Benzyl (5-methylpyrazin-2-yl)carbamate

2-(Cbz-Amino)-5-methylpyrazine

Molecular Formula:	C13H13N3O2
Molecular Weight:	243.266 g/mol

 

 

Benzyl (5-methylpyrazin-2-yl)carbamate

CAS 1033418-57-3

Mp 191.4 °C.

IR 1719, 1567, 1353, 1226, 1054, 759, 744, 706 cm–1.

1H NMR (DMSO-d6, 500 MHz) 10.45 (br, 1H), 8.93 (s, 1H), 8.20 (s, 1H), 7.42–7.32 (m, 5H), 5.18 (s, 2H), 2.41 (s, 3H).

13C NMR (DMSO-d6, 125.7 MHz) 153.6, 147.7, 146.7, 141.7, 136.5, 134.3, 128.7 (2C), 128.4, 128.2 (2C), 66.5, 20.4.

HRMS elemental calculated for C13H14N3O2 (MH+): 244.1086; found: 244.1080.

NMR PREDICT

1H NMR

13 C NMR PREDICT

Use of a Curtius Rearrangement as Part of the Multikilogram Manufacture of a Pyrazine Building Block

Alan Steven*†  and Phillip Hopes‡

† Pharmaceutical Technology & Development, AstraZeneca, Charter Way, Macclesfield, SK10 2NA, United Kingdom

‡ Cyton Biosciences Ltd., 68 Macrae Road, Bristol, BS20 0DD, United Kingdom

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00340

 

*E-mail: Alan.Steven@astrazeneca.com.

http://pubs.acs.org/doi/10.1021/acs.oprd.7b00340

 

 

MORE...............

 

A modular flow reactor for performing Curtius rearrangements as a continuous flow process

Marcus Baumann,a  Ian R. Baxendale,a  Steven V. Ley,*a  Nikzad Nikbin,a  Christopher D. Smitha  and Jason P. Tierneyb 

*Corresponding authors

aInnovative Technology Centre, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK
E-mail: svl1000@cam.ac.uk
Fax: +44 1223 336442
Tel: +44 1223 336398

bNeurology Lead Discovery Chemistry, Neurology CEDD, GlaxoSmithKline R and D, New Frontiers Science Park (North), Third Avenue, Harlow, UK

Abstract

The use of a mesofluidic flow reactor is described for performing Curtius rearrangement reactions of carboxylic acids in the presence of diphenylphosphoryl azide and trapping of the intermediate isocyanates with various nucleophiles.

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O=C(OCc1ccccc1)Nc2cnc(C)cn2

Hypericin

Hypericin

Hypericin is a naphthodianthrone, an anthraquinone derivative which, together with hyperforin, is one of the principal active constituents of Hypericum (Saint John's wort).[2][3] Hypericin is believed to act as an antibiotic, antiviral[2] and non-specific kinaseinhibitor. Hypericin may inhibit the action of the enzyme dopamine β-hydroxylase, leading to increased dopamine levels, although thus possibly decreasing norepinephrine and epinephrine.

It was initially believed that the anti-depressant pharmacological activity of hypericin was due to inhibition of monoamine oxidase enzyme. The crude extract of Hypericum is a weak inhibitor of MAO-A and MAO-B. Isolated hypericin does not display this activity, but does have some affinity for NMDA receptors.[citation needed] This points in the direction that other constituents are responsible for the MAOI effect. The current belief is that the mechanism of antidepressant activity is due to the inhibition of reuptake of certain neurotransmitters.[2]

The large chromophore system in the molecule means that it can cause photosensitivity when ingested beyond threshold amounts.[citation needed] Photosensitivity is often seen in animals that have been allowed to graze on St. John's Wort. Because hypericin accumulates preferentially in cancerous tissues, it is also used as an indicator of cancerous cells. In addition, hypericin is under research as an agent in photodynamic therapy, whereby a biochemical is absorbed by an organism to be later activated with spectrum-specific light from specialized lamps or laser sources, for therapeutic purposes. The antibacterial and antiviral effects of hypericin are also believed to arise from its ability for photo-oxidation of cells and viral particles.[2]

Hypericin derives from polyketides cyclisation.[4][5]

The biosynthesis of hypericins is in the polyketide pathway where an octaketide chain goes through processes of cylizations and decarboxylations form emodin anthrone which are believed to be the precursors of hypericin. Oxidization reactions yield protoforms which then are converted into hypericin and pseudohypericin. These reactions are photosensitive and take place under exposure to light and using the enzyme Hyp-1. [6][7][8][9][10]

References

1. Jump up^ Merck Index, 11th Edition, 4799
2. ^ Jump up to:a b c d Mehta, Sweety (2012-12-18). "Pharmacognosy of St. John's Wort". Pharmaxchange.info. Retrieved 2014-02-16.
3. Jump up^ Oubre, Alondra (1991). "Hypericin: the active ingredient in Saint John's Wort". Archived from the original on September 28, 2007. Retrieved September 18, 2006.
4. Jump up^ Loren W. Walker (1999). "A Review of the Hypothetical Biogenesis and Regulation of Hypericin synthesis via the Polyketide Pathway in Hypericum perforatum and Experimental Methods Proposed to Evaluate the Hypothesis".
5. Jump up^ Christian Hertweck (2009). "Polyketide Biosynthesis". Angew. Chem. Int. Ed. 48: 4688–4716. doi:10.1002/anie.200806121.
6. Jump up^ Karioti A, Bilia AR (2010) Hypericins as potential leads for new therapeutics. Int J Mol Sci 11:562-594
7. Jump up^ Falk H (1999) From the photosensitizer hypericin to the photoreceptorstentorian—the chemistry of phenanthroperylene quinines. AngewChem Int Ed 38:3116–3136
8. Jump up^ Bais HP, Vepachedu R, Lawrence CB, Stermitz FR, Vivanco JM (2003)Molecular and biochemical characterization of an enzyme responsible for the formation of hypericin in St. John’s wort(Hypericum perforatum L.). J Biol Chem 278:32413–32422
9. Jump up^ Michalska K, Fernades H, Sikorski M, Jaskolski M (2010) Crystal structure of Hyp-1, a St. John’s wort protein implicated in the biosynthesis of hypericin. J Struct Biol 169:161–171
10. Jump up^ Murthy, Hosakatte Niranjana et al. “Hypericins: Biotechnological Production from Cell and Organ Cultures.” Applied Microbiology and Biotechnology 98.22 (2014): 9187–9198. PubMed. Web.

  

An Efficient Multigram Synthesis of Hypericin Improved by a Low Power LED Based Photoreactor

http://pubs.acs.org/doi/10.1021/acs.oprd.7b00317

Renato S. Gonçalves*† , Bruno R. Rabello‡, Gabriel B. César†, Paulo C. S. Pereira†, Marcos A. S. Ribeiro†, Eduardo C. Meurer∥, Noboru Hioka†, Celso V. Nakamura§, Marcos L. Bruschi§, and Wilker Caetano†

† Department of Chemistry, State University of Maringá, Avenue Colombo, 5790, Maringá, Paraná 87020-900, Brazil

‡Instituto Federal de Educação, Ciência e Tecnologia Catarinense, 283, Concórdia, Santa Catarina 89703-720, Brazil

§ Department of Pharmacy, State University of Maringá, Avenue Colombo, 5790, Maringá, Paraná 87020-900, Brazil

∥Federal University of Parana, Jandaia do Sul, Paraná 86900-000, Brazil

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00317

 

*E-mail: rsgoncalves2@uem.br.

Universidade Estadual de Maringá

Location

• Maringá, Brazil

Department

• Chemistry Department

Position

• Professor

Abstract

In this work, an improved synthesis process was developed for the multigram production of hypericin. An inexpensive and efficient low power Light Emission Diode (LED) based photoreactor was designed and employed to perform the protohypericin photocyclization reaction allowing its photoconversion in hypericin. This closed system overcomes safety issues related to scale-up hypericin preparation typically described in the literature which combines the use of open systems, organic solvents, and high-power light sources. The photoreactor designed allows a solution to, mainly, the intrinsic effect of hypericin photobleaching inherent to the protohypericin photocyclization reaction, implying an increase in the yield of the final product and consequently the final cost. Using a red-LED based photoreactor, a safety protocol was carried out in a 5-g scale hypericin preparation with quantitative yield.

C30H16O8;

1H NMR (CD3CN, 25 °C, 500 MHz): δH 14.75 (s, 2H, OH-1, OH-6), 14.13 (s, 2H, OH-7, OH-12), 7.31 (s, 2H, Ar-H8, Ar-H11), 6.55 (s, 2H, Ar-H2, Ar-H5), 2.71 (s, 6H, Ar-CH3) ppm; UV–vis (EtOH) λmax 392, 480, 513, 552, 596.

13C NMR (CD3CN, 25 °C, 500 MHz): δC 185.2, 175.7, 169.8, 162.8, 144.6, 128.4, 127.6, 122.7, 122.1, 120.5, 119.6, 109.9, 106.6, 103.5.

The identification of molecular formula of Hypericin (C30H16O8) was confirmed on its negative HRMS ion of m/z 503.0854 (calcd for [M – H]− 503.0845). The MS2 experiment showed fragment ions characteristic for this compound of m/z 487.0202 [M–H–CH4]−, 458.0504 [M–H–CO2–H·]−, 433.0361 [M–H–CH2═C═O–CO]−, 431.0601 [M–H–CO2–CO]−, and 405.0425 [M–H–CH2═C═O–2CO]−.

The characterization data of hypericin are in agreement with the literature.(35-39)

• 35.
  
  Kapinus, E. I.; Falk, H.; Tran, H. T. N. Monatsh. Chem. 1999, 130, 623– 635 DOI: 10.1007/s007060050222
• 36.
  
  Piperopoulos, G.; Lotz, R.; Wixforth, A.; Schmierer, T.; Zeller, K.-P. J. Chromatogr., Biomed. Appl. 1997, 695, 309– 316 DOI: 10.1016/S0378-4347(97)00188-6
• 37.
  
  Brolis, M.; Gabetta, B.; Fuzzati, N.; Pace, R.; Panzeri, F.; Peterlongo, F. J. Chromatogr. A 1998, 825, 9– 16 DOI: 10.1016/S0021-9673(98)00697-9
• 38.
  
  Riedel, K.-D.; Rieger, K.; Martin-Facklam, M.; Mikus, G.; Haefeli, W. E.; Burhenne, J. J. Chromatogr. B: Anal. Technol. Biomed. Life Sci. 2004,813, 27– 33 DOI: 10.1016/j.jchromb.2004.09.061

Hypericin[1]

Names
IUPAC name 1,3,4,6,8,13-hexahydroxy-10,11-dimethylphenanthro[1,10,9,8-opqra]perylene-7,14-dione
Other names 4,5,7,4',5',7'-Hexahydroxy-2,2'-dimethylnaphthodianthrone
Identifiers
CAS Number	548-04-9
3D model (JSmol)	Interactive image
ChEBI	CHEBI:5835
ChemSpider	4444511
ECHA InfoCard	100.008.129
PubChem CID	5281051
UNII	7V2F1075HD
InChI[show]
SMILES[show]
Properties
Chemical formula	C30H16O8
Molar mass	504.45 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

/////////////Hypericin

A practical synthesis of 2,3-dihydro-1,5-benzothiazepines

A practical synthesis of 2,3-dihydro-1,5-benzothiazepines

Green Chem., 2017, 19,5703-5707
DOI: 10.1039/C7GC02097J, Paper

Domenico C. M. Albanese, Nicoletta Gaggero, Meng Fei
Hexafluoro-2-propanol as the solvent allows a catalyst free domino approach to 2,3-dihydro-1,5-benzothiazepines in up to 98% yield.

 

A practical synthesis of 2,3-dihydro-1,5-benzothiazepines

 

Domenico C. M. Albanese,^a  Nicoletta Gaggero*^b  and  Meng Fei^b 

*Corresponding authors

^aDepartment of Chemistry, Università degli Studi di Milano, via C. Golgi 19, Milano, Italy

^bDepartment of Pharmaceutical Sciences, Università degli Studi di Milano, via L. Mangiagalli 25, Milano, Italy
E-mail:nicoletta.gaggero@unimi.it

Domenico C. M. Albanese

University of Milan

LocationMilano, Italy

DepartmentDepartment of Chemistry

Positionassociate professor

Domenico Albanese received his Ph.D. degree in 1993 with Prof. Dario Landini working on phase transfer catalysis. After short stays at Imperial College London and the Technical University of Denmark, he gained a permanent position at the Università degli Studi di Milano, where he was appointed associate professor in 2008. His research interests include novel developments of phase-transfer catalysis, green chemistry and the development of new environmentally friendly antifouling agents.

Nicoletta Gaggero

Nicoletta Gaggero received her Ph.D. degree in 1992 working on stereoselective reactions with natural proteins, enzymes and models of enzymes. After working at the Laboratoire de Chimie de Coordination du CNRS of Toulouse, she obtained a permanent position at the Università degli Studi di Milano. Her research interests cover the field of biocatalysis and asymmetric synthesis.

Abstract

2,3-Dihydro-1,5-benzothiazepines have been obtained through a domino process involving a Michael addition of 2-aminothiophenols to chalcones, followed by in situ cyclization. Up to 98% chemical yields have been obtained at room temperature under essentially neutral conditions by using hexafluoro-2-propanol as an efficient medium.
http://pubs.rsc.org/en/Content/ArticleLanding/2017/GC/C7GC02097J?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+rss%2FGC+%28RSC+-+Green+Chem.+latest+articles%29#!divAbstract

 

 

2,4-Diphenyl-2,3-dihydro-1,5-benzothiazepine (4a)

 

Yellow solid; mp 114-116 C [lit.1 , 114-115 °C], AcOEt/PE 1:9. 1H NMR (300 MHz, CDCl3,): 3.07 (t, J = 12.6 Hz, 1 H), 3.32 (dd, J = 4.7, 13.1 Hz, 1 H), 4.99 (dd, J = 4.5, 12.0 Hz, 1 H), 7.12-7.17 (m, 1 H), 7.25-7.30 (m, 5 H), 7.44-7.51 (m, 4 H), 7.62 (d, J = 6.1 Hz, 2 H), 8.06 (d, J = 7.5 Hz, 2 H). Isolated Yield: 339 mg, 86%.

 

2-(4-Hydroxyphenyl)-4-phenyl-2,3-dihydro-1,5-benzothiazepine (4e)

Light brown solid; mp 131-134 °C. AcOEt/PE 40:60.

1H NMR (CDCl3, 300 MHz):  = 3.01 (t, J = 12.7 Hz, 1 H), 3.28 (dd, J = 4.8, 12.9 Hz, 1 H), 4.95 (dd, J = 4.7, 12.5 Hz, 1 H), 5.10 (bs, 1 H), 6.76 (d, J = 8.5 Hz, 2 H), 7.18-7.21 (m, 3 H), 7.35 (d, J = 8.5 Hz, 1 H), 7.46- 7.55 (m, 4 H), 7.63 (dd, J =1.5, 7.7 Hz, 1 H), 8.06 (m, 2 H).

13C NMR (CDCl3, 75 MHz): 37.99 (CH2), 60.07 (CH), 115.53 (CH), 123.08 (C), 127.40 (CH), 128.79 (CH), 131.17 (CH), 136.54 (C), 141.59 (C), 155.24 (C). IR (KBr): 1599, 2921, 3350 cm-1 .

MS (ESI): m/z= 332.24 (MH)+ .

Anal. Calcd. for C21H17NOS: C, 76.10; H, 5.17; N, 4.23, found: C, 76.21; H, 5.15; N, 4.24.

Isolated Yield: 360 mg, 87%.

 

 

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'

“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This 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

Ruthenium-Catalyzed Tandem C–H Fluoromethylation/Cyclization of N-Alkylhydrazones with CBr3F: Access to 4-Fluoropyrazoles

4-Fluoropyrazoles are accessible in a single step from readily available aldehyde-derived N-alkylhydrazones through double C–H fluoroalkylation with tribromofluoromethane (CBr3F). RuCl2(PPh3)3 has been proven to be the most efficient catalyst for this transformation when compared to a range of other Cu-, Pd-, or Fe-based catalyst systems.

Alexis Prieto

Alexis Prieto, Didier Bouyssi*, and Nuno Monteiro* 

Univ Lyon, Université Claude Bernard Lyon 1, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS, CNRS UMR 5246), F-69622 Villeurbanne, France

J. Org. Chem., 2017, 82 (6), pp 3311–3316

DOI: 10.1021/acs.joc.7b00085

*E-mail: didier.bouyssi@univ-lyon1.fr., *E-mail: nuno.monteiro@univ-lyon1.fr.

Ruthenium-Catalyzed Tandem C–H Fluoromethylation/Cyclization of N-Alkylhydrazones with CF3BR: Access to 4-Fluoropyrazoles

http://pubs.acs.org/doi/10.1021/acs.joc.7b00085

---

The importance of fluorine-containing pyrazoles to the pharmaceutical and agrochemical industries has been steadily increasing in recent years. As a consequence, the development of methods suitable for the incorporation of fluorine or fluoroalkyl groups into the pyrazole ring continues to be the subject of intense research.

Predicated on their previous copper-catalyzed synthesis of 4-substituted pyrazoles, Bouyssi, Monteiro and their co-worker from the Institut de Chemie et Biochemie Moléculaires et Supramoléculaires reported a ruthenium-catalyzed synthesis of substituted-4-fluoropyrazoles ( J. Org. Chem. 2017, 82, 3311). The requisite starting materials, aldehyde derived N,N-dialkylhydrazones, were readily synthesized. Tribromofluoromethane served as the source of fluorine.

The commercially available and inexpensive ruthenium complex, RuCl2(PPh3)3, was discovered to be a very effective catalyst for this transformation. Diglyme was the preferred solvent for the reaction. The reaction displayed good tolerance for a variety of functional groups, including cyano, ester, formyl, and halide.

In general, higher yields were obtained with electron-withdrawing substituents. This novel methodology affords substituted-4-fluoropyrazoles in good yields in one step from readily available starting materials.

                                                 2K

3-(Benzo[d][1,3]dioxol-5-yl)-4-fluoro-1-methyl-1H-pyrazole (2k)

Chromatography using ethyl acetate/cyclohexane (gradient elution 30:70 to 50:50) gave the title compound as a pale yellow solid (79 mg, 60%).

Mp = 82–85 °C.

1H NMR (400 MHz, CDCl3) δ 7.35–7.31 (m, 2H), 7.27 (d, J = 4.8 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 5.97 (s, 2H), 3.83 (s, 3H).

13C NMR (101 MHz, CDCl3) δ 148.0, 147.2, 146.8 (d, J = 248.0 Hz), 136.7 (d, J = 6.2 Hz), 125.3 (d, J = 4.2 Hz), 119.8 (d, J = 4.7 Hz), 117.5 (d, J = 28.6 Hz), 108.6, 106.6 (d, J = 3.7 Hz), 101.1, 40.0 (s).

19F NMR (282 MHz, CDCl3) δ −178.2 (s). HRMS (ESI): Calcd for C11H10FN2O2 [M + H+]: 221.0721, found 221.0728.

Alexis prieto

Chercheur postdoctoral chez Melchiorre group, ICIQ

Melchiorre group, ICIQ

Didier Bouyssi

Univ Lyon, Université Claude Bernard Lyon 1, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS, CNRS UMR 5246), F-69622 Villeurbanne, France

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“ALL FOR DRUGS” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This 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