Ethyl 5-amino-2- thieno

Thieno[2,3-6]pyridine, 6-amino-2,3,4,5-tetracyano-synthesis, 4, 805 Thieno[2,3-6]pyridine, 5-ethyl-nitration, 4, 1014... 

CN 2-amino-4,5,6,7-(etrahydro-6-(phenylmethyl)thieno[2,3-f]pyridine-3-carboxylic acid ethyl ester monohydrochloride... 

Condensation (FeCl, ZnClj, HCl) of these amine salts with methyl vinyl ketone produced 4-methylthleno[2,3-/>]thieno[2,3-h]pyridine and 4-methylthieno[3,2-6]thieno[2,3-6]pyridine, respectively , while acetylacetone (ZnClj) afforded the 2,4-dimethyl derivatives. 5-Ethyl-2-formylthieno[2,3-Z>]thiophene (211) and nitromethane by the Knoevenagel method gave 2-/3-nitrovinyI-5-ethylthienol2,3-6]-thiophene (212) (73%) reduction (LAH) of 212 led to the 2-/3-amino-ethyl analog (213) lEq. (69)]. 

The examples above open up synthetic approaches that involve manipulating either the amino or carboalkoxy moieties. The following examples illustrate the variety of ways in which these transformations have been used to synthesize thieno[3,2-4 pyrimidines. Scheme 37 describes one such method in which an intermediate urea derivative 456 is formed from 455 by reaction with ethyl isothiocyanatoformate. Cyclization to 457 occurs upon heating in an ethanolic alkoxide medium <2003BML107>. 

One Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) utilized optically pure (R)-(2-chloro-phenyl)-hydroxy-acetic acid (20), a mandelic acid derivative, available from a chiral pool. After formation of methyl ester 21, tosylation of (/ )-21 using toluene sulfonyl chloride led to a-tolenesulfonate ester 22. Subsequently, the Sn2 displacement of 22 with thieno[3,2-c]pyridine (8) then constructed (-i-)-clopidogrel (2). Another Sanofi synthesis of enantiomerically pure (-i-)-clopidogrel (2) took advantage of resolution of racemic a-amino acid 23 to access (S)-23. The methyl ester 24 was prepared by treatment of (S)-23 with thionyl chloride and methanol. Subsequent Sn2 displacement of (2-thienyl)-ethyl para-toluene-sulfonate (25) assembled amine 26. 

A further synthesis of thieno[2,3-6]pyridines (79JHC603) resembles quite closely the preparation of pyrrolo[2,3-fc]pyridines (76AP597). 2-Amino-3-cyanothiophenes (e.g. 268 Scheme 62) were reacted with ethyl aminocrotonate to give enamines, which were cyclized with sodium ethoxide yielding 4-aminothieno[2,3-5]pyridines. 

Fused pyrroles have been prepared by the condensation of an amino group with a suitably positioned carbonyl function. Thus, reduction of ethyl (3-nitro-2-thienyl)pyruvate (226) with tin(IV) chloride gave 5-ethoxycarbonyl thieno[3,2-6]pyrrole (47), by the spontaneous cyclization of the intermediate amino derivative (227 Scheme 76) (64JOC2160). The formation of indolo[3,2-6]indole (229), a dibenzannelated pyrrolopyrrole, by the cyclization of (228) with tin(IV) chloride (Scheme 77) is an example of a case where reduction of the imino function in the starting material is necessary before cyclization will occur (78AHC(22)183). 

THIENO(2,3-c)PYRIDINE-3-CARBOXYLIC ACID, 2-AMINO-6-BENZYL-4.5.6.7-TETRAHYDRO-, ETHYL ESTER. HYDROCHLORIDE... 

Ethyl 4,5-diamino-2-(dimethylamino)thieno[2,3-z/]pyrimidine-6-carboxylate (142) was prepared in 93% yield from 4-amino-6-chloro-2-(di-methylamino)pyrimidine-5-carbonitrile (143) with ethyl 2-mercaptoacetate in refluxing EtOH-THF (5 1) (2000S255). 

A number of densely substituted 3-aminothiophene derivatives, including several fused systems, have been obtained by cyclization reactions of suitable acrylonitriles or similar precursors with ethyl mercaptopyruvate in the presence of a base, as illustrated by the conversion of the pyridine-1-oxide 4 into the pyridothiophene 5 <05JHC661>. Similar annulations involving 2-amino-4,6-dichloropyrimidine-5-carboxaldehyde and methyl mercaptoacetate leading to thieno[2,3-t/]pyrimidine derivatives have also been reported <05JHC1305>. 

Benzamido-3-cyano-4,5-dihydrothiophenes (321) cyclize at 120°C with cyclohexylamine, morpholine, piperidine, and pyrrolidine to the corresponding 4-amino-2-phenyl-5,6-dihydrothieno [2,3-d ] pyrimidines (322).181 However, when 321 and 2 equivalents of dimethylamine hydrochloride in pyridine were refluxed for 5 hr, the 4-oxothieno [2,3-d] pyrimidine 323 was formed nearly quantitatively181 (Scheme 92). Ethyl iV-(3-cyano-4,5-dihydro-2-thienyl)oxamates (324) give, with cyanomethylene compounds in the presence of triethylamine, thieno[2,3-d]pyrimidines (325).182... 

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... 

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