GUEST BLOGGER, Dr Pravin Patil, A New Combination of Cyclohexylhydrazine and IBX for Oxidative Generation of Cyclohexyl Free Radical and Related Synthesis of Parvaquone

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Apr 292017

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As a GUEST BLOGGER, myself Dr Pravin Patil, presenting my paper as below

A New Combination of Cyclohexylhydrazine and IBX for Oxidative Generation of Cyclohexyl Free Radical and Related Synthesis of Parvaquone

Pravin C Patil*^a and Krishnacharya G Akamanchi

Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai-400 019.

^aPresent address: Department of Chemistry, University of Louisville, Louisville, KY, USA.

*Corresponding Author: Email-pravinchem@gmail.com

Tetrahedron Letters 2017, 58 (19), 1883-1886 (Recently published)

[Link: http://www.sciencedirect.com/science/article/pii/S004040391730429X]

Graphical Abstract:

Abstract: The present paper demonstrate a single-step and straightforward synthesis of parvaquone through intermediacy of cyclohexyl radical generated from novel combination of cyclohexylhydrazine and o-iodoxybenzoic acid and subsequently trapped by 2-hydroxy-1,4-naphthoquinone. Formation of cyclohexyl free radical using this new combination was reaffirmed by cyclohexylation of readily available 2-amino-1, 4-naphthoquinone.

Scheme: Literature methods for synthesis of parvaquone

Scheme: IBX mediated oxidative arylation towards synthesis of 1 (Parvaquone)

Scheme : Cyclohexyl radical mediated postulated mechanism for formation of Parvaquone, 1

Synthesis of 2-cyclohexyl-3-hydroxy-1,4-naphthoquinone (parvaquone) (1): To a solution of 3 (1.0 g, 5.74 mmol) in acetonitrile (20 mL) was added IBX (3.80 g, 13.6 mmol) in one lot and stirred for 5 min at room temperature. To this was added dropwise a solution of 8 (0.78 g, 6.8 mmol) dissolved in 10 mL of acetonitrile over the course of 20 min. During the addition of 8 exotherm (up to 35 °C) was observed with evolution of nitrogen gas in the form of bubbles. Reaction progress was monitored by TLC (using mobile phase, hexane: ethyl acetate/5:95). After satisfactory TLC, water (20 mL) was added to the reaction mixture and acetonitrile was evaporated using rotary evaporator. To the residue obtained was added dichloromethane (30 mL). Oganic layer was separated and washed with saturated sodium bicarbonate solution followed by saturated solution of sodium sulphite. Separated organic layer was dried over anhydrous sodium sulphate and evaporated to obtain crude 1 which was further purified by column chromatography (mobile phase – hexane: ethyl acetate/5:95) to afford 1 as yellow solid, (0.88 g, 60% yield); mp 136-138 °C (lit.¹⁸135-136°C); FT-IR (KBr): 3585, 3513, 3071, 2926, 2853, 1666, 1604, 1590 cm^-1;

¹H NMR (300 MHz; CDCl₃): δ 8.10-8.06 (d, J = 12 Hz, 2H), 7.74-7.67 (d, J = 22 Hz, 2H, 7.45 (s, 1H, OH), 3.11-3.03 (t, J = 16 Hz, 1H), 1.99-1.34 (m, 10H); ¹³C NMR (75 MHz; CDCl₃): δ 184.5, 181.9, 152.8, 135.1, 134.9, 132.7, 129.2, 127.9, 126.9, 125.9, 35.1, 29.2, 26.7, 25.9.

Highlights

New method of generating cyclohexyl radical by using IBX and cyclohexylhydrazine.
Parvaquone synthesized in 60% yield using metal, hazardous peroxide free conditions.
Described method has advantages of single step and mild reaction conditions.
The mechanism for cyclohexyl radical mediated synthesis of parvaquone is postulated.

please note………

Image result for A new combination of cyclohexylhydrazine and IBX for oxidative generation of cyclohexyl free radical and related synthesis of parvaquone

ABOUT GUEST BLOGGER

Dr. Pravin C. Patil

Postdoctoral Research Associate at University of Louisville

see…….http://oneorganichemistoneday.blogspot.in/2017/04/dr-pravin-patil.html

Dr. Pravin C Patil completed his B.Sc. (Chemistry) at ASC College Chopda (Jalgaon, Maharashtra, India) in 2001 and M.Sc. (Organic Chemistry) at SSVPS’S Science College Dhule in North Maharashtra University (Jalgaon, Maharashtra, India) in year 2003. After M.Sc. degree he was accepted for summer internship training program at Bhabha Atomic Research Center (BARC, Mumbai) in the laboratory of Prof. Subrata Chattopadhyay in Bio-organic Division. In 2003, Dr. Pravin joined to API Pharmaceutical bulk drug company, RPG Life Science (Navi Mumbai, Maharashtra, India) and worked there for two years. In 2005, he enrolled into Ph.D. (Chemistry) program at Institute of Chemical Technology (ICT), Matunga, Mumbai, aharashtra, under the supervision of Prof. K. G. Akamanchi in the department of Pharmaceutical Sciences and Technology.

After finishing Ph.D. in 2010, he joined to Pune (Maharashtra, India) based pharmaceutical industry, Lupin Research Park (LRP) in the department of process development. After spending two years at Lupin as a Research Scientist, he got an opportunity in June 2012 to pursue Postdoctoral studies at Hope College, Holland, MI, USA under the supervision of Prof. Moses Lee. During year 2012-13 he worked on total synthesis of achiral anticancer molecules Duocarmycin and its analogs. In 2014, he joined to Prof. Frederick Luzzio at the Department for Chemistry, University of Louisville, Louisville, KY, USA to pursue postdoctoral studies on NIH sponsored project “ Structure based design and synthesis of Peptidomimetics targeting P. gingivalis.

During his research experience, he has authored 23 international publications in peer reviewed journals and inventor for 4 patents.

//////////////Parvaquone, guest blogger, pravin patil

Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease

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Mar 132017

Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease

Med. Chem. Commun., 2017, Advance Article
DOI: 10.1039/C6MD00707D, Research Article

E. Lattmann, J. Sattayasai, R. Narayanan, N. Ngoc, D. Burrell, P. N. Balaram, T. Palizdar, P. Lattmann
Arylated 5-hydroxy-pyrrol-2-ones were prepared in 2 synthetic steps from mucochloric acid and optimised as CCK₂-selective ligands using a range of assays.

Cholecystokinin-2/gastrin antagonists: 5-hydroxy-5-aryl-pyrrol-2-ones as anti-inflammatory analgesics for the treatment of inflammatory bowel disease

E. Lattmann,*^a J. Sattayasai,^b R. Narayanan,^c N. Ngoc,^a D. Burrell,^a P. N. Balaram,^d T. Palizdar^a and P. Lattmann^d

*Corresponding authors

^aSchool of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK
E-mail: e.lattmann@aston.ac.uk

^bDepartment of Pharmacology, Faculty of Medicine, Khon Kaen University, 40002 Khon Kaen, Thailand

^cDepartment of Medicine, University of Tennessee Health Science Center, Memphis, USA

^dPNB Vesper Life Science PVT, Cochin, India

Med. Chem. Commun., 2017, Advance Article

DOI: 10.1039/C6MD00707D

Arylated 5-hydroxy-pyrrol-2-ones were prepared in 2 synthetic steps from mucochloric acid and optimised as CCK₂-selective ligands using radiolabelled binding assays. CCK antagonism was confirmed for the ligands in isolated tissue preparations. DSS (dextran sulfate sodium)-induced inflammation was analysed for derivative 7 and PNB-001 with L-365,260 as a standard. The IC₅₀ of PNB-001 was determined to be 10 nM. Subsequent in vivo evaluation confirmed anti-inflammatory activity with respect to IBD assays. The best molecule, PNB-001, showed analgesic activity in the formalin test and in the hotplate assay, in which the analgesic effect of 1.5 mg kg⁻¹ PNB-001 was equivalent to 40 mg kg⁻¹ tramadol. The CCK₂-selective antagonist PNB-001 protected rats against indomethacin-induced ulceration at similar doses. The GI protection activity was found to be more potent than that of the 10 mg kg⁻¹ dose of prednisolone, which served as a standard.

General Method: The relevant amine (2.5 times excess) was added to a solution of lactone A – E (0.7 mol) in ether (10 ml) and stirred on ice for 30 minutes, allowing to warm up to RT over the time. The resultant mixture was poured into 5 ml water and separated by separating funnel. The mixture was washed with water three times. The organic layer was dried over magnesium sulphate and the solvent was removed under vacuum. All compounds gave an oily solid which were passed through a column (80% ether, 20% petrol ether). The resulting fractions were dried from excess solvent under vacuum to yield crystals. 4-Chloro-1-cyclopropyl-5-hydroxy-5-phenyl-1,5-dihydro-pyrrol-2-one 1 Yield = 83 %; mp: 177-179 oC;

MS (APCI(+)): 193/195 (M+1), 250/252 (M+) m/z

1H NMR (CDCl3) 250 MHz:  = 7.41 (m, 5H), 6.09 (s, 1H), 3.50 (m, 1H), 2.18 (m, 1H), 0.95-1.04 & 0.38-0.69 (m, 4H);

13C NMR (CDCl3) 167.4, 154.8, 135.2, 129.2, 128.8, 126.1, 122.2, 93.5, 22.6 , 3.8, 5.1;

IR (KBr-disc)  max: 3416, 3260, 3105, 3011, 2363, 2338, 1671, 1602, 1490, 1450, 1409, 1369, 1256, 1144, 1032, 939, 833, 752, 702 cm-1 .

/////////////////Cholecystokinin-2/gastrin antagonists, 5-hydroxy-5-aryl-pyrrol-2-ones, anti-inflammatory analgesics, inflammatory bowel disease

Award for me, 100 Most Impactful Health care Leaders, Global listing

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Feb 142017

str6

At award function for my award “100 Most Impactful Health care Leaders Global listing”, conferred on me at Taj lands end, Mumbai, India on 14 Feb 2014 by World Health Wellness congress and awards

tert-butyl(3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

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Feb 092017

Abstract Image

tert-butyl(3aR,6aS)-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

tert-Butyl (3aR,6aS)-5-Oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1)

pure compound 1 (1.051 kg, 67%) as a white solid. Mp: 70–71 °C (uncorrected); [α]²⁵_D +0.40° (c 1.00 CHCl₃); % purity: 98.5% (HPLC);

¹H NMR (CDCl₃, 400 MHz) δ: 1.46 (s, 9H), 2.15 (dd, J₁ = 4.8 Hz, J₂ = 19.6 Hz, 2H), 2.47 (dd, J₁ = 7.4 Hz, J₂ = 19.6 Hz, 2H), 2.93 (bs, 2H), 3.16–3.28 (m, 2H), 3.65–3.67 (m, 2H).;

¹³C NMR (CDCl₃, 100 MHz) δ: 38.49, 39.36, 42.32, 50.51, 50.77, 79.49, 154.39, 217.65; IR (KBr): ν = 638, 771, 877, 1118, 1166, 1247, 1367, 1402, 1691, 1741, 2877, 2910, 2958, 2976, 3005 cm^–1;

TOFMS: [C₁₂H₁₉NO₃ + H⁺]: calculated 226.1438, found 152.0663 (M-OtBu)⁺ (100%), 170.0755 (M-tBu + H)⁺ (40%), 248.1166 (M + Na)⁺ (5%).

Anal. Calcd for C₁₂H₁₉NO₃: C, 63.98; H, 8.50; N, 6.22. Found: C, 63.89; H, 8.27; N, 5.97.

HPLC conditions were as follows for compound ; Agilent 1100 series, column: YMC J’SPHERE C18 (150 mm X 4.6 mm) 4µm with mobile phases A (0.05% TFA in water) and B (acetonitrile). Detection was at 210 nm, flow was set at 1.0 mL/min, and the temperature was 30 °C (Run time: 45 min). Gradient: 0 min, A = 90%, B = 10%; 5.0 min, A = 90%, B = 10%; 25 min, A = 0%, B = 100%; 30 min, A = 0%, B = 100%, 35 min, A = 90%, B = 10%; 45 min, A = 90%, B = 10%.

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00399

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00399

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tert-Butyl 3a,4,7,7a-Tetrahydro-1H-isoindole-2(3H)-carboxylate

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Feb 042017

tert-Butyl 3a,4,7,7a-Tetrahydro-1H-isoindole-2(3H)-carboxylate

tert-Butyl 3a,4,7,7a-Tetrahydro-1H-isoindole-2(3H)-carboxylate

as a brown oil. % Purity: 93.72% (GC);

¹H NMR (CDCl₃, 400 MHz) δ: 1.47 (s, 9H), 1.89–194 (m, 2H), 2.20–2.33 (m, 4H), 3.08 (dd, J₁ = 6.2 Hz, J₂= 10.2 Hz, 1H), 3.17 (dd, J₁ = 4.8 Hz, J₂ = 10.4 Hz, 1H), 3.37–3.43 (m, 2H), 5.65 (s, 2H);

¹³C NMR (CDCl₃, 100 MHz) δ: 24.63, 24.68, 28.49, 33.35, 34.23, 50.86, 50.92, 78.88, 124.19, 124.50, 155.22;

IR (CHCl₃): ν = 756, 1128, 1170, 1217, 1411, 1685, 2937, 2978, 3009 cm^–1;

TOFMS: [C₁₃H₂₁NO₂ + H⁺]: calculated 224.1645, found 168.0958 (M-tBu + H)⁺ (100%), 246.1382 (M + Na)⁺ (5%).

GC conditions were as follows for compound 4; Agilent GC-FID 7890A, column: ZB-5MSi (30 m X 0.32 mm, 0.25 µm) with injector temperature 250 ºC and detector temperature 280 ºC, diluent was Methanol, Oven temperature was at 70 ºC isocratic for 3 min. then raised up to 250 ºC @ 20 ºC/min then 15 min. hold.

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00399

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00399

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2,2′-(1-(tert-Butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic Acid

spectroscopy, SYNTHESIS, Uncategorized Comments Off

Feb 012017

2,2′-(1-(tert-Butoxycarbonyl)pyrrolidine-3,4-diyl)diacetic Acid

as a white solid. Mp: 162–163 °C, % purity: 94.09% (HPLC);

¹H NMR (DMSO-d₆, 400 MHz) δ: 1.38 (s, 9H), 2.10–2.18 (m, 2H), 2.28–2.32 (m, 2H), 2.49–2.50 (m, 2H, merged with DMSO peak), 2.97–3.03 (m, 2H), 3.33–3.40 (m, 2H), 12.23 (bs, 2H); ¹H NMR (CD₃OD, 400 MHz) δ: 1.46 (s, 9H), 2.26 (ddd, J₁ = 2.8 Hz, J₂ = 9.2 Hz, J₃ = 16.0 Hz, 2H), 2.43 (dd, J₁ = 5.2 Hz, J₂ = 16.0 Hz, 2H), 2.69 (m, 2H), 3.16 (dd, J₁ = 5.2 Hz, J₂ = 10.8 Hz, 2H), 3.49–3.54 (m, 2H);

¹³C NMR (DMSO-d₆, 100 MHz) δ: 28.49, 32.97, 36.49, 37.31, 50.10, 50.20, 78.67, 154.05, 173.96;

IR (KBr): ν = 871, 933, 1143, 1166, 1292, 1411, 1689, 1708, 2881, 2929, 2980, 3001 cm^–1;

TOFMS: [C₁₃H₂₁NO₆ – H⁺]: calculated 286.1296, found 286.1031(100%).

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00399

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00399

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Dimethyl 4,4′-(Benzylazanediyl)(2E,2′E)-bis(but-2-enoate)

spectroscopy, SYNTHESIS, Uncategorized Comments Off

Jan 312017

Dimethyl 4,4′-(Benzylazanediyl)(2E,2′E)-bis(but-2-enoate)

IR (CHCl₃): ν = 758, 1215, 1278, 1437, 1660, 1720, 2806, 2953, 3020, 3421 cm^–1;

¹³C NMR (CDCl₃, 100 MHz) δ: 51.53, 53.42, 58.37, 122.66, 127.28, 128.41, 128.55, 128.76, 138.24, 145.84, 166.58;

¹H NMR (CDCl₃, 400 MHz) δ: 3.23 (dd, J₁ = 1.6 Hz, J₂ = 6.0 Hz, 4H), 3.62 (s, 2H), 3.75 (s, 6H), 6.07 (dt, J₁ = 1.6 Hz, J₂ = 16.0 Hz, 2H), 6.97 (dt, J₁ = 6.0 Hz, J₂ = 16.0 Hz, 2H), 7.25–7.34 (m, 5H-merged with CDCl₃ proton);

TOFMS: [C₁₇H₂₁NO₄ + H⁺]: calculated 304.1543, found 304.1703(100%).

UPLC conditions were as follows for compound 11; Acquity Waters, column: BEH C18 (2.1 mm X 100 mm) 1.7 µm with mobile phases A (0.05% TFA in water) and B (acetonitrile). Detection was at 220 nm, flow was set at 0.4 mL/min, and the temperature was 30 °C (Run time: 9 min). Gradient: 0 min, A = 90%, B = 10%; 0.5 min, A = 90%, B = 10%; 6.0 min, A = 0%, B = 100%; 7.5 min, A = 0%, B = 100%; 7.6 min, A = 90%, B = 10%; 9.0 min, A = 90%, B = 10%.

Dimethyl 4,4′-(Benzylazanediyl)(2E,2′E)-bis(but-2-enoate) (11)

as a yellow oil. % purity: 93.4% (UPLC);

¹³C NMR (CDCl₃, 100 MHz) δ: 51.53, 53.42, 58.37, 122.66, 127.28, 128.41, 128.55, 128.76, 138.24, 145.84, 166.58;

IR (CHCl₃): ν = 758, 1215, 1278, 1437, 1660, 1720, 2806, 2953, 3020, 3421 cm^–1;

TOFMS: [C₁₇H₂₁NO₄ + H⁺]: calculated 304.1543, found 304.1703(100%).

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00399

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00399

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1-Bromo-4-fluoro-2-((2-iodobenzyl)oxy)benzene

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Jan 252017

1-Bromo-4-fluoro-2-((2-iodobenzyl)oxy)benzene

CAS 1161931-51-6

Mp 89.8–92.3 °C.

IR (neat, ATR): 3072 (w), 1482 (s), 1451 (s), 1294 (s), 1294 (s) cm^–1.

¹H NMR (399 MHz, DMSO-d₆) δ 5.12 (s, 2H), 6.81 (td, J = 8.49, 2.77 Hz, 1H), 7.14 (td, J = 7.64, 1.65 Hz, 1H), 7.18 (dd, J = 10.90, 2.82 Hz, 1H), 7.46 (td, J = 7.52, 0.92 Hz, 1H), 7.60 (dd, J = 7.64, 1.41 Hz, 1H), 7.62 (dd, J = 8.66, 6.23 Hz, 1H), 7.92 (dd, J = 7.83, 0.83 Hz, 1H).

¹³C NMR (100 MHz, DMSO-d₆) δ 74.5, 99.2, 102.4 (d, J = 27.1 Hz), 105.8 (d, J = 3.4 Hz), 108.9 (d, J = 22.5 Hz), 128.5, 129.8, 130.3, 133.6 (d, J = 9.9 Hz), 138.0, 139.2, 155.4 (d, J = 10.7 Hz), 162.2 (d, J = 244.3 Hz).

GCMS: m/z [M]⁺ calcd for C₁₃H₉BrFIO: 405.88600; found: 405.88620.

1H AND 13C NMR PREDICT

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00368

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

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Brc2ccc(F)cc2OCc1ccccc1I

One-Pot Reductive Cyclisations of Nitroanilines to Imidazoles

spectroscopy, SYNTHESIS, Uncategorized Comments Off

Jan 252017

Hana and co-workers ( Synlett 2010, 18, 2759−2764) from Genentech have developed a single-step procedure for conversion of 2-nitro aromatic amines to benzimidazoles. Addition of ammonium chloride proved necessary as Fe powder and formic acid alone was ineffective for nitro reduction. These conditions were compatible with a variety of functional groups on the aromatic, including boronate esters. The methodology was also extended to nitro aminopyridines but failed to deliver the desired product with isoxazole or pyrazole reactants.

Mild and General One-Pot Reduction and Cyclization of Aromatic and Heteroaromatic 2-Nitroamines to Bicyclic 2H-Imidazoles

Emily J. Hanan*, Bryan K. Chan, Anthony A. Estrada, Daniel G. Shore, Joseph P. Lyssikatos

*Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA, Email: hanan.emilygene.com

E. J. Hanan, B. K. Chan, A. A. Estrada, D. G. Shore, J. P. Lyssikatos, Synlett, 2010, 2759-2764.

DOI: 10.1055/s-0030-1259007

see article for more reactions

Abstract

A one-pot procedure for the conversion of aromatic and heteroaromatic 2-nitroamines into bicyclic 2H-benzimidazoles employs formic acid, iron powder, and NH₄Cl as additive to reduce the nitro group and effect the imidazole cyclization with high-yielding conversions generally within one to two hours. The compatibility with a wide range of functional groups demonstrates the general utility of this procedure.

see article for more examples

//////////One-Pot, Reductive Cyclisations, Nitroanilines, Imidazoles

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent

Telcagepant Revisited

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Jan 252017

Telcagepant, MK-0974

Molecular FormulaC₂₆H₂₇F₅N₆O₃
Average mass566.523 Da

1-piperidinecarboxamide, N-[(3R,6S)-6-(2,3-difluorophenyl)hexahydro-2-oxo-1-(2,2,2-trifluoroethyl)-1H-azepin-3-yl]-4-(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]pyridin-1-yl)-

CAS 781649-09-0

ChemSpider 2D Image | Telcagepant | C26H27F5N6O3

OriginatorMerck & Co
ClassAntimigraines; Piperidines
Mechanism of ActionCalcitonin gene-related peptide receptor antagonists

Migraine is a neurovascular disorder characterized by severe, debilitating, and throbbing unilateral headache. Though a leading cause of disability, it is a highly prevalent disease with a clear unmet medical need. With the significant progress achieved in the field of pathophysiology in the past decades, to date, it is well recognized that the neuropeptide calcitonin gene-related peptide (CGRP), which is expressed mainly in the central and peripheral nervous system, plays a crucial role in migraine. Antagonism of CGRP receptors, as a potential new therapy for the treatment of migraine, could offer the advantage of avoiding the cardiovascular liabilities associated with other existing antimigraine therapies.

Image result for Telcagepant

Telcagepant (INN) (code name MK-0974) is a calcitonin gene-related peptide receptor antagonist which was an investigational drug for the acute treatment and prevention of migraine, developed by Merck & Co. In the acute treatment of migraine, it was found to have equal potency to rizatriptan^[1] and zolmitriptan^[2] in two Phase III clinical trials. The company has now terminated development of the drug.

Mechanism of action

The calcitonin gene-related peptide (CGRP) is a strong vasodilator primarily found in nervous tissue. Since vasodilation in the brain is thought to be involved in the development of migraine and CGRP levels are increased during migraine attacks, this peptide may be an important target for potential new antimigraine drugs.

Telcagepant acts as a calcitonin gene-related peptide receptor (CRLR) antagonist and blocks this peptide. It is believed to constrict dilated blood vessels within the brain.^[3]

Termination of a clinical trial

A Phase IIa clinical trial studying telcagepant for the prophylaxis of episodic migraine was stopped on March 26, 2009 after the “identification of two patients with significant elevations in serum transaminases”.^[4] A memo to study locations stated that telcagepant had preliminarily been reported to increase the hepatic liver enzyme alanine transaminase (ALT) levels in “11 out of 660 randomized (double-blinded) study participants.” All study participants were told to stop taking the medication.^[5]

On July 29, 2011, it was reported that Merck & Co. were discontinuing the clinical development program for telcagepant. According to Merck, “[t]he decision is based on an assessment of data across the clinical program, including findings from a recently completed six-month Phase III study”.^[6]

CLIP

Image result for telcagepant

CLIP

Image result for telcagepant

CLIP

Asymmetric Synthesis of Telcagepant

http://pubs.acs.org/doi/abs/10.1021/jo101704b

Abstract Image

As part of the process of bringing a new API to market, it is often required to use an alternative synthetic strategy to the initial medicinal chemistry approach. Here Xu et al. of Merck Rahway disclose their efforts towards an improved multikilogram synthesis of telcagepant, a CGRP receptor antagonist for the treatment of migraines ( J. Org. Chem. 2010, 75, 7829−7841). The route described in the report is an example of a synthetic target driving the discovery of new chemistries.

Of note are the challenges they faced and overcame in particular the asymmetric Michael addition of nitromethane to a cinnamyl aldehyde. Initial attempts under Hayashi’s conditions gave promising results (50−75% yield) and moreover confirmed a high enantioselectivity could be achieved using the Jorgensen−Hayashi catalyst. However, the use of benzoic acid as the acidic cocatalyst gave rise to undesired byproducts. After performing a comprehensive screen of conditions Xu showed that the combination of the weak acids t-BuCO₂H (5 mol %) and B(OH)₃(50 mol %) minimized the level of impurities. Of specific note is that this is the first reported application of iminium organocatalysis on industrial scale.

The second milestone achieved in the strategy was the prevention of the protodefluorination under hydrogenative conditions. During the initial studies between 1.06−2.5% of the desfluoro compounds were formed by using Pd(OH)₂/C in 100% conversion. To suppress the by product formation Xu screened a range of inorganic additives and found that 0.3 eq of LiCl gave a reproducible reaction where less than 0.2% of the desfluoro compounds were generated.

telcagepant as its crystalline potassium salt ethanol solvate in 92% yield with >99.9% purity and >99.9% ee.

¹H NMR (400 MHz, d₄-MeOH): δ 7.75 (dd, J = 5.3, 1.4 Hz, 1 H), 7.38 (dd, J = 7.6, 1.4 Hz, 1 H), 7.15 (m, 3 H), 6.70 (dd, J = 7.6, 5.3 Hz, 1 H), 4.85 (d, J = 11.4 Hz, 1 H), 4.55 (m, 1 H), 4.45 (dq, J = 15.4, 9.5 Hz, 1 H), 4.27 (m, 3 H), 4.05 (dq, J = 15.4, 9.0 Hz, 1 H), 3.61 (q, J = 7.1 Hz, 2 H), 3.46 (d, J = 15.4 Hz, 1 H), 3.16 (m, 1 H), 3.0 (m, 2 H), 2.42 (dq, J = 12.7, 4.4 Hz, 1 H), 2.27 (dq, J = 12.7, 4.4 Hz, 1 H), 2.16 (m, 3 H), 1.81 (m, 3 H). 1.18 (t, J = 7.1 Hz, 3 H).

¹³C NMR (100 MHz, d₄-MeOH): δ 176.8, 166.1, 159.3, 157.4, 152.1 (dd, J = 246.8, 13.6 Hz), 149.4 (dd, J = 245.1, 13.1 Hz), 139.2, 134.7 (d, J = 11.9 Hz), 127.7, 126.3 (q, J = 279.7 Hz), 126.2 (dd, J = 7.1, 4.8 Hz), 124.3 (t, J = 3.4 Hz), 116.8 (d, J = 17.1 Hz), 114.5, 113.8, 58.5, 55.3, 55.2, 51.6, 49.9 (q, J = 33.6 Hz), 45.4, 45.3, 39.8, 35.9, 32.7, 30.74, 30.72, 18.5.

References

Jump up^ Ho, Tw; Mannix, Lk; Fan, X; Assaid, C; Furtek, C; Jones, Cj; Lines, Cr; Rapoport, Am; Mk-0974, Protocol, 004, Study, Group (Apr 2008). “Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine”. Neurology. 70 (16): 1304–12. doi:10.1212/01.WNL.0000286940.29755.61. PMID 17914062.
Jump up^ Ho TW, Ferrari MD, Dodick DW, et al. (December 2008). “Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial”. Lancet. 372 (9656): 2115–23. doi:10.1016/S0140-6736(08)61626-8. PMID 19036425.
Jump up^ Molecule of the Month February 2009
Jump up^ Clinical trial number NCT00797667 for “MK0974 for Migraine Prophylaxis in Patients With Episodic Migraine” at ClinicalTrials.gov
Jump up^ Merck & Co.: Memo to all US study locations involved in protocol MK0974-049
Jump up^ Merck Announces Second Quarter 2011 Financial Results

Telcagepant
Clinical data


Routes of administration	Oral
ATC code	none
Legal status
Legal status	Development terminated
Pharmacokinetic data
Biological half-life	5–8 hours
Identifiers
IUPAC name [show]
CAS Number	781649-09-0
PubChem (CID)	11319053
IUPHAR/BPS	703
ChemSpider	9494017
UNII	D42O649ALL
KEGG	D09391
ChEMBL	CHEMBL236593
Chemical and physical data
Formula	C₂₆H₂₇F₅N₆O₃
Molar mass	566.5283 g/mol
3D model (Jmol)	Interactive image

1 to 10 of 14

Patent ID	Patent Title	Submitted Date	Granted Date
US7534784	CGRP receptor antagonists	2008-11-13	2009-05-19
US7452903	CGRP receptor antagonists	2007-09-27	2008-11-18
US7235545	CGRP receptor antagonists	2005-11-17	2007-06-26
US6953790	CGRP receptor antagonists	2004-11-18	2005-10-11

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US8394767	Methods of treating cancer using the calcitonin-gene related peptide (â??CGRPâ??) receptor antagonist CGRP8-37	2011-01-10	2013-03-12
US8080544	PRODRUGS OF CGRP RECEPTOR ANTAGONISTS	2010-11-25	2011-12-20
US7893052	CGRP RECEPTOR ANTAGONISTS	2010-11-25	2011-02-22
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US7772224	CGRP RECEPTOR ANTAGONISTS	2009-07-30	2010-08-10
US7745427	Cgrp Receptor Antagonists	2008-04-17	2010-06-29
US7718796	Process for the preparation of Caprolactam Cgrp Antagonist	2009-05-14	2010-05-18
US2010009967	SOLID DOSAGE FORMULATIONS OF TELCAGEPANT POTASSIUM	2010-01-14
US2009176986	Process for the Preparation of Pyridine Heterocycle Cgrp Antagonist Intermediate	2009-07-09

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