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Saturday 10 December 2016

OMARIGLIPTIN INTERMEDIATE



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



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:




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





Abstract Image
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

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

Tuesday 6 December 2016

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

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.

Abstract

Abstract Image
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.

//////////

Monday 5 December 2016

Lumefantrine

Image result for lumefantrine synthesis
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]
Image result for lumefantrine synthesis
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
str0
One-dimensional 1H NMR spectrum of B) a lumefantrine standard,
A CLIP
Image result for lumefantrine synthesis
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 ...
str0
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

 str0

str1

13C NMR PREDICT
str0

str1
Image result for lumefantrine synthesis
Image result for lumefantrine synthesis

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 disease1 (3): 177–9. doi:10.1016/j.tmaid.2003.09.002PMID 17291911.
  2. Jump up^ White, Nicholas J.; van Vugt, Michele; Ezzet, Farkad (1999). "Clinical Pharmacokinetics and Pharmacodynamics of Artemether-Lumefantrine". Clinical Pharmacokinetics37 (2): 105–125. doi:10.2165/00003088-199937020-00002ISSN 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 Therapy7 (8): 999–1013. doi:10.1586/eri.09.68PMC 2778258Freely accessiblePMID 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 Med11: e1001773. doi:10.1371/journal.pmed.1001773PMC 4280121Freely accessiblePMID 25549086.
Lumefantrine
Lumefantrine.svg
Clinical data
AHFS/Drugs.comInternational Drug Names
MedlinePlusa609024
Routes of
administration
Oral
ATC codeP01BF01 (WHO) (combination with artemether)
Legal status
Legal status
  • US: C
Identifiers
CAS Number82186-77-4 
PubChem (CID)6437380
DrugBankDB06708 Yes
ChemSpider4941944 Yes
UNIIF38R0JR742 Yes
KEGGD03821 Yes
ChEBICHEBI:156095 Yes
ChEMBLCHEMBL38827 Yes
Chemical and physical data
FormulaC30H32Cl3NO
Molar mass528.939 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

Wednesday 30 November 2016

1-(2-Methoxyphenoxy)-2,3-epoxypropane



Abstract Image

An efficient process for the preparation of 1-(2-methoxyphenoxy)-2,3-epoxypropane, a key intermediate for the synthesis of ranolazine is described.

http://pubs.acs.org/doi/suppl/10.1021/op300056k

str0


Preparation of 1-(2-Methoxyphenoxy)-2,3-epoxypropane 4.
To a stirring solution of 2-methoxy phenol 2 (10 kg, 80.55 mol) and water (40 L) at about 30 °C was added sodium hydroxide (1.61 kg, 40.25 mol) and water (10 L). After stirring for 30−45 min, epichlorohydrin 3 (22.35 kg, 241.62 mol) was added and stirred for 10−12 h at 25−35 °C. Layers were separated, and water (40 L) was added to the organic layer (bottom layer) containing product. Sodium hydroxide solution (3.22 kg, 80.5 mol) and water (10 L) were added at 27 °C and stirred for 5−6 h at 27 °C.
The bottom product layer was separated and washed with sodium hydroxide solution (3.0 kg 75 mol) and water (30 L). Excess epichlorohydrin (3) was recovered by distillation of the product layer at below 90 °C under vacuum (650−700 mmHg) to give 13.65 kg (94%) of title compound with 98.3% purity by HPLC, 0.2% of 2- methoxy phenol 2, 0.1% of epichlorohydrin 3, 0.1% of chlorohydrin 11, 0.3% of dimer 12 and 0.3% of dihydroxy 13.

1 H NMR (400 MHz, CDCl3, δ) 6.8−7.0 (m, 4H), 4.3 (dd, J = 5.6 Hz, 5.4 Hz, 1H), 3.8 (dd, J = 5.6 Hz, 5.3 Hz, 1H), 3.7 (s, 3H), 3.2−3.4 (m, 1H), 2.8 (dd, J = 5.6 Hz, 5.4 Hz, 1H), 2.7 (dd, J = 5.6 Hz, 5.3 Hz, 1H);

IR (KBr, cm−1 ) 2935 (C−H, aliphatic), 1594 and 1509 (CC, aromatic), 1258 and 1231 (C−O−C, aralkyl ether), 1125 and 1025 (C−O−C, epoxide);

MS (m/z) 181 (M+ + H).



Compound Details

Properties
MWt180.2
MFC10H12O3

CAS 2210-74-4
Glycidyl 2-methoxyphenyl ether


Guaiacol glycidyl ether









1H NMR PREDICT

13C NMR PREDICT




COSY PREDICT







logo
CREDIT..........http://www.molbase.com/en/synthesis_2210-74-4-moldata-95563.html




str0
RakeshwarBandichhor
DR REDDYS LABORATORIES

An Efficient Synthesis of 1-(2-Methoxyphenoxy)-2,3-epoxypropane: Key Intermediate of β-Adrenoblockers

 Innovation Plaza, IPD, R&D, Dr. Reddy’s Laboratories Ltd., Survey Nos. 42, 45,46, and 54, Bachupally, Qutubullapur – 500073, Andhra Pradesh, India
 Institute of Science and Technology, Center for Environmental Science, JNT University, Kukatpally, Hyderabad – 500 072, Andhra Pradesh, India
Org. Process Res. Dev.201216 (10), pp 1660–1664
DOI: 10.1021/op300056k
Publication Date (Web): September 14, 2012
Copyright © 2012 American Chemical Society
*Telephone: +91 4044346000. Fax: +91 4044346285. E-mail: rakeshwarb@drreddys.com.

////////////////1-(2-Methoxyphenoxy)-2,3-epoxypropane,  β-Adrenoblockers, ranolazine

COc2ccccc2OCC1CO1


OTHER COMPD
Glycidyl 2-methylphenyl ether technical grade, 90%