Download Conversion of Racemic Ibuprofen to (S)

Conversion of Racemic
Ibuprofen to (S)-Ibuprofen
David Chavez-Flores
Ph.D. James Salvador
Outline
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Introduction
Objective
Experimental
Results
Conclusions and future work
Acknowledgments
Chiral Molecules
• A molecule that is not identical to its mirror image is
asymmetric and named chiral. The most common chiral
compounds which exist are enantiomers.
• Enantiomers are typically characterized by an asymmetric
tetrahedral carbon
Solomons, T.W. 1994
Rules for Specification of Chirality
http://tigger.uic.edu
Metabolism Selectivity
The drug metabolism is highly enantioselective
and lead different pharmacological activities of
the enantiomers
Faber., 1999
Thalidomide
•
•
Thalidomide was used in the 1950s and 1960s on pregnant women
to avoid the morning sickness
The (R)-enantiomer is the effective against the morning sickness but
the (S)- enantiomer is tetarogenic and causes birth deffects.
O
O
Na
OH
C
Na
O
(S)
Sodium (S)-glutamate
flavor enhancer
H
H2N
OH
C
(R)
O
Sodium (R)-glutamate
O
Enantiomers
O
O
NH2
H
O
(S)
(R)
(R)
(S)
(S)-carvone
caraway seed
(S)-limonene
lemon fragance
(R)-carvone
spearmint
(R)-limonene
orange fragance
O
O
(R)
N
(S)
N
O
NH
NH
(R)-thalidomide
tranquilizer
O
O
(S)-thalidomide
tetarogenic
O
O
O
O
O
NH
NH
(R)
(S)
(S)-ketamine
anesthetic
(R)-ketamine
psychotic
Cl
Cl
HO
HO
H
H
HO
NH 2
NH2
(R)
(S)
C
H2
C
(S)-alpha-methyl-dopa
hypertensive
O
HO
OH
OH
(S)
O
(S)-2-(4-isobutylphenyl)propanoic acid
C
H2
C
(R)-alpha-methyl-dopa
inactive
O
HO
OH
(R)
O
(R)-2-(4-isobutylphenyl)propanoic acid
Top 10 Drug 2003
Chemical and Engineering News (vol. 78, Oct. 23, 2004)
Top 10 Drug 2004
Chemical and Engineering News (vol. 78, Oct. 23, 2004)
Top 10 Drug 2005
Pharmaceutical Technology., April 2nd 2006
Example
• Albuterol
– Racemic
– Single enantiomer
R-enantiomer of albuterol is responsible for
the drug’s bronchodilating effects
S-enantiomer is responsible for adverse
effects, including tachycardia, tremors, and
nervousness.
Racemic Switch
• Is a reprocess and reformulation of a
racemic mixture, into its single enantiomer
product
• AstraZeneca marketed racemic Omeprozole
as Prilosec and had the patent until April
2001 but now has a new patent on the (S)enantiomer, know as Nexium or
esomeprazole, for 17 more years
Enantiomer Separation
•Chromatography (A. M.)
•Asymmetric Synthesis
•Crystallization
•Enzymatic Resolution
Enzymatic Resolution
• Develop a clean synthesis “Green Chemistry”
• Enzyme-catalyzed resolution of enantiomers
stereospecifically
Candida rugosa Lipase
• Lipase is a water-soluble enzyme that catalyzes
hydrolysis of ester bonds in water-insoluble lipid
substrates
• Candida rugosa Lipase has been used to resolve
the enantiomers of naproxen, ibuprofen and
suprofen due to its ability to catalyze reactions in
non-aqueous based media
• Commercial availability
• Recoverability
Structural Classification of Proteins http://scop.berkeley.edu
Ibuprofen
• Belongs to the Nosteroidal Antiinflammatory
Drugs family
• Sold and administered as racemic mixture
• (S)-Ibuprofen is the active enantiomer
OH
C
O
2-(4-isobutylphenyl)propanoic acid
(S)-Ibuprofen Activity
• Acts in 15 minutes, 3 times faster as the
racemic mixture
• Reduce the side effects in a 50%
• The dose is the half of the racemic mixture
Ibuprofen Toxicity
• Most common adverse effects are dyspepsia,
gastrointestinal ulceration/bleeding, salt and
fluid retention, hypertension
Enantiomeric Excess (ee) and
Enantioselectivity (E)
• In an enantiomerically
enriched mixture, the excess
of one enantiomer over the
other is called an
enantiomeric excess (ee).
• E describes how well the
enzyme discriminates
between the enantiomers of a
substance under given
reaction conditions
Objective
• Our goal is to develop an environmentally
friendly method to convert the racemic
mixture to the active enantiomer of
ibuprofen ((S)-Ibuprofen) in a cost
effective efficient way.
Part I
Ibuprofen was extracted with acetone from commercial
ibuprofen tablets (200 mg/pill Member’s Mark) because it
was really inexpensive
•4 ¢ gram Sam’s Club
• $12 gram Aldrich
Synthesis of (S)-Decyl Ibuprofen Ester
O
OH
+
O
HO-(CH2)9-CH3
Candida Rugosa
Lipase
O
Cyclohexane
40 oC
+
OH
O
H2O
Progress of the Reaction
Progress of the Reaction
(S)-decyl ibuprofen ester
(R)-Ibuprofen
HPLC Spectra Area %
60
(S)-ibuprofen
50
40
30
20
10
0
0
10
20 Time Hours 30
40
50
Ibuprofen Ester Separations
• Bulb to bulb distillation
• Radial Chromatography
• Extraction
Separation
• Chromatography
• Extraction
• Distillation
(S)-Ibuprofen Ester Hydrolysis
O
R
+
O
Candida rugosa
Lipase
H2O
OH
+
O
Buffer pH 7.2
R-OH
•Low concentration of Candida rugosa Lipase
•Potassium phosphate pH 7.2 Buffer solution media
•40 ºC and magnet agitation
•In the hydrolysis, acid or base racemization, was the major concern
H
O
H
R'
O
R'
O
H
H
O
R'
O
H
H+
R
O
R
R
OH
H
R
O
R'
O
H
R
O
O
O
R'
R
O
R'
O
R
O
R'
Summary Part I
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Esterification
– Decan-1-ol
• 48 hours to get a 47 % conversion at 40 C
• High enantioselectivity up to 130 at 24 hours
• Enantiomeric excess of 83 %
– Butan-1-ol
• 96 hours to get a 48 % conversion
• High enantioselectivity up to 46 at 48 hours
• Enantiomeric excess of 63 %
All separation methods distillation good for decan-1-ol
– Chromatography good for both, extraction not good.
•
Hydrolysis
– 98 % enantiomeric excess in both reactions
– 96 hours for the (S)-Decyl Ibuprofen Ester
– 48 hours for the (S)-Butyl Ibuprofen Ester
Additional Work
• Temperature Effect
• Alcohol effect
– Primary, secondary and tertiary
– Different long chain
• Fisher esterification
Temperature Effect
25°C
30°C
45°C
50°C
35°C
40°C
100
90
80
Conversion
70
60
50
40
30
20
10
0
0
50
100
150
Time hours
200
250
300
Alcohols
• Candida rugosa lipase as catalyst showed
a preference for the esterification of
primary alcohols, while the secondary
alcohols had a low rate and the tertiary
ones could not be catalyzed
Esterification with different
length of alcohols
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Methan-1-ol Slower
Ethan-1-ol
Butan-1-ol
Penta-1-ol
Octan-1-ol
Decan-1-ol Faster
Esterification eith Ethan-1-ol
55
50
45
40
35
30
25
20
15
10
5
0
Ester
R-Ibuprofen
S-Ibuprofen
0
20
40
60
80
100
120
140
50
45
40
HPLC spectra area
HPLC spectra area
Esterification w ith Methanol
35
30
25
20
15
Ester
R-Ibuprofen
S-Ibuprofen
10
5
0
0
160
20
40
60
HPLC spectra area
Conversion
Ester
10
20
Time in Hours
100
120
140
160
Esterification with Pentanol
Esterification with Butanol
55
50
45
40
35
30
25
20
15
10
5
0
0
80
Tim e in Hours
Time in Hours
30
40
55
50
45
40
35
30
25
20
15
10
5
0
Ester
R-Ibuprofen
S-Ibuprofen
0
5
10
15
20
25
30
35
40
T i me i n Hour s
Esterification with Octanol
Esterification with Decanol
55
50
45
40
35
30
25
20
15
10
5
0
Conversion
Conversion
55
50
45
40
35
30
25
20
15
10
5
0
Ester
0
5
10
Time in Hours
15
20
Ester
0
5
10
Time in Hours
15
20
Fisher Esterification
OH
45 °C
O
H
CH3
Methanol
O
• 99% conversion
• 4 hours rxn
O
OH
C. R. Lipase
O
CH3
O
• ee = 76 %
• E = 92
O
Buffer pH 7.2
45 °C
O
CH3
O
Part II
• Produce the (S)-ibuprofen ester by
enantioselective enzymatic esterification with
racemization of the (R)-ibuprofen by acid, base
addition or by photochemical reaction
OH
CH3
O
C
H2 9
Candida Rugosa
Lipase
O
O
+ Decan-1-ol
OH
Cyclohexane
45 oC
+
H2O
O
H
O
H
R'
O
R'
O
H
H
O
R'
O
H
OH
H+
R
O
R
R
H
O
R'
O
H
R
R
O
O
O
R'
R
O
R'
O
R
O
R'
Acids
O
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•
•
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p-toluenesulfonic acid
Phenyl dimethyl chlorosilane
Boric Acid
Pyruvic Acid
Isolute Si-Propylsulfonic Acid
Isolute Si-TsOH
p-toluene sulfonyl chloride
S
O
O
H
100
OH
OH
O
H
O
H
R-Alchohol
45 °C
C R Lipase
Cyclohexane
O
R
80
O
60
40
H
H
OH
OH
20
0
CRL Activity
[Acid]
Bases
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PL-HCO3 MP Resin
PL-OH MP Resin
PL-CO3 MP Resin
Tributyl amine
Diethyl amine
Ethyl diisopropylamine
100
90
80
70
60
50
40
30
20
10
0
CRL Activity
[Base]
More Attempts
More Attempts
•Cyclohexane
•(S)-alkyl ibuprofen ester
•Ibuprofen sodium salt
•pH = 7.6 with NaOH
•Candida rugosa Lipase
•Alcohol
Photochemical racemization
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R-ibuprofen
S- ibuprofen
R-methyl ibuprofen ester
S-methyl ibuprofen ester
• All the samples were exposed directly to the
sun rays for different time periods, only the
esters showed complete racemization after
24 hours.
Photochemical racemization
• UV Vis (absorption between 200 and 270 nm)
• Experiments with the UV lamp at 254 nm
Reaction Mechanism
Allowed by Woodward-Hoffmann Rules
CH3
CH3
H
H
O
O
CH3
O
O
hv
[1,3] Sigmatropic
Rearrengement
CH3
CH3
OH
Candida rugosa Lipase
45 °C
hv
[1,3] Sigmatropic
Rearrengement
CH3
O
CH3
O
H
Aqueous Conditions
O
Current and future work
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Reaction characterization
Test the method with more NSAID drugs
Complete my Ph. D. degree
Publication
Patent
Acknowledgments
• PhD James Salvador
• All the attendants
• Education Department of Chihuahua Mexico
Government
• Chemistry department of University of Texas at El Paso
• U. S. Army Research Laboratory and U.S. Army
Research Office under Contract W911NF0410052
• Consejo Nacional de Ciencia y Tecnologia (CONACyT)
• Green Chemistry Institute-NSF (Travel Scholarship)
Thank You
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