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6,7-methylenedioxy-4-phenylcoumarin

 SYNTHESIS, Uncategorized  Comments Off on 6,7-methylenedioxy-4-phenylcoumarin
Aug 262014
 


6,7-methylenedioxy-4-phenylcoumarin

8-Phenyl-6H-[1,3]dioxolo[4,5-g]chromen-6-one

6H-1,3-Dioxolo[4,5-g][1]benzopyran-6-one, 8-phenyl-
Molecular Formula: C16H10O4
Molecular Weight: 266.2482
Coumarins are naturally occurring molecules that are found in plants that have numerous uses in the medical field because of its biological activity.  The wide varieties of its uses include antibiotics, anticoagulants, and sometimes even used in the perfume industry.   
SYNTHESIS
Synthesis of 6,7-methylenedioxy-4-phenylcoumarin from sesamol and ethyl phenylpropiolate using a Pd(OAc)2 catalyst to illustrate coumarin synthesis. This procedure is simple and easy and can be applied to the synthesis of other coumarins that have electron-rich phenol groups. The reaction is conducted by stirring a solution of Pd(OAc)2, sesamol and ethyl phenylpropiolate in trifluoroacetic acid at room temperature (15-20 degrees C) under atmospheric conditions.
STEP 1
scheme-2-coumarin-synthesis
phenyl acetylene is the starting material
Ethyl Phenylpropiolate: 
Phenylacetylene (500 mg, 4.896 mmol, 1 equivalent) was added to a round bottom flask and flushed with nitrogen.  A septum and balloon of nitrogen was then attached and 3-4mL of THF was added by syringe.  The flask was cool to -78oC in a dry ice and acetone bath.  Next, n-butyllithium (2.36 mL, 1.2 equivalent) was added to the solution and allowed to warm to 0oC for 1 hour.  The solution was cooled to -78oC again for 15 minutes, and then ethyl chloroformate (0.702 mL, 7.344 mmol, 1.5 equivalent) was added dropwise by syringe and allowed to warm again to 0oC.  The reaction mixture was then quenched by adding 10mL of saturated aqueous NaHCO3 and allowed to stir for 15 minutes. The resulting substance Ethyl Phenylpropiolate was a yellowish-orange liquid.  
1H NMR (200 MHz, CDCl3) δ 7.60-7.26 (m, 5H),
4.38 (m, 2H),      -O CH2 CH3
1.44 (m, 3H);   -O CH2 CH3
IR (neat, NaCl)
3551.4, 3399.9, 3958.2, 2934.4, 2872.2, 2236.4, 2211.6, 1744.0, 1709.5 cm-1
The conversion of phenylacetylene to ethyl phenylpropiolate was made apparent by the comparison of IR spectras.  The phenylacetylene reference IR spectra found on the Spectral Database of Organic Compounds shows a strong peak at about 3300 that the IR of the intermediate lacks.  Also the intermediate’s IR contains strong peaks at 3000 and 2230 which are both absent from the starting material’s IR spectrum.  Both of these changes indicate a successful conversion of phenylacetylene to the intermediate ethyl phenylpropiolate. 
STEP 2
This specific reaction will result in a ring closure and addition of the ethyl phenylpropiolate aided by the palladium acetate catalyst.  The palladium catalyst allows for the addition of an ester to a phenol resulting in a ring closure and product coumarin derivative.
scheme-1-coumarin-synthesis
6,7-methylenedioxy-4-phenylcoumarin:  
Sesamol (0.075g, 0.5167mmol, 0.9 equivalent) and ethyl phenylpropiolate (102mg, 0.57405 mmol,1 equivalent) and Palladium acetate (Pd(OAc)2)(0.00394g, 3mol%) were added to a 1 dram vial and cooled to 0oC in an ice water bath.  Trifluoroacetic acid (0.5mL) was added to the vial, then the vial was capped and the reaction allowed to proceed overnight. The resulting solid was a brown, sticky, crystalline (0.387 mmol, 67 %yield). 
 1H NMR (300 MHz, CDCl3)
δ 7.55-7.38 (m, 5H),
6.90 (s, 1H),
6.83 (s, 1H),
6.24 (s, 1H),
6.05 (s, 2H);  CH2 SANDWICHED BETWEEN 2 OXYGEN ATOMS
IR (DCM, NaCl)
3553.8, 3401.9, 2958.2, 2872.2, 2236.3, 2211.4, 1744.4, 1717.4 cm-1
References

Kotani, M., Yamamoto, K., Oyamada, J., Fujiwara, Y., Kitamura, T.,Synthesis20049, 1466-1470.

Oyamada, J., Jia, C., Fujiwara, Y., Kitamura, T., 2002Chemistry Letters,20023, 380-381.

Kitamura, T., Yamamoto, K., Kotani, M., Oyamada, J., Jia, C., Fujiwara, Y.,Bulletin of the Chemical Society of Japan200376, 1889-1895

http://www.ncbi.nlm.nih.gov/pubmed/17446885

http://wenku.baidu.com/view/ce68818683d049649b665879.html

Mech

scheme-3-possible-mechanism

 

The insertion of the ethyl phenylpropiolate to the sesamol-palladium intermediate is initially achieved in a cis confirmation.  There is then an internal rearrangement of the palladium and CO2Et ligands to the trans confirmation which then allows for an electrophilic aromatic substitution to close the ring.

 

ETHYL PHENYL PROPIOLATE

Ethyl phenylpropiolateEthyl phenylacetylenecarboxylate~Phenylpropiolic acid ethyl ester

1H NMR

13 C NMR

 

 

MASS

 

 

 

IR

 

RAMAN

 

UNDERSTAND SPECTRA WITH METHYLENE DIOXY GROUP USING  A DIFFERENT EXAMPLE

2635-13-4 Structure4-Bromo-1,2-(methylenedioxy)benzene

1H NMR

13 C NMR

 

IR

 

MASS

 

 

RAMAN

 

 

PRESENTING TO YOU COUMARIN TO UNDERSTAND SPECTRA

COUMARIN

91-64-5 Structure

1H NMR

 

13 C NMR

IR

 

MASS

 

RAMAN

 

 

NOW PHENYL ACETYLENE

536-74-3 Structure

1H NMR

 

 

 

 

13 C NMR

 

MASS

 

IR

AND

 

 

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Industry slams FDA draft guidance on biosimilarity

 Uncategorized  Comments Off on Industry slams FDA draft guidance on biosimilarity
Aug 262014
 

BIO, PhRMA and Genentech all take particular issue with the FDA’s four possible outcomes for the analytical comparison of a proposed biosimilar product with its reference product

Industry slams FDA draft guidance on biosimilarity

By Zachary Brennan+, 15-Aug-2014

Industry groups BIO and PhRMA, as well as biotech company Genentech, are taking issue with US FDA draft guidance  that is designed to help companies design and use clinical pharmacology studies to help prove that a developing biosimilar is similar to its reference product.

READ AT

http://www.biopharma-reporter.com/Markets-Regulations/Industry-slams-FDA-draft-guidance-on-biosimilarity

http://www.biopharma-reporter.com/Markets-Regulations/Industry-slams-FDA-draft-guidance-on-biosimilarity?nocount

 

 

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