RALTEGRAVIR

CAS No.......518048-05-0 (free acid)
871038-72-1 (monopotassium salt)IUPAC Name:- N-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)
Organic Process Research and Development, 2011 ,  vol. 15,  1  pg. 73 - 83,
143 - 144.1 °C(free acid)
MW: 444.42
..........................................................
K SALT
C₂₀H₂₀FN₆O₅*K, 482.513
MP..275 - 277 °C
European Journal of Medicinal Chemistry, 2012 ,  vol. 50, pG. 361 - 369
Drug information:- Raltegravir is an Anti-microbial drug further classified as anti-viral agent of the class integrase inhibitor. It is used either signally or in combination with other drugs for the treatment of human immunodeficiency virus (HIV) and further clinical trials are in process.


 RALTEGRAVIR

CAS NO. 518048-05-0, Raltegravir H-NMR spectral analysis 


 






 k salt





............

http://www.google.com/patents/WO2011123754A1?cl=en

Raltegravir, also referred to as Raltegravir free hydroxy, N-(2-(4-(4- fluorobenzylcarbamoyl)-5 -hydroxy- 1 -methyl-6-oxo- 1 , 6-dihydropyrimidin-2-yl)propan-2- yl) -5-methyl-l,3,4-oxadiazole-2-carboxamide, having the following formula;

is an antiretroviral drug used to treat HIV infection. Raltegravir targets integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes, a critical step in the pathogenesis of HIV. Raltegravir potassium salt is marketed under the trade name ISENTRESS™ by Merck & Co.
Raltegravir and its preparation are described in US Patent No. 7,169,780. US Publication No. US 2006/0122205, WO 2010/140156 and WO 2011/024192 describe potassium salt of Raltegravir including amorphous and crystalline forms I, II, III and HI as well as amorphous and crystalline forms of Raltegravir free-hydroxy. The present invention relates to salts of Raltegravir, as well as solid state forms of Raltegravir and Raltegravir salts. These properties can be influenced by controlling the conditions under which Raltegravir potassium, Raltegravir sodium, Raltegravir calcium, Raltegravir tert-butyl amine, Raltegravir lithium, Raltegravir diethylamine, Raltegravir diisopropylamine, Raltegravir meglumine and Raltegravir free hydroxy, are obtained in solid form.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis - "TGA", or differential scanning calorimetry - "DSC"), X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.

http://www.google.com/patents/WO2012103105A1?cl=en

U.S. Patent No. 7, 169,780 discloses Raltegravir and preparation thereof, as described in the following reaction scheme:

Scheme 1
J. Med. Chem. 2008, 51 , 5843-5855 discloses another process for preparing Raltegravir as described in the following reaction scheme:

RLT K-salt
Scheme 2 U.S. Publication No. US 2006/0122205 describes an alternative process for preparing Raltegravir, in which the alkylation step does not include a step for protecting the 5-hydroxy group. The process is described in the following reaction scheme:

Scheme 3
Provided herein is an industrially applicable process for preparing RLT-7', RLT-8, RLT-9 and RLT-9-OP, intermediates in the synthesis of Raltegravir, as well as processes for preparing Raltegravir and crystalline forms thereof.
US Publication No. US 2006/0122205, WO 2010/1401 56 and WO 201 1 /
024192 describe the potassium salt of Raltegravir, including amorphous and crystalline forms I, II, III and H I , as well as amorphous and crystalline forms of Raltegravir free- hydroxy. PCT publication No. WO 201 1/123754 describes certain Raltegravir salts and polymorphs, including form V of Raltegravir potassium.

Example 9: Preparation of Raltegravir
To a 0.5 liter reactor was added acetonitrile ( 15 vol), N-methylpyrrolidinone ( 1 vol) and N-methylmorpholine (0.5 g). The resulting solution was cooled to about 0°C and then methyl oxadiazole- potassium (8g) was added. Pivaloyl chloride (7.22 ml) was then added dropwise (over 10 min). The resulting mixture was stirred for about 6 h.
N-Methylmorpholine (5.9 g) and RLT-9 were then added. The resulting mixture was then heated to 20°C and stirred for 16h. The solvent was then evaporated to provide a residue. Water (75 ml) and isopropyl alcohol (25 ml) were added to the residue. The resulting solution was stirred overnight at RT. A precipitate formed and was filtered and washed with water (10 ml) and IPA (20 ml). The product was dried under vacuum at 60°C overnight to give 8.76g Raltegravir (85.7% assay, 77% yield). The obtained crude product was purified by slurry in MeOH/Water mixture


https://web.stlawu.edu/library/system/files/course_readings/Discovery%20of%20Raltegravir,%20a%20Potent,%20Selective%20Orally%20Bioavailable.pdf

Journal of Medicinal Chemistry, 2008, Vol.51 no 18 pg 5854
free base

NMR (DMSO-d6)δ

12.19 (s, 1 H), 9.83 (s, 1 H), 9.25-8.90 (bs,1 H), 7.39 (dd,J)8.5, 5.6 Hz, 2 H), 7.16 (app. t,J)8.8 Hz, 2H), 4.51 (d,J)6.4 Hz, 2 H), 3.48 (s, 3 H), 2.56 (s, 3 H), 1.74 (s,6 H). MSm/z445 (M+H)+. HRMS calcd for C20H22O5N6F(M+H)+

: 445.16302. Found: 445.16278. Melting point 216°C.

k salt 

1H NMR (DMSO-d6) 11.70-11.20 (bs, 1 H), 9.75 (s, 1H), 7.33 (dd,J)8.8, 5.8 Hz, 2 H), 7.12 (app. t,J)

8.8 Hz, 2 H),4.44 (d,J)5.8 Hz, 2 H), 3.40 (s, 3 H), 2.56 (s, 3 H), 1.70 (s, 6H). Melting point 282°C

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nmr
Imp roved synthesis of raltegravir
GUO D i2liang et al
Department ofM edicinal Chem istry, China PharmaceuticalUniversity, N anjing 210009;
Journal of China Pharmaceutical University　2009, 40 (4) : 297 - 301
http://star.sgst.cn/upload/attach/attach20091230100028d4masjzgcv.pdf

1H NMR (CD3OD) δ: 7.40 (m, 2H) , 7.04 (m , 2H) ,
4.56 (s, 2H ) , 3.46 ( s, 3H ) , 2.65 (s, 3H ) , 1.83 (s,
6H);
13C NMR (CD3OD ) δ: 168.4, 164.8, 163.2,
162.0, 161.9, 160.1, 155.3, 145.8, 136.0, 134.9,
131.0, 116.7, 116.6, 60.2, 43.8, 41.3, 34.8, 27.6,
11.4;
ESI2MS m /z 443 (M )-; LR2MS (EI) m /z 444(M )+; HR2MS ( E I) m /z C20 H21 FN6O5(M )+
calcd444, 155,  7, found 444, 154,  2
second set
WO2009088729 , US20100280244
lH NMR (399.87 MHz₅ CDCI3) δ 12.04 (s, IH), 8.45 (s, IH), 7.94 (t, J = 6.2 Hz, IH), 7.41-736 (m, 2H), 7.08-7.02 (m, 2H)₅ 4.61 (d, J - 6.2 Hz, 2H), 3.68 (s, 3H), 2.63 (s, 3H), 1.87 (s, 6H).
13C NMR (100.55 MHz, CDCI3) δ 168.3, 166.7, 162.6 (d, JCF=245.7 Hz), 159.6, 159.1, 152.O₅ 150.4, 147.2, 133.4 (d, JCP=3.2 Hz)₅ 129.9 (d, JcF=8.0 Hz), 124.1, 115.9 (d, JcF=21.7 Hz), 58.0, 42.7, 33.5, 26.7, 11.4.
.........................
IR
WO2011024192, WO2011024192A3
absorption bandsKBR (cm^"1) at 832, 1017, 1248, 1350, 1510, 1682, 2995, and 3374
...................
K SALT

Org. Process Res. Dev., 2011, 15 (1), pp 73–83

DOI: 10.1021/op100257r

http://pubs.acs.org/doi/full/10.1021/op100257r
mp 274.2−275.2 °C. ¹H NMR (500 MHz, DMSO-d₆) δ: 11.65 (t, J = 6.0 Hz, 1 H), 9.75 (s, 1 H), 7.36 (dd, J = 8.6, 5.7 Hz, 2 H), 7.14 (app. t, J = 8.6 Hz, 2 H), 4.48 (d, J = 6.0 Hz, 2 H), 3.43 (s, 3 H), 2.58 (s, 3 H), 1.73 (s, 6 H);
¹³C NMR (125 MHz, DMSO-d₆) δ: 168.7, 167.0, 166.6, 162.1 (d, J_CF = 243 Hz), 159.7, 158.3, 153.1, 139.6, 138.0 (d, J_CF = 3 Hz), 130.2 (d, J_CF = 8 Hz), 123.7, 116.0 (d, J_CF = 22), 58.4, 42.1, 33.3, 28.1 (2 C), 11.7.
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China Pharmaceutical University (CPU), located in the "ancient capital city of six dynasties" - Nanjing, is one of the "211 project" key universities ...
 
 

DHAKA BANGLADESH

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Steamers and ferries in Sadarghat Port

Kawran Bazar

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Dry fish sellers at the Karwan Dry Fish Market (Bazar), Dhaka, Bangladesh.

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Grapefruit flavor NOOTKATONE

D. Srinivasa Reddy of CSIR-National Chemical Laboratory Pune devised (J. Org. Chem. 2013, 78, 8149. DOI: 10.1021/jo401033j) a cascade protocol of Diels-Alder cycloaddition of 8 to the diene 7 followed by intramolecular aldol condensation, to give the enone 9. Oxidative manipulation followed by methylenation completed the synthesis of the commercially important grapefruit flavor Nootkatone (10).

A simple and efficient synthesis of functionalized cis-hydrindanes and cis-decalins was achieved using a sequential Diels–Alder/aldol approach in a highly diastereoselective manner. The scope of this method was tested with a variety of substrates and was successfully applied to the synthesis of two natural products in racemic form. The highlights of the present work provide ready access to 13 new cis-hydrindanes/cis-decalins, a protecting group-free total synthesis of an insect repellent Nootkatone, and the first synthesis of a Noreremophilane using the shortest sequence.

A simple and efficient synthesis of functionalized cis-hydrindanes and cis-decalins was achieved using a sequential Diels–Alder/aldol approach in a highly diastereoselective manner. The scope of this method was tested with a variety of substrates and was successfully applied to the synthesis of two natural products in racemic form. The highlights of the present work provide ready access to 13 new cis-hydrindanes/cis-decalins, a protecting group-free total synthesis of an insect repellent Nootkatone, and the first synthesis of a Noreremophilane using the shortest sequence.
(4R*,4aS*,6R*)-4,4a-Dimethyl-6-(prop-1-en-2-yl)-4,4a,5,6,7,8-hexahydronaph thaen-2(3H)-one ((±)-Nootkatone 20)

(±)-Nootkatone 20 (19 mg, 65%).

 IRυmax(film) 2923, 1668, 1606, 1459 cm–1;

1H NMR (400 MHz, CDCl3) δ 5.77 (s, 1 H), 4.74 (s, 1 H), 4.72(s, 1 H), 2.50 (ddt, J = 15.3, 5.0, 1.8 Hz, 1 H), 2.40–2.24 (m, 4 H), 2.04–1.89 (m, 3 H),1.74 (s, 3 H), 1.40–1.29 (m, 2 H), 1.11 (s, 3 H), 0.96 (d, J = 6.7 Hz, 3 H);

13C NMR (100 MHz, CDCl3) δ 199.9, 170.7, 149.3, 124.8, 109.4, 44.0, 42.2, 40.6, 40.5, 39.5, 33.2, 31.7, 21.0, 17.0, 15.0.


 CAS NO. 4674-50-4, NOOTKATONE H-NMR spectral analysis predicted




 CAS NO. 4674-50-4, NOOTKATONE C-NMR spectral analysis

 

Nootkatone

Names
IUPAC name 4-α,5-Dimethyl-1,2,3,4,4α,5,6,7-octahydro-7-keto-3-isopropenylnaphthalene
Other names (+)-nootkatone
Identifiers
CAS number	4674-50-4
ChEMBL	ChEMBL446299
ChemSpider	1064812
InChI[show]
Jmol-3D images	Image
KEGG	C17914
PubChem	1268142
SMILES[show]
Properties
Molecular formula	C15H22O
Molar mass	218.33 g·mol−1
Appearance	Viscous yellow in its liquid form
Density	0.968 g/mL
Melting point	36 °C (97 °F; 309 K)
Boiling point	170 °C (338 °F; 443 K)
Hazards
S-phrases	S23 S24 S25
Flash point	~ 100 °C (212 °F)

Nootkatone is a natural organic compound and is the most important and expensive aromatic of grapefruit.^[1] It is a sesquiterpeneand a ketone.
Nootkatone was previouslythought to be one of the main chemical components of the smell and flavour of grapefruits. In its solid form it is usually found as crystals. As a liquid, it is viscous and yellow. Nootkatone is typically extracted from grapefruit, but can also be manufactured with genetically modified organisms, or through the chemical or biochemical oxidation of valencene. It is also found in Alaska yellow cedar trees^[2] and vetiver grass.^[3]

Uses

Nootkatone in spray form has been shown as an effective repellent/insecticide against deer ticks^[3][4][5] and lone star ticks.^[4][5] It is also an effective repellent/insecticide against mosquitos, and may repel bed bugs, head lice and other insects.^[6] It is environmentally friendly insecticide, because it is a volatile essential oil that does not persist in the environment.^[6] It is nontoxic to humans, is an approved food additive,^[6] and "is commonly used in foods, cosmetics, and pharmaceuticals".^[3]
The CDC has licensed patents to two companies to produce an insecticide and an insect repellant.^[6] Allylix, of San Diego, CA, is one of these licensees ^[7] and has developed an enzyme fermentation process that will produce nookatone more cost effectively.^[8]

References

1.  Furusawa, Mai; Toshihiro Hashimoto; Yoshiaki Noma; Yoshinori Asakawa (November 2005). "Highly Efficient Production of Nootkatone, the Grapefruit Aroma from Valencene, by Biotransformation". Chem. Pharm. Bull. 53 (11): 1513–1514. doi:10.1248/cpb.53.1513.PMID 16272746.
2.  Panella, NA.; Dolan, MC.; Karchesy, JJ.; Xiong, Y.; Peralta-Cruz, J.; Khasawneh, M.; Montenieri, JA.; Maupin, GO. (May 2005). "Use of novel compounds for pest control: insecticidal and acaricidal activity of essential oil components from heartwood of Alaska yellow cedar.". J Med Entomol 42 (3): 352–8. doi:10.1603/0022-2585(2005)042[0352:UONCFP]2.0.CO;2. PMID 15962787.
3. Jan Suszkiw (January 2011). "Lignin + Nootkatone = Dead Ticks". USDA.
4. Dolan, MC.; Jordan, RA.; Schulze, TL.; Schulze, CJ.; Manning, MC.; Ruffolo, D.; Schmidt, JP.; Piesman, J.; Karchesy, JJ. (Dec 2009). "Ability of two natural products, nootkatone and carvacrol, to suppress Ixodes scapularis and Amblyomma americanum (Acari: Ixodidae) in a Lyme disease endemic area of New Jersey". J Econ Entomol 102 (6): 2316–24. doi:10.1603/029.102.0638. PMID 20069863.
5.  Jordan, Robert A.; Schulze, Terry L.; Dolan, Marc C. (January 2012). "Efficacy of Plant-Derived and Synthetic Compounds on Clothing as Repellents Against Ixodes scapularis andAmblyomma americanum (Acari: Ixodidae)". Journal of Medical Entomology 49 (1): 101–106. doi:10.1603/ME10241. PMID 22308777.
6.  Richard Knox (April 18, 2011). "Repelling Bugs With The Essence Of Grapefruit". NPR.
7.  Bigelow, Bruce (2011-04-28). "Nootkatone, So A-peeling in Grapefruit, is Repellent to Mosquitoes and Ticks". xconomy.com. Retrieved 10 August 2012.
8. "Cost effective fermentation replaces costly exration". Allylix. Retrieved 10 August 2012.

External links

• Description of nootkatone at Leffingwell.com
• Allylix website

Dr. D. Srinivasa Reddy

https://www.linkedin.com/pub/d-srinivasa-reddy-dsreddy/1/75a/139

Research areas

• Total Synthesis
• Medicinal Chemistry

Our group research interests are broadly in total synthesis of biologically active compounds and medicinal chemistry. Current projects include the total synthesis of bioactive natural products such as antiinflammatory agents, antibacterial agents, antimalarial compounds and anti-cancer agents. Targets are chosen for their interesting biological activity and moderate complexity, which drives our creative solutions to their synthesis. Our ability to achieve an efficient synthesis enables us to access sufficient quantities of target molecule for biological profiling and ready access to different analogs that may prove to be more selective and efficacious as a drug-like molecule. We have plans to divert our total synthesis projects into medicinal chemistry projects by simplifying the complex structures. In medicinal chemistry front, our main interest is to use "silicon-switch approach" to discover novel drugs or drug-like molecules with improved pharmacokintetic (PK) and pharmacodynamic (PD) properties.

DEC2014 NCL PUNE INDIA
DR ANTHONY WITH DR REDDY

Contact

• Dr. D. Srinivasa Reddy
  Senior Scientist
  Office: R.No-282, Main building
  Organic Chemistry Division
  National Chemical Laboratory
  Dr. Homi Bhabha Road
  Pune 411008, India
  Phone  +91 20 2590 2445
  Fax +91 20 2590 2624
  E-mail ds.reddy@ncl.res.in 

Reference:

Furusawa, Mai; Hashimoto, Toshihiro; Noma, Yoshiaki; Asakawa, Yoshinori Chemical and Pharmaceutical Bulletin, 2005 , vol. 53, # 11 p. 1513 - 1514

Furusawa, Mai; Hashimoto, Toshihiro; Noma, Yoshiaki; Asakawa, Yoshinori Chemical and Pharmaceutical Bulletin, 2006 , vol. 54, # 6 p. 861 - 868

Sauer, Anne M.; Crowe, William E.; Henderson, Gregg; Laine, Roger A. Organic Letters, 2009 , vol. 11, # 16 p. 3530 - 3533