MODANAFIL

Efficient atom and step economic (EASE) synthesis of the "smart drug" Modafinil

Green Chem., 2017, Advance Article
DOI: 10.1039/C6GC02623K, Communication

Shivam Maurya, Dhiraj Yadav, Kemant Pratap, Atul Kumar
We developed a post-sulfoxidation protocol for the synthesis of Modafinil that exhibits improved sustainability credentials, utilizing the recyclable heterogeneous catalyst Nafion-H.

Efficient atom and step economic (EASE) synthesis of the “smart drug” Modafinil

Shivam Maurya,^ab   Dhiraj Yadav,^a   Kemant Pratap^ab and  Atul Kumar*^ab  

 *Corresponding authors

^aMedicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, P.O. Box 173, Lucknow 226031, India
E-mail: dratulsax@gmail.com, atul_kumar@cdri.res.in

^bAcademy of Scientific and Innovative Research, New Delhi 110001, India

Green Chem., 2017, Advance Article

DOI: 10.1039/C6GC02623K

http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C6GC02623K?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

Atul Kumar

Professor, Academy of Scientific and Innovative Research (AcSIR)/ Senior Principal Scientist at CSIR-CDRI

Central Drug Research Institute

Medicinal and Process Chemistry Division (CDRI)

Lucknow, Uttar Pradesh, India

Modafinil (2-[(diphenylmethyl)sulfinyl]acetamide, MOD) is a key psychostimulant drug used for the treatment of narcolepsy and other sleep disorders that has a very low addiction liability. Recently, MOD has been clinically investigated for the treatment of cocaine addiction and used by astronauts in long-term space missions. We have developed a synthetic strategy for “smart drug” Modafinil. An efficient atom and step economic (EASE) synthesis has been carried out by the direct reaction of benzhydrol and 2-mercaptoacetamide using the recyclable heterogeneous catalyst Nafion-H along with post-sulfoxidation. This protocol exhibits improved sustainability credentials. We have also developed a superior pre-sulfoxidation approach for the synthesis of Modafinil.

Modafinil Physical State – White solid; M.p. 158-159ºC,

IR (KBr): 3383, 3314, 3256, 1690, 1 1616, 1494, 1376, 1027, 702 cm-1;

H NMR (CDCl3) δ(ppm): 3.14(d, J=14.3 Hz, 1H); 3.48(d, J=14.3 Hz, 1H); 5.24(s, 1H); 5.88(br s, 1H); 7.09(br s, 1H); 7.29-7.43(m, 7H); 7.43-7.51(m, 3H);

13C NMR (CDCl3) δ(ppm): 52.00, 71.61, 128.80, 128.98, 129.10, 129.58, 129.62, 134.30, 134.74, + 166.46; Molecular formula C15H15NO2S;

ESI-MS (m/z): 274.1 (M+H) .

Dr. Atul Kumar

Senior Principal Scientist

///////Efficient atom,  step economic (EASE) synthesis, Modafinil

OMARIGLIPTIN INTERMEDIATE

N-[(2R,3S)-2-(2,5-Difluorophenyl)tetrahydro-5-oxo-2H-pyran-3-yl]carbamic Acid 1,1-Dimethylethyl Ester

Chemical name:	N-[(2R,3S)-2-(2,5-Difluorophenyl)tetrahydro-5-oxo-2H-pyran-3-yl]carbamic Acid 1,1-Dimethylethyl Ester
Synonyms:	tert-Butyl-((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)carbamate
CAS Number:	951127-25-6
Molecular form.:	C₁₆H₁₉F₂NO₄
Mol. Weight:	327.32

Applications:	N-[(2R,3S)-2-(2,5-Difluorophenyl)tetrahydro-5-oxo-2H-pyran-3-yl]carbamic Acid 1,1-Dimethylethyl Ester is a useful synthetic intermediate in the synthesis of Omarigliptin (O633100); a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor used for the treatment of type 2 diabetes.
References:	Biftu, T., et. al.: J. Med. Chem., 57, 3205 (2014)

tert-butyl ((2R,3S)-2-(2,5-difluorophenyl)-5-oxotetrahydro-2H-pyran-3-yl)carbamate

 1 with dr>99:1, >99.9% ee, 94.12% purity in 70.8% yield from 11.


1H NMR (600 MHz, CDCl3) δ 7.21 (d, J = 3.3 Hz, 1H), 7.06 - 6.93 (m, 2H), 4.82 (s, 1H), 4.65 (s, 1H), 4.28 (dd, J = 16.3, 1.6 Hz, 1H), 4.16-4.00 (m, 2H), 3.09-2.99 (m, 1H), 2.72 (s, 1H), 1.30 (s, 9H).

13C NMR (151 MHz, CDCl3) δ 205.12(s), 159.54 (d, J= 243.1 Hz), 156.78 (d, J= 244.1 Hz), 154.97 (s), 127.82 (dd, J= 16.0, 7.7 Hz), 117.01 (dd, J= 24.3, 8.8 Hz), 115.42 (s), 115.23 (s), 80.70 (s), 75.61 (s), 75.01 (s), 52.91 (s), 45.31 (s), 28.66 (s).


HRMS [M+H-isobutylene]+ for C16H19F2NO4 calculated 272.0729; found 272.0739. [α]25 D = +4.92 (c = 1.0 in MeOH);

Melting range: 158 oC-160 oC.

13C NMR

1H NMR

1H NMR PREDICT

13C NMR PREDICT

An alternative scalable process for the synthesis of the key intermediate of omarigliptin is described. The asymmetric synthesis relies on the initial diastereoselective alkylation and subsequent aluminum-catalyzed substrate-controlled Meerwein–Ponndorf–Verley reduction. A highly regioselective 5-exo-dig iodocyclization followed to afford 11b, which was then subjected to ring-opening cycloetherification to give product 1 with >99:1 dr and >99% ee in 31.2% overall yield in nine steps. This synthetic strategy has been successfully applied for multikilogram scale production

An Alternative Scalable Process for the Synthesis of the Key Intermediate of Omarigliptin

Guodong Sun, Mingjie Wei, Zhonghua Luo, Yongjun Liu, Zhijun Chen, and Zhongqing Wang*

HEC Research and Development Center, HEC Pharm Group, Dongguan 523871, P. R. China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00295

Publication Date (Web): November 23, 2016

Copyright © 2016 American Chemical Society

*E-mail: wangzhongqing@hecpharm.com.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.6b00295

//////////////c1c(c(ccc1F)F)[C@@H]2C(CC(CO2)=O)NC(=O)OC(C)(C)C

L-Perfluoro-tert-butyl tyrosine

1H NMR (400 MHz, CD3OD) δ 7.35-7.32 (dd, J = 5.5 Hz, 5.2 Hz, 2H), 7.11-7.06
(dd, J = 8.7 Hz, 8.7 Hz, 2H), 3.78-3.75 (dd, J = 6.4 Hz, 6.1 Hz, 1H), 3.28-3.27 (d, J = 4.4 Hz,
1H), 3.06-3.00 (m, 1H).


13C NMR (150.8 MHz, CD3OD) δ 169.7, 163.7, 161.2, 131.1, 131.0,
130.8, 130.2, 123.5, 115.5, 115.3, 53.7, 35.0.


19F NMR (376.3 MHz, CD3OD) δ -70.27.

 HRMS
(HESI) m/z: [M]+ calcd for C13H11F9NO3 400.05998, found 400.05897.

1H NMR predict

13 C NMR PREDICT

Synthesis of Perfluoro-tert-butyl Tyrosine, for Application in 19F NMR, via a Diazonium-Coupling Reaction

Caitlin M. Tressler and Neal J. Zondlo*

Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States

Org. Lett., Article ASAP

DOI: 10.1021/acs.orglett.6b02858

Publication Date (Web): December 6, 2016

Copyright © 2016 American Chemical Society

*E-mail: zondlo@udel.edu.

http://pubs.acs.org/doi/suppl/10.1021/acs.orglett.6b02858

Abstract

A practical synthesis of the novel highly fluorinated amino acid Fmoc-perfluoro-tert-butyl tyrosine was developed. The sequence proceeds in two steps from commercially available Fmoc-4-NH2-phenylalanine via diazotization followed by diazonium coupling reaction with perfluoro-tert-butanol. In peptides, perfluoro-tert-butyl tyrosine was detected in 30 s by NMR spectroscopy at 500 nM peptide concentration due to nine chemically equivalent fluorines that are a sharp singlet by 19F NMR. Perfluoro-tert-butyl ether has an estimated σp Hammett substituent constant of +0.30.

//////////

Lumefantrine

lumefantrine

2-(dibutylamino)-1-[(9Z)-2,7-dichloro-9-[(4-chlorophenyl)methylidene]-9H-fluoren-4-yl]ethan-1-ol

(±)-2,7-Dichloro-9-((Z)-p-chlorobenzylidene)-α-((dibutylamino)methyl)fluorene-4-methanol

2-Dibutylamino-1-[2,7-dichloro-9-(4-chloro-benzylidene)-9H-fluoren-4-yl]-ethanol

2-Dibutylamino-1-{2,7-dichloro-9-[1-(4-chloro-phenyl)-meth-(Z)-ylidene]-9H-fluoren-4-yl}-ethanol

Benflumetol

dl-Benflumelol

UNII F38R0JR742
CAS number 82186-77-4
Weight Average: 528.94
Monoisotopic: 527.154947772
Chemical Formula C30H32Cl3NO

Lumefantrine (or benflumetol) is an antimalarial drug. It is only used in combination with artemether. The term "co-artemether" is sometimes used to describe this combination.^[1] Lumefantrine has a much longer half-life compared to artemether and so is therefore thought to clear any residual parasites that remain after combination treatment.^[2]

Lumefantrine, along with pyronaridine and naphtoquine, were synthesized in course of the Project 523 antimalaria drug research initiated in 1967; these compounds are all used in combination antimalaria therapies.^[3][4][5]

Lumefantrine is an antimalarial drug chemically known as 2-(dibutylamino)-1-[(9Z)-2, 7-dichloro-9-(4- chlorobenzylidene)-9H-floren-4-yl] ethanol, which is used in the prevention and treatment of Malaria in worm blooded animals. Lumefantrine is using the combination of β-Artemether in the treatment of Malaria

http://derpharmachemica.com/vol8-iss3/DPC-2016-8-3-91-100.pdf

REFERENCES

[1] Ulrich Beutler, C Peter.; Fuenfschilling.; and Andreas, Steinkemper.; Novartis Pharma AG; Chemical and Analytical Development: CH-4002 Basel, Switzerland, Organic Process Research & Development 2007, 11, 341- 345.

[2] Boehm, M. Fuenfschilling.; Krieger, P. C.; Kuesters, E. M.; Struber, F.; Org. Process Res. DeV. 2007, 11, 336- 340.

[3] (a) Rao, D. R.; Kankan, R. N.; Phull, M. S.; Patent Application CN 1009-3724 20060424, 2005. (b) Deng, R.; Zhong, J.; Zhao, D.; Wang, J.; Yaoxue, X. 2000, 35 (1), 22. (c) Allmendinger, Th.; Wernsdorfer, W. H. PCT WO 99/67197.

[4] Perrumattam, J.; Shao, Ch.; Confer, W. L. Synthesis 1994, 1181.

[5] Fuenfschilling, P. C.; Hoehn P.; Mutz J.-P. Organic Process Res. Dev. 2007, 11, 13.

[6] Di Nunno, L.; Scilimati, A. Tetrahedron 1988, 44, 3639.

[7] Pharmacopeial Forum, Vol. 36(2) [Mar.-Apr. 2010]

Preparation of 2-(dibutylamino)-1-[(9Z)-2, 7-dichloro-9-(4-chlorobenzylidene)-9H-floren-4-yl] ethanol (Lumefantrine) 1.

To a stirred solution of NaOH (1.97 g 0.0492 mol) in methanol (100 ml) there was added 1-(2, 7- dichloro-9 H-fluren-4-yl)-2-(dibutyl amino) ethanol (10 g, 0.0246 mol) and para chloro benzaldehyde (5.24 g 0.0372). The suspension obtained was stirred at reflux temperature till the absence of starting material by TLC. After confirming the product formation reaction mixture was cooled to room temperature and further stirred at same temperature for overnight. The precipitated solids were filtered and washed with methanol and dried under vacuum at 50°C to get desired compound.  (Purity by HPLC: 99%).

IR (cm-1): 3408, 3092, 2953, 2928, 2870, 2840, 1634, 1589, 1487, 1465, 1443, 1400, 1365, 1308, 1268, 1241, 1207, 1173, 1156, 1085, 1071, 1014, 980, 933, 874, 839, 815, 806, 770;

1H NMR (CDCl3, δ ppm): 7.75 (d, 1H, CH, J 1.5 Hz), 7.68 (d, 1H, CH, J 1.5 Hz), 7.60-7.63 (m, 1H, CH), 7.32-7.35 (dd, 1H, CH, J 1.7,8.3 Hz), 7.45-7.50 (m, 1H, CH), 5.35-5.39 (dd, 1H, CH, J 3.0,9.9 Hz), 2.41-2.74 (m, 1H, CH2Ha), 2.86-2.92 (m, 1H, CH2Hb), 2.41-2.74 (m, 4H, CH2), 1.25-1.56 (m, 8H, CH2), 0.97 (t, 1H, CH, J 7.2 Hz), 7.60-7.63 (m, 1H, CH), 7.45-7.50 (m, 4H, CH), 4.54 (broad, 1H, OH),

13C NMR (CDCl3, δ ppm): 138.2, 141.5, 120.6, 133.2, 126.3, 135.0, 135.0, 136.4, 123.9, 128.3, 132.8, 123.0, 139.8, 65.5, 60.0, 53.5, 29.1, 20.6, 14.0, 127.6, 134.7, 130.5, 129.1, 133.2;

MS: m/z: 528 [M+H]+ ; Analysis calcd. for C30H32Cl3NO: C, 68.12; H, 6.10; N, 2.65% Found: C, 68.38; H, 6.14; N, 2.63 %.

CLIP

One-dimensional 1H NMR spectrum of B) a lumefantrine standard,

A CLIP

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532012000100010&lng=en&nrm=iso

CLIP

A simple and precise method for quantitative analysis of lumefantrine ...

https://www.ncbi.nlm.nih.gov › NCBI › Literature › PubMed Central (PMC)

by P Hamrapurkar - ‎2010 - ‎Cited by 2 - ‎Related articles

[2–4] Thus, today lumefantrine is a drug of choice in antimalarial treatment against P. .... The NMRspectra observed triplet at 0.943-0.989 (methyl protons of alkyl ...

The spectroscopic techniques were used to confirm the identity of lumefantrine. The IR spectra, showed strong absorption band at 3404.67 cm^-1 (OH), 2953.28 cm^-1 (aliphatic and aromatic CH), 1757.31 cm^-1 (-C=C-), 933 cm^-1 (alkanes) and 696.37-373.22 cm^-1 (Cl). Thus, IR spectra confirmed the presence of these functional groups in the structure of lumefantrine.

The mass spectrum showed a sharp molecular ion peak at 528.0 m/z in Q1 MS (m/z, parent ion) parameter at negative polarity confirming the molecular weight of lumefantrine.

The NMR spectra observed triplet at 0.943-0.989 (methyl protons of alkyl chain); a multiplet at 1.372-1.498 (methylene protons of alkyl chains); a multiplet at 2.449-2.909 (methylene protons of alkyl chain); broad singlet at 4.573 (OH proton); and multiplet at 7.314-7.733 (aromatic proton), thus confirming identity of lumefantrine.

 IH NMR PREDICT

 

13C NMR PREDICT

References

1. Jump up^ Toovey S, Jamieson A, Nettleton G (2003). "Successful co-artemether (artemether-lumefantrine) clearance of falciparum malaria in a patient with severe cholera in Mozambique". Travel medicine and infectious disease. 1 (3): 177–9. doi:10.1016/j.tmaid.2003.09.002. PMID 17291911.
2. Jump up^ White, Nicholas J.; van Vugt, Michele; Ezzet, Farkad (1999). "Clinical Pharmacokinetics and Pharmacodynamics of Artemether-Lumefantrine". Clinical Pharmacokinetics. 37 (2): 105–125. doi:10.2165/00003088-199937020-00002. ISSN 0312-5963.
3. Jump up^ Cui, Liwang; Su, Xin-zhuan (2009). "Discovery, mechanisms of action and combination therapy of artemisinin". Expert Review of Anti-infective Therapy. 7 (8): 999–1013. doi:10.1586/eri.09.68. PMC 2778258. PMID 19803708.
4. Jump up^ http://aac.asm.org/content/56/5/2465.full
5. Jump up^ Laman, M; Moore, BR; Benjamin, JM; Yadi, G; Bona, C; Warrel, J; Kattenberg, JH; Koleala, T; Manning, L; Kasian, B; Robinson, LJ; Sambale, N; Lorry, L; Karl, S; Davis, WA; Rosanas-Urgell, A; Mueller, I; Siba, PM; Betuela, I; Davis, TM (2014). "Artemisinin-naphthoquine versus artemether-lumefantrine for uncomplicated malaria in Papua New Guinean children: an open-label randomized trial". PLoS Med. 11: e1001773. doi:10.1371/journal.pmed.1001773. PMC 4280121. PMID 25549086.

Lumefantrine

Clinical data
AHFS/Drugs.com	International Drug Names
MedlinePlus	a609024
Routes of administration	Oral
ATC code	P01BF01 (WHO) (combination with artemether)
Legal status
Legal status	US: C
Identifiers
IUPAC name[show]
CAS Number	82186-77-4
PubChem (CID)	6437380
DrugBank	DB06708
ChemSpider	4941944
UNII	F38R0JR742
KEGG	D03821
ChEBI	CHEBI:156095
ChEMBL	CHEMBL38827
Chemical and physical data
Formula	C30H32Cl3NO
Molar mass	528.939 g/mol
3D model (Jmol)	Interactive image

Title: Lumefantrine

CAS Registry Number: 82186-77-4

CAS Name: (9Z)-2,7-Dichloro-9-[(4-chlorophenyl)methylene]-a-[(dibutylamino)methyl]-9H-fluorene-4-methanol

Additional Names: 2-dibutylamino-1-[2,7-dichloro-9-(4-chlorobenzylidene)-9,11-fluoren-4-yl]ethanol; dl-benflumelol; benflumetol; BFL

Manufacturers' Codes: CPG-56695

Molecular Formula: C30H32Cl3NO

Molecular Weight: 528.94

Percent Composition: C 68.12%, H 6.10%, Cl 20.11%, N 2.65%, O 3.02%

Literature References: Racemic aryl alcohol originally synthesized in the 1970's by the Academy of Military Medical Sciences in Beijing, China. Inhibits hemozoin formation. Prepn: R. Deng et al., CN 1042535 (1990 to Acad. Military Med. Sci., Microbiol. & Epidemic Dis. Instit.); C.A. 114, 6046 (1991). LC determn in plasma: A. Annerberg et al., J. Chromatogr. B 822, 330 (2005). In vitro activity against Plasmodium falciparum: B. Pradines et al., Antimicrob. Agents Chemother. 43, 418 (1999).

Properties: Odorless, yellow powder. Poorly sol in water, oil, and most organic solvents. Sol in unsaturated fatty acids.

 

Derivative Type: Co-artemether

CAS Registry Number: 141204-94-6

Manufacturers' Codes: CPG-56697

Trademarks: Coartem (Novartis); Riamet (Novartis)

Literature References: Fixed 6:1 mixture with artemether, q.v. Clinical pharmacokinetics and bioavailability: F. Ezzet et al., Br. J. Clin. Pharmacol. 46, 553 (1998). Clinical trial in children against P. falciparum malaria: C. Hatz et al., Trop. Med. Int. Health 3, 498 (1998); in adults: S. Looareesuwan et al., Am. J. Trop. Med. Hyg. 60, 238 (1999). Review of comparative clinical trials in malaria: A. A. Omari et al., Trop. Med. Int. Health 9, 192-199 (2004).

 

Therap-Cat: Antimalarial.

Keywords: Antimalarial.

///////////lumefantrine

CCCCN(CCCC)CC(O)C1=C2C(=CC(Cl)=C1)\C(=C/C1=CC=C(Cl)C=C1)C1=C2C=CC(Cl)=C1