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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5429_Библиотеки_им_академика_М_И_Перельмана
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O
HO
3
3
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Misoprostol 301
O
OCH
3
OH
OCH
OH
O
O
OCH
3
O
O
3
norprostol
O
OCH
O
O
3
O
O
OCH
X
O
CH3OH
HO
O
OH
suberic acid
O
O
OCH
3
HO
O
The alkenylcuprate reagent is formed from the alkyne. (Draw the structures for one route to the alkenylcuprate reagent from
the alkyne. Draw the structure of the alkenylcuprate showing all the ligands attached to copper.) The alcohol
4- methyl- 1- octyn- 4- ol is protected. 4- Methyl- 1- octyn- 4- ol is formed by addition of propargylmagnesium bromide to
2-
hexanone (Grignard Reaction). Propargylmagnesium bromide is formed from propargyl bromide. Propargyl bromide is
formed from propargyl alcohol.
Cu
CH
2
OP
3
CH
3
3
2
OCH
P
CH
OHCH
3
CH
3
MgBr Br
CH
O
CH
3
3
OH
M302
O
OH
O
NH
O
O
3
H
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Extended Discussion
Draw the structures of an alternative route to an alkenylcuprate reagent used in the synthesis of misoprostol. Draw the
structure of the alkenylcuprate reagent showing all the ligands attached to copper.
Moxifloxacin
Anti- infective Medicines/Antibacterials/Antituberculosis Medicines
Nucleophilic aromatic substitution is often facilitated
F
by an electron-
withdrawing group (NO
CN) on an ortho or para ring carbon. No electron-
H
NN
OCH
3
H
withdrawing group is required when the displacement
results in formation of a five-
or six- membered ring.
Leaving groups for nucleophilic aromatic substitution
include fluorine, chlorine, and nitro.
Discussion. In the final step, fluoride at C8 is replaced by methoxide. The carboxylic acid is formed by ester hydrolysis.
Fluoride at position 7 is replaced by the more nucleophilic nitrogen of the diamine.
, SO2R, COOR,
2
O
F
H
NH
H
NH
7
8
OCH
H
F
F
H
NN
3
O
NN
O
OH
OCH2CH
N
H
H
NH
3
H
F
NN
F
H
O
F
N
NH
F
F
O
OH
CH3OH
O
OCH2CH
Moxifloxacin 303
O
O
F
F
F
F
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Intramolecular fluoride displacement by nitrogen of the cyclopropanamine forms the quinolone ring. Cyclopropanamine
is introduced by displacement of ethanol from the enol ether. The β-
with triethyl orthoformate. The βdiethyl malonate is the reaction partner. (The four-
ketoester is formed from 2,3,4,5- tetrafluorobenzoyl chloride. In one preferred approach,
step conversion of the 2- fluorobenzoyl chloride to the quinolone is
ethoxyacrylate is formed by reaction of the β- ketoester
known as the Grohe–Heitzer Sequence.) The acid chloride is formed from the carboxylic acid.
O
F
F
F
F
F
F
N
O
F OCH2CH
O
Cl
F
OCH2CH
O
OCH2CH
CH3CH2O
3
3
NH
2
3
O
O
F
F F NH
F
F
F F
F
OCH2CH
3
F
F F
O
O
OCH2CH
O
OCH2CH
HC(O CH2CH3)
O
OH
3
3
3
(S,S)- Octahydro- 1H- pyrrolo[3,4- b]pyridine is formed by debenzylation of the pyrrolidine nitrogen. The (S,S)- and (R,R)-
enantiomers of 6- benzyloctahydro- 1H- pyrrolo[3,4- b]pyridine are separated by resolution. The pyrrolidine is formed by
reduction of the imide. The pyridine ring is reduced. The imide is formed from pyridine- 2,3- dicarboxylic acid (quinolinic
acid) and benzylamine.
M304
H
O
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Ph
H
NH
N
H
H
O
H
Ph
N
H
Ph
N
N
H
H
O
N
H
H
H
N
H
H
N
Ph
N
O
N
H
H
O
O
H
Ph
N
N
H
H
N
O
Ph
N
N
quinolinic acid
OH
OH
Ph NH
O
2
Extended Discussion
An alternative route to moxifloxacin begins with 2,4,5- trifluoro- 3- methoxybenzoic acid. Draw the structures of the retrosynthetic analysis of this starting material and then draw the structures of the retrosynthetic analysis of the alternative
route. List the pros and cons for the two routes.
N
HO
O
HO
HO
CH
3
O
CH
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Naloxone
Antidotes and Other Substances Used in Poisonings/Specific
O
N
OH
305
A single- enantiomer molecule with multiple chiral carbons
is often formed by the modification of a natural product
which has most or all of the chiral carbons already in place.
Discussion. The tertiary amine is formed by bromide displacement from allyl bromide by the secondary amine, noroxymorphone.
Noroxymorphone is formed by hydrolysis of acetate esters at C3 and C14 and hydrolysiscyanamide is formed by Noxymorphone with acetic anhydride. Oxymorphone is formed by O-
3
O
O
3
O
14
OH
8
O
O
O
7
BrCN
CH
3
6
demethylation of the tertiary amine with cyanogen bromide. The diacetate is formed by the reaction of
demethylation of oxycodone.
3
O
O
17
N
HO
N
CH
O
O
3
O
noroxymorphone
O
O
oxymorphone oxycodone
O
NH
OH
Br
N
OH
O
CH
CH3O
3
O
O
CH
3
O
O
decarboxylation of the cyanamide at N17. The
N
CN
O
O
N
CH
OH
Routes to Essential Medicines: A Workbook for Organic Synthesis, First Edition. Peter J. Harrington.
© 2022 John Wiley & Sons, Inc. Published 2022 by John Wiley & Sons, Inc.
Companion website: www.wiley.com/go/Harrington/routes_essential_medicine
CH
O
3
CH
3
N306
CH3O
CH3O
CH3O
3
thebaineoxycodone
HO
HO
HO
3
oxymorphone oripavine
3
CH
CH
CH
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Oxycodone is manufactured in two steps from the alkaloid thebaine. Oxidation of the thebaine 6,8(14)- diene to the hydroxyenone is followed by reduction of the alkene. Thebaine is the main alkaloid isolated from Papaver bracteatum (Persian
poppy).
3
CH3O
O
N
CH
O
N
OH
O
CH
O
N
3
O
OH
CH
Oxymorphone can also be produced in two steps from the alkaloid oripavine. Oxidation of oripavine 6,8(14)- diene to the
hydroxyenone is followed by reduction of the alkene. Oripavine is isolated from the opium poppy Pavaver somniferum.
3
CH3O
O
N
CH
O
N
OH
O
CH
O
N
3
O
OH
CH
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route from oxymorphone to noroxymorphone. List the
pros and cons for both routes and select one route as the preferred route.
Neostigmine Methylsulfate
Muscle- relaxants (Peripherally- acting) and Cholinesterase Inhibitors
O
OS
3
O
Discussion. The quaternary ammonium salt is formed in the final step by methylation of the tertiary amine with dimethyl
sulfate. The carbamate is formed from the phenol and dimethylcarbamoyl chloride (dimethylcarbamyl chloride).
CH
O
CH
3
3
N O N
3
3- Dimethylaminophenol is formed from resorcinol and dimethylamine.
3
A meta- amino phenol is often formed from 1,3-
dihydroxybenzene (resorcinol).
CH
O
Nevirapine 307
CH
CH
CH
O
O
3
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CH3OS
O
CH3OS
O
CH
3
N OH
3
3
3
N O N
3
CH
3
N O N
3
(CH3)2NH
CH
3
CH
3
O
3
CH
CH
CH
Cl N
O
O
OCH
3
CH
3
O
CH
3
CH
3
O
HO OH
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to neostigmine methylsulfate that does not utilize
dimethylcarbamoyl chloride. Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw materials. List the pros and cons for both routes. Is one route preferred?
Nevirapine
Anti- infective Medicines/Antiviral Medicines/Antiretrovirals/Non- nucleoside Reverse Transcriptase Inhibitors
N
CH
NH
N
N
Discussion. Nevirapine is rapidly assembled from two components of similar complexity. The diazepine- 5- one ring is
formed by displacement of chloride from the 23- aminopyridine and the pyridine- 3- carbonyl chloride.
A nitrogen substituent on C2, C4, or C6 of a pyridine
ring is often introduced by displacement of chloride
by nucleophilic aromatic substitution. The substitution is facilitated by the ring nitrogen and can be further facilitated by an electron- withdrawing group
, SO2R, COOR, CN) on pyridine ring C3.
(NO
2
chloropyridine by the cyclopropanamine. The amide is formed from the
N308
CH
O
O
CH
H
CH
O
CH
3
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O
NH
CH
3
O
NH
CH
3
O
H2N
3
Cl
N
N
N
N
NH Cl
N
N
Cl
NH
Cl
2
N
The acid chloride is formed from the carboxylic acid. The carboxylic acid is formed by hydrolysis of the nitrile. 2- Cyclopropyla
3- pyridinecarbonitrile is formed by displacement of chloride from 2- chloro- 3- pyridinecarbonitrile by cyclopropanamine.
mino-
Cl
N
NH
2
N
NH
O
2
N
NH
N
Cl
CN
CN
Cl
NH
2
3- Amino- 2- chloro- 4- methylpyridine is formed from the pyridine- 3- carboxamide (Hofmann Rearrangement). The
carboxamide is formed by hydrolysis of the nitrile. 2- Chloro- 4- methylpyridine- 3- carbonitrile is formed from the
32-
pyridone. The 2- pyridone is formed from the mixture of enol ether and acetal formed by condensation of malononitrile
and acetylacetaldehyde dimethyl acetal.
NC
CH
N
CN
3
3
NC
N
H
CH
O
3
O
CH3O
OCH
3
3
N
2
Cl N
N
CH
3
NC
CN
H2N
OCH
Cl
CH
NC
CN
CH3O
3
NC
Cl
3
OCH
3
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to nevirapine from 2- chloropyridine- 3- carbonitrile,
3- amino- 2- chloro- 4- methylpyridine, and cyclopropanamine. List the pros and cons for both routes and select one route as the preferred route.
Niclosamide
NO
2
Cl
OH
Cl
OH
N
2
O
N
O
N
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Anti- infective Medicines/Intestinal Anthelminthics
Nicotinamide 309
O
Amides are ubiquitous in drug structures. Amide formation from an amine and acid chloride, anhydride, ester,
or carboxylic acid is often very efficient.
N
H
Cl
Discussion. Niclosamide is formed in a single step from 5- chlorosalicylic acid and 2- chloro- 4- nitroaniline.
NO
O
OH
NO
2
N
H
Cl
Cl
O
OH
H2N
Cl
2
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to 2- chloro- 4- nitroaniline. List the pros and cons
for both routes and select one route as the preferred route.
Nicotinamide
Vitamins and Minerals
A pyridine with one carbon substituent is often formed
NH
Discussion. Nicotinamide (niacinamide) is manufactured by nitrile hydratase- mediated hydrolysis of nicotinonitrile.
NH
2
CN
from the methylpyridine (picoline).
N310
H
3
CH
CH
2
3
O
3
O
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Nifedipine
Oxytocics and Antioxytocics/Antioxytocics (Tocolytics)
NO
2
O
O
Dihydropyridines are often formed by Hantzsch Synthesis.
The key C3—C4 bond of the ring is formed by addition of
an enamine to an α,β-
unsaturated ketone or ester.
CH
OCH
3
O
3
CH
N
3
Discussion. Nifedipine is formed by the reaction of methyl 3- amino- 2- butenoate (methyl 3- aminocrotonate) with methyl
2formed from 2-
O
3
CH
nitrobenzaldehyde and methyl acetoacetate (Knoevenagel Condensation).
NO
2
O
N
3
H
O
CH
OCH
3
3
CH3O
CH
O
O
NH
NO
O
CH
2
3
OCH
3
NO
2
HO
O
OCH
3
O
CH
3
Extended Discussion
The many published methods for synthesis of 2- nitrobenzaldehyde suggest there may be more than one manufacturing
process. Draw the structures and the list the key reagents for three routes from 2-
Nifurtimox
Anti- infective Medicines/Antiprotozoal Medicines/Antitrypanosomal Medicines/African Trypanosomiasis
N
2
Discussion. Nifurtimox is a 1 : 1mixture of the (R)- and (S)- enantiomers of the (E)- hydrazone. The hydrazone is formed
by condensation of the aldehyde and the hydrazine in the final step. [Is the (Z)- hydrazone also formed in this condensation? If so, how is it separated from nifurtimox?] The aldehyde is formed by in situ hydrolysis of 5- nitro- 2- furaldehyde
diacetate. The hydrazine, 4- amino- 3- methylthiomorpholine- 1,1- dioxide is formed from 2- methyl- 1,4- oxathiane- 4,4- dioxid
e. (The hydrazone is likely formed directly from 5- nitro- 2- furaldehyde diacetate and the hydrazine. Explain.)
O
N
CH
nitrotoluene to 2- nitrobenzaldehyde.
N
S
O
A hydrazone is often formed by condensation of an
aldehyde or ketone with a hydrazine.
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