A new, one-step commercial process for the preparation of 3-(1-piperazinyl)-1,2-benzisothiazole hydrochloride, a key intermediate for the syntheses of some new, “atypical antipsychotic” drugs, was ...developed. Reaction of bis(2-cyanophenyl) disulfide with excess piperazine at 120−140 °C for 3−24 h in the presence of small amounts of DMSO and 2-propanol formed 3-(1-piperazinyl)-1,2-benzisothiazole in 75−80% yields. The DMSO oxidized the liberated 2-mercaptobenzonitrile to regenerate bis(2-cyanophenyl) disulfide, thereby enabling the utilization of both halves of the symmetrical disulfide to generate product. The reaction mechanism for the conversion of the bis(2-cyanophenyl) disulfide to 3-amino-1,2-benzisothiazole involves the formation of ring-opened sulfenamide and benzamidine intermediates and then their subsequent ring closure to regenerate the 1,2-benzisothiazole nucleus. A safe, efficient, and robust process to prepare 3-(1-piperazinyl)-1,2-benzisothiazole under very concentrated reaction conditions was developed and successfully scaled up in the pilot plant to support the development of ziprasidone.
Thermal reaction of β-cellobiosyl fluoride heptaacetate with ticogenin in toluene or
o-xylene at 112–142 °C gave ticogenyl β-cellobioside heptaacetate in 69–75% yields with good stereoselectivity. ...The procedure avoids the use of Lewis acid or traditional glycosidation promotors. The deacetylated product is a hypocholesterolemic and anti-atherosclerosis agent.
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Fast atom bombardment mass spectral examination of molecules containing a 1,2-benzisothiazole ring, using a thiol reducing agent matrix, promotes reductive ring opening of the benzisothiazole ring, ...giving an M+H
+ two daltons higher than expected. Measurements using a non-reducing matrix produce the expected M+H
+. This is a general phenomenon, observed with a number of molecules containing the benzisothiazole ring. The ring-opened structure has been confirmed by chemical synthesis and observed in metabolic studies.
FAB mass spectral examination of molecules containing a 1,2-benzisothiazole ring, using a reducing thiol matrix, promotes reductive ring opening of the benzisothiazole ring. The ring-opened structure has been confirmed by chemical synthesis.
A detailed commercial process for the synthesis and purification of the activated disaccharide, alpha-D-cellobiosyl bromide heptaacetate (1) was developed. Reaction of alpha-D-cellobiose octaacetate ...(CBO) with HBr in glacial acetic acid or in glacial acetic acid/methylene chloride combination affords alpha-D-cellobiosyl bromide heptaacetate in high yield and excellent quality. Process variables such as reaction solvent, reaction time, reaction temperature, HBr stoichiometry, isolation methods and product purification options were optimized for large-scale synthesis. alpha-D-Cellobiosyl bromide heptaacetate was successfully prepared in a commercial manufacturing plant.
The early effects of tissue-type plasminogen activator (t-PA) on the "culprit" coronary lesion in patients presenting with unstable angina or non-Q wave myocardial infarction were determined by ...quantitative arteriography.
Of 391 such patients, 306 satisfied clinical and arteriographic requirements for eligibility and received a 90-minute front-loaded infusion of t-PA (0.8 mg/kg i.v.; maximum, 80 mg) or placebo plus conventional antianginal therapy. All patients received full heparinization and a follow-up arteriogram 18-48 hours after treatment. A non-Q wave myocardial infarction (MI) was diagnosed in 97 patients (32%) after entry. In the entire patient population, among t-PA- and placebo-treated patients, respectively, 25% versus 19% (p = 0.25) of all culprit lesions achieved the primary study end point, measurable improvement (by > or = 10% reduction of stenosis or two Thrombolysis in Myocardial Infarction TIMI flow grades) at follow-up. Substantial improvement (by > or = 20% reduction of stenosis or two TIMI grades) was seen with t-PA in 15% of all culprit lesions versus 5% with placebo (p < 0.003). Arteriographically apparent thrombus was present at baseline in the culprit lesion of 107 patients (35%). Substantial improvement was more frequent with t-PA among lesions containing apparent thrombus (in 36% with t-PA versus 15% with placebo; p < 0.01), as it was among patients evolving a non-Q wave MI (33% versus 8%; p < 0.005). By multivariate analysis, the significant, independent predictors of substantial improvement include apparent thrombus (p = 0.0001), non-Q wave MI (p = 0.003), and t-PA use (p = 0.01). Both non-Q wave MI status and thrombus had been specified a priori as important variables.
Arteriographically apparent intraluminal thrombus and improvement of the culprit lesion with either of these regimens were only moderately frequent in patients with unstable angina or non-Q wave MI. Substantial improvement of culprit lesions was more frequent with t-PA than with placebo overall and in two prospectively defined subgroups. The clinical relevance of these observations is being tested in the larger, ongoing clinical TIMI IIIB study.
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