Thiophene 3- methyl-, ring synthesis

Thiophene, 2-amino-3-cyano-5-phenyl-synthesis, 4, 888-889 Thiophene, 3-amino-4,5-dihydro-cycloaddition reactions, 4, 848 Thiophene, 2-amino-3-ethoxycarbonyl-ring opening, 4, 73 Thiophene, 2-amino-5-methyl-synthesis, 4, 73 Thiophene, 2-anilino-synthesis, 4, 923-924 Thiophene, aryl-synthesis, 4, 836, 914-916 Thiophene, 2-(arylamino)-3-nitro-synthesis, 4, 892 Thiophene, azido-nitrenes, 4, 818-820 reactions, 4, 818-820 thermal fragmentation, 4, 819-820 Thiophene, 3-azido-4-formyl-reactions... 

Synthesis of Thiophens by Ring-closure Reactions.—The reaction of dipotassium nitroethylenedithiolate and a-chlorocarbonyl derivatives, followed by oxidation with iodine, gave (1). Treatment of pentane-2,4-dione with carbon disulphide in the presence of potassium hydroxide, followed by treatment with ethyl bromoacetate, methyl iodide, and alkali, gave (2). Compounds of type (3) were formed in the reaction of 1-cyanomethylpyridinium chloride with carbon disulphide and alkylating agents such as chloroacetonitrile, ethyl bromoacetate, phenacyl bromide, or chloroacetamide in the presence of alkali, and intramolecularly cyclized to (4). After 5-methylation, the pyridine ring could be cleaved by reaction with phenylsulphonylacetonitrile and alkali in DMSO... 

Synthesis of Thiophens by Ring-closure Reactions.— The Hinsberg reaction between a-diketones and dialkyl thiodiacetate has been used for the synthesis of a series of 3,4-disubstituted thiophen-2-carboxylates and -2,5-dicarboxylates. The corresponding condensation of ethyl phenyl glyox-ylate and methyl pyruvate with dialkyl thiodiacetate, which yields 3-phenyl-and 3-methyl-4-hydroxythiophen-2,5-dicarboxylates, proceeds through a... 

The first synthesis of the parent compound of the benzo[4,5]thieno[2,3-f]pyrrole ring system 387 <2003T1477> and its derivatives was accomplished using the same synthetic sequence (Scheme 42). Starting with 2-methyl-benzo[ ]thiophene-3-carbaldehyde 388, an intermediate 389 was obtained. Treatment of bromo compound 389 with sodium azide in ethanol led to the stable triazoline 390. 1,3-Dipolar cycloreversion of 390 was induced by a catalytic amount of />-TsOH to give the parent 2//-benzo[4,5]thieno[2,3-c]pyrrole 387. Alternatively, direct treatment of bromo compound 389 with excess ammonia furnished 387 in one step. Compound 387 was treated with di-/-butyl dicarbonate and 4-dimethylaminopyridine (DMAP) to give iV-BOC derivative 391. Reaction of 389 with... 

The nature of the aromatic substituents is apparently not critical for SSRI activity, as indicated by the structure of duloxetine (23-5), where one ring is replaced by thiophene and the other by naphthalene. The synthesis starts as above by the formation of the Mannich base (23-1) from 1-acetyl thiophene with formaldehyde and dimethyl-amine. Treatment of that intermediate with the complex from lithium aluminum hydride and the 2R,3S entantiomer of dimethylamino-l,2-diphenyl-3-methyl-butane-2-ol gives the S isomer (23-2) in high enantiomeric excess. Treatment of the aUcoxide from (23-2) and sodium hydride with 1-fluoronaphthalene leads to the displacement of halogen and thus the formation of ether (23-2). The surplus methyl group is then removed by yet another variant of the von Braun reaction that avoids the use of a base for saponifying the intermediate urethane. Thus, reaction of (23-3) with trichloroethyl formate leads to the A -demethylated chlorinated urethane (23-4). Treatment of that intermediate with zinc leads to a loss of the carbamate and the formation of the free secondary amine duloxetine (23-5) [23]. 

Cen at the Shanghai Institute of Pharmaceutical Industry has recently published a synthesis of olanzapine (Scheme 7). The thiophene 22 was treated with 2-chloronitrobenzene m the presence of lithium hydroxide to give 23. Reduction of the nitro group and subsequent ring closure gave 24. Addition of piperazine to the amidine 24 followed by methylation provided olanzapine (2) in an overall yield of 29%. 

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