DR ANTHONY MELVIN CRASTO,WorldDrugTracker, helping millions, A 90 % paralysed man in action for you, I am suffering from transverse mylitis and bound to a wheel chair, With death on the horizon, nothing will not stop me except God................DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai) , INDIA 25Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK GENERICS at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.Million hits on google, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution

Wednesday, 27 November 2013



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Star fruit neurotoxin identified, Caramboxin

Star fruit neurotoxin identified

Neurotoxin from Star Fruit

Patients with kidney disease have to watch what they eat: bananas, oranges, tomatoes, nuts, broccoli, and beans are all off-limits. Putting star fruit or carambola on the menu would be downright dangerous. This fruit contains a substance that is a deadly neurotoxin for people with kidney disease. Brazilian researchers have now isolated and identified this neurotoxin. As they report in the journal Angewandte Chemie, it is an amino acid similar to phenylalanine.
Caramboxin: Patients suffering from chronic kidney disease are frequently intoxicated after ingesting star fruit. The main symptoms of this intoxication are named in the picture. Bioguided chemical procedures resulted in the discovery of caramboxin, which is a new phenylalanine-like molecule that is responsible for intoxication. Functional experiments in vivo and in vitro point towards the glutamatergic ionotropic molecular actions of caramboxin, which explains its convulsant and neurodegenerative properties.

Sweet Poison

star fruit (Averrhoa carambola) or carambola has been cultivated in Malaysia, Southern China, Taiwan, India and Brazil. It is rather popular in the Philippines and Queensland, Australia and moderately so in some of the South Pacific Islands, particularly Tahiti, New Caledonia and Netherlands New Guinea, Guam and in Hawaii and south Florida. There are some subspecies in the Caribbean Islands, in Central America and in tropical West Africa. The fruits are also available in many European countries and Canada. Range of soluble oxalate salts concentrations obtained from many cultivars varies from 80 to 730 mg/100 g of the fruit
Structural Elucidation and Spectroscopic Data of Caramboxin (1)
Most 1H and 13C NMR data from the isolated compound were easily assigned due to the relationship
of this compound with well-known aromatic amino acids such as phenylalanine. The side chain is
identical to phenylalanine as attributed in the NMR data below. The tetra-substituted pattern of the aromatic ring was also easily recognized by the only two signals for aromatic protons at δ 6.42 and6.37 with a coupling constant (2.0 Hz) typical of aromatic meta coupling. The positioning of
substituents in the aromatic ring were attributed due to the 13C chemical shifts and confirmed by
HMBC experiment. In this way acetyl group was placed at C-6 due to the low chemical shift (104.1ppm) of this aromatic carbon; methoxyl was placed at C-3 due to its highest chemical shift (165.2ppm) among aromatic protons, which was confirmed by HMBC experiment; finally the hydroxyl group was placed at the remaining C-5. Comparison of the observed accurate mass measurement with theoretically calculated formulae for the signal at m/z 256.0823 allows only a few reasonable [MH]+ ion formulae within a standard deviation of 50 ppm. The ion formula [C11H13NO6 + H]+ had the best mass accuracy (0.7 ppm error) and correlation with the NMR spectra. The MS/MS spectrum of m/z 256 shows an intense ion at m/z 192 in addition to neutral elimination of H2O (m/z 238) and CO2 (m/z 212) from the carboxylic acid group. In source dissociation followed by MS/MS analysis revealed that m/z 192 was only obtained from m/z 238, due to the elimination of CH2O2 (46 massunits) as a neutral molecule by 1,2 elimination. The same mechanism was also observed for the m/z166 formation from the ion at m/z 212. Finally, 2D NMR data from HMQC and HMBC confirmed the entire spectral assignment
Caramboxin: 1H-NMR (400 MHz, D2O) δ 6.42 (d, J = 2.0 Hz, 1H, H-4), 6.37 (d, J = 2.0 Hz, 1H, H-2), 4.25 (dd, J = 5.5, 8.0 Hz, 1H, H-8), 3.80 (s, 3H, H-11), 3.66 (dd, J = 14.0, 5.5 Hz, 1H, H-7A),3.18 (dd, J = 14.0, 8.0 Hz, 1H, H-7B);

13C-NMR (100 MHz, DMSO-d6) δ 172.8 (C, C-9), 171.2 (C,C-10), 165.2 (C, C-5), 162.2 (C, C-3), 138.8 (C, C-1), 110.0 (CH, C-2), 104.1 (C, C-6), 100.5 (CH,C-4), 55.4 (CH3, C-11), 53.5 (CH, C-8), 35.9 (CH2, C-7); 15N-NMR (50 MHz, DMSO-d6) δ -268(nitromethane as internal reference).
HMBC (500 MHz, DMSO-d6): H-2 → C-3, C-4, C-7; H-4 →C-2, C-3, C-5; H-7 → C-1, C-2, C-8, C-9; H-8 → C-1, C-7, C-9; H-11 → C-3;

HRMS (m/z): [MH]+calcd for C11H14NO6, 256.0816; found: 256.0818


Shimoga - Wikipedia, the free encyclopedia

Shimoga, officially renamed as Shivamogga, is a city and the district headquarters of Shimoga District in the central part of the state of Karnataka, India. The city ...
Map of shimoga city.

Shimoga–Talaguppa railway

Kundadri, Shimoga

Shimoga Photos - Kudli Temple

Ornate baluster in Thripuranthakeshwara temple at Balligavi, Shimoga district.jpg

sigandur - Shimoga


Monday, 25 November 2013

Aripiprazole spectral data


A mixture of 7-(4-Bromobutoxy)-2(1H)-quinolinone (297 g, 1.0 mol), NaI (234 g, 1.56 mol),
triethylamine (173.7 g, 1.72 mol) and 1-(2, 3-dichlorophenyl)-piperazine hydrochloride (381
g, 1.43 mol), in acetonitrile (750 mL) was refluxed for 4 h with stirring. Progress of reaction
was monitored by TLC; using benzene: ethyl acetate (7:3) solvent system. The reaction
mixture was filtered, and the filtrate was evaporated to dryness in vacuo. The residue was
extracted with CHCl3, and the extract was washed, dried, and evaporated in vacuo.
Recrystallization from MeOH-CHCl3 gave the desired product as colorless needles. Product
Yield: 407.0 g, 84 %


3368 (N-H stretching),
3109 (aromatic C-H stretching),
2944(aliphatic C-H stretching),
1677 (C=O stretching),
1594-1445(aromatic region),
1174 (C-N stretching),
779 (C-Cl stretching).

ð 1.77-1.72 ppm (t, 2H, -CH2),
1.83-1.79 (t, 2H, -CH2),
2.50-2.45(t, 2H, -CH2),
2.63-2.58 (m, 6H, CO-CH2-CH2 of carbostyryl,CH2 of piperazine),
2.91-2.86 (m, 2H, -CH2 of piperazine),
3.06(s, 4H, -CH2 of piperazine),
6.30-6.29 (s, 1H, -ArH),
6.53-6.50 (dof d, 1H,-ArH),
6.98-6.93 (m, 1H, -ArH),
7.05-7.02 (d, 1H, -ArH),
7.16-7.10 (d, 2H, -ArH),
7.79 (s, 1H, -NH)

1H NMR spectrum of Aripiprazole (CDCl3, 298 K, 600 MHz): 8.52 (s,1H),
7.14-7.15 (m,2H), 7.04 (d,1H,J=8.30 Hz), 6.96 (dd,1H,J=7.10,2.52Hz), 6.52
(dd,1H,J=8.30,2.30 Hz), 6.36 (d,1H,J=2.30 Hz), 3.96 (t,2H,J=6.25 Hz), 3.07 (m,4H), 2.89
(t,2H,J=7.50 Hz), 2.65 (m,4H), 2.62 (t,2H,J=7.50 Hz), 2.48 (t,2H,J=7.55 Hz), 1.82
(m,2H), 1.71 (m,2H).

1H-NMR spectral data of Aripiprazole (DMSO-d6, 298 K, 600 MHz): 9.98 
(s,1H), 7.28-7.30 (m,2H), 7.12 (dd,1H,J=7.10,2.35 Hz), 7.04 (d,1H,J=8.30 Hz), 6.48 
(dd,1H,J=8.30,2.35 Hz), 6.45 (d,1H,J=2.35 Hz), 3.96 (t,2H,J=6.45 Hz), 2.97 (m,4H), 2.78 
(t,2H,J=7.45 Hz), 2.52 (m,4H), 2.41 (t,2H,J=7.45 Hz), 2.38 (t,2H,J=7.15 Hz), 1.72 
(m,2H), 1.58 (m,2H)

1H NMR spectrum of Aripiprazole (CD3OH, 298 K, 500 MHz): 9.80 (bs,1H), 
7.18-7.24 (m,2H), 7.02-7.09 (m,2H), 6.54 (dd,1H,J=8.25,2.45 Hz), 6.44 (d,1H,J=2.49 
Hz), 3.97 (t,2H,J=6.15 Hz), 3.06 (m,4H), 2.85 (t,2H,J=7.35 Hz), 2.67 (m,4H), 2.47-2.54 
(m,4H), 1.79 (m,2H), 1.73 (m,2H). 

  1. Sixth polymorph of Aripiprazole - an antipsychotic drug.


    NMR spectrum of Aripiprazole (CDCl3, 298 K, 600 MHz): 8.52 (s,1H),. 7.14-7.15 (m,2H), 7.04 (d,1H,J=8.30 Hz), 6.96 (dd,1H,J=7.10,2.52Hz), 6.52. (dd,1H ...

    Spectroscopic studies of aripiprazoleDownload the full textDownload the full text
    Author:Li Jianfeng 1, Liu Aixiang 1, Xia Guang-xin 1, 2, was also abundant, Shen Jing Shan 1 *
    Journal Name:Spectroscopy and Spectral Analysis
    Title:200 727 (05)
    Post time:2006.12.18
    Download URL:www.gpxygpfx.com/qikan/manage/wenzhang/2007-05-0863.pdf


Aripiprazole (7-[4-[4- (2,3-dichlorophenyl) piperazin-1-yl] butoxy]-3,4- dihydro- 1H quinolin-2-one) is an anti - psychotic drug.

1H-NMR spectrum (DMSO-d6, TMS) shown in FIG. 23. Specifically, it has characteristic peaks at 1.55-1.63 ppm (m, 2H), 1.68-1.78 ppm (m, 2H), 2.35-2.46 ppm (m, 4H), 2.48-2.56 ppm (m, 4H 4-DMSO), 2.78 ppm (t, J=7, 4 Hz, 2H), 2.97 ppm (brt, J=4.6 Hz, 4H), 3.92 ppm (t, J=6.3 Hz, 2H), 6.43 ppm (d, J=2.4 Hz, 1H), 6.49 ppm (dd, J=8.4 Hz, J=2.4 Hz, 1H), 7.04 ppm (d, J=8.1 Hz, 1H), 7.11-7.17 ppm (m, 1H), 7.28-7.32 ppm (m, 2H) and 10.00 ppm (s, 1H);

 IR (KBr) spectrum shown in FIG. 21. Specifically, it has clear infrared absorption bands at 2943, 2817, 1686, 1377, 1202, 969 and 774 cm−1.

HPLC purity: 99.39%, Methanol content: 6.57% Elemental analysis: C: 59.88%, H: 6.60%, N: 8.62% and calculated values for C2IH3ICl2N3O3. C: 59.95%, H: 6.45%, N: 8.74%
IR Spectrum (KBr, cm-1): 3196, 3108, 2948, 2819, 1675, 1628, 1595, 1578, 1522, 1449, 1378, 1335, 1274, 1243, 1197, 1173, 1140, 1127, 1040, 997, 960, 859, 830, 809, 784, 748, 713 and 532.
1H NMR (300 MHz, CDCl3, ppm) : 1.65 - 1.85 («ι, 4H), 2.49 (t, 2H), 2.51 (t, 2H), 2.59 - 2.64 (m, 4H), 2.89 (t, 2H), 3.08 (m, 4H), 3.49 (s, 3H),
3.97 (t, 2H), 6.32 (d, IH), 6.51- 6.54 (dd, IH), 6.94 - 6.97 (m, IH), 7.05 (d, IH), 7.11 - 7.17 (m, 2H), 8.04 (s, IH).
13C NMR (300 MHz, DMSO-d6, ppm): 23.19, 24.38, 27.14, 30.90, 50.17, 51.08, 53.12, 58.07, 67.7, 102.2, 108.7, 115.5, 118.5, 124.39, 127.31, 127.34, 128.4, 133.8, 138.1, 151.1, 158.5 and 172.41.
Mass Spectrum (M+): 448.2, 285.1/ 218.1, 176.0, and 164.1. The XRD shows the peaks at 9.4, 10.7, 11.4, 11.8, 12.3, 13.3, 17.3, 18.4, 19.8, 23.3, 24.3, 25.6, 26.8, 28.0, 28.9, 31.2° + 0.2 2 theta values

Sunday, 24 November 2013


   Reaction Scheme: <img src="/images/empty.gif" alt="" />Protection of phenyl glycinol using <span id="csm1374586974145" class="csm-chemical-name" title="phthalic anhydride">phthalic anhydride</span><img src="/images/empty.gif" alt="" />

Equimolar ratios of both heated at 145 deg c for 4 hrs and then the oil  titurated in DCM , Dried over sodium sulphate , evapn gives oil , used as such for next step. is a method of protection of amino gp


ChemSpider 2D Image | 2-[(1R)-2-Hydroxy-1-phenylethyl]-1H-isoindole-1,3(2H)-dione | C16H13NO3205380-30-9  cas no


1H NMR (400 MHz, 298 K, CDCl3) δH 7.83 – 7.74 (2H, m, Pht), 7.70 – 7.60 (2H, m, Pht), 7.49 (2H, d, 3JHH = 7.4 Hz, Ph), 7.41 – 7.23 (3H, m, Ph), 
5.51 (1H, dd, 3JHH = 8.9 Hz, 3JHH = 5.0 Hz, CH), 
4.76 – 4.66 (1H, m, CH2), 
4.24 (1H, dd, 3JHH = 11.4 Hz, 4JHH = 4.9 Hz, CH2), 
3.47 (1H, s, OH).

13C NMR (100 MHz, 298 K, CDCl3) δC 168.89 (C=O), 
136.88, 134.08 (Pht), 131.72, 128.70, 128.13, 127.97 (Ph), 123.31 (Pht), 
61.98 (CH2), 57.46 (CH).

MS (ESI+) m/z 290.1 ([M+Na]+)

IR (cm-1) ν 3457, 1772, 1700, 1611, 1585, 1495, 1467, 1388, 1358, 1332, 1288, 1266, 1185, 1172, 1120, 1065, 1040, 1013, 999, 962, 919, 877, 838, 793, 765, 719, 698.

M. D. Chen, M. Z. He, X. Zhou, L. Q. Huang, Y. P. Ruan and P. Q. Huang, Tetrahedron, 2005, 61, 1335-1344http://dx.doi.org/10.1016/j.tet.2004.10.109

Aguilar, Nuria; Moyano, Albert; Pericas, Miquel A.; Riera, Antoni 
Synthesis, 1998 ,  3,   p. 313 - 316

Late-stage success for Sanofi/Regeneron RA drug sarilumab « New Drug Approvals

Late-stage success for Sanofi/Regeneron RA drug sarilumab « New Drug Approvals:

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   Reaction Scheme: <IMG src="/images/empty.gif">Trifluoromethylation of <SPAN id=csm1378730185970 class=csm-chemical-name title=p-Anisaldehyde grpid="1">p-Anisaldehyde</SPAN><IMG src="/images/empty.gif">



Physical Properties
Melting Point: n/a
Boiling Point: 87-88 ºC (1 mmHg)
Density: n/a
Refractive Index: n/a
H1 NMR Spectrum:



1H NMR (CDCl3, 400 MHz) d ppm 3.24 - 3.37 (m, 1 H)
3.80 (s, 3 H) O-CH3
4.91 (q, J=6.85 Hz, 1 H) C-H
6.92 (d, J=8.80 Hz, 2 H) arom-H ortho to oxygen
7.37 (d, J=8.80 Hz, 2 H) arom-H

 13C NMR (CDCl3, 101 MHz) d ppm
55.51 (CH3) O-CH3
72.60 (q, JC-C-F = 31.50 Hz, CH) CH-(OH)-CF3
114.28 (CH) AROM-C
120.44 – 128.84 (q, JC-F = 281.70 Hz, CF3)
160.60 (C) AROM C-O-CH3

 19F NMR (CDCl3, 377 MHz) d ppm -78.61 (d, = 6.81 Hz) 

GC-MS (EI) 206 ([M]+, 37%), 137 (100%), 109 (27%), 94 (28%), 77 (25%), 69 (4%).

Kelly, C. B.; Colthart, A. M.; Constant, B.D.; Corning, S.R.; Dubois, L. N. E.;  Genovese, J. T.; Radziewicz, J. L.; Sletten, E. M.; Whitaker, K. R.; Tilley, J. J. Org. Lett.201113, 1646.

Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S.  J.  Org. Chem. 199156, 984.
DOI: 10.1021/jo00001a002

Saturday, 23 November 2013

Elvitegravir dimer impurity spectral data

Elvitegravir dimer impurity, WO2011004389A2
Isolation of 1-[(2S)-1-({3-carboxy-6-(3-chloro-2-fluorobenzyl)-1 -[(2S)-I- hydroxy-3-methylbutan-2-yl]-4-oxo-1 , 4-dihydroquinolin-7-yl}oxy)-3- methylbutan-2-yl 6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid (elvitegravir dimer impurity, 13)
After isolation of the elvitegravir from the mixture of ethyl acetate-hexane, solvent from the filtrate was removed under reduced pressure. The resultant residue purified by column chromatography using a mixture of ethyl acetate-hexane (gradient, 20-80% EtOAc in hexane) as an eluent. Upon concentration of the required fractions, a thick solid was obtained which was further purified on slurry washing with ethyl acetate to get pure elvitegravir dimer impurity (13). The 1H-NMR, 13C-NMR and mass spectral data complies with proposed structure.
Figure imgf000041_0001
1H-NMR (DMSO-Cf6, 300 MHz, ppm) – δ 0.79 (m, d=6.3 Hz, 6H, 20 & 2O’)\ 1.18 & 1.20 (d, J=6.3 Hz & J=6.2 Hz, 6H, 21 & 21′)1, 2.42-2.49 (m, 2H, 19 & 19′), 3.81-3.89 (m, 3H, T & 17′Ha), 3.94-4.01 (m, 1 H, 17′Hb), 4.01 (s, 3H, 23), 4.11 (s, 2H, 7), 4.83-4.85 (m, 3H, 17 & 18′), 5.22 (t, J=4.7 Hz, 1H, OH), 5.41-5.44 (m, 1 H, 18), 6.73-6.78 (t, J=7.1 Hz, 1 H, 11)1‘ 2, 6.92-6.98 (t, J=8.0 Hz, 1H, 3′) 12, 7.12-7.22 (m, 2H, 1 & 3), 7.34-7.39 (m, 1H, 2′),
7.45-7.48 (m, 1 H, 2), 7.49, 7.56 (s, 2H, 15 & 15′), 7.99, 8.02 (s, 2H, 9 & 9′), 8.89, 9.01 (s, 2H, 13 & 13′), 15.30, 15.33 (s, 2H, COOH’ & COOH”).
13C-NMR (DMSO-Cf6, 75 MHz, ppm)- δ 18.87, 19.03 (2OC, 20′C), 19.11 , 19.24 (21 C, 21 ‘C), 27.94 (7′C), 28.40 (7C), 28.91 , 30.08 (19C, 19′C), 56.80(23C), 60.11 (171C), 63.59 (18C), 66.52 (18′C), 68.53 (17C), 97.86, 98.97 (15, 15′), 107.43, 108.16 (12C, 12′C),
118.77, 119.38 (1OC, 10′C), 119.57 (d, J=17.6 Hz, 41C), 119.61 (d, J=17.9 Hz, 4C),
124.88 (d, J=4.3 Hz, 31C), 125.18 (d, J=4.2 Hz, 3C), 126.59, 126.96 (9C1 9′C), 127.14 (8′C), 127.62 (d, J=15.9 Hz, 61C), 127.73 (8C), 127.99 (d, J=15.2 Hz, 6C), 128.66 (2′C),
128.84 (11C), 128.84 (2C), 130.03 (d, J=3.4 Hz, 1C), 142.14, 142.44 (14C, 14′C), 144.37, 145.56 (13C, 131C), 155.24 (d, J=245.1 Hz, 5′C)1 155.61 (d, J=245.1 Hz, 5C),
160.17 (16′C), 162.04 (16C), 166.00, 166.14 (22C, 22′C), 176.17, 176.22 (11C, 111C).
DIP MS: m/z (%)- 863 [M+H]+, 885 [M+Na]+.


European Commission Approves Gilead’s VitektaTM, an Integrase Inhibitor for the Treatment of HIV-1 Infection

697761-98-1 CAS
FOSTER CITY, Calif.–(BUSINESS WIRE)–Nov. 18, 2013– Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the European Commission has granted marketing authorization for VitektaTM (elvitegravir 85 mg and 150 mg) tablets, an integrase inhibitor for the treatment of HIV-1 infection in adults without known mutations associated with resistance to elvitegravir. Vitekta is indicated for use as part of HIV treatment regimens that include a ritonavir-boosted protease inhibitor.http://www.pharmalive.com/eu-oks-gileads-vitekta Vitekta interferes with HIV replication by blocking the virus from integrating into the genetic material of human cells. In clinical trials, Vitekta was effective in suppressing HIV among patients with drug-resistant strains of HIV.http://www.pharmalive.com/eu-oks-gileads-vitekta
Elvitegravir (EVG, formerly GS-9137) is a drug used for the treatment of HIV infection. It acts as an integrase inhibitor. It was developed[1] by the pharmaceutical company Gilead Sciences, which licensed EVG from Japan Tobacco in March 2008.[2][3][4] The drug gained approval by U.S. Food and Drug Administration on August 27, 2012 for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination known as Stribild.[5]
According to the results of the phase II clinical trial, patients taking once-daily elvitegravir boosted by ritonavir had greater reductions in viral load after 24 weeks compared to individuals randomized to receive a ritonavir-boosted protease inhibitor.[6]
 Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency disease syndrome (AIDS).  After over 26 years of efforts, there is still not a therapeutic cure or an effective vaccine against HIV/AIDS.  The clinical management of HIV-1 infected people largely relies on antiretroviral therapy (ART).  Although highly active antiretroviral therapy (HAART) has provided an effective way to treat AIDS patients, the huge burden of ART in developing countries, together with the increasing incidence of drug resistant viruses among treated people, calls for continuous efforts for the development of anti-HIV-1 drugs.  Currently, four classes of over 30 licensed antiretrovirals (ARVs) and combination regimens of these ARVs are in use clinically including: reverse transcriptase inhibitors (RTIs) (e.g. nucleoside reverse transcriptase inhibitors, NRTIs; and non-nucleoside reverse transcriptase inhibitors, NNRTIs), protease inhibitors (PIs), integrase inhibitors and entry inhibitors (e.g. fusion inhibitors and CCR5 antagonists).

  1.  Gilead Press Release Phase III Clinical Trial of Elvitegravir July 22, 2008
  2.  Gilead Press Release Gilead and Japan Tobacco Sign Licensing Agreement for Novel HIV Integrase Inhibitor March 22, 2008
  3.  Shimura K, Kodama E, Sakagami Y, et al. (2007). “Broad Anti-Retroviral Activity and Resistance Profile of a Novel Human Immunodeficiency Virus Integrase Inhibitor, Elvitegravir (JTK-303/GS-9137)”J Virol 82 (2): 764. doi:10.1128/JVI.01534-07PMC 2224569PMID 17977962.
  4.  Stellbrink HJ (2007). “Antiviral drugs in the treatment of AIDS: what is in the pipeline ?”. Eur. J. Med. Res. 12 (9): 483–95. PMID 17933730.
  5.  Sax, P. E.; Dejesus, E.; Mills, A.; Zolopa, A.; Cohen, C.; Wohl, D.; Gallant, J. E.; Liu, H. C.; Zhong, L.; Yale, K.; White, K.; Kearney, B. P.; Szwarcberg, J.; Quirk, E.; Cheng, A. K.; Gs-Us-236-0102 Study, T. (2012). “Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: A randomised, double-blind, phase 3 trial, analysis of results after 48 weeks”.The Lancet 379 (9835): 2439–2448. doi:10.1016/S0140-6736(12)60917-9PMID 22748591edit
  6.  Thaczuk, Derek and Carter, Michael. ICAAC: Best response to elvitegravir seen when used with T-20 and other active agents Aidsmap.com. 19 Sept. 2007.
 The life cycle of HIV-1.  1. HIV-1 gp120 binds to CD4 and co-receptor CCR5/CXCR4 on target cell; 2. HIV-1 gp41 mediates fusion with target cell; 3. Nucleocapsid containing viral genome and enzymes enters cells; 4. Viral genome and enzymes are released; 5. Viral reverse transcriptase catalyzes reverse transcription of ssRNA, forming RNA-DNA hybrids; 6. RNA template is degraded by ribonuclease H followed by the synthesis of HIV dsDNA; 7. Viral dsDNA is transported into the nucleus and integrated into the host chromosomal DNA by the viral integrase enzyme; 8. Transcription of proviral DNA into genomic ssRNA and mRNAs formation after processing; 9. Viral RNA is exported to cytoplasm; 10. Synthesis of viral precursor proteins under the catalysis of host-cell ribosomes; 11. Viral protease cleaves the precursors into viral proteins; 12. HIV ssRNA and proteins assemble under host cell membrane, into which gp120 and gp41 are inserted; 13. Membrane of host-cell buds out, forming the viral envelope; 14. Matured viral particle is released
Elvitegravir, also known as GS 9137 or JTK 303, is an investigational new drug and a novel oral integrase inhibitor that is being evaluated for the treatment of HIV-1 infection. After HIVs genetic material is deposited inside a cell, its RNA must be converted (reverse transcribed) into DNA. A viral enzyme called integrase then helps to hide HIVs DNA inside the cell’s DNA. Once this happens, the cell can begin producing genetic material for new viruses. Integrase inhibitors, such as elvitegravir, are designed to block the activity of the integrase enzyme and to prevent HIV DNA from entering healthy cell DNA. Elvitegravir has the chemical name: 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1 -hydroxy -methyl-2- methylpropyl]-7-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid and has the following structural formula:
Figure imgf000002_0001
WO 2000040561 , WO 2000040563 and WO 2001098275 disclose 4-oxo-1 , 4-dihydro-3- quinoline which is useful as antiviral agents. WO2004046115 provides certain 4- oxoquinoline compounds that are useful as HIV Integrase inhibitors.
US 7176220 patent discloses elvitegravir, solvate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof or pharmaceutical composition containing them and their method of treatment. The chemistry involved in the above said patent is depicted below in the Scheme A. Scheme-A
Toluene, DIPEA
SOCl2 ,COCl (S)-(+)-Valinol
Figure imgf000003_0001
,4-Difluoro-5-iodo- benzoic acid
Figure imgf000003_0003
Figure imgf000003_0002
palladium argon stream,
Figure imgf000003_0004
Elvitegravir Form ] Elvitegravir (residue) US 7635704 patent discloses certain specific crystalline forms of elvitegravir. The specific crystalline forms are reported to have superior physical and chemical stability compared to other physical forms of the compound. Further, process for the preparation of elvitegravir also disclosed and is depicted below in the Scheme B. The given processes involve the isolation of the intermediates at almost all the stages.
Scheme B
Figure imgf000004_0001
CK Br THF CU “ZnBr dιchlorobis(trιphenylphos
Figure imgf000004_0002
Elvitegravir WO 2007102499 discloses a compound which is useful as an intermediate for the synthesis of an anti-HIV agent having an integrase-inhibiting activity; a process for production of the compound; and a process for production of an anti-HIV agent using the intermediate.
WO 2009036161 also discloses synthetic processes and synthetic intermediates that can be used to prepare 4-oxoquinolone compounds having useful integrase inhibiting properties.
The said processes are tedious in making and the purity of the final compound is affected because of the number of steps, their isolation, purification etc., thus, there is a need for new synthetic methods for producing elvitegravir which process is cost effective, easy to practice, increase the yield and purity of the final compound, or that eliminate the use of toxic or costly reagents.
US Patent No 7176220 discloses Elvitegravir, solvate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof or pharmaceutical composition containing them and ■ their method of treatment. US Patent No 7635704 discloses Elvitegravir Form II, Form III and processes for their preparation. The process for the preparation of Form Il disclosed in the said patent is mainly by three methods – a) dissolution of Elvitegravir followed by seeding with Form II, b) recrystallisation of Elvitegravir, and c) anti-solvent method.
The process for the preparation of Form III in the said patent is mainly by three methods – a) dissolution of Form Il in isobutyl acetate by heating followed by cooling the reaction mass, b) dissolution of Form Il in isobutyl acetate by heating followed by seeding with Form III, and c) dissolving Form Il in 2-propanol followed by seeding with Form III.
Amorphous materials are becoming more prevalent in the pharmaceutical industry. In order to overcome the solubility and potential bioavailability issues, amorphous solid forms are becoming front-runners. Of special importance is the distinction between amorphous and crystalline forms, as they have differing implications on drug substance stability, as well as drug product stability and efficacy.
An estimated 50% of all drug molecules used in medicinal therapy are administered as salts. A drug substance often has certain suboptimal physicochemical or biopharmaceutical properties that can be overcome by pairing a basic or acidic drug molecule with a counter- ion to create a salt version of the drug. The process is a simple way to modify the properties of a drug with ionizable functional groups to overcome undesirable features of the parent drug. Salt forms of drugs have a large effect on the drugs’ quality, safety, and performance. The properties of salt-forming species significantly affect the pharmaceutical properties of a drug and can greatly benefit chemists and formulators in various facets of drug discovery and development.
Figure imgf000020_0003
chemical synthesis from a carboxylic acid 1 starts after conversion to the acid chloride iodide NIS 2 , and with three condensation 4 . 4 and the amino alcohol 5 addition-elimination reaction occurs 6 , 6 off under alkaline conditions with TBS protected hydroxy get the ring 7 , 7 and zinc reagent 8 Negishi coupling occurs to get 9 , the last 9 hydrolysis and methoxylated
Egypt for Raltegravir (Elvitegravir) -2012 August of anti-AIDS drugs approved by the FDA