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Scheme 3.1: Ritter reaction.
3.6 Other dopaminergic agonists 69
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Scheme 3.2: Amantadine synthesis through the Ritter reaction.
The four bridgehead positions are identical and surprisingly reactive. After halogenation with an excess of Cl
acid leads to an amide through an apparent S
or Br2, the subsequent reaction with acetonitrile in sulfuric
2
1 reaction (Ritter reaction), and subse-
N
quent hydrolysis yields amantadine. Amantadine is a very basic amine and therefore
fully protonated, but the extreme lipophilicity of the adamantyl moiety allows its passage through the BBB. In addition, its volume and chemical inertia hinder the oxidative metabolism of the drug, and amantadine is excreted unchanged in the urine.
3.6 Other dopaminergic agonists
Finally, another dopaminergic alternative for treating Parkinson’s disease can be by
means of dopaminergic agonists, other than dopamine, among which apomorphine
stands out. Apomorphine is obtained as a semisynthesis product of morphine by heating
with concentrated HCl (Scheme 3.3).
When explaining a chemical process, we must look at the starting point and what
the final product is: This way, we will know what type of chemical modifications we
should carry out. In the case at hand, morphine has five rings and apomorphine has
four. In addition to this, the piperidine ring (six-membered ring with the N atom) joins
in a different way in the final product, so throughout the synthetic process, a molecular
rearrangement has to occur. Finally, the loss of the cycle in apomorphine probably
comes from the five-membered ring with the oxygen atom (derived from dihydrofuran)
and in addition, the cycle containing initially the allyl alcohol, must be aromatized,
transforming it into a benzene ring. Now the next question is how to carry out these
transformations. Where do cascade reactions begin? Allyl alcohol (in blue in the structure of morphine) is a point of high reactivity, because in a strongly acidic medium, its
OH group will be protonated to give a highly stable allylic carbocation. From here, and
through the rearrangement of a C–C bond, a very stable tertiary carbocation is created,
which, on the other hand, triggers a series of elimination reactions that lead to the creation of the second benzene ring.
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Scheme 3.3: Semisynthesis of apomorphine.
Apomorphine effectively controls Parkinson’s symptoms, but it is only active parenterally, its action is brief, and it leads to violent vomiting.
3.7 Dopaminergic antagonists
Neuroleptic drugs (also known as antipsychotic medications are used to treat and manage symptoms of many psychiatric disorders) are selective D
lar level at which they act is not known. They comprise the following groups, of which
we will study only the first two:
– Tricyclic neuroleptics
– Butyrophenones
– Benzamides
– Rauwolfia serpentina alkaloids
3.7.1 Tricyclic neuroleptics: phenothiazines and thioxanthenes
Although phenothiazine has been used as an anthelmintic, the first known drugs derived from this heterocyclic system found utility as antihistaminics (see Chapter 7 of
this volume). An example is promethazine (Fig. 3.9), an antihistaminic designed by
structural variation of ethylenediamines, compounds that constituted one of the first
groups of antihistaminics, which are useful as antiallergics.
antagonists. The molecu-
2
3.7 Dopaminergic antagonists 71
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Fig. 3.9: Development of chlorpromazine from phenothiazine.
Promethazine is an antihistaminic that has sedative-like side effects. This effect became dominant in chlorpromazine, a neuroleptic prototype that comes from a structural variation of promethazine.
3.7.1.1 Synthesis of the tricyclic system
There are three syntheses:
(a) Sulfuration (or thionation) reaction of diphenylamine, in which the heterocy-
clic nucleus is formed, and which must then be N-alkylated (Scheme 3.4). Note the
formation of two isomers in the sulfuration step.
Allotropy is the property of some simple substances having different atomic or molecular
structures. Molecules formed by a single element and that have different molecular structures are called allotropes. Although elemental sulfur has been known since prehistoric
times, it was not until just 30 years ago that the allotropy of this element was clarified.
The most common allotrope of sulfur in nature is S
(octasulfurorcyclooctasulfane).It
8
adopts a crown conformation (Fig. 3.10).
3.7.1.1.1 Mechanism for the conversion of diarylamines to phenothiazines
A possible mechanism for the conversion reaction of diarylamines to phenothiazines by
reaction with sulfur and a catalytic amount of iodine is indicated in Scheme 3.5. Iodine
can be added to an S–SbondofthecyclicS
molecule giving an intermediate that would
8
electrophilically attack one of the activated benzene rings of diarylamine, forming one of
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Scheme 3.4: Synthesis of chlorpromazine.
Fig. 3.10: Crown conformation of the allotrope S8.
the C–S bonds (SEAr) at ortho-position. Obviously, this reaction can also take place at
para-position, which would give rise to by-products of this reaction. The ortho-reaction
product could again undergo an electrophilic attack, this time intramolecularly, on the
second ring forming the nucleus of the phenothiazine. In this process, iodine, which is
used in catalytic quantity, is transformed into hydroiodic acid, which is oxidized by sulfur
to give iodine again, which can repeat the S
Ar cycle. When R ≠ H, the majority product
E
of this reaction is the 2-substituted phenothiazine, and the 4-substituted isomer derived
from the electrophilic attack at the ortho-position of the substituted ring can also be
formed, in a smaller proportion (due to the greater steric effect during S
(b) Synthesis of Ullmann: aromatic S
of halogens activated by nitro groups.A
N
E
Ar).
halogen bound to a saturated carbon atom is often easily displaced by a suitable
nucleophile at temperatures below 100 °C. In contrast, chlorobenzene and bromobenzene are inert to this reaction under such conditions. They react with sodium
hydroxide in water, for example, only at temperatures above 300 °C. Thus, a halogen atom attached to an aromatic ring (or to a C = C double bond, e.g., vinyl bromide) is generally reasonably inert to substitution by nucleophiles (in any of its
mechanisms, S
2orSN1). However, substitution can very easily occur if there is a
N
strongly electron-withdrawing group attached to the aromatic ring at ortho-or
para-positions with respect to the halogen (Scheme 3.6).
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Scheme 3.5: Proposed mechanism for the conversion of diarylamines to phenothiazines.
Scheme 3.6: Greater ease of substitution of the chlorine atom, when there is a strongly electron-
withdrawing group attached to the aromatic ring at ortho or para positions with respect to the halogen atom.
These are reactions of nucleophilic aromatic substitutions. The mechanism involves
the formation of an intermediate that is analogous to that formed in electrophilic aromatic substitutions, but in which an anionic intermediate (Meisenheimer complex) is
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formed. If there are two or more electron-withdrawing groups at the ortho and para
positions of the aromatic ring, the intermediate is even more stable, and the substitution reaction proceeds even more easily. Thus, any aromatic compound containing a
good leaving group, such as halide, and a moderately strong (or rather several) “activating groups” at the ortho-orpara-positions, will be exposed to sub stitution by an
adequately effective nucleophile (Scheme 3.7).
Scheme 3.7: SNAr reactions proceeding through the Meisenheimer complex.
A Meisenheimer complex is a 1:1 reaction adduct between an arene, which carries
electron-attracting groups, and a nucleophile. They are reactive intermediates in aromatic nucleophilic substitution. Herein lies the synthesis of Ullmann to obtain chlorpromazine (Scheme 3.8).
Scheme 3.8: Ullmann synthesis of chlorpromazine.
(c) Smiles rearrangement (it is simply an intramolecular nucleophilic substitution,
Scheme 3.9).
After the synthesis of antipsychotic phenothiazines, a large number of molecular
modifications were carried out, both in the aminoalkyl side chain and in the tricyclic
nucleus.
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Scheme 3.9: Synthesis of chlorpromazine through the Smiles rearrangement.
Replacement of phenothiazine by a thioxanthene nucleus was the most successful,
leading to chlorprothixene [cis-2-chloro-9-(3-dimethylaminopropylidene) thioxanthene],
a drug prepared by the Ullmann condensation between p-chlorothiophenol and o-
bromobenzoic acid (or between p-chlorobromobenzene and o-mercaptobenzoic acid),
followed by cyclization and introduction of the side chain (Scheme 3.10).
3.7.1.2 Pharmacophore of tricyclic neuroleptics
The general structure is shown in Fig. 3.11.
Gordon et al. postulated in 1964 that phenothiazines interact with the receptor in
three specific zones, A, B, and C, to produce the neuroleptic response (Fig. 3.12).
1. Normally the tranquilizing activity is optimal with X = Cl, CF
,SOCH3,etc.,i.e.,
3
electron-withdrawing groups.
2. The optimal side chain has three carbon atoms between both nitrogen atoms. The
depressant character is conserved with two carbon atoms, but the antihistaminic
one predominates.
3. Something similar occurs with the branching in the side chain: if R’ =CH
,the
3
tranquilizing character is reduced and the antihistaminic one increases. Other
substituents in the side chain (with the exception of inclusion in a piperidine
cycle) greatly reduce the neuroleptic action.
4. As for the aminic nitrogen atom (basic), its quaternization cancels the activity
(probably due to lac k of distribution in the CNS). It is possible to include this N
atom in a cycle (such as the piperazine ring, Fig. 3.13).
The presence of the OH group in carfenazine or fluphenazine allows its esterification
with intermediate- or long-chain acids (heptanoic acid = enanic acid, decanoic acid =
capric acid), thus obtaining latent drugs of very prolonged action (even several weeks).
Scheme 3.11 illustrates the synthesis of carfenazine.
The hydroxyethyl derivative of piperazine can be prepared as outlined in Scheme 3.12.
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Scheme 3.10: Synthesis of chlorprothixene.
Fig. 3.11: Pharmacophore of phenothiazines and thioxanthene derivatives.
Fig. 3.12: Boat-like arrangement of the phenothiazine ring.
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3.7 Dopaminergic antagonists 77
Fig. 3.13: Carfenazine and fluphenazine.
3.7.2 Butyrophenones and analogs
Development of butyrophenones is related to molecular modifications aimed at enhancing the analgesic effects of pethidine, an opioid-related analgesic (Fig. 3.14).
Modification of the butyrophenone analog, by introducing fluoride at the paraposition of the acylated ring and changing the ester by the OH group, allowed the isolation of the neuroleptic action, separating it from the analgesic one. The prototype obtainedwas haloperidol, 4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-4ʹ-fluorobutyrophenone
(Fig. 3.15).
3.7.2.1 Mannich reaction
Compounds that are enolic or potentially enolic react with a mixture of an aldehyde
(usually formaldehyde) and a primary or secondary amine in the presence of an acid
to give, after basification, an aminomethyl derivative. For example, by refluxing a mixture of acetone, diethylamine hydrochloride, paraformaldehyde (it is the polymeric
form of formaldehyde. It is a solid. Formaldehyde is a gas which when dissolved in
water gives a formaldehyde solution), methanol, and a little concentrated hydro-
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