An explosion that caused extensive damage to a 20-L rotary evaporator and nearby equipment in a kilo laboratory was determined to have been caused by diazidomethane accumulated in the condenser. Factors contributing to this incident are discussed, and safer alternative procedures are recommended.
A large scale synthesis of the topical carbonic anhydrase
inhibitors AL-4623A (13a·HCl) and AL-4862 (13b) from
3-acetyl-2,5-dichlorothiophene (“DCAT”, 1) is described. Reaction of 1 with NaSBn gave thioether 2, which was converted
via sulfenyl chloride 3 and sulfenamide 5 to sulfonamide 6.
Bromination of 6 gave bromo ketone 7, which upon reduction
with (+)-B-chlorodiisopinocampheylborane and cyclization of
the resulting bromohydrin produced S thieno[3,2-e]-1,2-thiazine
8a (96% ee) after chromatography. Treatment of 8a in THF
with n-BuLi at −70 °C resulted in Li−Cl exchange. Reaction
of the thienyllithium with SO2 and hydroxylamine O-sulfonic
acid afforded bis-sulfonamide 11a. Protection of 11a as the
acetimidate 12a, followed by tosylation and amination, gave R
amine 13a. The synthesis of 13b proceeded via primary
sulfonamide 16, which was brominated, reduced, and cyclized
to give S thieno[3,2-e]-1,2-thiazine 18 (>98% ee). By virtue of
the ionizable NH, 18 was separable from reduction byproducts
by base extraction. Alkylation of 18 with 3-bromopropyl methyl
ether afforded 8b, which was converted as above, via 11b, to
AL-4862 (13b). These procedures provided multihundred gram
lots of 13a and 13b.
Ethyl N‐(2‐methoxycarbonylphenyl)thiocarbamate (2), N‐(2‐ethoxycarbonylphenyl)‐4‐methoxythiobenz‐amide (3b), and 2‐(4‐methoxyphenyl)‐4H‐3,1‐benzothiazin‐4‐one (4a), react with nucleophilic reagents containing at least one primary amino group to yield a variety of 2‐substituted and 2,4‐disubstituted 4(3H)quinazolinones, as well as some tricyclic and tetracyclic products.
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