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Interchapter Medicinal Chemistry - Problems in Organic Synthesis
Interchapter Medicinal Chemistry - Problems in Organic Synthesis
Interchapter Medicinal Chemistry - Problems in Organic Synthesis
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INTERCHAPTER
Medicinal Chemistry - Problems in Organic Synthesis
The synthesis of most of the drugs in this problem set can be found in one or the
other of the following references.
The Organic Chemistry of Drug Synthesis, Vol. 1-6, by D. Lednicer et al., John Wiley &
Sons, Inc.
1980 - 1999.
Pharmaceutical Chemistry, Volume 1, drug synthesis, by H. J. Roth and A.
Kleemann, Ellis
Horwood Series in Pharmaceutical Technology, Halsted Press, 1988.
MC.1 Following is an outline for this synthesis of diazepam.
H
N
O
CH3
Cl
Ac2 O
(1)
CH3
Cl
4-Chloro-Nmethylaniline
NaOH, H2
O
(3)
O
PhCCl, A lCl3
(2)
CH3
N
H
O
Cl
CH3
O
Cl
Cl
(4)
N
Cl
CH3
O
O
NH3
Cl
O
Cl
(B)
(5)
(A)
CH3
N
Cl
CH3
NH2
(6)
Cl
Diazepam
Step 1: The amine nitrogen is first protected by treatment with acetic anhydride
(Section 18.7B).
Whereas a 2 amine is a good nucleophile and will react with benzoyl chloride to
give an amide (Section 18.7A), the nucleophilicity of an amide nitrogen is so
reduced that it will no longer react with an acid chloride.
Step 2: Friedel-Crafts acylation (Section 21.1C) is directed by the amide nitrogen,
which is
activating and ortho, para directing (Section 21.2A). Chlorine is also ortho, para
directing but it
is deactivating and, therefore, the amide nitrogen takes precedence in directing the
position of further electrophilic aromatic substitution.
Step 3: The acetyl protecting group is removed by treatment with aqueous NaOH
(Section 18.5D)
to give (B).
Step 4: Treatment of the amino group of (B) with chloroacetyl chloride results in
acetylation
(Section 18.7A) to form the amide group of (A).
Step 5: Treatment of (A) with ammonia results in nucleophilic displacement of chlorine
by an SN2
reaction (Section 8.3) to form a primary amine.
Step 6: Intramolecular reaction of the ketone and 1 amine of (A) results in formation
of an imine
(a Schiff base, Section 16.10A) and completes this synthesis of diazepam.
Et
OOC
Cl
Cl
Cl
O
COOE
t
N Br
N
CH3
OH
Cl
COOEt
COOE
t
C O
Cl
Cl
COOE
t
H2N
(1)
H
Br2
NH2
OEt
Cl
(A)
Cl
h ydrolysis and
O
COOE decarboxylation
t
of the
ketoacid
N OCH3
(2)
Cl
(B)
(3)
(4)
Cl
(C )
H
N
N
Cl
(D)
H
N
O
OCH3
Cl
BBr 3
(5)
O
OH
Cl
N
Cl
Lorazepam
Step 1: This step is divided into two parts. In the first part, reaction of the 1 amino
group of
diethyl 2-aminopropanedioate with the carbonyl group of the diaryl ketone gives an
imine (a Schiff base, Section 16.10A). In the second part of this step, reaction
between the 1aromatic amine and an ester group gives an amide by nucleophilic
acyl substitution (Section 18.7C).
Step 2: Bromination of this -ketoester proceeds by way of keto-enol tautomerism
(Section 16.11)
followed by reaction of the enol with bromine (Section 16.12C).
Step 3: Solvolysis of the tertiary bromide proceeds by an SN1 mechanism (Section
8.3).
Step 4: Hydrolysis of the ester to a carboxylic acid (Section 18.5C) followed by heating
results in decarboxylation of the -ketoacid (Sections 17.9A and 19.3D).
Step 5: Boron tribromide, BBr3, is widely used to cleave ethers under very mild
conditions. This
reagent is a colorless liquid most commonly supplied as a 1.0 M solution in CH2Cl2 or
hexane.
It is highly sensitive to moisture and reacts rapidly with water to give B(OH)3
and HBr. Cleavage of an ether requires one mole of BBr3 per mole of ether.
RCH2 OCH3 + BBr 3
RCH2 OBBr 2 + 3 H2 O
The first step in this ether cleavage reaction is an acid-base reaction between boron
tribromide (a Lewis acid) and the ether (a Lewis base) followed by loss of bromide ion.
Bromide ion then participates in an SN2 reaction, attacking the methyl carbon and
displacing oxygen to give an alkylborate ester. Hydrolysis of this ester gives the
alcohol.
Br
Br
RCH2 - O-CH3 +B Br
Br
loss of
bromide ion
B Br
RCH2 -O
CH3
Br
B
Br
Br
Br
RCH2 - O-B
+ CH3 Br
Br
SN 2
RCH2 -O
+ :Br
CH3
MC.3 The synthesis of clonazepam is very similar to that of diazepam (MC.1) and
lorazepam (MC.2).
HO
Cl
Cl
O
Cl
SOCl2
(1)
AlCl3
2-Chlorobenzoic
acid
NH2
(3)
O
NHCCH
Ac2 O
(2)
O2N
O
NHCCH NaOH
3
O2N
(4)
Cl
O2N
p-Nitroaniline
NH2
O2N
O
Cl
Cl
O Cl
O2N
(5)
O2N
O
O NH2
Cl
NH3
(6)
Cl
Cl
H
N
O
N
HN
(7)
Clonazepam
N
O2N
Cl
Step 1: 2-Chlorobenzoic acid is treated with thionyl chloride to give an acid chloride
(Section 17.8).
O+
Cyclohexanone
COOE
t
OH
COOEt
NaOEt
(1)
COOE
t
(2)
NaCN
(5)
(1)
COOEt
COOE
t
Tetrahedral
carbonyl addition
intermediate
Diethyl
malonate
COOEt
COO
H
heat
COO
H
(3)
CN
COOE
t
Pt /
C
(6)
Et OH, H+
COO
H
NH2
COOE
t
(4)
ester
hydrolysis
(7)
COOEt
NH2
COOH
Gabapentin
Step 1: When treated with sodium ethoxide, diethyl malonate is converted to its
enolate anion
(Section 19.7) and then, in a carbonyl condensation related to the aldol reaction
(Section 19.2)
and the Claisen condensation (Section 19.3), adds to the carbonyl carbon of
cyclohexanone to
NH2
NH3 +
COO
H
Gabapentin
COO-
CHO
Benzaldehyde
CN
COOE
t
Ethyl
cyanoacetate
NaOE
t
CN
H
COOEt
(A)
KCN
CN
COOEt
NC
(B)
1 . NaOH, H2
O
2 . HCl, H2 O
3. heat
Et OH,
H+
HOOC
(C
)
COO
H
Et OOC
(D)
COOE
t
CH3
NH2
O
N
CH3
Phensuximide
(a) As shown in the following table, a cyano group has about the same acidstrengthening effect
on an -hydrogen as does an ester group. Thus, the acidity of an -hydrogen of
ethyl
cyanoacetate is comparable to that of an -hydrogen in diethyl malonate (pKa 13,
Section 19.7).
pK a
O
RCH2
COEt
24-25
25
RCH2 C
N
pK a
O
O
Et OCCH2
COEt
13
11
N CCH2 C N
When treated with sodium ethoxide, ethyl cyanoacetate is converted to its enolate
anion
(Section 19.7) and then, in a carbonyl condensation related to the aldol reaction
(Section 19.2)
and the Claisen condensation (Section 19.3), adds to the carbonyl carbon of
benzaldehyde to
give a tetrahedral carbonyl addition compound. Dehydration of this addition
compound gives
an -unsaturated cyanoester.
(b) Treatment of (A) with KCN results in Michael addition (Section 19.8A) of cyanide ion
to the - carbon of the -unsaturated cyanoester.
(c) Treatment of (B) with NaOH, H2O results in base-promoted hydrolysis of the ester
and cyano
groups (Sections 18.5C and 18.5E)) to carboxylic salts. Acidification with HCl and
heating results in decarboxylation of the -dicarboxylic acid (Section 17.9B).
(d) Treatment of the dicarboxylic acid with ethanol in the presence of an acid catalyst
such as ptoluenesulfonic acid (Fischer esterification, Section 17.7A) converts each carboxyl
group to an ethyl ester.
(e) Treatment of the diester with methylamine results in conversion of one ester and
then the
other to an amide (Section 18.7C). Each reaction is an example of nucleophilic acyl
substitution
(Section 18.4).
HOOC
COO
H
CH3 NH2 ,
heat
N
CH3
Phensuximide
+ H2 O
(f) For the synthesis of methsuximide, use acetophenone as the starting carbonyl
compound. For
the synthesis of ethosuximide, use 2-butanone as the starting material and
ammonia as the amine to form the five-membered imide ring.
CN
COOE
t
O
Acetophenone
+
O
2-Butanone
CN
COOE
t
Ethyl
cyanoacetate
Ethyl cyanoacetate
O
N
CH3
Methsuximide
NH3
Et
OOC
COOE
t
N
H
Ethosuximide
(g) Only ethosuximide has a hydrogen on the imide nitrogen. It is the most acidic and has
an acidity comparable to that of succinimide (pKa 11, Section 18.2). The imide anion is
stabilized by
resonance interaction with the carbonyl groups on either side of it.
OH
CH3
NH2
Ethylene
Methylamine
OH
(1)
SOCl2
(2)
NH3
(3)
Cl
N
O
OEt
(4)
N
N-Methylpiperazine
oxide
Cl
N
N
OEt
O
N
(5)
N
Diethylcarbamazine
-Cl that is displaced and not the -OEt group; chloride is a more stable anion
than ethoxide ion and, therefore, is more readily displaced from ethyl
chloroformate than ethoxide ion.
OEt
Cl
(4')
Cl
(5')
N- Methylpiperazine
Diethylcarbamazine
H3
PO4
(2)
(1)
COO
H
(A)
HO
O
(B)
( CH3 ) 2 NH
HBr
(3)
(4)
N
Br
(C )
(D)
Amitriptyline
C OH
+ H- O-PO3
H2
C +
O H
:O- PO3 H2
+
+ H- O-PO3 H2
C+
O
An acyl cation
-:
HO- PO3
O
2
Step 3: This transformation is initiated by proton transfer to the -OH group of the 3
alcohol to
give an oxonium ion followed by loss of H2O to give a tertiary carbocation. What must
be done next is opening of the highly-strained three-membered ring and formation of
a primary
bromide. Because it is not acceptable to propose a primary carbocation, propose
that opening
of the three-membered ring and formation of the primary bromide are concerted
(simultaneous).
H O
+
H
HO
Br- H
+
:Br
Br
In an alternative synthesis of amitriptyline, the ketone (B) is treated with the Grignard
reagent
formed from 3-dimethylaminopropyl bromide to give a tertiary alcohol. Acidcatalyzed dehydration of the alcohol gives amitriptyline.
BrMg
N
HCl
O
(B)
(2')
HO
N
(3')
N
Amitriptyline
O
H
HO
(A)
(B)
(C )
(D)
OH
F3
C CH ONa
3
SOCl2
NaBH4
(1)
Cl
O
F3
C
O
Cl
OEt
C
N
F3
C
(E)
OEt
(F)
COOH
1 . NaOH, H2
O
2 . HCl, H2 O
H
O
F3 C
F3
C
An N-substituted
carbamic acid
Fluoxetine
on the nitrogen of the amide. Nucleophilic attack of chloride (an SN2 reaction,
Section 8.3) on one of the two methyl group and displacement of nitrogen gives the
ethyl carbamide and chloromethane.
O:
CH3
N
CH3
Cl
Cl
OEt
OEt
CH3
R +N
CH3
OEt
C
CH3
R +N
CH3
A TCAI
OEt
O
R
:Cl-
C
N
CH3
+ CH3 Cl
(1)
F3
C
F3 C
4-Trifluoromethylfluorobenzene
O
N2H4
(2)
F3
C
NH2
O
Cl
H
N
OEt
(3)
F3
C
(4)
LiA
lH4
OEt
F3 C
N
Fluoxetine
O
+
CH3 O
Anisole
Cl
Cl
AlCl3
(1)
Chloroacetyl
chloride
N
O
(2)
CH3 O
CH3 O
O
N a BH 4
(3)
Mg ,
SOCl2
OH
CH3
O
Cl
(4)
CH3
O
N
OH
(5)
CH3 O
Venlafaxine
O
Morpholine
O
KN3
(1)
OH
N
O
N3
Ethylene
oxide
SOCl2
(4)
Cl
N
O
(2)
(5)
H2 / Pt
NH3
NH2
N
O
(3)
(7)
Cl
HO
SOCl2
(6)
H
N
Cl
N
Cl
O
O
Cl
O
Moclobemide
aziridine amide. Treatment of the aziridine ring with morpholine results in nucleophilic
opening
of the ring to give moclobemide.
Cl
Cl
NH +
Cl
Aziridine
N
O
Cl
H
N
O
N
O
O
Moclobemide
CH3 O
O
NaOEt ,
Cl
CH2 O, HCl
(1)
7
CH3 O
COOEt
(2)
2-Methoxynaphthalene
HCl, H2 O
NaOH, H2 O
CH3 O
COOE
t
(3)
(4)
COONa+
CH3
O
CH3 O
COO
H
O
heat
(5)
CH3
O
Nabumetone
H
H
+H
O
O: + HCl
H
+
H
H
O
: Cl -
CH2
OH
CH3 O
+
CH3 O
6
CH3 O
+
7
CH2 OH
+H
O
H
+
7
CH3 O
+
CH2
CH3 O
H
OH
CH2 OH
Proton transfer from cation 6 to chloride ion completes the electrophilic aromatic
substitution
and gives the hydroxymethyl group.
H
6
:
Cl -
CH2 OH
CH3 O
+
CH2
OH
CH3 O
+
CH2 OH2
CH2
OH
+ HCl
CH3 O
CH3
O
CH2
CH2 Cl
:Cl-
CH3 O
CH3
O
(b) The steps in the acetoacetic ester synthesis (Section 19.6) are shown in the
outline for the
synthesis.
(c) Following are structural formulas of 6-methoxynaphthylacetic acid, ibuprofen, and
naproxen.
COO
H
CH3 O
COOH
COO
H
6-Methoxynaphthylacetic
acid
CH3
O
Naproxen
Ibuprofen
H
O N
H2N
LiA lH4
H3 PO4
(3)
CH3 O
(1)
(2)
(A)
(B)
CH3 O
(C )
H
N
N
NaBH4
N
H3 PO4
(redraw)
(5)
(4)
CH3 O
(D)
CH3
(E)
CH3 O
(E)
O
H
Et O
H
Et O
H3 C
N
H
Cl
(6)
CH3 O
CH3
O
(F)
LiA
lH4
(7)
CH3 O
(G)
Racemethorphan
(a) Lithium aluminum hydride reduction of the nitrile gives a primary amine (Section
18.11C).
(b) The reagent is 4-methoxybenzoyl chloride. Reaction of this acid chloride with the
primary amine gives an amide (Section 18.7A).
(c) This intramolecular cyclization is initiated by protonation of the carbonyl group of
the amide.
The resulting cation (a Lewis acid) reacts with the carbon-carbon double bond of the
alkene (a Lewis base) to give a carbocation intermediate, loss of a proton from which
gives the carbon- carbon double bond of the newly formed six-membered ring. Loss
of H2O from the -amino alcohol gives the imine (Schiff base). In this mechanism,
phosphoric acid is represented by HA.
H
A -H
H
+ N
H O
:O N
H
HO N
+
H
CH3 O
CH3 O
(C
)
:A -
CH3
O
H
HO N
N
- H2
O
CH3
O
CH3
O
(D)
(d) Conversion of (E) to (F) involves an electrophilic aromatic substitution like that
described in
Section 21.1D. In this case, the attacking electrophile is the carbocation
generated by protonation of the carbon-carbon double bond of the
substituted cyclohexene ring.
H- A
H
+
CH3
O
(E)
CH3 O
N
H
CH3 O
+ H
:A
-
N
H
CH3 O
(F)