Temocapril: Difference between revisions
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==Synthesis== |
==Synthesis== |
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[[File:Temocapril synthesis.png|thumb|center|700px|Temocapril synthesis:<ref>{{Cite |
[[File:Temocapril synthesis.png|thumb|center|700px|Temocapril synthesis:<ref>{{Cite journal|doi=10.1021/jm00394a009}}</ref>]] |
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The enantioselective synthesis of this ACE inhibitor starts with the conjugate addition of the protected derivative '''1''' from L-cysteine to the condensation product from [[2-Thiophenecarboxaldehyde]] and [[nitromethane]]; [[asymmetric induction]] from the chiral center in the amino acid leads to the formation of '''3''' as a single enantiomer. [[Catalytic hydrogenation]] of the adduct reduces the nitro group to afford the amino acid '''4'''. Reaction of that compound with the acid activating reagent, [[Diphenylphosphoryl azide]] ([[DPPA]]), closes the ring by forming an amide bond to give thiazepinone '''5'''. The [[BOC]] [[protecting group]] is then removed by means of [[trifluoroacetic acid]] (TFA) to give the free amine '''6'''. The basic nitrogen is then used to displace the triflate group in the resolved derivative '''7''' from [[ethyl 2-hydroxy-4-phenylbutyrate]],<ref> |
The enantioselective synthesis of this ACE inhibitor starts with the conjugate addition of the protected derivative '''1''' from L-cysteine to the condensation product from [[2-Thiophenecarboxaldehyde]] and [[nitromethane]]; [[asymmetric induction]] from the chiral center in the amino acid leads to the formation of '''3''' as a single enantiomer. [[Catalytic hydrogenation]] of the adduct reduces the nitro group to afford the amino acid '''4'''. Reaction of that compound with the acid activating reagent, [[Diphenylphosphoryl azide]] ([[DPPA]]), closes the ring by forming an amide bond to give thiazepinone '''5'''. The [[BOC]] [[protecting group]] is then removed by means of [[trifluoroacetic acid]] (TFA) to give the free amine '''6'''. The basic nitrogen is then used to displace the triflate group in the resolved derivative '''7''' from [[ethyl 2-hydroxy-4-phenylbutyrate]],<ref>{{cite journal|doi=10.1186/s40643-015-0037-9}}</ref><ref>{{Cite journal|pmid=24120725}}</ref><ref>{{Cite journal|doi=10.1109/iCBEB.2012.85}}</ref><ref>{{Cite journal|doi=10.1016/S0040-4039(00)80112-4}}</ref> an intermediate used for several other ACE inhibitors, to give the alkylation product '''8'''. The anion from treatment of the amide is then alkylated using [[tert-Butyl bromoacetate]]. Reaction of this last product with [[hydrogen chloride]] cleaves the ''tert''-butyl ester to give the free acid temocapril, as a single enantiomer. |
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==References== |
==References== |
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Revision as of 00:57, 18 November 2015
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| Formula | C23H28N2O5S2 |
| Molar mass | 476.608 g/mol g·mol−1 |
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Temocapril (also known as Temocaprilum [Latin]; brand name Acecol) is an ACE inhibitor. It was not approved for use in the US.
Synthesis
The enantioselective synthesis of this ACE inhibitor starts with the conjugate addition of the protected derivative 1 from L-cysteine to the condensation product from 2-Thiophenecarboxaldehyde and nitromethane; asymmetric induction from the chiral center in the amino acid leads to the formation of 3 as a single enantiomer. Catalytic hydrogenation of the adduct reduces the nitro group to afford the amino acid 4. Reaction of that compound with the acid activating reagent, Diphenylphosphoryl azide (DPPA), closes the ring by forming an amide bond to give thiazepinone 5. The BOC protecting group is then removed by means of trifluoroacetic acid (TFA) to give the free amine 6. The basic nitrogen is then used to displace the triflate group in the resolved derivative 7 from ethyl 2-hydroxy-4-phenylbutyrate,[2][3][4][5] an intermediate used for several other ACE inhibitors, to give the alkylation product 8. The anion from treatment of the amide is then alkylated using tert-Butyl bromoacetate. Reaction of this last product with hydrogen chloride cleaves the tert-butyl ester to give the free acid temocapril, as a single enantiomer.
References
- ^ . doi:10.1021/jm00394a009.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1186/s40643-015-0037-9.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help)CS1 maint: unflagged free DOI (link) - ^ . PMID 24120725.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1109/iCBEB.2012.85.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help) - ^ . doi:10.1016/S0040-4039(00)80112-4.
{{cite journal}}: Cite journal requires|journal=(help); Missing or empty|title=(help)
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