Manufacturing Process
(a) cis-5,6,7,8-Tetrahydro-1,6,7-naphthalenetriol: A solution of 29.2 g (0.2
mol) of 5,8-dihydro-1-naphthol and 40 ml of acetic anhydride in 100 ml of
pyridine is prepared. After 16 hours the solvent is removed in vacuo and the
residue dissolved in ether and washed with 200 ml of 5% hydrochloric acid,
water, 200 ml of 10% sodium hydroxide, saturated salt solution and dried.
Solvent removal gives 34.2 g (90.5%) of crude acetate which is dissolved in
900 ml of acetic acid and 36 ml of water. 53.3 g (0.32 mol) of silver acetate is
added followed by 40.6 g (0.16 g-atom) of iodine. The slurry is heated with
good stirring at 85°10°C for 3 hours under nitrogen, cooled and filtered. The
filtrate is evaporated in vacuo and the residue dissolved in 250 ml of methanol
and cooled to 0°C.
A solution of 40 g of sodium hydroxide in 200 ml of water is added under
nitrogen and the mixture stirred overnight. The bulk of the methanol is
removed in vacuo whereupon a solid forms. The solid is separated by
filtration, dissolved in 150 ml of water and acidified with 20 ml of
concentrated hydrochloric acid. Cooling gives a solid which is filtered and dried
to give 16.5 g cis-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol, melting point 184.5°C to 187°C. Three recrystallizations from absolute ethanol give the
analytical sample, melting point 188°C to 188.5°C.
(b) 2,3-cis-1,2,3,4-Tetrahydro-5-[2,3-(epoxy)-propoxy]-2,3-naphthalenediol:
A solution of 1.20 g (0.03 mol) of sodium methoxide and 5.4 g (0.03 mol) of
cis-5,6,7,8-tetrahydro-1,6,7-naphthalenetriol in 200 ml of methanol is
prepared under nitrogen. The residue obtained upon solvent removal is stirred
overnight with 200 ml of dimethylsulfoxide and 4.65 g (0.05 mol) of
epichlorohydrin under nitrogen. The bulk of the solvent is removed at 50°C at
0.1 mm and the residue dissolved in 100 ml of water. Extraction with
chloroform (10 x 200 ml) gives a solid which is recrystallized from 150 ml of
hexane-ethyl acetate to give epoxy diol of the above title.
(c)2,3-cis-1,2,3,4-Tetrahydro-5-[2-hydroxy-3-(tert-butylamino)propoxy]-2,3-
naphthalenediol: A mixture of 2,3-cis-1,2,3,4-tetrahydro-5-[2,3-
(epoxy)propoxy]-2,3-naphthalenediol (melting point 104°C to 107°C, one spot
on TLC-alumina, 5% methanol in chloroform, iodine visualization) and 22 ml
of tert-butylamine is heated at 85°C to 95°C for 15 hours in a Parr bomb and
the excess amine removed in vacuo. The solid obtained by trituration of the
residue with ether is filtered and recrystallized from benzene to give 3.4 g,
melting point 124°C to 136°C.
Drug interactions
Potentially hazardous interactions with other drugs
Anaesthetics: enhanced hypotensive effect. Analgesics: NSAIDs antagonise hypotensive effect.
Anti-arrhythmics: increased risk of myocardial
depression and bradycardia; increased risk of
bradycardia, myocardial depression and AV block
with amiodarone; increased risk of myocardial
depression and bradycardia with flecainide.
Antidepressants: enhanced hypotensive effect with
MAOIs.
Antihypertensives: enhanced hypotensive effect;
increased risk of withdrawal hypertension with
clonidine; increased risk of first dose hypotensive
effect with post-synaptic alpha-blockers such as
prazosin.
Antimalarials: increased risk of bradycardia with
mefloquine.
Antipsychotics enhanced hypotensive effect with
phenothiazines.
Calcium-channel blockers: increased risk of
bradycardia and AV block with diltiazem;
hypotension and heart failure possible with
nifedipine and nisoldipine; asystole, severe
hypotension and heart failure with verapamil.
Cytotoxics: possible increased risk of bradycardia
with crizotinib.
Diuretics: enhanced hypotensive effect.
Fingolimod: possibly increased risk of bradycardia.
Moxisylyte: possible severe postural hypotension.
Sympathomimetics: severe hypertension with
adrenaline and noradrenaline and possibly with
dobutamine.
