3-Thiophenacetic acid → Thiophene

In the first set of experiments, amine and carboxylic acid terminated thiophene intermediates were prepared (FIG. 4) and subsequently coupled with carbohydrate moieties. In the second set, the distance between thiophene and carbohydrate was extended by iminothiolane hydrochloride (compound 30) and a thiol was generated after extension. (The reaction conditions specified in FIG. 4(a) are as follows: cat. DIPEA/CHCl3, r.t., 95% yield; FIG. 4(b) are as follows: CHCl3 (highly diluted), r.t., overnight, 83-96% yield; FIG. 4(c) are as follows: BOC-ON, Et3N/CHCl3, r.t., 52% yield; FIG. 4(d)(i) are as follows: 3-(3-Thienyl)acrylic acid (compound 19), HOBt/EDC, DIPEA, CHCl3, r.t., 6 h, 93% yield; FIG. 4(d)(ii) are as follows: 30% TFA/CH2Cl2, r.t., 3 h, 93% yield; FIG. 4(d)(iii) are as follows: 1 M NaOH, quantitative). These thiols were prepared in situ and coupled with compounds 2 or 5 by Michael type addition to give another set of thiophene-carbohydrate monomers. The two types of carbohydrate moieties are summarized in FIG. 5 and FIG. 6. Commercially available 3-thiopheneacetic acid (compound 6) (Acros Organics, Fisher Scientific, Pittsburgh, Pa.) was converted into the corresponding methyl ester (compound 7) in 88% yield by thionyl chloride in methanol. Thiopheneacetyl chloride (compound 8) was prepared in situ, by thionyl chloride in dioxane. Direct addition of N-hydroxysuccinimide (NHS) in the presence of diisopropylethylamine (DIPEA) at 0° C. afforded thiophene active ester (compound 9) in 75% overall yield. Compound 9 was stable under dry conditions and could be prepared in bulk quantities.

ORD record

ord-3e5007e2bb26461f9ba337f100fea1fb

Source dataset

uspto-grants-2003_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06660484B2