RJC Chemistry H3 (Pharmaceutical Chem) with Ans

RAFFLES JUNIOR COLLEGE PRELIMINARY EXAMINATION 2008 HIGHER 3 PHARMACEUTICAL CHEMISTRY 9812/01 Paper 1 28 August 2008 2 hour 30 minutes Candidates answer on separate paper. Additional Materials: Answer Paper Data Booklet READ THESE INSTRUCTIONS FIRST DO NOT open this question booklet until you are told to do so. Write your name, civics tutorial group and index number in the spaces provided on the Cover Page and the writing papers. Write in dark blue or black pen on both sides of the writing papers. You may use a soft pencil for any diagrams, graphs or rough working. Do not use staples, paper clips, highlighters, glue or correction fluid. Answer any five questions. Begin each question on a fresh sheet of paper. A Data Booklet is provided. Do not write anything on it. You are reminded of the need for good Englis h and clear presentation in your answers. The number of marks is given in brackets [ ] at the end of each question or part question. At the end of the examination, fasten all your work securely together. This question booklet consists of 12 printed pages. © RJC 2008 [Turn over

2 1(a) Reserpine is a natural o ccurring drug that has been used for centuries in ancient India to treat hypertension, c holera and snakebites. It competes with neurotransmitters such as serotonin and dopamine for the storage vesicles in the pre–synaptic nerve. N H N O O OCH3 OR N H H2N HO reserpine serotonin (i) Based on the structure of serotonin as shown, copy out the structure of the reserpine molecule and circle t he most likely part(s) of reserpine that is responsible for its action. (ii) Suggest two physiological effects of t he neurotransmitters mentioned above. Two of the steps involved in the synthesis of reserpine are shown below. O OH H H H H H O Step 1 Br2 X Step 2 NaOMe MeOH O H H H H H O O H OMe 2 1 (iii) Predict the structure for X. Show the mechanism involved in Step 1 and include the stereochemis try of the intermediate X. State also the configurations (R or S) of the two carbon centres (C–1 and C–2). (iv) Step 2 involves two reactions to give the desired product as shown above. What is / are the type of reaction(s) involved? (v) Name the side reaction that might occur in Step 2. [10] © RJC 2008

3 Pseudoreserpine is another nat ural product which is ex tracted from the roots of plants. Pseudoreserpine and rese rpine are shown below, and both molecules contain a chromophore that absorbs UV radiation. N H N O O OH OR N H N O O OCH3 OR pseudoreserpine reserpine (vi) Explain the term chromophore and draw the chromophore that is responsible for the UV absorption. (vii) Pseudoreserpine has λmax = 282 nm and molar absorptivity, ε = 11.900 x 10 3 L cm ─1 mol ─1. What is the concentration of pseudoreserpine in a solution whose absorbance, A = 0.065 with a sample path length, l = 1.00 cm? (viii) State a solvent which is suitabl e for dissolving pseudoreserpine for UV analysis. [5] 1(b) Parkinson’s disease is a result of the deficiency in dopamine transmission to certain parts of the brain. The prodr ug Levodopa is supplied as a medication that acts on the sympathetic nervous system to increase dopamine levels in the body. Although there are some adverse effe cts associated wit h Levodopa, it has fewer of these than other anti–Parkinson’s drugs such as Parlodel. (i) Despite having these side effects, Levodopa has certain characteristics of an ideal drug. Other than having no side effects, suggest two general characteristics that an ideal drug should have. (ii) Parlodel is a dopamine agonist. Explain how agonists and antagonists differ in their interactions with r e c e p t o r s . [ 5 ] © R J C 2 0 0 8 [Turn over

4 2 Propranolol was the first clinically successful “pioneer drug” that serves as the neurotransmitter– and endocrine–deriv ed agonists for beta–adrenergic receptors associated with the ma mmalian sympathetic nervous system. However, propranolol is a nonselecti ve beta–blocker and can cause cardiac depression. OCH2CHCH2NHCH(CH3)2 OH propranolol (a) The synthesis of propranolol is outlined below. OH O O propranolol Step 1 Step 2 (i) Suggest reagents for Steps 1 and 2. (ii) Suggest a mechanism for both Step 1 and Step 2. [6] A new selective beta–blocking agent, neb ivolol, was launched in the late 1990s. F ONO F HOH OH H H nebivolol (b) State the number of chiral carbon c entres in nebivolol. Indicate the stereochemistry of these chiral carbon centres as R or S. [2] (c) Draw the structure of the enantiomer of nebivolol. [1] (d) Suggest what structural features propranolol and nebivolol have in c o m m o n . [ 2 ] © RJC 2008

5 (e) Suggest why (i) propranolol is a nonselective beta–blocker whereas nebivolol is a highly selective beta–blocking agent. (ii) nebivolol exhibits nearly 200 times higher beta–adrenergic binding affinity than its enantiomer. (iii) nebivolol is marketed as its racemic mixture. [4] (f) Compound W, C 11H13FO2, is used in the synthesis of nebivolol . W reacts with sodium hydroxide to form two compounds X and Y. F OO OH H F OO H OH H X Y (i) What is the stereochemical relationship between X and Y? (ii) Deduce the structure of compound W using the IR, NMR and mass spectra data given below: The IR spectra showed the following absorptions: 3500, 3350, 3045, 2990, 1650, 1200, 650 cm –1 The 1H NMR spectra showed the following peaks: δ value relative area comment 2.25 2 multiplet 2.55 2 triplet 3.95 2 doublet 5.45 – 5.70 2 multiplet 4.5 1 disappears with D2O 7.0 1 disappears with D2O 6.72 – 6.50 3 multiplet The mass spectra showed the mass numbers of major peaks observed: m/z 195, 75, 41 [5] © R J C 2 0 0 8 [Turn over

6 3 Nicocodeine was first introduced in t he late 1950s by Lannacher Heilmittel of Austria and it has been used as a cough suppressant and analgesic. Nicocodeine, a derivative of codeine, can be synthesized in the laboratory. H3CO O O H NCH3 H O N nicocodeine codeine (a) Suggest the reagents and conditions required for the one–step synthesis. You are allowed to use additional organic molecule(s) if n e c e s s a r y . [ 1 ] (b) Codeine is unstable under strong acid conditions. When heated with hydrogen iodide, it reac ts to form compound A which is aromatic. Suggest the structure of A, showing any stereochemistry involved. [2] (c) Codeine is a narcotic analgesic. De scribe briefly how narcotic and non–narcotic analgesics act differently to prevent pain. [2] (d) One of the N–containi ng rings in codeine can be represented as shown below. N CH3 R1 R2 R3 Draw the boat conformation and chair conformation showing the positioning of the substituents on t he ring. State which of these two conformations is the more stable one. Give your reasons. [4] Nicocodeine contains a pyridine ring. Like benzene, pyridine is an aromatic compound. (e) Explain why the pyridine ring undergoes electrophilic substitution less readily than benzene. [1] © RJC 2008

7 (f) Pyridine derivatives, such as 2–bromopyridine, undergo nucleophilic substitution readily. Describe the mechanism for the reaction shown b e l o w . [ 3 ] Besides pyridine, pyrrole is another common nitrogen–cont aining aromatic heterocycle. Pyrrol