subsequently evaporated to dryness, yielding crude bromodi- mixture was stirred for 5 hours at 25°C. Subsequently, the re-
phenylmethane. The system was automatically cleaned once actor module was charged with a solution of 4-amino-1-me-
more, the reactor was charged with 2-(dimethylamino)etha- thyl-3-n-propyl-1H-pyrazole-5-carboxamide
in
nol and 10 ml of toluene, and the bromodiphenylmethane dichloromethane and triethylamine and cooled to 10°C. The
was transferred to the reactor with three portions of toluene. crude acid chloride solution was pumped from the filter mod-
The mixture was heated to reflux for 20 hours. After cooling ule to the reactor and the mixture was stirred for 16 hours at
below 30°C, the reaction was quenched with aqueous sodium 25°C. After quenching the reaction with water, the layers
hydroxide. The layers were separated, and the organic layer were separated, the organic layer was dried over activated
was extracted with 2M aqueous hydrochloric acid three times. molecular sieves and evaporated to dryness, yielding 4-[2-eth-
Equimolar aqueous sodium hydroxide was added to the com- oxy-5-(4-methyl-1-piperazinylsulfonyl)-benzamido]-1-methyl-
bined aqueous layers and the mixture was extracted with di- 3-propyl-1H-pyrazole-5-carboxamide as an off-white solid.
ethyl ether three times. The combined etheric layers were For the subsequent cyclization, the crude amide was trans-
evaporated to dryness, yielding crude diphenhydramine free ferred back to the reactor by dissolving it with a solution of
base. The jacketed filter module was then charged with potassium tert-butoxide in tert-butanol, and the mixture was
etheric hydrochloric acid and the crude free base was slowly heated at reflux for 8 hours. After cooling to 10°C, the reac-
transferred to the filter with three portions of diethyl ether. tion was quenched with water, and the solution was trans-
The precipitate formed was collected by filtration, dried un- ferred to the filter module. To induce precipitation of the
der a stream of argon, and recrystallized from isopropanol, sildenafil, the mixture was neutralized with aqueous hydro-
yielding pure diphenhydramine hydrochloride as white crys- chloric acid. After filtration, the solid was washed with water
talline powder.
and dried under a stream of argon at 50°C, yielding the title
compound as white crystalline powder.
Synthesis of rufinamide
The reactor was charged manually with 2,6-difluoroben-
zyl bromide. An aqueous solution of sodium azide was added
to the reactor, the mixture was heated to 75°C for 12 hours
and subsequently transferred to the jacketed filter module.
Neat methyl propiolate was added and the mixture was
heated to 65°C for 4 hours. An aqueous solution of ammonia
was subsequently added and the mixture was held at 75°C for
an additional 12 hours, precipitating the target compound.
Filtration followed by three aqueous washes yielded pure ru-
finamide as white crystalline powder.
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First release: 29 November 2018
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