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12th May 2012 @ 01:13
MW29-1-81.png
MW29-1-81, MW29-2, MW29-3N-Cyclohexanoyl-protection of the amine intermediate MW7-2-27 of PZQ (MW29-1 to MW29-3)
N-Cyclohexanoyl-protection of the amine intermediate MW7-2-27 of PZQ: Upscale (MW29-4)

MW28-1-80.png
MW28 Attempts to the acid-mediated Pictet-Spengler cyclization of MW14 (MW28-1-80)
MW36-2, -5 Optimizing conditions for the Ugi reaction (MW36-2 to MW36-5)

MW14-3-79.png
MW14-3 (MeO)2-derivative of PZQ: preparation of starting material (MW14-3-79)

MW39.png
MW39 Repeating the preparation of (+/-)-BINOL-N-triflyl phosphoramide (MW39-2)
Preparation of (+/-)-BINOL-N-triflyl phosphoramide (MW39)

MW38
Preparation of trifluoromethane sulfonamide (MW38)

MW40.png

MW40 Preparation of the dimethoxy ‘Ugi-intermediate’ via Ugi reaction (MW40)
MW36 Preparation of the Ugi-intermediate via Ugi reaction (MW36-1)
MW32-3 N-Cyclohexanoyl-protection of the amine intermediate MW14 of (MeO)2-PZQ (MW32)
MW32-1 N-Cyclohexanoyl-protection of the amine intermediate MW14 of (MeO)2-PZQ (MW32)

MW37.png
MW37 Preparation of 2-(3,4-Dimethoxyphenyl)ethyl isocyanide (MW37)



MW34.png

MW34 Scale-up - Preparation of 2-Phenylethyl isocyanide (MW34-2)
Preparation of 2-Phenylethyl isocyanide (MW34-1)

MW31.png

MW33

Cbz-protection of the amine intermediate of PZQ MW7-2-27 (MW33)

MW31-x.png

MW31 Attempts to the acid-mediated Pictet-Spengler cyclization of the ‘Ugi intermediate’ MW29 (MW31)

MW43.png

MW43 Repetition of the synthesis of N,N’-bis[3,5-bis(trifluoromethyl)phenyl]thiourea (MW43-2)

PZQ-Ph.png

Attempts to the Bronstedt-acid catalysed Pictet-Spengler cyclization using N,N’-bis[3,5-bis(trifluoromethyl)phenyl]thiourea (MW44)

MeO-PZQ-Ph.png

Attempts to the Bronstedt-acid catalysed Pictet-Spengler cyclization using N,N’-bis[3,5-bis(trifluoromethyl)phenyl]thiourea (MW44)

MeO-PZQ.png

Attempts to the Bronstedt-acid catalysed Pictet-Spengler cyclization using N,N’-bis[3,5-bis(trifluoromethyl)phenyl]thiourea (MW44)






Attached Files
9th February 2012 @ 11:12
KAB1
The dimethoxy praziquantel analogue via the Pictet-Spengler cyclisation of the peptide acetal precursor.
Systematic Name: 2-(Cyclohexylcarbonyl)-9,10-dimethoxy-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one
SMILES: COc1cc2c(cc1OC)C3CN(CC(=O)N3CC2)C(=O)C4CCCCC4
InChI: InChI=1S/C21H28N2O4/c1-26-18-10-15-8-9-23-17(16(15)11-19(18)27-2)12-22(13-20(23)24)21(25)14-6-4-3-5-7-14/h10-11,14,17H,3-9,12-13H2,1-2H3
KAB1.png
Acid-catalyzed Pictet-Spengler of MNR8-1 using binapthalenedisulfonic acid to give KAB1-1
Acid-mediated PS cyclisation to give racemic PZQ (KAB3-3), the dimethoxy N-benzoyl PZQ analogue (KAB8-1), the dimethoxy PZQ analogue (KAB1-2) and the N-benzoyl PZQ analogue (KAB7-1)
TfOH catalysed PS* reaction to give the dimethoxy PZQ analogue (KAB1-3)
TfOH catalysed PS* reaction to give the dimethoxy PZQ analogue (KAB1-4)
TfOH catalysed PS* reactions to give the dimethoxy PZQ analogues (KAB8-14 & KAB1-5)
AgOTf catalysed PS reaction to give the dimethoxy PZQ analogue (KAB1-6)

KAB3
Racemic praziquantel via the Pictet-Spengler cyclisation of the peptide acetal precursor.
KAB3.png
Stoichiometric acid-mediated Pictet-Spengler of MW29-4 to give racemic PZQ (KAB3-1 and KAB3-2)
Acid-mediated PS cyclisation to give racemic PZQ (KAB3-3), the dimethoxy N-benzoyl PZQ analogue (KAB8-1), the dimethoxy PZQ analogue (KAB1-2) and the N-benzoyl PZQ analogue (KAB7-1)
Acid-mediated Pictet-Spengler reaction to give PZQ (KAB3-4) and the N-benzoyl PZQ analogue (KAB7-2)
Acid-mediated Pictet-Spengler reaction to give PZQ (KAB3-5)
Reattempt acid-mediated Pictet-Spengler reaction to give PZQ (KAB3-6)
Reducing decomposition in the acid mediated Pictet-Spengler to give PZQ (KAB3-7).
The Pictet-Spengler reaction to give PZQ (KAB3-8) in neat acid
The metal triflate catalysed Pictet-Spengler to give racemic PZQ (KAB3-9 & KAB3-10)
TfOH catalysed PS* reaction to give PZQ (KAB3-11)
TfOH catalysed PS* reaction to give PZQ (KAB3-12 to KAB3-16)
TfOH catalysed PS* reaction to give PZQ (KAB3-17)

KAB4
Preparation of (2-isocyanoethyl)benzene component from phenylethylamine, for the Ugi four-component reaction.
KAB4.png
Preparation of (2-isocyanoethyl)benzene (KAB4-1)
Preparation of (2-isocyanoethyl)benzene (KAB4-2)

KAB5
Ugi four-component reaction to give the praziquantel peptide acetal precursor.
KAB5.png
Preparation of the PZQ analogue Ugi-intermediate (KAB5-1)
Preparation of the PZQ peptide acetal Ugi-intermediate (KAB5-2)

KAB6
Ugi four-component reaction to give the praziquantel N-benzoyl analogue peptide acetal precursor.
KAB6.png
Preparation of the N-benzoyl PZQ analogue Ugi-intermediate (KAB6-1)


KAB7
Racemic N-benzoyl praziquantel analogue via the Pictet-Spengler cyclisation of the peptide acetal precursor.
Systematic Name: 2-Benzoyl-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinolin-4-one
SMILES: O=C4N2CCc1c(cccc1)C2CN(C(=O)c3ccccc3)C4
InChI: InChI=1S/C19H18N2O2/c22-18-13-20(19(23)15-7-2-1-3-8-15)12-17-16-9-5-4-6-14(16)10-11-21(17)18/h1-9,17H,10-13H2
KAB7.png
Acid-mediated PS cyclisation to give racemic PZQ (KAB3-3), the dimethoxy N-benzoyl PZQ analogue (KAB8-1), the dimethoxy PZQ analogue (KAB1-2) and the N-benzoyl PZQ analogue (KAB7-1)
Acid-mediated Pictet-Spengler reaction to give PZQ (KAB3-4) and the N-benzoyl PZQ analogue (KAB7-2)
TfOH catalysed PS* reaction to give the N-benzoyl PZQ analogue (KAB7-3)

See Also
Acid-mediated Pictet-Spengler of the N-benzoyl-Ugi intermediate (MW53-1 to MW53-3)
Synthesis of the N-benzoyl-derivative of PZQ via Pictet-Spengler reaction (MW53-4)


KAB8
The racemic dimethoxy N-benzoyl praziquantel analogue prepared via the Pictet-Spengler cyclisation of the peptide acetal precursor.
KAB8.png
Acid-mediated PS cyclisation to give racemic PZQ (KAB3-3), the dimethoxy N-benzoyl PZQ analogue (KAB8-1), the dimethoxy PZQ analogue (KAB1-2) and the N-benzoyl PZQ analogue (KAB7-1)
Acid-catalyzed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-2)
The copper(II) triflate catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-3)
The silver(I) triflate catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-4)
Controls for the AgOTf catalysed PS* to give the dimethoxy N-benzoyl PZQ analogue (KAB8-5 & KAB8-6)
TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-7 & KAB8-8)
TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-9)
AgOTf catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-10)
The TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-11)
The TfOH catalysed PS* reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-12)
AgCl catalysed PS to give the dimethoxy N-benzoyl PZQ analogue (KAB8-13)
TfOH catalysed PS* reactions to give the dimethoxy PZQ analogues (KAB8-14 & KAB1-5)
AgOTf catalysed PS reaction to give the dimethoxy N-benzoyl PZQ analogue (KAB8-15)

See Also
Acid-mediated Pictet-Spengler of the dimethoxy-N-benzoyl-Ugi intermediate (MW54-1 to MW54-2)
Synthesis of the dimethoxy-N-benzoyl-derivative of PZQ via Pictet-Spengler reaction (MW54-3)


KAB10
Hydrolysis of racemic praziquantel to give racemic praziquanamine.
KAB10.png
Hydrolyis of rac-Praziquantel to give PZQamine (KAB10-1)

KAB11
Preparation of the dimethoxy N-benzoyl praziquantel analogue Pictet-Spengler reaction enediamide intermediate from the peptide acetal precursor.
KAB11.png
Lewis acid catalysed preparation of the dimethoxy N-benzoyl PZQ enediamide (KAB11-1)
Silver(I) triflate catalysed preparation of the dimethoxy N-benzoyl PZQ enediamide (KAB11-2)
Copper(II) triflate catalysed preparation of the dimethoxy N-benzoyl PZQ enediamide (KAB11-3)

KAB12
Preparation of the dimethoxy N-benzoyl praziquantel analogue from the Pictet-Spengler reaction enediamide intermediate.
KAB12.png
Enediamide intermediate cyclisation to give the dimethoxy N-benzoyl PZQ analogue (KAB12-1)

KAB13
Preparation of the praziquantel Pictet-Spengler reaction enediamide intermediate.
Systematic Name:
4-(Cyclohexylcarbonyl)-1-(2-phenylethyl)-3,4-dihydro-2(1H)-pyrazinone
SMILES: O=C(N1/C=C\N(C(=O)C1)CCc2ccccc2)C3CCCCC3
InChI: InChI=1S/C19H24N2O2/c22-18-15-21(19(23)17-9-5-2-6-10-17)14-13-20(18)12-11-16-7-3-1-4-8-16/h1,3-4,7-8,13-14,17H,2,5-6,9-12,15H2
KAB13.png
Partial PS* reaction to give the PZQ enediamide intermediate (KAB13-1)
TfOH catalysed partial PS* reactions to give the enediamide intermediates of PZQ and the N-benzoyl analogue (KAB13-2 & KAB17-1)
AgOTf catalysed PS reaction to give the PZQ enamide (KAB13-3)

KAB15
Preparation of the imidobis(sulfuryl chloride) component for the synthesis of
the racemic 1,1'-binaphthyl-2,2'-bis(sulfuryl)imide acid catalyst.
KAB15.png
Preparation of Imidobis(sulfuryl chloride) (KAB15-1)

KAB16
Synthesis of 1,1'-Binaphthyl-2,2'-bis(sulfuryl)imide·1/2Et2O (KAB16-1)

KAB17
Systematic Name:4-Benzoyl-1-(2-phenylethyl)-3,4-dihydro-2(1H)-pyrazinone
SMILES:
InChI:
TfOH catalysed partial PS* reactions to give the enediamide intermediates of PZQ and the N-benzoyl analogue (KAB13-2 & KAB17-1)

KAB18
Systematic Name:
SMILES:
InChI:
Synthesis of N-benzylidene-N-phenethylamine (KAB18-1)
Synthesis of N-benzylidene-N-phenethylamine (KAB18-2)

KAB19
Systematic Name:
SMILES:
InChI:
Synthesis of N-[2-(3,4-Dimethoxyphenyl)ethyl]-1-phenylmethanimine (KAB19-1)
Synthesis of N-[2-(3,4-Dimethoxyphenyl)ethyl]-1-phenylmethanimine (KAB19-2)

KAB20
Systematic Name:
SMILES:
InChI:
KAB20.png
AgOTf catalysed synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB20-1)
Synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB20-2)
Synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB20-3)
Synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB20-4)

KAB21
Systematic Name:
SMILES:
InChI:
AgOTf catalysed synthesis of 1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB20-1)
Synthesis of 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB21-2)
TFA mediated synthesis of 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB21-3)
TFA catalysed synthesis of 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB21-4)
Lewis acid-catalyst screen for the PS reaction to give KAB21 and KAB24
Yb(OTf)3 catalysed PS reaction to give 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB21-9)

KAB22
Systematic Name: N-(4-nitrobenzylidene)-2-phenylethanamine
SMILES: O=[N+]([O-])C1=CC=C(/C=N/CCC2=CC=CC=C2)C=C1
InChI: InChI=1S/C15H14N2O2/c18-17(19)15-8-6-14(7-9-15)12-16-11-10-13-4-2-1-3-5-13/h1-9,12H,10-11H2/b16-12-
InChIKey: VVVXMEABOODTDX-VBKFSLOCSA-N
Synthesis of N-(4-nitrobenzylidene)-2-phenylethanamine (KAB22-1)

KAB23
Systematic Name: 2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine
SMILES: O=[N+]([O-])C1=CC=C(/C=N/CCC2=CC(OC)=C(OC)C=C2)C=C1
InChI: InChI=1S/C17H18N2O4/c1-22-16-8-5-13(11-17(16)23-2)9-10-18-12-14-3-6-15(7-4-14)19(20)21/h3-8,11-12H,9-10H2,1-2H3/b18-12-
InChIKey: LMBMXYXQVBPKHJ-PDGQHHTCSA-N.
Synthesis of 2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine (KAB23-1)
Preparation of the 2-(3,4-dimethoxyphenyl)-N-(4-nitrobenzylidene)ethanamine starting material (KAB23-2)

KAB24
TFA mediated synthesis of 6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (KAB24-1)
TFA mediated synthesis of 6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (KAB24-2)
TFA mediated synthesis of 6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (KAB24-3)
TFA catalysed synthesis of 6,7-dimethoxy-1-(4-nitrophenyl)-1,2,3,4-tetrahydroisoquinoline (KAB24-4)
Lewis acid-catalyst screen for the PS reaction to give KAB21 and KAB24

KAB25
KAB25.png
Systematic Name: 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline
SMILES: COC[0]=C(OC)C=C[3]C(CCNC@4C[11]=CC=CC=C@11)=C@1
InChI: InChI=1S/C17H19NO2/c1-19-15-10-13-8-9-18-17(12-6-4-3-5-7-12)14(13)11-16(15)20-2/h3-7,10-11,17-18H,8-9H2,1-2H3
InChIKey: GZGZWZVAJDFXJK-UHFFFAOYSA-N
Yb(OTf)3 catalysed PS to give 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB25-1)
Yb(OTf)3 catalysed PS to give 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB25-2)
Yb(OTf)3 catalysed PS to give 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline (KAB25-3)

KAB26
KAB26.png
Systematic Name: 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone
SMILES: O=[N+]([O-])C1=CC=C(C2N(C(C)=O)CCC3=CC(OC)=C(OC)C=C32)C=C1
InChI: InChI=1S/C19H20N2O5/c1-12(22)20-9-8-14-10-17(25-2)18(26-3)11-16(14)19(20)13-4-6-15(7-5-13)21(23)24/h4-7,10-11,19H,8-9H2,1-3H3
InChIKey: OIFIJKJQAGAGKY-UHFFFAOYSA-N
AuCl3/AgOTf catalysed acyl-PS reaction to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-1 & KAB26-2)
AuCl3/AgOTf catalysed acyl-PS reaction to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-3)
Yb(OTf)3 catalysed acyl-PS to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-4)
Yb(OTf)3 catalysed acyl-PS to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-5)
Optimising Yb(OTf)3 catalysed acyl-PS to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-6)
Yb(OTf)3 (1 mol%) catalysed acyl-PS to give 1-(6,7-dimethoxy-1-(4-nitrophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethanone (KAB26-7)
Extending the Yb(OTf)3 catalysed acyl-Pictet-Spengler reaction time at -30 &degC (KAB26-8)
Isolating byproducts in the Yb(OTf)3 catalysed acyl Pictet-Spengler reaction (KAB26-9)
Attached Files