi whence she sailed on 16th October. Under the command of Captain the Hon. Carr Glynn and escorted by the frigates H.M.S. Pallas and Hercules, she made brief stops at Cairo and Aden before making Bombay on 8th November. The Prince left for Ceylon to shoot elephant, before arriving at Calcutta to a tumultuous welcome on 23rd December.
The visit heralded the first by a future sovereign and was a huge success. When Serapis finally sailed for home, she was laden with jewellery, trophies of every description and a large menagerie of wild animals, all of which had been specially presented to the Prince.
Serapis departed Bombay on 13th March, 1876 for the journey home, again calling at Cairo as well as Lisbon. The morning of 11th May saw Captain Glynn stopping engines off the Needles to allow the Princess of Wales, who had travelled out on the yacht Osborne, to come aboard to greet him. Once the Princess had been safely transferred, the royal convoy proceeded on its way to Portsmouth, where Serapis docked later the same day, to be greeted by scenes of wildly patriotic rejoicing to mark the safe return home of a most popular Prince.
24 x 30 inches; 61 x 76 cms.


The board of governors for the Academy of Motion Picture Arts and Sciences is now making sweeping changes to help the Academy Awards become more diverse moving forward. The Friday announcement of the changes comes amidst criticism of the 2016 Oscars, for which no black actors or actresses were nominated. On Thursday night, the board of governors unanimously approved policies designed to double the number of women and minorities in the Academy by 2020.
AMPAS President Cheryl Boone Isaacs said in a statement released Friday that the board is committed to "begin the process of significantly changing our membership composition," and that "the Academy is going to lead and not wait for the industry to catch up." Starting later this year, new members can vote for 10 years, and only have their status renewed if they've been active in movies during that decade. Lifetime voting rights, which used to be a given, will only go to those receiving three 10-year terms in a row, or if a member has been nominated for or won an Academy award.


Arsenal Colorado is pleased to announce a new community partnership and two-year jersey sponsorship with OtterBox. The OtterBox logo, which uses their corporate colors, will feature prominently on the front of Northern Colorado's premier soccer club's home and away competitive jerseys.
The new kits will make their debut this fall and will be worn through the 2019-2020 season. In addition to the jersey sponsorship, OtterBox will also begin to offer Arsenal Colorado branded products such as phone cases, tumblers and coolers at a discount to members. As this partnership grows, we will keep our members informed about all of the great opportunities this partnership will provide.
OtterBox was founded in 1998 in Fort Collins and recently celebrated 20 years of growth and innovation. They have grown into a global technology leader and are one of the most respected and successful brands in Colorado and beyond. Similarly, Arsenal Colorado was founded in F ort Collins in 1978 and will celebrate its 40th anniversary by adding its first-ever game jersey sponsor, a significant event in the history of the club.
Arsenal Colorado is a nonprofit organization and uses proceeds from advertising and sponsorship to benefit its families by contributing to the cost of program services as well as completing new projects. Immediately, thanks to the OtterBox sponsorship, a new lightning prediction and warning system to increase safety will be installed at the Fort Collins Soccer Complex in part thanks to sponsorship dollars.


Okay, you might need to brace yourself for this one. Samantha Jay Photography and A Garden Party sent over this incredibly stylish shoot that proves that you can have a garden wedding no matter the time of the year or the location. With how lush this entire shoot looks, it's almost impossible to believe there was a snow storm outside just the day before!
From the photographer, Samantha Jay Photography: The magic that happens when several unbelievably talented vendors come together to make a styled shoot is undeniable in these romantic photos. What hoped to be a spring garden styled shoot was transformed into a breathtaking snowy adventure when southern NJ was hit with a huge snow storm the day prior. Loads of fresh greenery, yards of peach tulle and glistening gold accents make you forget about the snow on the ground and help to inspire what your romantic garden wedding could be like, in any season.
How adorable is this floral bracelet for the flower girl?
Not to leave out any ideas for the ring bearer, we love this idea of stashing the rings on a potted plant and writing "I Do" on the leaves for a beautiful display before the ceremony!
Yep, we're pretty much speechless over this tablecloth — talk about impact! The addition of metallic elements really ups the ante in terms of elegance, too.
Even the table numbers have a hint of garden charm, made by pressing greenery between two sheets of glass in a picture frame!
I love that ceremony space, so romantic and elegant!
That is the cutest pup! What breed? Beautiful.


text:
REVEALED: The Bizarre 'Anti-Arsenal' Clause In Roberto Firmino's Liverpool Contract
By Vishal Singh | December 7, 2016 | 0
Reuters / Phil Noble
Liverpool's Brazilian star Roberto Firmino has a massive €98 million release clause which can be triggered by any suitors except arch rivals Arsenal, as per the latest Football Leaks releases in Le Soir.
The Gunners apparently frustrated the Liverpool officials back in 2013 when they launched a £40m + £1 bid for Luis Suarez in a tricky way to trigger a buyout clause in the striker's contract. The results were drastic, with Reds owner John W. Henry even tweeting: "What do you think they're smoking over there at the Emirates?"
And now, it seems Liverpool have taken some sort of retributive action to specify in Firmino's deal that he can be signed for €98m (£82m) "if the interested club is not Arsenal".
In June 2015, Firmino joined Liverpool from Hoffenheim, agreeing a "long-term" contract at Anfield.
After scoring 10 times in 31 matches in his first Premier League season, the Brazilian forward now enjoys a status of one of the league's top attacking players in 2016-17, with five goals and three more assists in 13 matches.
That lethal form and telepathic partnership with his compatriot Philippe Coutinho has guided Liverpool to sit third in the English top flight.
The disclosure about his contract was published as part of the latest series of releases by Football Leaks, who have so far successfully exposed substantial amounts of information regarding the contracts of top players and clubs over the past 2 years.
The most recent leaks, which raised fierce controversy claims, involved the clients of Jorge Mendes' agency Gestifute. The info stated that the likes of Cristiano Ronaldo, Jose Mourinho and Mesut Ozil have evaded taxes owed to the countries where they have played. However, Gestifute have strongly denied any wrongdoing.
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Why don't you beat those bank holiday blues and download your free copy at Amazon.co.uk or Amazon.com.
First free promo a roaring success!


text:
Home » cancer » LAPATINIB, GW572016, An EGFR-ErbB-2 inhibitor.
LAPATINIB, GW572016, An EGFR-ErbB-2 inhibitor.
Lapatinib in 3d
LAPATINIB
CAS Name: N-[3-Chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5[[[2-(methylsulfonyl)ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)furan-2-yl)quinazolin-4-amine
Manufacturers' Codes: GW-572016, Smithkline Beecham Corporation
Trademarks: Tykerb (GSK)
Molecular Formula: C29H26ClFN4O4S
Percent Composition: C 59.94%, H 4.51%, Cl 6.10%, F 3.27%, N 9.64%, O 11.01%, S 5.52%
Systematic (IUPAC) name
N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-
[5-[(2-methylsulfonylethylamino)methyl]-2-furyl]
quinazolin-4-amine
Tykerb, Tyverb
AHFS/Drugs.com
EMA:Link, US FDA:link
Pregnancy cat.
AU: D
US: D
AU: Prescription Only (S4)
CA: ℞-only
UK: POM
US: ℞-only
Pharmacokinetic data
Variable, increased with food
Hepatic, mostly CYP3A-mediated (minor 2C19 and2C8 involvement)
Mostly fecal
388082-78-8 (ditosylate)
L01XE07
CID 208908
0VUA21238F
C29H26ClFN4O4S
Mol. mass
581.058 g/mol
Lapatinib (INN), used in the form of lapatinib ditosylate, (USAN) (Tykerb/Tyverb, GSK) is an orally active drug for breast cancerand other solid tumours.[1] It is a dual tyrosine kinase inhibitor which interrupts the HER2/neu and epidermal growth factor receptor(EGFR) pathways.[2] It is used in combination therapy for HER2-positive breast cancer. It is used for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 (ErbB2).[3]
On March 13, 2007, the U.S. Food and Drug Administration (FDA) approved lapatinib in combination therapy for breast cancer patients already using capecitabine (Xeloda, Roche).[2][3] In January 2010, Tykerb received accelerated approval for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses the HER2 receptor and for whom hormonal therapy is indicated.[3]
Pharmaceutical company GlaxoSmithKline (GSK) markets the drug under the propriety names Tykerb (mostly US) and Tyverb (mostly Europe).[4] The drug currently has approval for sale and clinical use in the US,[2][4] Australia,[2] Bahrain,[2] Kuwait,[2] Venezuela,[2]Brazil,[5] New Zealand,[5][6] South Korea,[5] Switzerland,[4] Japan, Jordan, the European Union, Lebanon, India and Pakistan.[4]
On the 2nd of August 2013, India's Intellectual Property Appellate Board revoked the patent for Glaxo's Tykerb citing its derivative status, while upholding at the same time the original patent granted for Lapatinib.[7]
The drug lapatinib ditosylate is classified as S/NM (a synthetic compound showing competitive inhibition of the natural product) that is naturally derived or inspired substrate (Gordon M. Cragg, Paul G. Grothaus, and David J. Newman, Impact of Natural Products on Developing New Anti-Cancer Agents, Chem. Rev. 2009, 109, 3012–3043)
Lapatinib ditosylate, an ErB-1 and ErB-2 dual kinase inhibitor, was launched in the U.S. in 2007 for the treatment of advanced or metastatic HER2 (ErbB2) positive breast cancer in women who have received prior therapy, including Herceptin(R) (trastuzumab), in combination with Xeloda(R) (capecitabine). The compound was approved in 2007 in Switzerland and Australia and in 2009 in Canada, for this indication. Regulatory approval has also been obtained in Japan. In December 2007, a positive opinion was received in the E.U. In 2008, the CHMP issued a revised positive opinion confirming the positive benefit-risk profile for lapatinib following review by the CHMP of new data received in February 2008 from GlaxoSmithKline arising from a standard pharmacovigilance evaluation of clinical trial and post-marketing data. The CHMP confirmed that these data do not essentially change the positive benefit-risk profile for lapatinib in its proposed indication. In 2008, the MAA was approved in the E.U. and the product was subsequently commercialized in Germany. In 2009, regulatory applications were filed in the U.S. and the E.U. seeking approval for use of lapatinib as first-line treatment of patients with hormone-sensitive, metastatic (or advanced) breast cancer in combination with anti-hormonal therapy. In 2010, lapatinib was launched on the U.S. market as first-line treatment in combination with Femara(R) to treat hormone positive and HER2-positive advanced breast cancer in postmenopausal women for whom hormonal therapy is indicated. In 2010, the compound was approved and launched in the E.U. for the oral treatment of post-menopausal women with hormone receptor-positive, HER2 (ErbB2) over-expressing metastatic breast cancer and for whom chemotherapy is currently not intended, in combination with an aromatase inhibitor. In 2012, GlaxoSmithKline filed regulatory applications in the U.S. and the E.U. for the oral treatment of patients with HER2 (ErbB2)-positive metastatic breast cancer that has progressed on prior trastuzumab regimens, in combination with trastuzumab. In July 2012, GlaxoSmithKline withdrew this application in the U.S. In 2013, the product was approved for this indication in the E.U.
In terms of clinical development, the National Cancer Institute (US) is currently conducting phase II/III trials for the treatment of bladder cancer. Phase III trials are under way to evaluate the use of lapatinib as first-line treatment of breast cancer. The compound is also being evaluated for several oncologic indications in the treatment of brain, gallbladder, prostate, ovary, endometrium, bladder cancer, cervical and hepatobiliary cancers in collaboration with the National Cancer Institute (NCI). Lapatinib in combination with everolimus is also in early clinical studies for the treatment of lymphoma and non-Hodgkin's lymphoma (NHL). A phase II combination trial is evaluating lapatinib for the treatment of advanced or metastatic colorectal cancer. The National Cancer Institute (NCI) is developing the compound in phase II trials for the treatment of peritoneal cancer, ovarian and ductal carcinoma in situ of the breast (DCIS), while Brown University is conducting combination trials with gemcitabine for the treatment of pancreas metastatic cancer, and Cedars-Sinai Medical Center is conducting phase II clinical trials for treatment for pituitary cancer. Phase III clinical study for the treatment of head and neck was terminated because the study didn´t meet primary endpoint.
Lapatinib was granted fast-track status by the FDA in 2005 for the treatment of refractory advanced or metastatic breast cancer patients who have documented ErbB-2 overexpression and who have failed previous therapy. In 2009, Orphan Drug Designation was received in the U.S. by GlaxoSmithKline for the treatment of ErbB2 positive gastric cancer and for the treatment of ErbB2 positive esophageal cancer.
Lapatinib is used as a treatment for women's breast cancer in treatment naive, ER+/EGFR+/HER2+ breast cancer patients(now often called "triple positive") and in patients who have HER2-positive advanced breast cancer that has progressed after previous treatment with other chemotherapeutic agents, such as anthracycline, taxane-derived drugs, or trastuzumab (Herceptin, Genentech).
A 2006 GSK-supported randomized clinical trial on female breast cancer previously being treated with those agents (anthracycline, a taxane and trastuzumab) demonstrated that administrating lapatinib in combination with capecitabine delayed the time of further cancer growth compared to regimens that use capecitabine alone. The study also reported that risk of disease progression was reduced by 51%, and that the combination therapy was not associated with increases in toxic side effects.[11] The outcome of this study resulted in a somewhat complex and rather specific initial indication for lapatinib—use only in combination with capecitabine for HER2-positive breast cancer in women whose cancer have progressed following previous chemotherapy with anthracycline, taxanes and trastuzumab.
Product patent
US6727256
http://www.google.co.in/patents/WO1999035146A1
W09935146 (GSK company, filed on 8 February 1999, I) propose a 2_ chlorine _4_ nitrophenol as the starting material, by addition, catalytic hydrogenation, replace, Suzuki coupling Union, such as reductive amination reaction was prepared by lapatinib
First, the method of the protected aldehyde group, deprotection after the completion of the coupling reaction for the reductive amination reaction, the reaction step so long; due to the use of expensive and highly toxic organic heteroaryl stannane reagent 5 – (_ 1,3-dioxolan-2 – yl) -2 – (tributylstannyl group) _ furan, intermediates for drugs and have greater safety and environmental risks; Furthermore, the process requires the synthesis of intermediate purified by column chromatography, post-processing is more complex.
CN102295638A (Qilu Pharmaceutical Co., Ltd., June 24, 2010 application) proposed a method of preparing lapatinib is mixture of 5 – formyl-furan-2 – boronic acid, N-[3 – chloro-4 – [(3 – fluorophenyl) methoxy] phenyl] -6 – iodo-4 – quinazolinamine 2 – methylsulfonyl – ethylamine and the catalyst to the solvent, Mr. into transitional intermediate, and then reducing agent such as sodium triacetoxy borohydride reduction to give the desired product, the synthesis route is as follows:
W02005120504A2 (Glaxo, in June 2005 I filed) proposed an alternative approach: a 4 – chloro-6 – iodine quinazoline as the starting material, with 5 – formyl-furan-2 – boric acid instead of highly toxic tin compounds alkylfuryl prepared lapatinib. The synthetic route is as follows:
http://www.google.com/patents/EP2550269A1?cl=en
Lapatinib has the structural formula (I) and chemical name N-[3- chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-2- furyl] quinazolin-4-amine.
BACKGROUND ART
Lapatinib is a tyrosine kinase inhibitor that is used as an orally administered drug as its ditosylate salt to treat certain types of advanced or metastatic breast cancer and other solid tumors. Lapatinib ditosylate was approved by the FDA in 2007 and the EMEA in 2008 and is marketed by GlaxoSmithKline (GSK) under the trade name of Tykerb® in the USA and Tyverb® in Europe.
Lapatinib substance is claimed in US 6,713,485 B2 and US 6,727,256 Bl and lapatinib ditosylate and its crystalline forms are claimed in US 7,157,466 B2. A synthesis of lapatinib that utilises a palladium mediated coupling of a substituted 4-anilino-6-iodo-quinazoline (II) with a 2- (tributylstannyl)furan (Ilia) is disclosed in US 6,727,256 Bl and is also presented in US 7,157,466 B2. In US 7,157,466 B2 a second generation approach was disclosed that utilises a palladium catalysed coupling of a substituted 4-anilino-6-iodo-quinazoline (II) with furan-2-yl-boronic acids (Illb). Following the palladium catalysed coupling reactions utilised in the two synthetic methods of US 6,727,256 Bl and US 7,157,466 B2, only one (US 7,157,466 B2) or two (US 6,727,256 Bl and US 7,157,466 B2) synthetic modification of the structure are utilised before the lapatinib substance is provided (Scheme 1). The EMEA's COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE (CHMP) has published guidelines titled GUIDELINE ON THE SPECIFICATION LIMITS FOR RESIDUES OF METAL CATALYSTS OR METAL REAGENTS and recommendations are presented for oral exposure to metals, including palladium. For a drug being consumed in quantities not exceeding a 10 g daily dose, a limit of 10 ppm (parts per million) concentration of palladium in the drug substance is recommended. Given this, there is still an unmet need for an alternative synthetic method that can be used for preparation of lapatinib in which the palladium mediated coupling step is performed early in the synthetic route, thereby being capable to provide .
Scheme 1
There are a number of ways that the levels of a metal, such as palladium, can be controlled in a drug substance through purging of the metal by treatment of the drug substance or its synthetic intermediates or both, including crystallisation, aqueous extraction, filtration through metal absorbent filter aids (Organic Process Research & Development 2005, 9, 198-205), precipitation of the metal from solution, chromatography, and treatment with metal scavenging reagents (Organic Process Research & Development 2003, 7, 733-742). By placing the palladium mediated coupling step downstream in the synthetic route, however, to take advantage of synthetic convergence, the opportunity to reduce the level of palladium in the drug substance is reduced. In contrast, however, by redesigning the synthetic route to move the palladium mediated coupling step upstream, further away from the drug substance, increases the opportunity to control the palladium level in the drug substance. Furthermore, by careful operational design (such as in a precipitation and crystallisation step), the palladium level in the intermediates can be consistently controlled. Given that there is a need, the present invention has addressed these two latter points and utilised them in a novel and efficient process for the manufacture of lapatinib and lapatinib ditosylate.
Scheme 2 – Synthesis of lapatinib and lapatinib ditosylate
In contrast to the prior art methods disclosure in US 6,727,256 Bl and US 7,157,466 B2, the present invention has performed a transition metal catalysed coupling reaction at the most upstream point in the synthetic route based on the utilization of commercially available starting materials SMla (6-iodoquinazolin-4(3H)-one) and SM2a (5-formylfuran-2-ylboronic acid), or their analogues SMI and SM2, to provide IM1. Thus, in one aspect of the present invention, lapatinib is made from a novel compound (IM1) (Scheme 2).
In another aspect of the present invention, a lapatinib ditosylate monohydrate is prepared by crystallizing lapatinib ditosylate in a mixture of water, DMSO and MeCN.
In another aspect of the present invention, novel compound IM1 is synthesized by the cross- coupling of commercially available SMla and SM2a, or their analogues SMI and SM2, in suitable solvents comprised of an organic solvent and water in the presence of a base and a catalyst formed from a transition metal and a ligand (scheme 3).
X = CI, Br, I, OTf Y = CHO, or CH(OR)2
BZ = B(OH)2, B(OR)2, [BF3]M or BR2
Example 1: Synthesis of 5-(4-oxo-3,4-dihydroquinazolin-6-yl)furan-2-carbaldehyde (IMl)
A 5:2 v/v mixture of DMSO and H20 (1400 mL) was degassed for 30 min at ambient temperature using nitrogen. 5-Formylfuran-2-ylboronic acid (SM2a; 26.8 g, 193 mmol) was added dissolved in this mixture. [HP(i-Bu)3] BF4 " (840 mg, 2.94 mmol) and Pd(OAc)2 (680 mg, 2.94 mmol) was added and the mixture was stirred at ambient temperature under an atmosphere of nitrogen for 20 min. AcOK (18.8 g, 192 mmol) was added into the reactor and was stirred for 20 min at ambient temperature. 6-Iodoquinazolin-4(3 /)-one (SMla; 40 g, 147 mmol) was added and heated to 80±5°C (internal temperature) in an oil bath under nitrogen, Upon completion of the reaction (HPLC), the reaction mixture was hot-filtered, then hot water (400 mL, 80±5°C) was added into the filtrate. This was slowly cooled to 0-15°C (solid started to precipitate at 70°C (internal temperature) and was then filtered. The filter cake was washed with H20 (80 mL), then with MeCN (60 mL), and dried in vacuo at 60+5°C for 6 h to provide 5-(4-oxo-3,4-dihydroquinazolin-6-yl)-furan-2- carbaldehyde (IMl; 34.6 g, 144 mmol) with 99.7 % HPLC purity in 97.6% HPLC yield. XH NMR (300 MHz, de-DMSO): δ 7.47 (d, / = 3.8 Hz, 1H), 7.69 (d, / = 3.8 Hz, 1H), 7.77 (d, / = 8.6 Hz, 1H), 8.17 (s, 1H), 8.27 (dd, / = 8.6, 2.1 Hz, 1H), 8.52 (d, = 2.1 Hz, 1H), 9.66 (s, 1H); 13C NMR (75 MHz, CDC13): δ 110.5, 122, 6, 123.9, 126.0, 127.5, 129.0, 131.4, 147.1, 150.1, 152.7, 157.6, 161.2, 178,8; ESI-MS, Pos: [M+H]+ mJz 241; IR (cm 1): 1713, 1671, 1604,1462; m.p.: 267°C. See Figure 2 for the DSC/TGA of IMl; See Figure 3 for the X-ray powder diffraction pattern of IMl; Residual concentration of palladium: 230 ppm.
Example 2: Synthesis of 5-(4-chloroquinazolin-6-yl)furan-2-carbaldehyde hydrochloride
(IM2a.HCl)
I 1 reflux IM2a.HCI
Over a 1.5 hour period under an atmosphere of N2, SOCb (86.2 g) in MeCN (145 mL) was added dropwise into a mixture, that had been preheated at reflux for 0.5 h, of IM1 (29 g, 0.121 mol), MeCN (435 mL) and DMF (0.88 g) at reflux. The reaction was terminated when less than 2% (HPLC) of IM1 was remaining. If the reaction did not achieve complete reaction, extra SOCI2was added. The mixture was cooled to about 25±5°C (internal temperature), and was then filtered and washed with MeCN (58 mL) to give ca. 55 g of IM2a.HCl (moist with MeCN) with 82A purity by HPLC. IM2a.HCl: ¾ NMR (300 MHz, d6-DMSO): δ 9.68 (s, 1 H), 9.17 (s, 1H), 8.57 (d, / = 2.0 Hz, 1H), 8.46 (dd, J = 8.6, 2.1 Hz, 1H), 8.02 (d, / = 8.6 Hz, 1H), 7.74 (d, = 3.8 Hz, 1H), 7.60 (d, J = 3.8 Hz, 1H). See Figure 5 for the XH NMR spectrum of IM2a.HCl; 13C NMR (75 MHz, d6– DMSO) δ 179.0, 159. 6, 156.4, 152.9, 149.5, 141.0, 132.6, 129.2, 125.9, 123.2, 122.9, 122.7, 111.5;
IM2a.HCl was purified by column chromatography (eluent: ) to give pure IM2a. IM2a: lH NMR (300 MHz, d6-DMSO): δ 7.53 (d, / = 3.3 Hz, 1H), 7.68 (d, J = 3.3 Hz, 1H), 8.02 (d, / = 8.7 Hz, 1H), 8.42 (d, / = 8.4 Hz, 1H), 8.54 (d, / = 2.1 Hz, 1H), 8.90 (s, 1H), 9.64 (s, 1H); 13C NMR (75 MHz, CDCI3): δ 111.5, 122.8, 122.9, 123.7, 125.9, 129.1, 132.5, 142.1 , 149.3, 152.9, 156.6, 159.7, 179.1.
Example 3: Synthesis of 5-(4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)
– uinazolin-6-yl)furan-2-carbaldehyde hydrochloride (IM3.HC1)
A mixture of IM2a.HCl (moist with MeCN solvent, prepared from 29 g IM1, 0.120 mol) and 3-chloro-4-(3-fiuorobenzyloxy)aniline (SM3; 27.3 g, 0.108 mol) in MeCN (580 mL) was stirred under reflux, until HPLC analysis showed that the reaction was completed (about 2 h). The mixture was cooled to room temperature (25±5°C), filtered, and washed with MeCN (58 mL). A mixture of the moist crude solid IM3 and THF (870 mL) was treated with a 2.0 N aqueous NaOH (348 mL) and stirred for 3-4 h until most of the solid had dissolved. The mixture was filtered through diatomite and was washed with a saturated aqueous solution of NaCl (87 mL). The organic layer was treated with 10% aqueous HCI (174 mL) and stirred for 0.5 h. The resulting solid was filtered, washed with THF (87 mL), and dried in vacuo at 60+5°C for 16 h to give the crude IM3.HC1 (34 g, 0.067 mol, HPLC purity: 99%).
IM3.HC1: :H NMR (300 MHz, d6-DMSO): δ 9.69 (s, 1H), 9.52 (s, 1H), 8.94 (s, 1H), 8.50 (dd, / = 8.8, 1.7 Hz, 1H), 8.01 (d, / = 8.8 Hz, 1 H), 7.97 (d, J =2.5 Hz, 1H), 7.77 (d, / = 3.8 Hz, 1H), 7.73 (dd, = 9.0, 2.5 Hz, 1H), 7.69 (d, / = 3.8 Hz, 1H), 7.49 (td, 7 = 8.0, 6.1 Hz, 1 H), 7.41-7.28 (m, 3H), 7.20 (td, / = 8.4, 2.2 Hz, 1H), 5.31 (s, 2H).
Free base IM3 is obtained by column chromatography (eluting with EtOAc/DCM, 1:4, v/v). IM3 XH NMR (300 MHz, d6-DMSO): δ 5.28 (s, 2H), 7.19 (td, /= 8.7 Hz, 7 = 2.1 Hz 1H), 7.34 (m, 4H), 7.43 (d, 7 = 3.6 Hz , 1H), 7.49 (m, 1H), 7.73 (dd, 7 = 8.7 Hz 7 = 2.7 Hz, 1H), 7.76 (d, 7 = 3.6 Hz, 1H), 7.88 (d, 7 = 9 Hz, 1H), 8.07 (d, 7 = 2.1 Hz, 1H), 8.32 (dd, 7 = 4.43 Hz, 7 = 1.95 Hz, 1H), 8.95 (d, 7 = 1.5 Hz, 1H), 9.68 (s, 1H).
Example 4: Synthesis of N-(3-chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2- (methylsulfonyl)ethylamino)methyl)furan-2-yl)quinazolin-4-amine ditosylate (lapatinib ditosylate)
To a suspension of 2-(methylsulfonyl)ethanamine hydrochloride (SM4.HC1; 12.2 g, 76.7 mmol) in THF (600 mL) was added acetic acid (14.1 g, 235 mmol) followed by DIPEA (30.3 g, 235 mmol) were added. After stirred at ambient temperature for 0.5 h, ¾0 (4.2 g, 233 mmol) and IM3.HC1 (30.0 g, HPLC assay >99%, 58.7 mmol) were added. After being stirred at ambient temperature (20°C) for 4 h, sodium triacetoxyborohydride (37.4 g, 176 mmol) was added and the mixture was stirred at ambient temperature (20°C±5°C; external temperature) until HPLC showed the completion of the reaction. A 10% aqueous solution of sodium hydroxide (90 mL) was added and the mixture was stirred for 30 min. The organic phase was washed with 25% aqueous NH4C1 (60 mL), filtered, treated with -TsOH (40.4 g, 135 mmol) and heated to reflux for 2 h. The mixture was cooled to ambient temperature and stirred for 3 h at ambient temperature. The mixture was filtered, and the filter cake was washed twice with THF (120 mL each) and was then dried under vacuum at 70±5°C for 6 h to give 43 g (46.5 mmol) lapatinib ditosylate with 99.4% HPLC purity.
Lapatinib ditosylate [H NMR (300 MHz, d6-DMSO): δ 11.41(s, 2H), 9.33 (s, 3H), 9.04 (d, / = 1.3 Hz, 2H), 8.93 (s, 2H), 8.41 (dd, J =8.8, 1.6 Hz, 2H), 7.91 (d, J = 2.6 Hz, 2H), 7.54-7.41 (m, 9H), 7.37 – 7.27 (m, 6H), 7.25 (d, / = 3.4 Hz, 2H), 7.22 – 7.13 (m, 2H), 7.08 (dd, / = 8.4, 0.6 Hz, 8H), 6.87 ( d, / = 3.5 Hz, 2H), 5.29 (s, 4H), 4.46 (s, 4H), 3.65 – 3.51 (m, 4H), 3.51 – 3.38 (m, 4H), 2.26 (s, 12H).
A solution of lapatinib ditosylate was converted to its free base form, lapatinib, by washing a solution with aqueous NaOH followed by concentration. Lapatinib: XH NMR (300 MHz, d6-DMSO): δ 2.98 (t, / = 6.75 Hz, 1H), 3.04 (s, 1H), 3.29 (t, J = 6.6 Hz, 1H), 3.83 (s, 1H), 5.28 (s, 1H), 6.50 (d, / = 3.0 Hz, 1H), 7.08 (d, / = 3.3 Hz, 1H), 7.20 (m, 1H), 7.33 (m, 4H), 7.48 (m, 1H), 7.76 (m, 1H), 7.80 (d, 7 = 9 Hz, 1H), 8.04 (d, 7 = 2.75 Hz, 1H), 8.17 (dd, / = 8.7 Hz, / = 1.8 Hz, 1H), 8.56 (s, 1H), 8.75 (d, J = 1.8 Hz, 1H).
Example 5a: Purification of lapatinib ditosylate
Lapatinib ditosylate (5.0 g, 5.4 mmol, 96.5% HPLC purity with the maximum individual impurity at 0.8%) was dissolved in DMSO (10 mL) at 70°C (internal temperature). MeCN (10 mL) was added dropwise into the mixture at 70-80°C (internal temperature) and was stirred at this temperature for 1 h. Over a 4 h period the mixture was cooled to room temperature. MeCN (30 mL) was added dropwise, and the mixture was stirred for lh, then filtered and washed with MeCN (10 mL). The filter cake was dried under vacuum at 60°C for 16 h to give 4.0 g lapatinib ditosylate as crystalline Form 1 (as disclosed in US 7,157,466 B2) with 99.6% HPLC purity in 78% HPLC yield.
Example 5b. Purification of lapatinib ditosylate.
Lapatinib ditosylate (3 g, 3.25 mmol, 99.3% HPLC purity was dissolved in DMF (18 mL) at 80°C and stirred for 1 hour. The mixture was hot-filtered. MeCN (18 mL) was added into the filtrate at 80°C. The temperature was cooled to 70°C and crystal precipitated. The mixture was kept at 70°C for 1 h and then 60°C for 1 h. The mixture was further cooled to 0°C and stirred for 2 h. The crystals of lapatinib ditosylate were isolated by filtration and were dried at 40°C under vacuum overnight. Lapatinib ditosylate (2.5 g, 2.70 mmol, 83% yield) with 99.9% HPLC purity was obtained. XRPD analysis (figure 9) indicated that this was Form 2 as disclosed in WO 2009/079541 Al.
Example 6: Preparation of lapatinib ditosylate monohydrate Lapatinib ditosylate (2.0 g, 96.7% HPLC purity, 2.1 mmol) was dissolved in DMSO (5 mL) at 80°C (internal temperature) and the solution was filtered whilst the lapatinib ditosylate was still dissolved. A mixture of MeCN (5 mL, 2.5 P) and water (0.3 mL) was then added dropwise into the filtered solution at 70-80°C (internal temperature). The mixture was cooled at a rate of 10°C/h until 60°C, and was kept at 60°C for 2 h and was then slowly cooled down to 50°C. After being kept at 50°C for 1 h, MeCN (15 mL) was added, and then the mixture was cooled to 20-30°C and stirred at 20-30°C for 2 h. The slurry was filtered, washed with MeCN (6 mL) and the filter cake was dried in vacuo at 60°C for 4 h to give lapatinib ditosylate monohydrate (1.7 g, 99.4A% purity, 1.8 mmol). XRPD analysis (figure 10) indicated that this was the monohydrate crystalline form as disclosed in US 7,157,466 B2.
http://www.google.com/patents/CN103159747A?cl=en
[0029] Under a nitrogen atmosphere, 2 – furaldehyde diethyl acetal 950g, 9000mL of dry tetrahydrofuran and transferred to the flask, the system was cooled to _40 ° C, n-butyl lithium in tetrahydrofuran (3180mL, 2.2mol / L ) was added dropwise to the reaction system to maintain -4 (T-5 (TC stirred for 2.5 ~ 3h, then triisopropyl borate was added dropwise 1536mL, and stirred for Ih at _60 ° C, after the system was allowed to warm to room temperature, 384mL of glacial acetic acid was slowly added dropwise, followed by stirring for 30min, then dropping 156mL water was added to 3780mL of ethanol, 776mL of triethylamine were then added N_ [3_ chloro _4-[(3_ fluorophenyl) methoxy] phenyl] -6 – iodo-4 – quinazolinamine 1124g, 10% palladium on carbon 134g, and the reaction system was heated to reflux temperature, the reaction 14h. temperature was lowered to room temperature, the reaction mixture was filtered, the filter cake was washed with tetrahydrofuran, The filtrates were combined. To the filtrate was added 240g of triethylamine were then added 2 – (methylsulfonyl) ethylamine 390g and 450mL of methanol, and stirred at room temperature lh, then potassium borohydride was added 137.9g, room temperature for 1.5h, then ice under cooling, a 5N aqueous sodium hydroxide was added dropwise 3600mL, stirred at room temperature 15min, standing layered organic phase was separated, the organic phase p-toluenesulfonic acid was added dropwise 2400g / 3600mL of tetrahydrofuran was stirred for 40min, the solid was filtered and the filter cake was washed with tetrahydrofuran, and then recrystallized from methanol and dried in vacuo to obtain pure final two pairs of p-toluenesulfonic acid lapatinib 1185g. yield 70.8%, purity 98.1%. HNMR (DMSO) 2.27 Cs, 6H) , 3.11 (s, 3H), 3.50 (t, 2H), 3.60 (t, 2H), 4.47 (s, 2H), 5.32 (s, 2H), 6.90 (s, lH), 7.1 (d, J = 7.8 Hz, 4H), 7.19 (t, lH), 7.20 (t, lH), 7.22 (d, J = 3.2Hz, 1H) ,7.23-7 .25 (m, 3H),
7.56 (d, J = 8.0Hz, 4H), 7.62 (dd, Jl = 8.7Hz, J2 = 8.0Hz, 1H), 7.87 (s, 1H), 7.91 (d, J = 8.9Hz, 1H), 8.42 ( d, J = 8.7Hz, 1H), 8.93 (s, lH), 9.03 (s, lH), 9.32 (s, 1H), 11.34 (s, 1H).
Beilstein J. Org. Chem. 2013, 9, 2265–2319.
http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-9-265
GlaxoSmithKline's lapatinib (3.38, Tykerb) is a novel dual kinase inhibitor used in the treatment of solid tumors such as those found in breast cancer and contains a quinazoline core structure. It consists of a 2,5-disubstituted furan ring, which is directly linked to the aminoquinazoline unit (Scheme 41). The quinazoline heterocycle was prepared starting from 5-iodoanthranilic acid (3.72) via initial condensation with formamidine acetate (3.73) followed by chlorination using oxalyl chloride or phosphorous oxychloride [101]. Performing a nucleophilic aromatic substitution on the chloride 3.74 with aniline 3.75renders the extended core of lapatinib. This intermediate (3.76) was then coupled with 5-formyl-2-furanoboronic acid (3.77) using standard Suzuki cross-coupling conditions. Finally, a reductive amination of the pendant aldehyde of3.78 with 2-(methylsulfonyl)ethylamine (3.79) furnishes the desired product lapatinib (Scheme 41).
Scheme 41: Synthesis of lapatinib.
get ref from
Guntrip SB, Lackey KE, Cockerill GS, Carter MC, Smith KJ Bicyclic heteroaromatic compounpds as protein tyrosine kinase inhibitors. EP 1047694; WO 9935146.
Quinazoline ditosylate salt compounds (US7157466)
A NOVEL PROCESS FOR THE PREPARATION OF Lapatinib AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS ( WO 2010061400)
Fresenius Kabi Oncology Ltd.WO 2013080218
Lahiri, Saswata; Gupta, Nitin; Singh, Hemant Kumar; Handa, Vishal; Sanghani, Sunil
6 JUNE 2013, http://www.google.com/patents/WO2013080218A1?cl=en
Lapatinib of Formula-(II), was first disclosed by SmithKline Beecham in US Patent No. 6,727,256.
The process for the preparation of Lapatinib of Formula-(II), disclosed in W099/35146, is given in the Scheme-I. Accordingly, 4-chloro-6-iodo-quinazoline of Formula-(IV), is reacted with 3-chloro-4-(3′-fluoro-benzyloxy)-aniline yielding N-[3- chloro-4-{(3′-fluorobenzyloxy) phenyl} ]-6-iodo-quinazoline of Formula-( l). The compound of the Formula-(l) reacts with 5-(l,3-dioxolan-2-yl)-2-(tributylstannyl)furan to get the compound of Formula-(2) which on deprotection with HC1, removes the 1,3- dioxolan-2-yl protecting group and liberates 5-(4-{3-chloro-4-(3-fluoro- benzyloxy)anilino}-6- quinazolinyl)-furan-2-carbaldehyde of Formula-(3). The compound of the Formula-(3) on reaction with 2-methanesulfonylethylamine, followed by reductive amination using sodium (triacetoxy)borohydride as the reducing agent gives the required compound Lapatinib of Formula-(II) as an organic residue, which is purified by column chromatography and subsequently converted into its hydrochloride salt (5).
Subsequently, US 7, 157,466 also discloses the preparation of Lapatinib and its ditosylate salt, which is given in Scheme-II.
Lapatinib ditosylate has been prepared by reacting the tosylate salt of 5-(4-[3- chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde of Formula (3) with 2-(methylsulfonyl)ethylamine in the presence of base (diisopropyl- ethylamine) followed by reduction with sodium triacetoxyborohydride to obtain Lapatinib base which is converted to Lapatinib ditosylate anhydrate by adding para- toulenesulfonic acid. Conversion to Lapatinib ditosylate monohydrate is carried out using THF/H20. Intercon vers ion to the anhydrate of the ditosylate salt and back to monohydrate is carried out with methanol and water respectively.
(lla)
WO201 1039759, filed by Natco Pharma also describes a process for the preparation of Lapatinib from 2-amino benzonitrile, as given in scheme-Ill. Firstly, 2- aminobenzonitrile (6) is reacted with iodine monochloride in acetic acid medium to form compound of Formula (7) which is recrystallized from mixture of hexane and toluene. The compound of Formula (1) is reacted with N,N-dimethylformamide dimethy|acetal in an organic solvent such as toluene or xylene to form novel compound of Formula (8). The compound of Formula (7) is then coupled with compound of Formula (8) in presence of acid catalyst such as trifluoroacetic acid, formic acid or acetic acid to form compound of Formula (3). The compound of Formula (3) is the subjected to Suzuki coupling with 5-formyl-2-furyl boronic acid in ethereal solvent in the presence of catalyst selected from palladium (II) acetate, palladium (II) chloride, and palladium on carbon to form aldehyde compound of Formula (4). The compound of Formula (4) is reacted with 2-methanesulphonyl ethylamine or its salt to produce imine compound of Formula (VI) which is reduced with sodium borohydride to form Lapatinib base (II). The crude Lapatinib base is purified by crystallization from organic solvents. The purified Lapatinib base is converted into Lapatinib ditosylate anhydrous by treating Lapatinib base in organic solvent with /7-toluenesulfonic acid monohydrate which is then recrystallized from aqueous alcohol to produce pharmaceutically acceptable Lapatinib ditosylate monohydrate. The process is depicted in Scheme-Ill.
-IH
Lapatinib (II) WO2010017387, filed by Teva relates to Lapatinib intermediates and process for the preparation of Lapatinib base and Lapatinib ditosylate. The application relates to highly pure intermediate of Formula (2), 3-chloro-4-(3-fluorobenzyloxy)aniline which is prepared by reducing a compound of Formula (1), 3-chloro-4-(3- fluorobenzyloxy)nitrobenzene, with iron and ammonium chloride system in the presence of a C1 -C4 alcohol and water at refluxing temperature. The application also relates to highly pure intermediate of Formula (3), N-[3-chloro-4-(3-fluorobenzyloxy)- phenyl]-6-iodoquinazolin-4-amine, which is prepared in one-pot process from compound of Formula (1 ) by reduction using iron and ammonium chloride system in presence of C1 -C4 alcohol and water. The compound of Formula (3) is reacted with 5- formyl-2-furanboronic acid in the presence of a palladium catalyst and a base in a polar organic solvent to obtain Lapatinib aldehyde base, compound of Formula (4). Optionally, Lapatinib aldehyde base is combined with /? oluenesulfonic acid to obtain Lapatinib aldehyde monotosylate, compound of Formula (5). The invention further provides a process for the preparation of Lapatinib base. Lapatinib aldehyde base or its salt is combined with methylsulfonylethylamine or its hydrochloride salt, acetic acid, an inorganic base in an organic solvent and a reducing agent (sodium triacetoxyborohydride) to form Lapatinib base. Lapatinib base is further purified by using organic solvents. Lapatinib base obtained is further converted to Lapatinib ditosylate. The process is depicted in scheme-IV.
Scheme-IV
Example-5
Preparation of Lapatinib Ditosylate
To a stirred mixture of Sodiumtriacetoxyborohydride (0.21 g) in Tetrahydrofuran (THF)(2.4 ml) was added N-(3-Chloro-4-(3-fluorobenzyloxy)phenyl)-6-(5-((2- (methylsulfonyl)ethylimino)- methyl)furan-2-yl)quinazolin-4-amine (0.2 g) in THF. The reaction mixture was stirred for 1 hour at 20-25 °C. Reaction was monitored by TLC and on completion of reaction, aqueous NaQH (0.16 g NaOH to 0.8 g demineralized water) was added. The organic layer was separated and added p- Toluenesulfonic acid (0.42) in THF (0.6 ml) and stirred for 3 hours. The solid was filtered and dried under vacuum at 60-65°C till constant weight.
Weight: 0.15 g
Yield: 46.9 %
Purity by HPLC: 96.16%
MS (ES+) m/z: 581 [M+H]+ & 583 [M+H+2]+
1H NMR (400 MHz; DMSO-d6): 2.28 (s, 6H), 3.14 (s, 3H), 3.44 (t, J=8.0 Hz, 2H), 3.55 (t, J=8.0 Hz, 2H), 4.46 (s, 2H), 5.31 (s, 2H), 6.89 (br s, 1H), 7.10 (d, J=7.2 Hz, 4H), 7.20 (m, 1H), 7.23 (br s, 1H), 7.31- 7.36 (m, 3H), 7.47 (d, J=7.2 Hz, 4H), 7.63 (d, J=8.8 Hz, IH), 7.89 (br s, IH), 7.92 (d, J=8.8 Hz, IH), 8.39 (d, J=8.8 Hz, IH), 8.89 (s, IH), 8.98 (s, IH), 9.28 (s, IH, NH), 11.18 (s, IH, NH).
http://www.google.com/patents/WO2008024439A2?cl=en
http://www.google.co.in/patents/US7157466
The free base and HCl salts of the compounds of Formulae (I), (II), (III), and (IV), may be prepared according to the procedures of International Patent Application No. PCT/EP99100048, filed Jan. 8, 1999, and published as WO 99/35146 on Jul. 15, 1999, referred to above. A schematic of such procedures is presented in Scheme A following. The specific page references given are to WO 99/35146. The free base of the compound of formula II is used as an example of the general scheme.
The compound of formula (II), i.e., N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl) ethyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate has been prepared in two distinct forms, an anhydrate form (Formula II′ in Scheme B) and a monohydrate form (Formula II″ in Scheme B). The relationship of these forms is illustrated in Scheme B below. The anhydrate form of N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate may be prepared by (a) reacting the tosylate salt of 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde (formula B in Scheme B) with 2-(methylsulfone)ethylamine in tetrahydrofuran in the presence of diisopropyl-ethylamine followed by (b) the introduction of this solution into to a slurry of sodium triacetoxyborohydride in tetrahydrofuran at room temperature, (c) adding 5N sodium hydroxide to adjust the pH to within a range of 10–11, (d) separating the organic tetrahydrofuran phase, and then (e) adding para-toulenesulfonic acid hydrate to the organic phase to provide the ditosylate anhydrate. Interconversion to the monohydrate and back to the anhydrate of the ditosylate salt compounds of the invention is as depicted in Scheme B. The tosylate salt of 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde is prepared from the HCl salt of the carbaldehyde (Formula A of Scheme B). Preparation of N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate and the anhydrate and monohydrate forms thereof are utilized as an example. As recognized by those skilled in the art, other compounds of formula I and anhydrate and hydrate forms thereof may be prepared by similar methods.
Compound A of Scheme B may be prepared by various synthetic strategies, other that the strategy recited in Scheme A above, utilizing the palladium(O) mediated coupling of quinazoline and substituted furan intermediates.
Preparation of N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate anhydrate (Anhydrate Form of Compound of Formula II)
To a 20 L reactor was added 13.3 vol of THF followed by 0.62 wt (2.93 mol) of NaBH(OAc)3. The 20 L reactor was set to maintain contents at 20° C. A second 20 L reactor was charged with 1000 grams, (1.55 mol) of 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde 4-methyl benzenesulfonate prepared by the procedure of Example 7 and 6.7 vol of THF. To the THF solution of 5-(4-[3-chloro-4-(3-fluorobenzyloxy)-anilino]-6-quinazolinyl)-furan-2-carbaldehyde 4-methylbenzenesulfonate was added 0.325 vol (1.86 mol) diisopropylethylamine followed by 0.32 wt of 2-(methylsulfone)ethylamine, (321 g, 2.6 mol) and 0.15 vol of IPA. After 1 hour, the preformed imine/THF solution was transferred by vacuum to the stirred suspension of NaBH(OAC)3 in the first 20 L reactor over 10 minutes. After 90 minutes, 4 vol of 5N NaOH was added over 40 min via a pump. This solution was allowed to stir for 15 minutes after which the stirrer was switched off and the layers were allowed to separate. The aqueous layer was drained from the bottom of the reactor and the organic layer transferred to the empty 20 L reactor through a teflon-lined stainless steel jacketed transfer hose outfitted with an in-line 0.45 μm filter. To this solution was added a 2 vol THF solution of 4 wt (1180 g, 6.2 mole) of p-toluenesulfonic acid monohydrate over 5 min. A yellowish precipitate was observed to come out of solution and this was allowed to stir at room temperature for 12 hours. The reaction was drained from the bottom of the reactor and filtered through a ceramic filter lined with paper. The yellow filter cake was washed with 1 vol of a 95:5 THF water solution and allowed to air dry overnight. After suctioning dry for 12 hours, the yellow filter cake was transferred to two glass trays and placed in the drying oven (42° C.) under house vacuum (18 in Hg) with a nitrogen bleed. The two glass trays were removed from the oven and allowed to cool to room temperature and sampled accordingly. The isolated yield of N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methane-sulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate (anhydrate) was 1264 grams (1.3 wt, 88%; 1443 g Th) and was a yellow solid.
Approximately 50 mg of the product was transferred to a Karl Fisher Volumetric Moisture Apparatus (model DL35, Mettler, Hightstown, N.J.), which was operated according to the manufacturer's instructions. The anhydrate water content was determined to be 0.31%.
Example 10Preparation of N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate monohydrate (Monohydrate Form of Compound of Formula II)
A 20 L reactor was charged with 1 wt (930 g, 1.0 mol) of N-{3-Chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine ditosylate anhydrate prepared using the procedure of Example 8. To this was added 10 volumes of a pre-mixed 8:2 THF:deionized water solution and the reactor was heated to 65° C. Complete dissolution was observed at 50° C. The clear reaction mixture was transferred to another 20 L reactor through a stainless steel jacketed transfer hose that was equipped with an in-line 5.0 μm cartridge filter. The empty 20 L reactor and the filter line were washed with 0.2 vol of the pre-mixed 8:2 THF:deionized water solution. An additional 1 vol of pre-mixed 8:2 THF:deionized water solution was used to wash the material into the reaction mixture. The 20 L reactor was heated to ˜80° C. The reaction temperature was then ramped down to 55° C. over 2 hours and then to 45° C. over 10 hours. After 10 hours, the temperature was adjusted to 25° C. and the reaction mixture allowed to stir at room temperature for 45 minutes. The yellow precipitate was drained from the bottom of the 20 L reactor into a ceramic filter lined with paper. The flow was fast and smooth and the filter rate very good. The yellow filter cake was washed with 0.6 volumes of a pre-mixed 8:2 THF:deionized water solution and the yellow solid was air dried for 4 hours and placed into a glass tray. The glass tray was placed in a vacuum oven under house vacuum (˜18 in Hg) at 60° C. with a nitrogen bleed for 2 days. After removal from the oven, the material was sampled accordingly. The yield was 743 grams (0.8 wt, 80%; 930 g th) as a bright yellow, crystalline solid.
Approximately 50 mg of the product was transferred to a Karl Fisher Volumetric Moisture Apparatus (model DL35, Mettler, Hightstown, N.J.), which was operated according to the manufacturer's instructions. The monohydrate water content was determined to be 1.99%, which is in agreement with the theoretical value of 1.92%.
Literature References:
Reversible dual inhibitor of ErbB1 and ErbB2 tyrosine kinases. Prepn: M. C. Carter et al., WO 9935146(1999 to Glaxo); eidem, US6727256 (2004 to SmithKline Beecham).
Mechanism of action study: W. Xia et al., Oncogene 21, 6255 (2002); and crystal structure in complex with epidermal growth factor receptor (EGFR, ErbB1): E. R. Wood et al., Cancer Res. 64, 6652 (2004).
In vitro antitumor activity in combination with anti-ErbB2 antibodies: W. Xia et al., Oncogene 24, 6213 (2005). Biologic effects on tumor growth: N. L. Spector et al., J. Clin. Oncol. 23, 2502 (2005).
Pharmacokinetics and clinical activity in metastatic carcinomas: H. A. Burris III et al., ibid. 5305.
Review of clinical development: T. E. Kim, J. R. Murren, IDrugs6, 886-893 (2003); H. A. Burris III, Oncologist 9, Suppl. 3, 10-15 (2004).
Lapatinib Ditosylate [USAN]
Lapatinib ditosylate monohydrate
Tykerb
Tyverb
UNII-G873GX646R
KS-1300; 388082-78-8
N-(3-Chloro-4-((3-fluorobenzyl)oxy)phenyl)-6-(5-(((2-(methylsulfonyl)ethyl)amino)methyl)furan-2-yl)quinazolin-4-amine bis(4-methylbenzenesulfonate) monohydrate
Dosages/Routes/Forms
Active Ingredient(s)
Form/Route
TE Code
TYKERB LAPATINIB DITOSYLATE EQ 250MG BASE TABLET;ORAL 1 1
Approval History
Efficacy Supplement with Clinical Data to Support
Labeling Revision
New or Modified Indication New or Modified Indication
Derivative Type: Ditoluenesulfonate monohydrate
CAS Registry Number: 388082-78-8; 388082-77-7 (anhydrous)
Additional Names: Lapatinib ditosylate
Manufacturers' Codes: GW-572016F
Molecular Formula: C29H26ClFN4O4S.2C7H8O3S.H2O
Percent Composition: C 54.74%, H 4.70%, Cl 3.76%, F 2.01%, N 5.94%, O 18.65%, S 10.20%
Properties: Yellow solid.
Therap-Cat: Antineoplastic.
Keywords: Antineoplastic; Tyrosine Kinase Inhibitors.
Burris HA (2004). "Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ErbB-2 inhibitor lapatinib". Oncologist. 9 Suppl 3: 10–5.doi:10.1634/theoncologist.9-suppl_3-10. PMID 15163842.
Higa GM & Abraham J (September 2007). "Lapatinib in the treatment of breast cancer". Expert Review of Anticancer Therapy (log in required) (Future Drugs) 7(9): 1183–92. doi:10.1586/14737140.7.9.1183. PMID 17892419.
Pazdur, Richard (14 January 2011). "FDA Approval for Lapatinib Ditosylate".Womens Health (Lond Engl) (Cancer.gov) 6 (2): 173. doi:10.2217/whe.10.11.PMID 20187722.
^ Jump up to:a b c d "GlaxoSmithKline receives marketing authorisation in the EU for Tyverb (lapatinib), the first oral targeted therapy for ErbB2-positive breast cancer" (Press release). GlaxoSmithKline. 2008-06-12. Retrieved 2008-06-21.
^ Jump up to:a b c "GlaxoSmithKline Reports Positive New Data On Tykerb (lapatinib) At The 2007 American Society Of Clinical Oncology (ASCO) Annual Meeting" (Press release). Medical News Today. June 4, 2007. Retrieved December 2, 2008.
"Data Sheet: TYKERB". Medsafe. New Zealand Medicines and Medical Devices Safety Authority. March 12, 2008. Retrieved December 2, 2008.
Jump up^ Kulkarni, Kaustubh (2 August 2013). "India revokes GSK cancer drug patent in latest Big Pharma blow". Reuters (Mumbai, India: Reuters). Retrieved 2 August 2013.
Wood, ER, Truesdale, AT, McDonald, OB, Yuan, D, Hassell, A, Dickerson, SH, Ellis, B, Pennisi, C et al. (2004). "A unique structure for epidermal growth factor receptor bound to GW572016 (Lapatinib): relationships among protein conformation, inhibitor off-rate, and receptor activity in tumor cells". Cancer Research 64 (18): 6652–9. doi:10.1158/0008-5472.CAN-04-1168. PMID 15374980.
Dr. Angel Rodriguez (April 2008). "New type of drug shrinks primary breast cancer tumors significantly in just six weeks; research provides leads to a new target in cancer treatment – the cancer stem cell".
Nelson MH, Dolder CR (February 2006). "Lapatinib: a novel dual tyrosine kinase inhibitor with activity in solid tumors". Ann Pharmacother 40 (2): 261–9.doi:10.1345/aph.1G387. PMID 16418322.
Jump up^ Geyer CE, Forster J, Lindquist D, et al. (December 2006). "Lapatinib plus capecitabine for HER2-positive advanced breast cancer". N. Engl. J. Med. 355 (26): 2733–43.doi:10.1056/NEJMoa064320. PMID 17192538.
J Burris HA, Hurwitz HI, Dees EC, et al. (August 2005). "Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas". J. Clin. Oncol. 23 (23): 5305–13.doi:10.1200/JCO.2005.16.584. PMID 15955900.
J NCI Cancer Drug Information. FDA Approval for Lapatinib Ditosylate (Tykerb®). Retrieved 27 January 2014.
|url=http://www.bioportfolio.com/news/article/1492867/GSK-Tykerb-Tyverb-Phase-III-gastric-cancer-study-fails-to-meet-primary.html
Lapatinib Ditosylate – National Cancer Institute
Canadian drug touted for advanced breast cancer
WO1999035146A1 Jan 8, 1999 Jul 15, 1999 Glaxo Group Ltd Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
WO2010017387A2 Aug 6, 2009 Feb 11, 2010 Teva Pharmaceutical Industries Ltd. Lapatinib intermediates
WO2011039759A1 Sep 29, 2009 Apr 7, 2011 Natco Pharma Limited A new process for the preparation of lapatinib and its pharmaceutically acceptable salts
US6727256 Jan 8, 1999 Apr 27, 2004 Smithkline Beecham Corporation 4-aminoquinazoline derivatives as anticarcinogenic agents
US7157466 Jun 28, 2001 Jan 2, 2007 Smithkline Beecham (Cork) Limited Quinazoline ditosylate salt compounds
WO1998002434A1 * Jul 11, 1997 Jan 22, 1998 Malcolm Clive Carter Fused heterocyclic compounds as protein tyrosine kinase inhibitors
WO2007121279A2 * Apr 12, 2007 Oct 25, 2007 Tona Morgan Gilmer Cancer treatment method
Tags: lapatinib
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text:
Facebook opens Instant Games to all developers
Sarah Perez	@sarahintampa / 4 years
Facebook's Instant Games are now open to all developers, Facebook announced this week in advance of the Game Developers Conference. First launched in 2016, the platform lets developers build mobile-friendly games using HTML5 that work on both Facebook and Messenger, instead of requiring users to download native apps from Apple or Google's app stores.
The Instant Games platform kicked off its launch a couple of years ago with 17 games from developers like Bandai Namco, Konami, Taito, Zynga and King, who offered popular titles like Pac-Man, Space Invaders, and Words with Friends. The following year, the platform had grown to 50 titles and became globally available. But it wasn't open to all – only select partners.
In addition to getting users to spend more time on Facebook's platform, Instant Games provides Facebook with the potential for new revenue streams now that Facebook is moving into game monetization.
In October, Facebook said it would begin to test interstitial and rewarded video ads, as well as in-app purchases. The tools were only available to select developers on what was then an otherwise closed platform for Facebook's gaming partners.
Now, says Facebook, all developers can build Instant Games as the platform exits its beta testing period.
Alongside this week's public launch, Facebook introduced a handful of new features to help developers grow, measure and monetize their games.
This includes the launch of the ads API, which was also previously in beta.
In-app purchases, however, are continuing to be tested.
Developers will also have access to Facebook's Monetization Manager, where they can track manage ads and track how well ad placements are performing; as well as a Game Switch API for cross-promoting games across the platform, or creating deep links that work outside Facebook and Messenger.
Facebook says it also updated how its ranking algorithm surfaces games based on users' recent play and interests, and updated its in-game leaderboards, among other things.
Soon, Instant Game developers will be able to build ad campaigns in order to acquire new players from Facebook. These new ad units, when clicked, will take players directly into the game where they can begin playing.
Since last year, Facebook Instant Games have grown to nearly 200 titles, but the company isn't talking in-depth about their performance from a revenue perspective.
It did offer one example of a well-performing title, Basketball FRVR, which is on track to make over 7-digits in ad revenue annually, and has been played over 4.2 billion times.
With the public launch, Facebook is offering Instant Games developer documentation page and a list of recommended HTML5 game engines to help developers get started. Developers can then build and submit games via Facebook's App page.


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Shellfish Growers Network helps oyster farmers produce more oysters in the Chesapeake Bay
Justina Coronel,
The Chesapeake Bay isn't what it used to be and it needs some help.
Right now, the oyster population is down about two percent from where it should be. We're told the last 40-50 years, it's been crashing through disease and over harvesting.
That's why the Chesapeake Bay Foundation (CBF) is reeling in some help to meet a goal: planting 10 billion oysters by 2025.
And that's where the Shellfish Growers Network comes in. "This is a great opportunity for these shellfish growers to learn from each other how to oyster farm, the tips and tricks to getting about it done in the water, what are the ways to get in product to market," Alan Girard, CBF Eastern Shore Director tells us.
The Shellfish Growers Network will help educate newer farmers. Madhouse Oysters, who's in the network says, they're ready to give some pearls of wisdom.
Owner Ted Cooney gives us one tip, "Knowing that every location that you farm oysters in is different. The bottom around this building is different than the bottom of another building. One clear difference would be the depth of the water. The area where you have your farm determines a lot of the processes and we can guide people in that."
Madhouse says they have plenty of tips to help growers be successful. We are told they have a great combination of skills and abilities. Beyond that, "When we need to have a piece of equipment, we try to make it ourselves, it saves a lot of money."
We're told the industry has shifted from wild harvest fishers to oyster farming, which means instead of going out and picking oysters, farmers are now planting oysters in a controlled environment. This has been quite a change for the industry.
This network will help anyone run through this new process. Besides that, the Chesapeake Bay Foundation hopes to grow oyster farming by 15% every year and hope that newcomers will join the network to continue growing the industry.
Categories: Check It Out, Local News, Local Politics, Maryland
Tags: chesapeake bay foundation, fishing creek, hoopers island, madhouse oysters, maryland, shellfish growers network
The 19-year-old pilot Zara Rutherford lands in Belgium, sets world record as youngest woman to fly solo around the world
Report faults retired Pope Benedict XVI for his handling of sexual abuse cases when he was an archbishop in Germany
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Can we have our history back?
You know, the story we all used to have by heart, of how our liberties were founded by Magna Carta, of defeating the Armada, of the Civil War, the Restoration, the Glorious Revo lution and the Golden Age that followed, of victory abroad and peace and prosperity at home?
There's time enough in later life to find out that the reality is more complicated.
by geography and nature, developing in two small islands one of the greatest civilisations the world has ever seen, based on individual liberty. Who wouldn't be proud and pleased to be living in such a place?
And who – knowing these things – wouldn't instinctively stand and defend those liberties against insolent authority, panic-mongering morons trying to make our flesh creep with exaggerated tales of terror, numbskull Ministers who can't see why Habeas Corpus matters, wooden-headed coppers who want to be continental gendarmes, demanding our papers?
To be deprived of this knowledge is to be like the beneficiary of a generous will, whose wicked stepfather keeps him from knowing that this document, which could change his life for ever, is locked away in a safe.
I would have liked my own children to learn such proper history, except that by the time I found out the sort of confusing, demoralising trash that passes for history in today's schools, it was too late.
As I gazed in disgust at the feeble, babyish pamphlets – designed in many cases to undermine the version I was taught – and scraps of photocopied paper which nowadays do the duty of textbooks, I wondered what had become of the histories I had studied.
They had vanished in some vast Sixties bonfire, in many ways as bad as Hitler's book burnings, part of the great destruction of knowledge and continuity that took place in that accursed decade.
The revolutionaries knew that one of the things they had to destroy was the decent, modest patriotism that had until then been pretty much universal. How better to do that than to slander our past and conceal it?
Now, the publishers Stacey International have had the superb idea of reprinting the fine, elegantly written school histories of Carter and Mears, whose rediscovered pages took me back in an instant to a long-ago classroom.
Reading them now, I find many things that I had forgotten come to life again in my memory.
My only worry is this. That our young have been so deprived of the background to this history that they may not be able to make sense of it.
The voices of the past are drowned out by TV and computer slurry. The memories of grandparents are ignored or never discussed.
The village churches are locked and disused.
Hideous new build ings and brutal modernisers have obliterated or obscured what Philip Larkin called our 'guildhalls and carved choirs' and the other great monuments that used to make a walk down a British street a history lesson.
I hope not. Poor Poland, wiped from the map by the two worst tyrannies in history, its cities and culture utterly destroyed and its best men and women massacred and thrown into pits, recovered in a generation.
Our fate is nothing like as bad. We can recover what was lost. Make sure your children read these books, and encourage this fine enterprise.