ZINGERONE SPECTRAL DATA

Spice

In everyday life, ginger is used in cooking for its hot taste as well as its pungent smell.

Ecologists have studied the relationships of food and culture for many years. During this time, they have found surprising ties between spices that taste good and health-promoting side effects. An example of one of these spices is ginger. The sensory perception of ginger in the mouth and the nose arises from two distinct groups of chemicals: The volatile oils, a mixture of terpenoids that give ginger its characteristic aroma and modifies its taste.    The non-volatile pungent chemicals like gingerols, shogaols, paradols and zingerone produce the “hot” taste in the mouth. It is these non-volatile pungent chemicals of ginger that give it, its real value.

Medicine

Ginger for many years has been the traditional remedy for colds. In modern medicine today, zingerone is used to treat a variety of medical problems. Zingerone reacts with free radicals that can cause tissue damage and inflammation. At Case Western University, research has been done showing that a topically applied extract containing zingerone may help prevent some skin cancers. In capsule form, ginger can also be used to replace anti-inflammatory drugs. In a recent study, ginger was found to be more effective than drugs in the treatment of nausea and motion sickness. Zingerone also has a major role in lipid oxidation since it is an anti-oxidant. It weakly inhibits oxidation of phospholipid liposomes in the presence of iron (III) and ascorbate to prevent heart-attacks.

Zingerone used in pharmaceuticals

It is these properties that have made zingerone a molecule of great importance and one that has been produced and synthesized for pharmaceutical use.

Structure

4-(4-hydroxy-3-methoxy-phenyl)-butan-2-one
Chemical Name	Structure of Zingerone	3D Structure of Zingerone

Physical Properties

Synonyms	Zingerone; Vanillyl Acetone
Odour Description	Sweet, Spicy, Ginger, Vanilla, Woody
Appearance	Yellow To Yellow-Brown Crystals
Mol./Wt.	194.2
Formula
Cas. #	122-48-5
Refractive Index	1.54400 – 1.54500 @ 20.00 �C.
Melting Point	40 – 41�C (Solvent – Aq. Ethanol)
Boiling Point	141 �C. @ 0.5 Torr
Boiling Point	290�C. @ 760.00 mmHg
Soluble in	Ethyl Alcohol, 1:1 In 50% Alcohol
Natural Occurrence	Ginger Root; Raspberry; Zingiber Officinale

Nuclear Magnetic Resonance (NMR) Spectrum of Zingerone

Table 1 : H NMR spectral data on Zingerone

Mass Spectrum of Zingerone

Pattern for Mass Fragmentation in the Spectrum

Infrared Spectrum of Zingerone

Table 3 : Infra Red spectral data on Zingerone

NOMURA METHOD

The Bunce & Reeves Method

Historical

Zingerone has been extracted from ginger for the past two thousand years.

A Brief History

Common Name:	Ginger
Latin Name:	Zingiber Officinale
Family:	zingiberaceae
Other Names:	Based on its origin: African ginger Black ginger Chochin (Asian ginger). Gan Jiang (Jamaican ginger).

The word ginger comes from the ancient Sanskrit ’singabera’, meaning ‘shaped like a horn’.  It first appeared in the writings of Confucius in the 5th century BC. and it has been used medicinally in the West for the past 2000 years. Various virtues have been ascribed to the spice; e.g. Henry VIII recommended it as a pro-phylactic against the plague. It was introduced by the Spaniards to the Americas and is now cultivated extensively in the West Indies. The Portuguese introduced it to West Africa. It is now used all over the world.

Only in the past century has zingerone been produced synthetically. A few interesting and unique syntheses have been chosen. Down the years, the technique of synthesis evolved. Though Lapworth & Wykes were the pioneers in the synthesis of zingerone, their method and reagents were not repeated. Below is a diagram of the apparatus used in their experiment.

Nomura, then Mannich and Merz founded the method used today. This is shown by Kim and Kim’s work. The other interesting method was formed by Bunce and Reeves. This method and the common one used today are elaborated on in the preparation section.

Year	Method	Reagents
1917	Reduction and Decarboxylation of ethyl vanillylideneacetoacetateLapworth & Wykes	The Pioneers in the synthesis.Na Amalgam and NaOH solution
1925	Reduction of 4-(4-hydroxy-3-methoxyphenyl)buten-2-one to 4-(4-hydroxy-3-methoxyphenyl)butan-2-one.Nomura	Na Amalgam and Water
1927	Reduction of 4-(4-hydroxy-3-methoxyphenyl)buten-2-one to 4-(4-hydroxy-3-methoxyphenyl)butan-2-one.Mannich & Merz	Pd Catalyst,
1979	Reaction of 4-benzyloxy-3-methoxybromomethylbenzene with the anion of acetone dimethylhydrazone, followed by oxidative hydrolysis, then hydrogenolysis to remove the benzyl group Enders D. et Al	Pd/C, Hydrogen, Methanol
1989	Amberlyst-15-catalyzed addition of 3-buten-2-one to the phenolBunce & Reeves	Amberlyst-15, Toluene, 20-50�C
2004	Reduction of 4-(4-hydroxy-3-methoxyphenyl)buten-2-one to 4-(4-hydroxy-3-methoxyphenyl)butan-2-one.Kim D. & Kim J. Y.	Pd/C Catalyst,

Spice

Ginger

As commented upon in the introduction, zingerone puts the ‘zing’ in ginger. In mustard oil, zingerone uses its properties to give it its flavour.

Zingerone has properties that give its strength of flavour. The higher molecular weight of zingerone in combination with the polar side-chain carbonyl group make zingerone molecules attract each other strongly. As a result, zingerone is not that volatile. The odour of ginger isn’t strong, but the hydrocarbon tail gives it a more intense flavour when it does come into contact with its receptor. Zingerone is also used in artificial flavouring and in fragrances.

A company called “Aroma Fragrance Fine Chemicals” (AFFC) have formulations are used globally for imparting attractive taste and aroma to processed foods and beverages. These chemicals can also add pleasing scents to perfumes, toiletries and detergents. Zingerone is one of their formulations. It is both a flavour and fragrance ingredient. This therefore means that zingerone is important in both processed foods and perfumes.

In industry, zingerone is therefore synthesised using the Kim & Kim’s method for this purpose.

Zingerone contains vanilloid (3-methoxy-4-hydroxy benzene) group in its structure. These phenolic hydroxyl groups provide the possibility to introduce a 4-ether-linked propanolamine side chain. Propanolamine derivatives were obtained by reacting zingerone with epichlorohydrin, and the obtained epoxide compounds were then reacted with isopropylamine, tert-butylamine or guaiacoxyethylamine, respectively, to yield 3 new derivatives shown below.

The syntheses above create third-generation β-adrenoceptor blockers, which possess ancillary cardiovascular actions other than β-adrenoceptor blockade, or cardioselective β-adrenoceptor blockers, have been shown to improve left ventricular function and decrease the risk of chronic heart failure. These β-adrenoceptor blockers are a break through in science and make the synthesis of zingerone very important in industry.

• Zingerone
  • Ginger : www.wrc.net/wrcnet_content/herbalresources/materiamedica/materiamedica.aspx?mmid=13
• Introduction
  • Picture of Bulbophyllum patens : Journal; Tan, Keng-Hong; Nishida, Ritsuo; JCECD8; J. Chem. Ecol.; EN; 26; 2; 2000; 533 – 546.
  • Ginger Flower:http://www-ang.kfunigraz.ac.at/~katzer/engl/generic_frame.html?Zing_off.html
  • Ecological Formulas Bottle : www.amazon.com
• Historical
  • Cotton Diagram
    Patent Number: US2381210
    Publication date: 1945-08-07
    Inventor(s): COTTON WILLIAM J
    Applicant(s): PENNSYLVANIA COAL PRODUCTS COM
    Requested Patent: US2381210
    Application Number: US19430499408 19430820
    Priority Number(s): US19430499408 19430820
    IPC Classification:
    EC Classification: C07C45/62Equivalents:
• Characterisation
  • NMR: Journal; Tan, Keng-Hong; Nishida, Ritsuo; JCECD8; J. Chem. Ecol.; EN; 26; 2; 2000; 533 – 546.
  • IR Spectrum and Mass Spectrum: NIST Mass Spec Data Center, S.E. Stein, director (http://webbook.nist.gov)
  • Mass Fragmentation: Journal; Locksley,H.D. et al.; JCPRB4; J. Chem. Soc. Perkin Trans. 1; EN; 1972; 3001-3006
  • IR Bands: Journal; Das, B.; Takhi, M.; Kumar, H. M. Sampath; Srinivas, K. V. N. S.; Yadav, J. S.; PYTCAS; Phytochemistry; EN; 33; 3; 1993; 697-700.
  • Physical Properties: http://www.thegoodscentscompany.com/data/rw1006231.html
• Spice
  •  http://www.ulg.ac.be/lcfi/licence/interros/interro10.html
• Medicine
  • Molecule: http://mcb.berkeley.edu/labs/berger/Structure%20images/Collaboration/lr5lab.jpeg
  • Reactions: Journal; Yeun-Chih Huang et al., Bioorganic & Medicinal Chemistry 9 (2001) 1739�1746
  • Graph and Table: Journal; Pearson, D. A. et al.; J. Agric. Food Chem. 1997, 45, 578-582
  • Diagram: http://images.medscape.com/pi/editorial/clinupdates/2002/2009/art-2009-1.fig16.gif           
• Phytochemistry
  • GC Diagram: Journal; Tan, Keng-Hong; Nishida, Ritsuo; JCECD8; J. Chem. Ecol.; EN; 26; 2; 2000; 533 – 546.
  • Bulbophyllum patens (Phytochemistry): http://www.ulg.ac.be/lcfi/licence/interros/interro10.html

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 ANTHONY MELVIN CRASTO

Ragaglitazar ……..Dr. Reddy’s Research Foundation

Ragaglitazar

NNC-61-0029, (-) – DRF-2725, NN-622,

(−)DRF 2725

cas   222834-30-2

222834-21-1 (racemate)

Hyperlipidemia; Hypertriglyceridemia; Lipid metabolism disorder; Non-insulin dependent diabetes

PPAR alpha agonist; PPAR gamma agonist

(2S)-2-ETHOXY-3-{4-[2-(10H-PHENOXAZIN-10-YL)ETHOXY]PHENYL}PROPANOIC ACID,

(2S)-2-ethoxy-3-[4-(2-phenoxazin-10-ylethoxy)phenyl]propanoic acid, DRF, 1nyx

Molecular Formula: C25H25NO5

Molecular Weight: 419.4697 g/mol

Dr. Reddy’s Research Foundation (Originator), Novo Nordisk (Licensee)

Reddy Research Foundation……….. Braj Bhushan Lohray,

Antidiabetic Drugs, ENDOCRINE DRUGS, Type 2 Diabetes Mellitus, Agents for, Insulin Sensitizers, PPARalpha Agonists, PPARgamma Agonists

Phase III

…………………..

J Med Chem 2001,44(16),2675

http://pubs.acs.org/doi/abs/10.1021/jm010143b

(−)DRF 2725 (6) is a phenoxazine analogue of phenyl propanoic acid. Compound 6 showed interesting dual activation of PPARα and PPARγ. In insulin resistant db/db mice, 6 showed better reduction of plasma glucose and triglyceride levels as compared to rosiglitazone. Compound 6 has also shown good oral bioavailability and impressive pharmacokinetic characteristics. Our study indicates that 6 has great potential as a drug for diabetes and dyslipidemia.

Scheme 1 a

a (a) NaH, DMF, 0−25 °C, 12 h; (b) triethyl 2-ethoxy phosphosphonoacetate, NaH, THF, 0−25 °C, 12 h; (c) Mg/CH3OH, 25 °C, 12 h; (d) 10% aq NaOH, CH3OH, 25 °C, 6 h; (e) (1) pivaloyl chloride, Et3N, DCM, 0 °C, (2) (S)-2-phenyl glycinol/Et3N; (f) 1 M H2SO4, dioxane/water, 90−100 °C, 80 h.

Compound 6 is prepared from phenoxazine using a synthetic route shown in Scheme 1. Phenoxazine 7 upon reaction with p-bromoethoxy benzaldehyde 89 gave benzaldehyde derivative 9. Reacting 9 with triethyl 2-ethoxy phosphonoacetate afforded propenoate 10 as a mixture of geometric isomers. Reduction of 10 using magnesium methanol gave propanoate 11, which on hydrolysis using aqueous sodium hydroxide gave propanoic acid 12 in racemic form. Resolution of 12 using (S)(+)-2-phenyl glycinol followed by hydrolysis using sulfuric acid afforded the propanoic acid 6 in (−) form.

Nate, H.; Matsuki, K.; Tsunashima, A.; Ohtsuka, H.; Sekine, Y. Synthesis of 2-phenylthiazolidine derivatives as cardiotonic agents. II. 2-(phenylpiperazinoalkoxyphenyl)thiazolidine-3-thiocarboxyamides and corresponding carboxamides. Chem. Pharm. Bull. 1987, 35, 2394−2411

(S)-3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-eth-oxypropanoic Acid (6).  as a white solid, mp: 89−90 °C.

[α]D 25 = − 12.6 (c = 1.0%, CHCl3).

1H NMR (CDCl3, 200 MHz): δ 1.16 (t, J = 7.0 Hz, 3H), 1.42−1.91 (bs, 1H, D2O exchangeable), 2.94−3.15 (m, 2H), 3.40−3.65 (m, 2H), 3.86−4.06 (m, 3H), 4.15 (t, J = 6.6 Hz, 2H), 6.63−6.83 (m, 10H), 7.13 (d, J = 8.5 Hz, 2H). Mass m/z (relative intensity):  419 (M+, 41), 197 (15), 196 (100), 182 (35), 167 (7), 127 (6), 107 (19).

Purity by HPLC: chemical purity: 99.5%; chiral purity: 94.6% (RT 27.5).

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TAK 733

TAK-733

CAS: 1035555-63-5

Synonym: TAK-733; TAK 733; TAK733.

IUPAC/Chemical name: 

(R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Chemical Formula: C17H15F2IN4O4

Exact Mass: 504.01060

Molecular Weight: 504.23

Elemental Analysis: C, 40.49; H, 3.00; F, 7.54; I, 25.17; N, 11.11; O, 12.69

Phase I clinical studies for cancer treatment.Takeda Pharmaceutical, 

Solid Tumors Therapy

US8436200

http://www.google.com/patents/US8436200?cl=en

The synthetic process of the present invention allows for the preparation of (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione while avoiding the use of a fluorinating reagent in the last step. That is, the present invention provides a valuable process for making (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione characterized by the reaction of a compound of formula (8) with 2-fluoro-4-iodoaniline to give a compound of formula (9). Such a process avoids the use of costly and possible hazardous fluorinating regents in later steps which has significant advantages in large-scale manufacture.

Example 8.1(R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione

Combine (R)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (24.75 g, 45.58 mmol) and ethanol (250 mL). Add aqueous 9N sulfuric acid (50 mL) over 5 minutes. Heat to 75° C. After 2 hour, cool to ambient temperature and then cool in an ice bath to give a solid. Collect the solid by filtration, rinse with ethanol (3×30 mL), and dry to give the title compound. 

 
 ¹H NMR (400 MHz, DMSO-d6) δ10.24 (s, 1H), 8.52 (s, 1H), 7.69 (dd, 1H, J=10.4, 1.8 Hz), 7.52 (d, 1H, J=8.6 Hz), 6.98 (m, 1H), 5.14 (brs, 1H), 4.83 (brs, 1H), 4.32 (dd, 1H, J=12.9, 2.5 Hz), 3.76 (m, 1H), 3.67 (dd, 1H, J=13.1, 12.9 Hz), 3.58 (s, 3H), 3.46 (ddd, 1H, J=10.9, 5.3, 5.1 Hz), 3.38 (m, 1H); 
 

 ¹³C NMR (100 MHz, DMSO-d6) δ161.3 (d, J=4.0 Hz), 155.6 (d, J=22.8 Hz), 154.6 (d, J=250 Hz), 152.0, 150.6, 134.3 (d, J=231 Hz), 133.8 (d, J=7.1 Hz), 133.1 (d, J=3.0 Hz), 127.8 (d, J=10.3 Hz), 125.3 (d, J=7.0 Hz), 123.9 (d, J=21.5 Hz), 95.0 (d, J=4.0 Hz), 87.1 (d, J=7.8 Hz), 68.0, 63.8, 50.1, 28.8; 

 








¹⁹F NMR (376 MHz, DMSO-d6) δ-124.4, −149.8; 
 

MS (M+H)+m/z calcd 505.0. found 505.0.

SEE

http://newdrugapprovals.org/2014/11/20/tak-733-clinical-studies-for-cancer-treatment/



http://newdrugapprovals.org/2014/11/20/tak-733-clinical-studies-for-cancer-treatment/



http://newdrugapprovals.org/2014/11/20/tak-733-clinical-studies-for-cancer-treatment/


http://newdrugapprovals.org/2014/11/20/tak-733-clinical-studies-for-cancer-treatment/