4,5,6,7-Tetrahydrothieno pyridine

N-Alkylation and subsequent reduction of both thieno[3,2-c]- (422) and thieno[2,3-c]pyridines (424) give predictably the 4,5,6,7-tetrahydrothieno-pyridines 423 and 425, respectively. Large excesses of borohydride were used, and the reductions were carried out in ethanol over 4-h periods at reflux temperatures. Yields of 57-78% are obtained. The relatively electron-rich thiophene ring resists reduction. 

Unchanged Ticlopidine (25) and three metabolites Ticlopidine N-oxide, (T-NO), Tetrahydrothieno pyridine (THTP), and 2,chloro-hyppuric acid (CI-HPA) were isolated from rat urine by differencial solvent extraction and characterized by their behaviour on TLC and GLC. Their identities were confirmed by comparison with authentic standards. A fourth metabolite (T-M) gave rise upon acid hydrolysis to a compound, which co-chromatographed with authentic (T), both on TLC and GLC. The original structure of this metabolites is not yet elucidated. (T) and (T-M) were also found in bile wxtracts, whereas (T-NO), (THTPj, and (CL-HPA) were not detected in the bile, under the conditions used. 

Chemical Name 5-[(2-Chlorophenyl)methyl] -4,5,6,7-tetrahydrothieno[3,2-c] pyridine Common Name —... 

Chemical Name 2-amino-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c] pyridine-3-carboxylic acid ethyl ester... 

A solution of 1-benzyl-4-piperidone, ethyl cyanoacetate, powdery sulfur and morpholine in ethanol is heated moderately under reflux for about 20 minutes to dissolve the powdery sulfur. The mixture is heated under reflux for one further hour to complete the reaction. On standing at room temperature, the mixture yields a precipitate. The precipitate is collected by filtration, washed well with methanol and recrystallized from methanol to give 2-amino-6-benzyl-3-ethoxycarbonyl-4,5,6,7-tetrahydrothieno(2,3-c)-pyridine as almost colorless needles melting at 112° to 113°C. 

In the first step, (R)-2-chlorobenzaldehyde cyanohydrin is prepared by the almond meal-catalyzed addition of HCN to 2-chlorobenzaldehyde. The cyanohydrin is then transformed into the corresponding 2-hydroxy ester by Pinner reaction. Subsequently, the hydroxy group is activated by sulfonylafion and reacted with tetrahydrothieno[3.2-c]pyridine to give, under complete inversion of configuration, the (5 ) — a-amino acid derivative CLOPIDOGREL. ... 

Table 2 Structure and Enhancing/Antagonistic Activity of 2-Amino-3-benzoyl-4,5,6,7-tetrahydrothieno [2,3-c]pyridines 3a-g and 4... 

Ticlopidine Ticlopidine, 5-(o-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (24.2.1), is synthesized in many different ways [33-39]. The first way consists of N-alky-lation of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine with 2-chlorobenzylchloride. 

Tetrahydrothieno[3,2-( ]pyridine undergoes an unusual reaction with ethyl propiolate to afford compound 62 instead of the expected ring opening to give a thiophene product (Equation 9) <2004CHE519>. 

Derivatives of 4,5,6,7-tetrahydrothieno[2,3-f]pyridines are capable of inhibiting lipopolysaccharide-stimulated production of tumor necrosis factor-a. The activity of the derivatives is linked to the substituents at positions 2 and 6. 

Tetrahydrothieno[3,2-r ]pyridines act as effective anticonvulsants <1996CPB778>. Octahydrothienopyridines, 161, serve as potent HIV-1 protease inhibitors and antivirals <1995BML2885, 1995BML2891>. 

Treatment of 7V-(2-hydroxy-2-phenylethyl)-2-aminomethylthiophene with polyphosphoric acid results in formation of 4-phenyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (1) in 89% yield. If trifluoroacetic acid is used, however, the product, obtained in 100% yield, is a 4 1 mixture of 7-phenyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine 2 and 1. 

Clopidogrel (SR 25990) (Plavix Sanofi-Aventis) is the hydrogen sulfate salt of the S enanthiomer of methyl 2-(2-chlorophenyl)-2-[4,5,6,7-tetrahydrothieno(3,4-c)pyridine-5-yl] acetate. Its molecular formula is CI6HI6CIN02S, H2S04 (molecular weight of 419.9) (Fig. 2). 

Most interest in biological activity has been centered on 4,5,6,7-tetra-hydrothieno 2,3-c, - or - 3,2-c pyridines. A considerable number of derivatives of these systems have been prepared by the sodium borohy-dride reduction of quaternary ammonium salts,90,91 or by reaction of the 4,5,6,7-tetrahydro base with a suitable halide,9,I°4 tosyl derivative,105 epoxide,106 or activated alkene.107 An alternative, and very convenient, synthesis of 2-amino-3,6-substituted 4,5,6,7-tetrahydrothieno[2,3-c[-pyridincs (89), used mostly by Nakanishi and his co-workers, involves reaction of an N-substituted 4-piperidone, a compound of the type 88 and sulfur, in the presence of morpholine. The group X can be CN,... 

Ttnoridine. 2-Amino-4tS,6, -tetrahydro-6-(phen-ylmethyl)thieno[2,3-c]pyridine-3-carboxyiic acid ethyl ester 2-amino-6-benzyl-4,S,6,7-tetrahydrothieno(2,3-cJpyridine-3-carboxylic acid ethyl ester 2-amino-3-ethoxycarbonyl-6-benzyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine ethyl 2-amtno -6 -benzyl -4,5,6,7 -tetrahydrolhieno[2,3 -cjpy ridine-3 -carboxylate Y-3642. CJ,Ha,Nj02S mol wt 316.42. C 64.53%, H 6.37%, N 8.85%, 0 10.11%. S 10.13%. Ptepn Nakanishi et al. Ger. pat. 1,812,404 eidem. 113. pat. 3,-563,997 (1969, 1971 both to Yoshitoml). Pharmacological... 

A number of reports detailing the preparation of novel fused thiophenes have appeared including tetrahydrobenzothieno[2,3- /]imidazole 226 , dihydrothieno[3,2-g]indazole 227 and dihydrothieno[3,2-AJquinazoline 228 , benzothieno[2,3-Z7]pyridine 229 , thieno[2,3-f ]thiadiazine 230 , thieno[5,6-fc]thiazin-4-one 231 , tetrahydrothieno[3,4-c]pyrid-4-one 232 , and dihydrothieno[4,3,2- /][1.4]benzoxazepine 233 . 

After filtration and recrystallization from ethanol, there are obtained 5-(2-chlorobenzyD-4,5,6,7-tetrahydrothieno[3,2-cl -pyridine hydrochloride crystals (yield 60%) having a melting point (Koefler block) of 190°C. 

Ticlopidine Hydrochloride is prepared (10) by the treatment of 4, 5, 6,7-tetrahydrothieno [3,2-C] pyridine with... 

Yamanochi et al (11) developed a method for the preparation of 4, 5. 6, 7-tetrahydrothieno [3,2,-C] pyridine by treating 2-(2 thienyl)ethylamine and HCHO at dO C for three hours. The reaction mixture was extracted with CeHe which was recrystallised with CeHe/hexane mixture to give 1, 3, 5-... 

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