1.1- Dimethyl-2,2,2-trichloroethyl carbamates

Methyl Carbamate 5. 9-Fluorenylmethyl Carbamate 8. 2,2,2-Trichloroethyl Carbamate 11. 2-Trimethylsilylethyl Carbamate 16. 1,1-Dimethylpropynyl Carbamate 20. 1-Methyl-1-phenylethyI Carbamate 22. 1-Methyl-l-(4-biphenylyl)ethyl Carbamate 24. 1,1 -Dimethy 1-2-haloethyl Carbamate 26. l,l-Dimethyl-2-cyanoethyl Carbamate 28. r-Butyl Carbamate... 

FIGURE 9.10 Derivatization of TMA and DMA. DMA and TMA were derivatized to form A,A-dimethyl-p-toluene sulfonamide and Af,A-dimethyl-2,2,2-trichloroethyl carbamate. These were isolated using gas chromatography and fragmented using electron impact ionization. 

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]. 

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