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 |
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
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);
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;
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.
SUPP INFO
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=S0103-50532013000400007PAPER
http://jpharmsci.org/article/S0022-3549(15)00007-6/abstract
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Jeju, South Korea, jeju islands
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.
.
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 Images1. 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 Planet2. 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 Planet3. 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 2.05. 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 Planet6. 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 Planet8. 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
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