was added and the aqueous phase was separated. Water (5
L) was added to the organic phase, followed by solid
d
C
6
) δ 49.1, 61.7, 127.1, 132.7, 133.3, 146.6. Anal. Calcd for
NO Cl: C, 30.06; H, 2.52; N, 5.84. Found: C, 30.14;
6
H
6
3 2
S
NaHSO
negative test. The phases were separated and the organic
solution was washed with saturated NaHCO to pH 8, then
with brine, dried (Na SO ), filtered, and concentrated. The
3
with agitation, until peroxide test paper gave a
H, 2.56; N, 5.80.
(S)-3,4-Dihydro-6-chloro-4-hydroxy-2-(3-methoxypro-
pyl)-4H-thieno[3,2-e]-1,2-thiazine 1,1-Dioxide (8b). To a
stirred mixture of 18 (350 g, 1.46 mol), DMSO (1.75 L),
3
2
4
residual semisolid was triturated with MTBE to give a solid
that was collected by filtration, washed with MTBE, and
dried in air to give 597 g (71%) of 16: mp 178-179 °C; H
2 3
and K CO (605 g, 4.38 mol) was added 3-bromopropyl
methyl ether (268 g, 1.75 mol) in eight equal portions spaced
1 h apart. After a further 1.5 h the mixture was poured into
saturated NaCl (18 L), extracted with MTBE (2 × 4 L), and
the combined extracts were washed with 1 M NaOH (2 L),
1:1 bleach/water (2 L), and brine (2 L), dried over Na SO
2 4
(500 g), filtered, and concentrated to provide 427 g (94%)
1
NMR (DMSO-d
exchanges); 13C NMR (DMSO-d
38.8, 145.9, 193.2. Anal. Calcd for C
H, 2.52; N, 5.84; S, 26.75. Found: C, 30.19; H, 2.51; N,
.80; S, 26.70.
-Bromoacetyl-5-chloro-2-thiophenesulfonamide (17).
To a stirred suspension of 16 (1.09 kg, 4.55 mol) and EtOAc
22 L) at 1 °C was added PBP (mfr. assay 98%, 1.30 kg,
.00 mol) in one portion. H SO (concentrated, 544 mL) was
6
) δ 2.55 (s, 3H), 7.70 (s, 1H), 7.72 (s, 2H,
) δ 30.0, 130.0, 131.5,
ClNO : C, 30.06;
6
1
H
6 6
S
3 2
5
of 8b as a light-yellow syrup. A sample was purified by
3
chromatography on silica (5% acetone-CH
2
Cl
) δ 1.83-2.04 (m,
2H), 3.25 (s, 3H), 3.28-3.81 (m, 6H), 4.08 (dd, 1H, J )
2
): [R]25
D
1
+11.4° (c ) 1, MeOH); H NMR (CDCl
3
(
1
3
4
2
4
15, 4), 4.64 (br s, 1H), 6.96 (s, 1H); C NMR (CDCl
28.9, 46.9, 53.5, 58.5, 61.3, 69.8, 126.0, 132.4, 135.9, 143.4.
Anal. Calcd for C10 Cl: C, 38.52; H, 4.53; N, 4.49.
3
) δ
added over 10 min, causing the temperature to rise to 5 °C.
The mixture was stirred for 1.5 h, water (5 L) was added,
the mixture was stirred for 5 min, and the phases were
separated. The organic solution was washed with brine to
4 2
H14NO S
Found: C, 38.65; H, 4.54; N, 4.47.
(S)-3,4-Dihydro-4-hydroxy-2-(3-methoxypropyl)-4H-
thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-Dioxide (11b).
pH 3 (4 × 5 L required), dried over Na
and concentrated. The residue was triturated with CH
2 L) and chilled for 15 min. The solid was collected by
filtration, washed with cold CH Cl (2 L), and dried in air
at room temperature to give 1.04 kg (72%) of 17. A sample
was recrystallized from CH Cl -EtOAc-hexane: mp 147-
48 °C; H NMR (acetone-d ) δ 4.76 (s, 2H), 7.11 (br s,
H, exchanges), 7.76 (s, 1H). Anal. Calcd for C NO
2
SO
4
(1 kg), filtered,
2
Cl
2
2
Under N , a solution of 8b (1.06 kg, 3.42 mol) in anhydrous
(
THF (27 L) was cooled to -70 °C using a dry ice/2-propanol
bath. n-BuLi (7.7 mol, 2.3 equiv, 3.08 L of a 2.5 M hexane
solution) was added dropwise over 2.5 h while the temper-
2
2
2
2
2
ature was kept below -66 °C. After 1 h, SO was introduced
1
1
2
6
into the mixture until an aliquot quenched into water showed
pH 4. The mixture was allowed to warm to room temperature
overnight and then concentrated. The residue was dissolved
in water (5 L), and this solution was added in one portion to
6
H
5
3 2
S -
ClBr: C, 22.62; H, 1.58; N, 4.40; S, 20.13. Found: C, 22.66;
H, 1.60; N, 4.35; S, 20.12.
(
S)-3,4-Dihydro-6-chloro-4-hydroxy-4H-thieno[3,2-e]-
,2-thiazine-1,1-dioxide (18). Under N , a stirred suspension
of 17 (855 g, 2.68 mol) and MTBE (12.5 L) was cooled to
40 °C using a dry ice/2-propanol bath. (+)-Ipc BCl (4.5
2
a 0 °C solution of NaOAc‚3H O (2.80 kg, 20.5 mol) and
1
2
hydroxylamine-O-sulfonic acid (1.55 kg, 13.7 mol) in water
(6 L), causing the temperature to rise to 25 °C. After being
stirred for 15 h at room temperature the solution was
extracted with EtOAc (3 × 4 L). The combined extracts were
-
2
L of a 1.2 M solution in MTBE, 5.4 mol, 2 equiv) was added
via a cannula over 30 min, causing the temperature to rise
to -32 °C. After 3.5 h at -25 to -20 °C, reduction was
complete. The bromohydrin solution was warmed to 0 °C
and 1 M aqueous NaOH (11 L) was added over 10 min,
causing the temperature to rise to 22 °C. The biphasic
mixture was stirred vigorously at room temperature for 2 h.
The phases were separated and the aqueous solution was
extracted with MTBE (3 L), acidified to pH 1 using 12 M
HCl, and extracted with EtOAc (2 × 4 L). The combined
washed with saturated NaHCO
3
until basic, then with brine,
Cl (6 L) was
2 4
dried (Na SO ), filtered, and concentrated. CH
2
2
added to the residual oil along with with 5 g of seed crystals,
and the mixture was chilled and agitated to induce crystal-
lization. The solid was collected by filtration, washed with
CH Cl , and dried in air at room temperature to give 748 g
2 2
(61%) of 11b of 98.5% purity by HPLC. Another run starting
with 700 g of 8b yielded 552 g (69%) of 11b of comparable
2
purity. A sample was recrystallized from MeOH-H O: mp
2
3
1
EtOAc extracts were washed with brine (3 L), dried (Na
SO , 1 kg), filtered, and concentrated to about 1 L. Toluene
2 L) was added. Upon further concentration, removing
EtOAc, the product crystallized and was collected by
filtration, washed with toluene (2 L) and CH Cl (2 L), and
2
-
111-113 °C; [R] 405 +21.9° (c ) 0.45, MeOH); H NMR
(DMSO-d ) δ 1.83 (pent, 2H, J ) 7), 3.21 (s, 3H), 3.3-3.4
4
6
(
(m, 4H), 3.73 (dd, 1H, J ) 15, 5.6), 3.92 (dd, 1H, J ) 15,
4.5), 4.82 (br q, 1H, J ) 5), 6.15 (d, 1H, J ) 6, exchanges),
1
3
2
2
7.60 (s, 1H), 8.05 (s, 2H, exchanges); C NMR (DMSO-
) δ 28.5, 46.6, 52.6, 57.9, 60.2, 68.8, 129.7, 135.4, 145.9,
148.8. Anal. Calcd for C10 : C, 33.69; H, 4.53;
dried in air at room temperature to give 498 g (77%) of 18.
HPLC analysis of this material showed >98% chemical
d
6
16 2 6 3
H N O S
purity and >98% ee. A sample was recrystallized from
N, 7.86. Found: C, 33.61; H, 4.55; N, 7.77.
: mp 126-127 °C; [R]25
-5.9° (c ) 1, MeOH); H
1
(R)-3,4-Dihydro-4-(ethylamino)-2-(3-methoxypropyl)-
4H-thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-Dioxide
(13b, AL-4862). A solution of 11b (438 g, 1.23 mol),
acetonitrile (4.0 L), and trimethyl orthoacetate (630 mL, 2.83
CHCl
3
D
NMR (DMSO-d
4
1
6
) δ 3.35-3.50 (m, 1H), 3.55-3.68 (m, 1H),
.58 (q, 1H, J ) 7), 5.90 (d, 1H, J ) 7, exchanges), 7.20 (s,
H), 8.15 (br t, 1H, J ) 6, exchanges); 13C NMR (DMSO-
Vol. 3, No. 2, 1999 / Organic Process Research & Development
•
119