Pagina 0 van 30
,Inhoudsopgave
Samenvatting ..................................................................................................................................................... 2
Summary............................................................................................................................................................ 2
Afkortingenlijst .................................................................................................................................................. 2
Inleiding ............................................................................................................................................................. 4
Retrosynthetische analyse overzicht ................................................................................................................ 5
De synthese route ............................................................................................................................................. 6
Synthese stap 1: Halogenering van 5-broom-6-ethyl-1H-indool naar 3,5-dibroom-6-ethyl-1H-indool .......... 7
Mogelijkheid 1 ............................................................................................................................................... 7
Mogelijkheid 2 ............................................................................................................................................... 8
Mogelijkheid 3 ............................................................................................................................................... 8
Synthese stap 2: Substitutie van 1-methylpyrrolidine-2-carbonzuur naar 1-methylpyrrolidine-2-
carbonylchloride ................................................................................................................................................ 9
Mogelijkheid 1 ............................................................................................................................................... 9
Mogelijkheid 2 ............................................................................................................................................. 10
Mogelijkheid 3 ............................................................................................................................................. 10
Mogelijkheid 4 ............................................................................................................................................. 11
Synthese stap 3: Van 1-methylpyrrolidine-2-carbonyl chloride en 3,5-dibroom-6-ethyl-1H-indool naar 5-
broom-6-ethyl-3-[(1-methylpyrrolidin-2-yl)methyl]-1H-indool ..................................................................... 12
Mogelijkheid 1 ............................................................................................................................................. 12
Mogelijkheid 2 ............................................................................................................................................. 13
Mogelijkheid 3 ............................................................................................................................................. 14
Synthese stap 4: Substitutie van 5-broom-6-ethyl-3-([1-methylpyrrolidin-2-yl)methyl]-1H-indool en
joodethaan naar 5-broom-1,6-diethyl-3-([1-methylpyrrolidin-2-yl)methyl]-1H-indool ................................ 16
Mogelijkheid 1 ............................................................................................................................................. 16
Mogelijkheid 2 ............................................................................................................................................. 17
Mogelijkheid 3 ............................................................................................................................................. 17
Mogelijkheid 4 ............................................................................................................................................. 18
Discussie .......................................................................................................................................................... 19
Conclusie.......................................................................................................................................................... 20
Referentielijst .................................................................................................................................................. 22
Bijlagen ............................................................................................................................................................ 27
Pagina 1 van 30
,Samenvatting
Voor dit onderzoeksverslag wordt er een retrosynthese route bedacht en aan de hand daarvan een
synthese route opgesteld. Dit gebeurt voor het targetmolecuul 5-broom-1,6-diethyl-3-[(1-methylpyrrolidin-
2-yl)methyl]-1H-indool.
De onderzoeksvraag die is opgesteld is: welke synthese routes kunnen worden toegepast voor de synthese
van 5-broom-6-ethyl-1H-indool vanuit 5-broom-1,6-diethyl-3-[(1-methylpyrrolidin-2-yl)methyl]-1H-indool,
en hoe kunnen deze routes verschillen in efficiëntie, bijproducten, opbrengst (yield), duurzaamheid,
veiligheid en kosten?
Alle mogelijkheden per stap zijn bediscussieerd en er is uiteindelijk een syntheseroute opgesteld. Deze is
weergegeven in figuur 8.
De reactietijd van het totale syntheseplan is ongeveer 18 uur. Verder is de geschatte opbrengst ongeveer
80-85%.
Summary
For this research report, a retrosynthesis route is investigated and based on this a synthesis route is
established. This occurs for the target molecule 5-bromo-1,6-diethyl-3-[(1-methylpyrrolidin-2-yl) methyl]-
1H-indole.
The research question that has been formulated is: which synthetic routes can be applied for the synthesis
of 5-bromo-6-ethyl-1H-indole from 5-bromo-1,6-diethyl-3-[(1-methylpyrrolidin-2-yl)) methyl]-1H-indole,
and how might these pathways differ in efficiency, by-products, yield, sustainability, safety, and cost?
All options per step were discussed and a synthesis route was eventually drawn up. This is shown in figure
8.
The reaction time of the total synthesis plan is approximately 18 hours. Furthermore, the estimated yield is
about 80-85%.
Afkortingenlijst
AlCl3: Aluminiumchloride
Br2: dibroom
CD2Cl2: dichloromethane-d2
CH2Cl2: dichloormethaan
CH3CH2MgBr: alkylmagnesiumbromide
DBDMH: 1,3-Dibroom-5,5-Dimethylhydantoïne
DCM: dichloormethaan
DMF: dimethylformamide
DMSO: dimethylsulfoxide
Et2O: diethyl ether
EtOAc: ethylacetaat
H2: diwaterstof
HCl: waterstofchloride
HIO3: waterstofjodaat of joodzuur
KBr: Kaliumbromide
KOH: kaliumhydroxide
LiBH4: lithiumboorhydride
Pagina 2 van 30
, LiAlH4: lithiumaluminiumhydride
MeOH: methanol
MgSO4: magnesiumsulfaat
NaCl: natriumchloride
NaH: natriumhydride
NaHCO3: natriumwaterstofcarbonaat
NaOH: natriumhydroxide
Na2SO4: natriumsulfaat
Na2S2O3: natriumthiosulfaat
NbCl5: Niobium(V)chloride
PCl5: fosforpentachloride
Pd/C: palladium op koolstof
PE: polyetheen
PTSA: p-tolueensulfonzuur
Shvo catalyst: 1-Hydroxytetraphenylcyclopentadienyl-(tetraphenyl-2,4-cyclopentadien-1-one)-μ-
hydrotetracarbonyldiruthenium(II)
TaCl5: Tantalum(V) chloride
THF: Tetrahydrofuraan
WCl6: Wolfraam(VI)chloride
Pagina 3 van 30
,Inhoudsopgave
Samenvatting ..................................................................................................................................................... 2
Summary............................................................................................................................................................ 2
Afkortingenlijst .................................................................................................................................................. 2
Inleiding ............................................................................................................................................................. 4
Retrosynthetische analyse overzicht ................................................................................................................ 5
De synthese route ............................................................................................................................................. 6
Synthese stap 1: Halogenering van 5-broom-6-ethyl-1H-indool naar 3,5-dibroom-6-ethyl-1H-indool .......... 7
Mogelijkheid 1 ............................................................................................................................................... 7
Mogelijkheid 2 ............................................................................................................................................... 8
Mogelijkheid 3 ............................................................................................................................................... 8
Synthese stap 2: Substitutie van 1-methylpyrrolidine-2-carbonzuur naar 1-methylpyrrolidine-2-
carbonylchloride ................................................................................................................................................ 9
Mogelijkheid 1 ............................................................................................................................................... 9
Mogelijkheid 2 ............................................................................................................................................. 10
Mogelijkheid 3 ............................................................................................................................................. 10
Mogelijkheid 4 ............................................................................................................................................. 11
Synthese stap 3: Van 1-methylpyrrolidine-2-carbonyl chloride en 3,5-dibroom-6-ethyl-1H-indool naar 5-
broom-6-ethyl-3-[(1-methylpyrrolidin-2-yl)methyl]-1H-indool ..................................................................... 12
Mogelijkheid 1 ............................................................................................................................................. 12
Mogelijkheid 2 ............................................................................................................................................. 13
Mogelijkheid 3 ............................................................................................................................................. 14
Synthese stap 4: Substitutie van 5-broom-6-ethyl-3-([1-methylpyrrolidin-2-yl)methyl]-1H-indool en
joodethaan naar 5-broom-1,6-diethyl-3-([1-methylpyrrolidin-2-yl)methyl]-1H-indool ................................ 16
Mogelijkheid 1 ............................................................................................................................................. 16
Mogelijkheid 2 ............................................................................................................................................. 17
Mogelijkheid 3 ............................................................................................................................................. 17
Mogelijkheid 4 ............................................................................................................................................. 18
Discussie .......................................................................................................................................................... 19
Conclusie.......................................................................................................................................................... 20
Referentielijst .................................................................................................................................................. 22
Bijlagen ............................................................................................................................................................ 27
Pagina 1 van 30
,Samenvatting
Voor dit onderzoeksverslag wordt er een retrosynthese route bedacht en aan de hand daarvan een
synthese route opgesteld. Dit gebeurt voor het targetmolecuul 5-broom-1,6-diethyl-3-[(1-methylpyrrolidin-
2-yl)methyl]-1H-indool.
De onderzoeksvraag die is opgesteld is: welke synthese routes kunnen worden toegepast voor de synthese
van 5-broom-6-ethyl-1H-indool vanuit 5-broom-1,6-diethyl-3-[(1-methylpyrrolidin-2-yl)methyl]-1H-indool,
en hoe kunnen deze routes verschillen in efficiëntie, bijproducten, opbrengst (yield), duurzaamheid,
veiligheid en kosten?
Alle mogelijkheden per stap zijn bediscussieerd en er is uiteindelijk een syntheseroute opgesteld. Deze is
weergegeven in figuur 8.
De reactietijd van het totale syntheseplan is ongeveer 18 uur. Verder is de geschatte opbrengst ongeveer
80-85%.
Summary
For this research report, a retrosynthesis route is investigated and based on this a synthesis route is
established. This occurs for the target molecule 5-bromo-1,6-diethyl-3-[(1-methylpyrrolidin-2-yl) methyl]-
1H-indole.
The research question that has been formulated is: which synthetic routes can be applied for the synthesis
of 5-bromo-6-ethyl-1H-indole from 5-bromo-1,6-diethyl-3-[(1-methylpyrrolidin-2-yl)) methyl]-1H-indole,
and how might these pathways differ in efficiency, by-products, yield, sustainability, safety, and cost?
All options per step were discussed and a synthesis route was eventually drawn up. This is shown in figure
8.
The reaction time of the total synthesis plan is approximately 18 hours. Furthermore, the estimated yield is
about 80-85%.
Afkortingenlijst
AlCl3: Aluminiumchloride
Br2: dibroom
CD2Cl2: dichloromethane-d2
CH2Cl2: dichloormethaan
CH3CH2MgBr: alkylmagnesiumbromide
DBDMH: 1,3-Dibroom-5,5-Dimethylhydantoïne
DCM: dichloormethaan
DMF: dimethylformamide
DMSO: dimethylsulfoxide
Et2O: diethyl ether
EtOAc: ethylacetaat
H2: diwaterstof
HCl: waterstofchloride
HIO3: waterstofjodaat of joodzuur
KBr: Kaliumbromide
KOH: kaliumhydroxide
LiBH4: lithiumboorhydride
Pagina 2 van 30
, LiAlH4: lithiumaluminiumhydride
MeOH: methanol
MgSO4: magnesiumsulfaat
NaCl: natriumchloride
NaH: natriumhydride
NaHCO3: natriumwaterstofcarbonaat
NaOH: natriumhydroxide
Na2SO4: natriumsulfaat
Na2S2O3: natriumthiosulfaat
NbCl5: Niobium(V)chloride
PCl5: fosforpentachloride
Pd/C: palladium op koolstof
PE: polyetheen
PTSA: p-tolueensulfonzuur
Shvo catalyst: 1-Hydroxytetraphenylcyclopentadienyl-(tetraphenyl-2,4-cyclopentadien-1-one)-μ-
hydrotetracarbonyldiruthenium(II)
TaCl5: Tantalum(V) chloride
THF: Tetrahydrofuraan
WCl6: Wolfraam(VI)chloride
Pagina 3 van 30
