Download CH 421, Post‐lab 9    Name___________________________  Spring 2015 

CH 421, Post‐lab 9 Name___________________________ Spring 2015 Section T am T pm R am R pm Synthesis of Bupropion Hydrochloride Reference: Perrine, D. M.; Ross, J. T.; Nervi, S. J.; Zimmerman, R. H. A Short, One‐Pot Synthesis of Bupropion (Zyban®, Wellbutrin®). J. Chem. Ed. 2000, 77, 1479‐1480. 1) In the synthesis of buproprion hydrochloride, excess tert‐butylamine is used for SN2 alkylation. If this amine is not thoroughly removed via aqueous extraction, its hydrochloride salt would be isolated along with the desired buproprion hydrochloride salt. Indicate “yes” or “no” if one could determine if the tert‐butylamine hydrochloride was present in the product mixture via the following methods: 1H NMR IR HPLC with UV detection 2) If methyl amine (MeNH2) was used instead of tert‐butylamine in the SN2 reaction, the rate would be: a. Slower b. Faster c. Unaffected 3) The SN2 alkylation to form buproprion is performed on a secondary alkyl bromide. If a strongly basic nucleophile were used in this reaction, a competing process would occur rather than a SN2 reaction. Draw the product of the competing reaction and indicate the mechanism of this competing pathway: O
Br
strong base
mechanism
Cl
4) Buproprion is marketed as a mixture of enantiomers since it racemizes in vivo as well as in a H2PO4‐ / HPO42‐ buffered solution at pH 7.4, since the ‐hydrogen acidity is increased due to two adjacent electron withdrawing groups. Draw the product obtained if buproprion is subjected to the following conditions for an extended period of time (ca 24 h). 5) Bupropion is metabolized via several pathways, one of which involves reduction of the ketone to the secondary alcohol. How many total stereoisomers can theoretically be formed in this reduction? 6) Predict the likelihood of a single enantiomer of the secondary alcohol metabolite of buproprion to undergo racemization at pH 7.4. OH
H HCl
N
a. Greater than buproprion b. Less than buproprion c. Similar to buproprion Cl
7) Another metabolic pathway of bupropion involves oxidation of the tert‐butyl group to generate an alcohol, which rapidly undergoes ring closure with the ketone. In theory, there are four possible products, though only two have been observed; this is attributed to sterics. Label the stereocenters below as R‐ or S‐. 8) Radafaxine, one stereoisomer of the hydroxybuproprion metabolite, is active in vivo ‐ it has a lower effect on dopamine reuptake though a higher effect on norepinephrine levels than buproprion. While radafaxine was initially considered for drug development, Glaxo Smith Kline discontinued this project. What functional group results from the cyclization of the alcohol onto the ketone? a. Hemiacetal HO O
b. Acetal NH
c. Hemiketal d. Ketal Cl
9) The oxidation of bupropion is catalyzed by the enzyme CYP2B6, an isoform of cytochrome P450 oxidase. Some drugs inhibit CYP2B6, while others induce expression of this metabolizing enzyme found predominately in the liver. St. John’s Wort is an herbal supplement that some people take for depression; it is known to induce CYP2D6. What effect does St. John’s Wort have on the in vivo concentration of buproprion? a. Lower levels of buproprion b. Higher levels of buproprion c. Can not predict 10) Varenicline (Chantix®) is a prescription medication for nicotine addiction that has been shown to be more effective than buproprion (Zyban®) in a randomized controlled trial. It is marketed as the tartrate salt. Draw the salt of this drug: OH
N
HN
HOOC
COOH
OH
N
1 equiv.
11) Bonus point – There are two acidic protons in L‐tartaric acid. What is the relationship between the conjugate bases formed from removal of one or the other proton? a. Enantiomers OH
OH
b. Diastereomers OOC
HOOC
c. Tautomers COOH
COO
d. Resonance forms OH
OH
e. Identical