azole to 3-(1-piperazinyl)-1,2-benzisothiazole has led to the
development of a new, robust commercial process to 1.
Reaction of 8 with excess piperazine in the presence of small
amounts of DMSO and IPA at 120-125 °C for 24 h affords
1 in 75-80% yield. DMSO is added to the reaction to
reoxidize the reaction-liberated 2-mercaptobenzonitrile to 8,
thereby utilizing both halves of the symmetrical disulfide to
generate product. A small volume of IPA is added to the
reaction mixture to fluidize a nearly neat reaction mixture
and to rinse solid condensed piperazine from the reactor’s
headspaces. Compound 8 is readily available and possesses
a major advantage of being a fairly innocuous starting
material that is easy to handle. The new disulfide route
represents a high-yielding, one-step process to 1, a nucleus
for exciting new antipsychotic drugs.
mL) and then further concentrated at reduced pressure to 30
mL. The solution was cooled to 0-5 °C; hexanes (50 mL)
was added over 0.5 h, producing yellow crystals. After
granulating for 1 h at 0-5 °C, the product was filtered; the
cake washed with hexanes (15 mL) and then dried for 18 h
at 20-25 °C affording 11.51 g (89% yield) of finely divided
1
yellow crystals: mp 67-71 °C; H NMR (CDCl3) δ 7.63
(m, 1H), 7.56 (m, 3H), 7.21 (m, 1H), 2.96 (m, 4H), 2.87
(m, 4H); 13C NMR (CDCl3) δ 142.69, 133.55, 132.67,
128.14, 126.69, 116.80, 110.24, 57.34, 47.06; HR MS found
220.0878; C11H13N3S requires (FAB P + 1) 220.0908.
Not unexpectedly, sulfenamide 6 is both thermally and
hydrolytically labile. When 6 was stored at room temperature,
it slowly converted to 1,4-bis-(2-cyanophenylthio)piperazine.
The isolated sulfenamide 6 contained ∼5% of the bissul-
1
fenamide by H NMR. Attempts to purify 6 by recrystalli-
Experimental Section
zation or chromatography were unsuccessful in completely
removing the bissulfenamide.
Commercial quantities of bis(2-cyanophenyl) disulfide can
be obtained from Zambon, Sumitomo Seika, or SEAC or is
easily prepared from S-benzyl-o-cyanothiophenol,8b 2-nitro-
benzonitrile,10a or 2,2′-dithiobenzoic acid.10b Anhydrous, flake
piperazine was obtained from Texaco or Berol Nobel.
Melting points were determined on a Thomas-Hoover
capillary melting point apparatus and were uncorrected. NMR
spectra were obtained on a Brucker WM 300 (300 MHz)
spectrometer in deuteriochloroform or dimethyl sulfoxide-
d6. Mass spectra were determined with a Finnigan 4510 mass
spectrometer. Elemental analyses were performed by Schwarz-
kopf Microanalytical Laboratory, Woodside, NY. Thin-layer
chromatography was conducted on Merck Kieselgel 60 F254
plates (5 × 10 cm) using 1:1 hexanes-EtOAc, 10:10:1
hexanes-EtOAc-triethylamine (TEA), or 15:5:1 CH2Cl2-
IPA-TEA eluants. The TLC plates were visualized with UV
light (254 nm). High-pressure liquid chromatography was
performed on an LDC Analytical ConstaMetric 3200 HPLC
pump using a Zorbax C8 column (4.6 × 150 mm) and a
mobile phase containing 40% acetonitrile, 15% methanol,
and 45% 0.05 M KH2PO4 which was adjusted to pH 6.0
with KOH; flow rate 1 mL/min; injection volume (10 µL);
UV detector (229 nm); retention times 13, 1.23 min; 9, 1.25
min; 12, 2.00 min; 6, 2.81 min; 1, 3.03 min; 8, 9.86 min;
10, 10.89 min; and 11, 22.75 min.
1-(2-Cyanophenylthio)piperazine (6). Anhydrous pip-
erazine (22.5 g, 261 mmol) and THF (100 mL) were
combined under a nitrogen atmosphere and then the mixture
was heated to 60-65 °C to afford a colorless solution.
3-Chloro-1,2-benzisothiazole (10.0 g, 59.0 mmol) was slowly
added over 1 h to the warm piperazine solution, and the
resulting amber solution was heated an additional 17 h at
60-65 °C. Thin-layer chromatography (SiO2, EtOAc-
hexanes-TEA, 10:10:1) showed that the reaction was
complete. The thin slurry was cooled to 30 °C and filtered.
Toluene (100 mL) was added to the filtrate and the resultant
mixture was concentrated at reduced pressure (40 °C) to half
of its volume. The concentrate was washed with water (100
3-[(2-Cyanophenyl)thio]-1,2-benzisothiazole (10). 8 (1.25
g, 4.66 mmol), anhydrous piperazine (4.01 g, 46.6 mmol),
and DMSO (0.80 g, 10.3 mmol) in 15 mL of THF were
added to a 50-mL round-bottom flask equipped with a
magnetic stirring bar, thermometer, and condenser topped
with a nitrogen inlet. After the flask was purged with
nitrogen, the mixture was heated at reflux (75 °C) for 25 h.
The reaction mixture was cooled to 25 °C, and THF was
removed at reduced pressure. The resulting solid was
dissolved in a 40 mL of a CH2Cl2-water (1:1), the layers
were separated, and the organic layer was washed with water
(20 mL). The CH2Cl2 solution was evaporated to afford a
crude solid (0.85 g) which was recrystallized from IPA (17
mL) to give light yellow crystals. After filtration, the product
was dried in vacuo at 40 °C to give 0.39 g (31% yield) of
1
10: mp 115.5-117 °C; H NMR (CDCl3) δ 8.03 (m, 1H),
7.92 (m, 1H), 7.77 (m, 1H), 7.70 (m, 1H), 7.57 (m, 2H),
7.48 (m, 2H); 13C NMR (CDCl3) δ 154.99, 152.30, 134.83,
134.56, 134.06, 133.24, 129.07, 128.51, 125.33, 123.29,
120.13, 117.13, 116.95. Anal. Calcd for C14H8N2S2 C, 62.66;
H, 3.00; N, 10.44; S, 23.90. Found: C, 62.43; H, 3.01; N,
10.68; S, 24.05.
3-(1-Piperazinyl)-1,2-benzisothiazole (1) from (5). A
mixture of anhydrous piperazine (76.2 g, 884 mmol) and 23
mL of pyridine was heated to 115 °C under a nitrogen
atmosphere. A solution of 3-chloro-1,2-benzisothiazole (30.0
g, 17.7 mmol) in 15 mL of pyridine was slowly added over
1 h to the piperazine solution to moderate an exothermic
reaction. Once the addition was complete, the amber solution
was heated for 24 h at 119 °C when thin-layer chromatog-
raphy (SiO2, CH2Cl2-IPA-TEA, 15:5:1) showed that the
reaction was complete. The solution was cooled to 90 °C
and water (154 mL) was added. The brownish slurry was
stirred for 1 h at 25 °C and filtered through Celite to remove
11, and then the cake was washed with 35 mL of pyridine-
water (1:4) solution. The wash and filtrate were combined
and the pH adjusted to 12.0-12.5 with 50% (w/w) aqueous
NaOH (10.2 mL). The solution was concentrated at reduced
pressure (60 mmHg at 45-50 °C) to 170 mL. Water (240
mL) and toluene (308 mL) were added to the concentrate
(10) (a) Beck, J. R., Yahner, J. A. J. Org. Chem. 1978, 34, 1604. (b) Saji, K.;
Nagata, H.; Muto, M.; Nakamua, T. Japanese Patent Appl. 93-27357, January
22, 1993; Chem. Abstr. 1995, 122, 31512.
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