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Monday 27 June 2016

EFAVIRENZ





 



 Figure 1




 EFAVIRENZ





Spectrum Plot

Fig . 1H NMR spectrum of C14H9ClF3NO2 in CDCL3 at 400 MHz.

Shifts

Index Name Shift (ppm)
24 H2 6.912
22 H3 7.513
18 H4 8.406
1 H9 0.541
3 H8 0.607
5 H5 1.350
9 H7 0.623
8 H6 0.535

Couplings

Index 1 Index 2 Coupling (Hz)
1 3 -4.50
1 5 6.15
1 8 9.00
1 9 6.39
3 5 8.95
3 8 6.35
3 9 9.00
5 8 6.03
5 9 8.96
8 9 -4.50
14 15 160.00
14 16 160.00
15 16 160.00
18 22 1.70
18 24 0.60
22 24 7.50

 Figure 1


PAPER

Correia et al. have published a three-step flow synthesis of rac-Effavirenz. This short synthetic route begins with cryogenic trifluoroacetylation of 1,4-dichlorobenzene. After quench and removal of morpholine using silica gel, this intermediate could either be isolated, or the product stream could be used directly in the next alkynylation step. Nucleophilic addition of lithium cyclopropylacetylide to the trifluoroacetate gave the propargyl alcohol intermediate in 90% yield in under 2 min residence time. This reaction was temperature-sensitive, and low temperatures were required to minimize decomposition. Again silica gel proved effective in the quench of the reaction. However, residual alkyne and other byproducts were difficult to remove. Thus, isolation of this intermediate was performed to minimize the impact of impurities on the final copper catalyzed cyanate installation/cyclization step to afford Effavirenz. Optimization of this step in batch mode for both copper source and ligand identified Cu(NO3)2 and CyDMEDA in a 1:4 molar ratio (20 mol % and 80 mol %, respectively) produced the product in 60% yield. Adaptation of this procedure to flow conditions resulted in poor conversion due to slow in situ reduction of the Cu(II) to Cu(I). Thus, a packed bed reactor of NaOCN and Cu(0) was used. Under these conditions, the ligand and catalyst loading could be reduced without compromising yield. Due to solubility limitations of Cu(NO3)2, Cu(OTf)2 was used with CyDMEDA in 1:2 molar ratio (5 mol % and 10 mol % loading, respectively). Under these optimized conditions, rac-Effavirenz was obtained in 62% isolated yield in reaction time of 1 h. This three-step process provides 45% overall yield of rac-Effavirenz and represents the shortest synthesis of this HIV drug reported to date
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1H NMR (400 MHz, CDCl3, ppm) δ9.45 (s, 1H), 7.49 (s, 1H), 7.35 (dd, J = 8.5, 1.5 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 1.43-1.36 (m, 1H); 0.93-0.85 (m, 4H);
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13C NMR (100 MHz, CDCl3, ppm) δ 149.2, 133.2, 131.7, 129.2, 127.8, 122.1 (q, JC-F = 286 Hz), 116.3, 115.1, 95.9, 79.6 (q, JC-F = 35 Hz), 66.1, 8.8, 0.6;
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19F NMR (376 MHz, CDCl3, ppm) δ -80.98.
1 T. J. Connolly; A. W.-Y Chan; Z. Ding; M. R. Ghosh; X. Shi; J. Ren, E. Hansen; R. Farr; M. MacEwan; A. Alimardanov; et al, PCT Int. Appl. WO 2009012201 A2 20090122, 2009.
2 (a) Z. Dai, X. Long, B. Luo, A. Kulesza, J. Reichwagen, Y. Guo, (Lonza Ltd), PCT Int. Appl. WO2012097510, 2012; (b) D. D. Christ; J. A. Markwalder; J. M. Fortunak; S. S. Ko; A. E. Mutlib; R. L. Parsons; M. Patel; S. P. Seitz, PCT Int. Appl. WO 9814436 A1 19980409, 1998 (c) C. A. Correia; D. T. McQuade; P. H. Seeberger, Adv. Synth. Catal. 2013, 355, 3517−3521.








A Concise Flow Synthesis of Efavirenz

  • DOI: 10.1002/anie.201411728
SUPP INFO
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 PAPER\


 






 



J. Braz. Chem. Soc. vol.24 no.4 São Paulo Apr. 2013

http://dx.doi.org/10.5935/0103-5053.20130071 

 http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532013000400007


 PAPER



 


 

 http://jpharmsci.org/article/S0022-3549(15)00007-6/abstract



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 Jeju,  South Korea, jeju islands


Map of jeju island
Jeju Province
Do
Jeju, a South Korean island in the Korea Strait, is defined by its volcanic landscape full of craters and cavelike lava tubes. Hallasan Mountain, a dormant volcano visible throughout the island, features hiking trails, nearby Gwaneumsa Temple and a crater lake at the 1,950m summit. The Geomunoreum Lava Tube System includes 7.4km-long Manjanggul, created centuries ago when Hallasan was still active.
 
 
 
 
 

 

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With easy to access dormant volcanoes, hearty seaside fare and a panoply of hiking trails that redefine contemporary notions of exploration, Jeju Island has much to offer the modern day adventurer seeking challenge, delight and cause to reflect.
There’s an array of choices, thanks to a bounty of natural treasures and a seemingly unstoppable train of commercial development, so making a checklist of priorities can seem overwhelming.
Sunrise Peak at Ilchul-bong tuff cone. Image by Michael Runkel / Getty Images Sunrise Peak at Ilchul-bong tuff cone. Image by Michael Runkel / Getty Images
Here is our list of recommended destinations and local food that deliver the essential Jeju-do experience.

1. Climb a volcano

Wake up 90 minutes before dawn and follow the path to the peak of Seongsan Ilchul-bong, a dormant volcano on the east coast of Jeju.
Seongsan Ilchul-bong makes for a great volcano climb. Image by Rob Whyte / Lonely Planet Seongsan Ilchul-bong makes for a great volcano climb. Image by Rob Whyte / Lonely Planet
Most people complete the steep 182-metre hike in about 25 minutes. Once at the top, grab a seat on the crater ridge, watch the sunrise and ponder the majesty of nature.

2. Walk Olle

Perhaps the best way to explore rural Jeju is to walk any of the Olle trails. In traditional Jeju dialect, Olle is the narrow path running from one’s front door to the street. Today, Olle refers to an integrated network of 26 well-marked hiking paths that spider across the island.
Vast views of the Jeju countryside from the Olle trail. Image by Rob Whyte / Lonely Planet Vast views of the Jeju countryside from the Olle trail. Image by Rob Whyte / Lonely Planet
Trail lengths vary between seven and 23 kilometres long, each offering an up-close connection with the land and people. Stroll farm roads trimmed by tangerine orchards, zigzag through narrow alleys passing humble homes with straw-thatched roofs and traverse rocky coastlines carved out of black lava rock.

3. Sunset on Hyeopjae Beach

With cobalt seas rippling alongside nine kilometres of soft white sand intermittently spliced by fingers of black lava rock, Hyeopjae in Hallim Village is arguably Jeju’s most scenic beach. Sure it’s a busy place in the summer, when families come to frolic in the waist-deep water, but it’s pretty quiet the rest of year. The real charm of this place, however, appears at dusk. Hugging the northwest corner of the island, it’s an ideal location to be still and admire the sunset.

4. Take the Halla Mountain challenge

Visible from every corner of the island when skies are clear, majestic Halla Mountain beckons.
Excellent walking trails lead up Halla Mountain. Image by Sungsub Jang / CC BY 2.0 Excellent walking trails lead up Halla Mountain. Image by Sungsub Jang / CC BY 2.0
Though not everyone might be equipped to challenge the 1950m summit via a 9km (five hours one-way) hike, there are less demanding trail options (ranging from 30 minutes to 3.5 hours) that deliver the Halla experience. Expect magnificent foliage, awe inspiring rock formations and hordes of fashionable hikers sporting the absolute latest in alpine gear.

5. Savour the simple fare

Jeju's food is mightily influenced by flavours from the sea, like haemul tang, a humble hot pot filled with shrimp, crab, clams and a host of delicious fish in a semi-clear seafood broth.
Haemul tang - Jeju's spicy seafood stew. Image by Rob Whyte / Lonely Planet Haemul tang - Jeju's spicy seafood stew. Image by Rob Whyte / Lonely Planet
Local variations supplement the colour and taste with scrumptious specialties like squash or seaweed. Served with seasonal vegetables and a bowl of rice, it’s eaten for lunch or dinner but even makes a hearty breakfast.

6. Stroll Lee Jung-Seop art street in Seogwipo

There’s an artistic zeitgeist on Jeju that’s quite apart from anything on the Korean mainland. Architecturally, this arty trend is evident in the use of pastel colours, asymmetrical lines and a considerable reliance on floor-to-ceiling glass walls that allow a connection with the beautiful natural environment. Artistically, that sensibility comes alive on Seogwipo’s Lee Jung-Seop Art Gallery & Park, an arty neighborhood packed with craft shops, chilled-out beer bars and Bauhaus-styled restaurants. Not to be missed is Architecture Cafe Utopia (409-10 Taepyeong-ro, Seogwipo City; +82 064-762-2597), an inspired multi-level complex that’s equal parts coffee shop, beer bar, art gallery and tree fort.

7. Meet Buddha in a cave in Sagae

Enlightenment doesn’t come easy. That’s the lesson to learn on a trip to Sanbang-gul-sa, a tiny but thoroughly intriguing Buddhist temple in the town of Sagye-ri on the island’s southwest corner.
Sanbang-gul-sa's cave Buddha. Image by Rob Whyte / Lonely Planet Sanbang-gul-sa's cave Buddha. Image by Rob Whyte / Lonely Planet
From the town centre, it’s a 2km walk to the base of Sanbang-san, an enormous rock formation jutting out of the earth, and another 150m up steep stairs that eventually lead to a cave housing a Buddha statue. Up top, fetch a drink from the pool of water, light a stick of incense and admire the view from this very special place.

8. Discover the unexpected on U-do

U-do, a 15-minute ferry ride off the northeast coast of Jeju, is a smaller island blessed with spectacular coastlines and serendipitous delights. Most travellers come for a day-trip to explore the rocky coast but an overnight stay provides a more reasonable amount of time to uncover its hidden spots. There’s decadent peanut butter ice cream, nourishing seaweed soup and oh-so-juicy hamburgers prepared by a gracious woman who operates a delightfully eccentric museum housing a nearly complete collection of Anne of Green Gables memorabilia, including a 1908 first edition by Lucy Maud Montgomery.

9. Sample barbecued black pork

It’s hard to say you fully experienced Jeju without trying the island’s most famous dish – barbecued black pork – which is available in every city and village on the island. In years gone by, this domestic creature was fed a steady supply of human waste, a practice thought to enhance the meat’s taste and texture. Thankfully, that practice ended several decades ago. Today, Koreans typically opt for a fatty cut called samgyupsal, while those who prefer lean order moksal. Cook slowly over charcoal briquettes and season with salt and black pepper on the grill for maximum flavour.

10. Time travel at Seongup Folk Village

Traditional architectural designs are alive and open for exploration at Seongeup Folk Village, about an hour outside Jeju City.
Traditional homes at Seongup Folk Village. Image by Rob Whyte / Lonely Planet Traditional homes at Seongup Folk Village. Image by Rob Whyte / Lonely Planet
Weave your way through narrow lanes and peek inside restaurants and shops amidst plumes of smoke from wood burning stoves. If time permits, set aside an hour for dinner at Gwandangnae Sikdang, a tiny restaurant outside the main gate; cramped, crowded and convivial, it’s the ultimate rustic Jeju barbecued meat experience.

 


 

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