dopamine itself is too hydrophilic to penetrate the brain from the circula-
tion. A tetrahydronaphthalene derivative that incorporates one of the
phenolic hydroxyls, as well as an ethylamine-like sequence of dopamine,
shows the same activity as the neurotransmitter. The lipophilicity ofrotigo-
tine( 52 ) allows it not only to cross the blood–brain barrier, but to also
reach the circulation when administered topically. The drug is in fact pro-
vided in a skin patch formulation that provides prolonged blood levels. The
preparation of this dopaminergic agent begins with the conversion of the
dihydroxynaphthalene ( 43 ) to its methyl ether by means of dimethyl
sulfate. Treatment of 44 with sodium in alcohol initially leads to the
dihydro intermediate ( 45 ). The regiochemistry follows from the fact that
only the right-hand ring has two open positions in a 1,4 relationship to
the methyl ether for forming the initial metal adduct. Treatment of 45
with acid then hydrolyzes the enol ether to afford theb-tetralone ( 46 ).
The carbonyl group is next converted to a Schiff base ( 47 ) by reaction
with propylamine. Catalytic hydrogenation of the intermediate then
affords the secondary amine. This intermediate is resolved via its dibenzoyl
tartrate salt ( 48 ). The methyl ether in the (S) enantiomer is cleaved by
means of hydrogen bromide to give the corresponding phenol ( 49 ).
Reaction with an activated form of 2-thienylacetic acid ( 50 ) followed by
reduction of the amide ( 51 ) with diborane gives the corresponding tertiary
amine, 52.^8
HOOH43(CH 3 ) 2 SO 4CH 3 OOCH 344Na
C 2 H 5 OH
CH 3 OOCH 345CH 3 OO46
C 3 H 7 NH 2CH 3 ONHC 3 H 747CH 3 ONHC 3 H 748ResolveHBrHONHC 3 H 749HON51HO 2 C S(^50) C 3 H 7
O
S
HO
N
52
C 3 H 7
BH 3 S
- TETRAHYDRONAPHTHALENES 75