CH4008 – Organic Pharmaceuticals 2 In-term assignment, Spring 2023 worth 14%
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Instructions:
? Hand write on pages your answers to the following 14 questions.
? Use your phone to photograph the pages, and ‘cut and paste’ the images into an MS Word document.
? Save your final MS Word document using the following filename format: name_ID no.doc, e.g. John
Smith_1723456.doc.
? Submit your final MS Word document to SULIS by the deadline. Marks may be deducted for late
submission.
Issued: Monday, Week 2
Deadline: 17:00, Monday, Week 4 (13-Feb-2023)
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Q. 1 Draw out both structures and clearly show the functional groups in each molecule.
(2 x 5 marks)
Q. 2 Complete these two mechanisms by drawing the structure of the product(s).
(2 x 5 marks)
Q. 3 Put in the curly arrows on the starting materials to show how the products are formed.
(5 marks)
Q. 4 Put in the curly arrows on the starting material to show how the products are formed.
(5 marks)
CH4008 – Organic Pharmaceuticals 2 In-term assignment, Spring 2023 worth 14%
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Q. 5 Draw curly arrow mechanisms for the reactions in the following sequence.
(3 x 5 marks)
Q. 6 Draw curly arrow mechanisms for each of these two reactions.
(2 x 10 marks)
Q. 7 The products of both reactions below are correct but the related mechanisms, as shown, are wrong. Draw
the correct mechanism for each reaction.
(2 x 5 marks)
CH4008 – Organic Pharmaceuticals 2 In-term assignment, Spring 2023 worth 14%
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Q. 8 The chemical structures of the two compounds below have been poorly drawn in terms of the bond angles
used. Draw a more appropriate chemical structure for each compound.
(2 x 5 marks)
Q. 9 Draw the curly arrow mechanisms for these reactions.
(2 x 10 marks)
Q. 10 Draw out the chemical structures of the two compounds with the following line formulas.
(a) C6H5CH(OH)(CH2)4COC2H5
(b) (CH3O)2CH=CHCH(OCH3)2
(2 x 5 marks)
Step 1 Step 2
1. Base
2. RCOCl
CH4008 – Organic Pharmaceuticals 2 In-term assignment, Spring 2023 worth 14%
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Q. 11 Draw the mechanism for each of the two reactions shown below.
(2 x 10 marks)
Q. 12 Draw the structure of the product (or products, you decide) for the low temperature reaction of
the compound below with an equimolar amount of lithium tri-t-butoxyaluminium hydride.
H
O
O
O CH3
H3C
O
O Cl
(10 marks)
Q. 13 Draw curly arrow mechanisms for the following three reactions.
(2 x 10 marks)
+ + H2O
(10 marks)
H
+
2. H+ 2. H+
/H2O /H2O
1. EtMgBr 1. LiAlH4
2. H+
/H2O
1. NaBH4
2. H+
/H2O
CH4008 – Organic Pharmaceuticals 2 In-term assignment, Spring 2023 worth 14%
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Q. 14 The synthetic scheme for the anti-hypertensive drug, valsartan, is presented below in
Scheme 1. The stoichiometric ratios of the reactants for Reactions a, b and c are included in
Scheme 1; for example, in Reaction a you need 1.3 moles of L-valine methyl ester hydrochloride
(2) for every mole of valeryl chloride (1).
Ignore the cost of all of the reagents listed below in Scheme 1, and calculate the cost of
producing 1,200 moles of valsartan using the prices of the key reactants shown in the table
below.
Reactant gram molar mass (GMM) Price: € / kg
valeryl chloride (1) 120.6 g mol-1 85
L-valine methyl ester hydrochloride (2) 167.6 g mol-1 135
1-bromo-4-(bromomethyl)benzene (4) 249.9 g mol-1 80
5-phenyl-1-trityl-1H-tetrazole (6) 388.5 g mol-1 265
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As shown in Scheme 1, the inexpensive and commercially readily available valeryl chloride (1) was
coupled with L-valine methyl ester hydrochloride (2) in the presence of triethylamine (Et3N) in
dichloromethane at 0 °C to afford methyl N-pentanoyl-L-valinate (3) in 95% yield. Compound 3 was
then N-protected with 1-bromo-4-(bromomethyl)benzene (4) in presence of sodium hydride (NaH) in
tetrahydrofuran to give methyl N-(4-bromobenzyl)-N-pentanoyl-L-valinate (5) in 70% yield. Orthometalation of 5-phenyl-1-trityl-1H-tetrazole (6) with n-butyllithium (n-BuLi) at 25 °C followed by
treatment with zinc chloride at -20 °C gave the desired organozinc chloride compound. Coupling of the
latter with the aryl bromide (5) in presence of a catalytic amount of Q-phos and palladium acetate in
tetrahydrofuran at 75 °C produced methyl N-pentanoyl-N-{[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-
yl]methyl}-L-valinate (7) in 80% yield. Hydrolysis of (7) with 3 N NaOH in methanol gave valsartan (8)
in 90% yield.
Scheme 1 – reagents list (ignore the cost of all of these reagents) and reaction yields (%)
Reaction a: Et3N, CH2Cl2, 0 °C, 95%; Reaction b: NaH, THF, 70%; Reaction c: n-BuLi, 25 °C, THF, anhyd
ZnCl2, -20 °C, Q-phos, Pd(OAc)2, 75 °C, 2 h, 80%; Reaction d: 3 N NaOH, MeOH, reflux, 90%.
(20 marks)
(5)
1 equiv.
a b
c
d
(1) (2)
1 equiv. 1.3 equiv.
(3) (4)
1.4 equiv. 1 equiv.
(6)
1.2 equiv.
(7) (8)
“equiv.” means
equivalent(s)