RI H3 PHARM CHEM QP WITH ANS

3 RAFFLES INSTITUTION 2011 YEAR 6 PRELIMINARY EXAMINATION Higher 3 PHARMACEUTICAL CHEMISTRY 9812/01 Paper 1 20 September 2 hours 30 minutes Additional Materials: Answer Paper Data Booklet READ THESE INSTRUCTIONS FIRST Write your index number, civics tutorial group and name on the Cover Page. Write in dark blue or black pen on both sides of the writing paper. You may use a soft pencil for any diagrams or graphs. Do not use staples, paper clips, highlighters, glue or correction fluid. Answer any five questions. Begin each question on a fresh sheet of paper. At the end of the examination, fasten all your work securely together, with the cover page on top. The number of marks is given in brackets [ ] at the end of each question or part question. You may use a calculator. You are reminded of the need for clear presentation in your answers. This document consists of 21 printed pages.

2 © Raffles Institution 2011 9812/01 [Turn Over 1 Analgesics are a group of drugs which are capable of relieving pain. Analgesic drugs act in various ways on the peripheral and central nervous systems. They are distinct from anaesthetics, which reversibly eliminate sensation. One class of analgesic drugs are the non-steroidal anti-inflammatory drugs (NSAIDs). As analgesics, NSAIDs are unusual in that they are non-narcotic . These drugs display analgesic and antipyretic (fe ver-reducing) effects and, in higher doses, have anti-inflammator y effects. The most prominent members of this group of drugs are aspirin and ibuprofen. (a) Outline the differences in the ways in which narcot ic and non-narcotic analgesics work in preventing pain. [2] Aspirin has analgesic property and is capable of an ti-inflammatory and anti-coagulant activities. (b) Briefly explain how aspirin acts as an anti-inflammatory. [2] Aspirin acts as an acylating agent to bring about c ovalent bond (ester) formation at the serine binding site in the enzyme receptor, as shown below. (c) Show the mechanism of the transesterification reaction. [3] Ibuprofen, another NSAID, is also analgesic and has anti-inflammatory properties. ibuprofen 2-(4-(2-methylpropyl)phenyl)propanoic acid Ibuprofen is produced industrially as a racemate. T he compound contains a chiral centre in the α-position of the propionate moiety. As such, there are two possible enantiomers of ibuprofen, (S)- and ( R)-ibuprofen, each with the potential for different biological effects and metabolism from the other. When a racemic mixture o f ibuprofen is esterified with butan-2-ol, four possible diastereomers can be obtained. (d) Draw the structures of ( S)-ibuprofen and the diastereomer, (R)-1-methylpropyl ( S)-2-(4-(2-methylpropyl)phenyl)propanoate. [2] transesterification serine enzyme OCOCH3 CO2H OH OH CO2H enzyme OCOCH 3

3 © Raffles Institution 2011 9812/01 [Turn Over (e) A proton-NMR analysis of an ibuprofen enantiomer in D 2O was done. (i) Explain the term chemical shift . (ii) The table below shows some 1H NMR data of the ibuprofen enantiomer. Copy the table on your answer sheet, and complete the table. [3] An enzyme, isomerase (alpha-methylacyl-CoA racemase ), is capable of converting one form of the ibuprofen enantiomers totally to anothe r. In a study to investigate such a conversion, ( R)-butan-2-ol is used to form esters with a racemic mixture of ibuprofen. 1H NMR analysis is conducted on the disastereomers formed. The 1H NMR spectrum shows that the benzylic methyl group s from the two diastereomers have different chemical shifts. The figures below s how an expansion of the 1 − 3 ppm regions of the 1H NMR spectra. The two forms can be distinguished b y the 1H NMR signals of the methyl doublets near 1.5 ppm. The doublet at 1.54 ppm is attributed to the (R,R ) diastereomer, whereas the doublet at 1.41 ppm comes from the ( R,S )-diastereomer. (f) Using evidence from the 1H NMR spectra from Figures A, B and C, what conclusion can you make about the activity of the enzyme isomerase? [2] δ / ppm Multiplicity of signal Ratio of number of protons 0.9 1.5 1.9 2.5 3.7 7.1 – 7.3 multiplet 4 12.0 singlet 1 C Figure C shows a higher resolution 1H NMR spectrum of the diastereomers formed by the addition of isomerase to ibuprofen, followed by reaction with ( R)-butan-2-ol. (R,S ) (R,R) (R,S) (R,S) (R,R) Fig. A Fig. B Fig. C 1H NMR spectra: Fig. A, 50:50 mixture of diastereomers formed from ibuprofen and (R)-butan-2-ol. Fig. B, mixture of diastereomers derived from reaction between (R)-ibuprofen and (R)-butan-2-ol.

4 © Raffles Institution 2011 9812/01 [Turn Over Acetaminophen and phenacetin are also non-narcotic analgesic and antipyretic agents. Acetaminophen has been reported to be a selective i nhibitor of COX-3, which is found in the brain. Although phenacetin is a prodrug of acetaminophen, it is no longer used clinically because of the hepatotoxicity of its metabolites. (g) What is a prodrug ? [1] (h) The molecular formula of phenacetin is C 10 H13 NO 2. The 1H NMR and mass spectra of phenacetin are shown below. Analyse the data and suggest the structure of phenacetin, explaining how you arrive at your conclusion. [5] 1H NMR spectrum of phenacetin Mass spectrum of phenacetin [Total: 20] 3 3 2 2 2 1 107 136 ppm m/z

5 © Raffles Institution 2011 9812/01 [Turn Over 2 Morphine, an opium alkaloid first isolated in 1804 by a German pharmacist, is a potent narcotic analgesic. It is known to have very high a ffinity for the µ -opioid receptors located mostly in the posterior horn of the spinal cord. Th ese receptors are integral membrane proteins which are made up of different α-amino acid residues. (a) In a research study, it was discovered that binding to morphine was significantly reduced when the aspartic acid residue in the µ -opioid receptor was replaced with asparagine. With the aid of a diagram, suggest why this might be the case. [2] (b) Naloxone is a competitive antagonist of the µ -opioid receptor and is used in emergency treatments for morphine overdose. (i) From the structure of naloxone, describe another fe ature that is necessary for binding to the µ -opioid receptor and suggest the type of binding interaction involved. (ii) With reference to the term competitive antagonist , explain how naloxone counters the effects of morphine overdose. [3]

6 © Raffles Institution 2011 9812/01 [Turn Over Papaverine is another opium alkaloid used primarily in the treatment of visceral spasm. While it is also found in the opium poppy, it diffe rs largely in structure and pharmacological action from the other opium alkaloids such as morph ine. The synthesis of papaverine from compounds A and B is shown in the reaction scheme below. R O NH2 O Cl R step1 R O NHO R NaBH4, ethanol R OH NHO R step2 NH H3CO H3CO OCH3 OCH3 OPOCl3 H3CO H3CO N OCH3 OCH3 step3 step4 A papaverine POCl3 N B C pyridine E D N pyridine H3CO H3CO =R (You can use R to represent the aryl functional group in your answers where necessary.) (c) Compounds A and B have similar structures. However, they can be diff erentiated from their infra red (IR) spectra. (i) Suggest one prominent IR absorption peak that could be used to distinguish A from B. (ii) How would you expect the C=O absorption peak of com pound A to differ from that of propanone? Explain your answer. [2] (d) The reaction progress of step 1 is followed using rev