Manufacturing Process
To a solution of 3-(2,5,5-trimethyl-1,3-dioxane-2-yl)thiophene (2.5 g, 11.7
mmol) in hexane (30 mL) cooled to 0°C was added via syringe n-butyl lithium
in hexane (2.5 M, 10.3 mL, 25.7 mmol) over 5 min. The mixture was stirred
at 0°C for 20 min, the ice bath was removed and the stirring was continued
for 30 min. At this time a white precipitate formed. The mixture was cooled to -60°C and THF (20 mL) was added. Sulfur dioxide was then passed through
the surface of the mixture for 30 min. The mixture was warmed to ambient
temperature and stirred for an additional 15 min. The volatiles were
evaporated and to the residue was added water (50 mL) and sodium acetate
trihydrate (9.55 g, 70.2 mmol). The solution was cooled on an ice bath and
hydroxylamine-O-sulfonic acid (4.62 g, 40.9 mmol) was added. The mixture
was stirred at ambient temperature for 1 h, extracted with ethyl acetate
(3x100 mL) and the combined extracts were washed with a sodium
bicarbonate solution, brine and dried over molecular sieves. Evaporation to
dryness gave a viscous liquid (4.93 g), which was chromatographed (silica,
eluting with 33% ethyl acetate-hexane) to give a solid 3-(2,5,5-trimethyl-1,3-
dioxane-2-yl)-2-thiophenesulfonamide (2.47 g, 72%): m.p. 200°-202°C.
The last compound (9.45 g, 32.5 mmol) and 1 N HCl (100 mL) in THF (100
mL) was heated at reflux for 1 h. The THF was evaporated and the aqueous
solution was made basic by the addition of sodium bicarbonate. The mixture
was cooled using an ice bath and the precipitate was filtered, washed with
cold water and dried in vacuo to give 5.83 g (88%) of a solid 3-acetyl-2-
thiophenesulfonamide: m.p. 193°-196°C.
The last product (5.73 g, 28.0 mmol) was dissolved in hot THF (200 mL). The
solution was cooled to 10°C and pyridinium bromide perbromide (10.73 g,
33.5 mmol) was added. The mixture was allowed to stir at ambient
temperature for 1 h. The volatiles were evaporated and the residue was mixed
with water. The precipitate was filtered, washed with cold water and dried in
vacuo overnight to give 7.77 g of a solid. A portion of this solid (3.49 g, 12.3
mmol) was suspended in ethanol (100 mL) and treated with sodium
borohydride (266 mg, 7.04 mmol). The suspension turned clear after 10 min
and was heated at reflux for 1 h. The ethanol was evaporated and the residue
was extracted with ethyl acetate, washed with brine and evaporated to give
3,4-dihydro-4-hydroxy-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide (1.80 g,
71%): m.p. 138°-140°C.
A solution of the above product (19.2 g, 0.093 mol) in DMF (125 mL) was
added to a suspension of sodium hydride (3.08 g, 80% oil dispersion, 0.103
mol) in DMF at 006. When the addition was completed the ice bath was
removed and the reaction 20 mixture stirred at ambient temperature for 1 h.
The reaction mixture was cooled to 0°C and 2-bromoethyl methylether (13.6
mL, 0.14 mol) was added. The reaction mixture was stirred at ambient
temperature for 18 h after which time it was evaporated to dryness. The
residue was suspended in brine (100 mL) and extracted with methylene
chloride (4x80 mL). The combined extracts were dried (MgSO4), filtered and
evaporated to a solid which was recrystallized from ethyl acetate to give the
desired subject (17.4 g). Chromatography of the mother liquor (silica, 3%
ethanol/methylene chloride) furnished more subject which was combined with
the first batch to give a total of 19.3 g (78%) of 3,4-dihydro-4-hydroxy-2-(2-
methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide.
3,4-Dihydro-4-hydroxy-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine 1,1-
dioxide (4.9 g, 50 18.6 mmol) was converted to the 4-(1-ethoxy)ethoxy-3,4-
dihydro-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine 1,1-dioxide (6.2 g,
99%) using the reaction with p-toluensulfonic acid and ethylvinyl ether at 0°C
in tetrahydrofuran for 2 hrs.
The last one (6.2 g, 18.4 mmol) was converted into 3,4-dihydro-4-hydroxy-2-
(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxide
(4.87 g, 77%) m.p. 187°C by using the reaction with n-butyl lithium in
anhydrous THF at -40°C for 40 min, and then bubbling sulfur dioxide gas for
20 min after which time the mixture was warmed to room temperature. After
30 min at room temperature the mixture was concentrated the residue was
dissolved in water, cooled (0°C), sodium acetate trihydrate was added
followed by hydroxylamine-O-sulfonic acid. The reaction mixture was stirred at
room temperature for 18 h after which time was basified with solid sodium
bicarbonate and extracted with ethyl acetate.
3,4-Dihydro-2-(2-methoxy)ethyl-4-propylamino-2H-thieno[3,2-e]-1,2-thiazine-
6-sulfonamide-1,1-dioxide hydrochloride was obtained by the reaction of 3,4-
dihydro-4-hydroxy-2-(2-methoxy)ethyl-2H-thieno[3,2-e]-1,2-thiazine-6-
sulfonamide-1,1-dioxide in THF containing triethylamine with tosyl chloride at
-16°C and the next stirring for 18 hrs at room temperature. After which time
the mixture was cooled to 0°C and propylamine was added, the desired
product (0.57 g, 46%) was obtained: m.p. 178°-181°C.
The desired 4-ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H-thieno[3,2-e]-
1,2-thriazine-6-sulfonamide-1,1-dioxide was prepared according to described
above procedure for 3,4-dihydro-4-hydroxy-2-(2-methoxy)ethyl-2Hthieno[
3,2-e]-1,2-thiazine-6-sulfonamide-1,1-dioxide substituting 2-
bromoethylmethylether for 2-(bromomethyl)ethyl-methylether.
