Thieno pyridine-5-carboxylates synthesis

The synthesis of the representative compound of this series, 1,4-dihydro-l-ethyl-6-fluoro (or 6-H)-4-oxo-7-(piperazin-l-yl)thieno[2/,3/ 4,5]thieno[3,2-b]pyridine-3-carboxylic acid (81), follows the same procedure as that utilized for compound 76. Namely, the 3-thienylacrylic acid (77) reacts with thionyl chloride to form the thieno Sjthiophene -carboxyl chloride (78). Reaction of this compound with monomethyl malonate and n-butyllithium gives rise to the acetoacetate derivative (79). Transformation of compound 79 to the thieno[2 3f 4,5]thieno[3,2-b]pyhdone-3-carboxy ic acid derivative (80) proceeds in three steps in the same manner as that shown for compound 75 in Scheme 15. Complexation of compound 75 with boron trifluoride etherate, followed by reaction with piperazine and decomplexation, results in the formation of the target compound (81), as shown in Scheme 16. The 6-desfluoro derivative of 81 does not show antibacterial activity in vitro. 

Thieno[3,2-c]pyridazine-3-carboxylic acid synthesis, 4, 819-820 Thienopyridazines, 4, 1015 Thieno[2,3- hjpyridazines nitration, 4, 1016 synthesis, 4, 791, 1015 Thieno[3,2-c]pyridazines synthesis, 4, 1016 Thieno[3,4-d]pyridazines synthesis, 4, 1016 Thieno[2,3-6]pyridine, 4-amino-synthesis, 4, 1005... 

Thieno[2,3-6]pyridine-2-carboxylic acid, 3-amino-synthesis, 4, 1005... 

In 1972 Wright prepared 3-chlorothieno[3,2-6]thiophene-2-carbonyl chloride (94) in 11-13% yield by heating 3-(2-thienyl)acrylic acid, thionyl chloride, and pyridine, a method of synthesis of benzo[6]-thiophene-2-carbonyl chloride derivatives. " Methyl 3,5-dichloro-thieno[3,2-6]thiophene-2-carboxylate (95) and methyl 2-chloro-3-(5-chloro-2-thienyl)acrylate were also isolated. When fte reaction was carried out in refluxing toluene or chlorobenzene, the acid chloride (94)... 

A simple two-step synthesis of 4-arylthieno[3,2-c]pyridine-6-carboxylic acids has recently been presented by Eweiss (Scheme 74) (B-81MI31703). The condensation of thiophene-2-carbaldehyde with an N -aroylated a-amino acid yields a thienylidene azlactone (281) which on treatment with AICI3 is converted to a thieno[3,2-c]pyridine (283). A nitrilium ion (282) resulting from a vinyl-oxygen fission is probably involved as an intermediate. Sandberg s method already mentioned in the previous section has also been applied to the synthesis of thieno[3,2-c]pyridines (Scheme 75). 

An alternative approach (1991JHC81) to the construction of the thieno[3,2-c] pyridine system is based on C(6)-C(7) bond formation (approach S). For example, heating carboxylic acid 279 in PPA resulted in its cyclization giving 9-oxo-4H, 9f/-pyrrolo[l,2-a]thieno[2,3-<7]pyridine (280) in low yield. An attempt to prepare this compound by an independent synthesis, viz., by cyclization of isomeric acid 281 under analogous conditions, failed. 

Compound (20) can be prepared in a facile synthesis (Scheme 55) involving the conversion of ethyl 3-aminothieno[2,3-6]pyridine-2-carboxylate (112), which is a readily available thieno[2,3-Z>] pyridine derivative <74JHC975,76JHC273). 

Oxo-4,7-dihydrothieno[2,3- ]pyridine-5-carbonitriles such as compoimd 53 are important intermediates in the synthesis of thieno[2,3-Z)]pyridine-5-carbonitrile kinase inhibitors [130, 131]. A facile three step synthesis of 4-oxo-4,7-dihydrothieno[2,3-i]pyridine-5-carbonitriles 53 from substituted 2-aminothiophene-3-carboxylate esters 7 was developed [132]. The key step of the synthesis is a thermally promoted elimination/decarboxylation followed by nucleophilic cyclization of 52 to give fused thieno-dihydropyridines 53 (Scheme 20) in good yields (Table 10). 

Synthesis.—The reactions of thiophen-2- and 3-acrylic acid with thionyl chloride in the presence of pyridine yield a mixture of chlorinated derivatives of thieno[3,2-b]thiophen-2-carboxylic acid and thieno[2,3-b]-thiophen-2-acrylic acid. From thiophen-2,5-diacrylic acid, (241) was obtained. Aromatization of (66) gives thieno[2,3-b]thiophens. Reaction of (242) with methyl thioglycolate yielded (243)." Ethylthiophen was... 

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