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9th February 2012 @ 00:15
MNR01.png

InChI=1S/C19H24N2O2/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/h4-6,9,15,17H,1-3,7-8,10-13H2/t17-/m1/s1

Resynthesising S-PZQ and recrystallization
N-Cyclohexanoyl-protection of MNR2-2 to give S-PZQ (MNR1-2)
N-Cyclohexanoyl-protection of MNR2-3 to give S-PZQ (MNR1-3)
Preparation of (2-isocyanoethyl)benzene (MNR21-4)

MNR02.png

InChI=1S/C12H14N2O/c15-12-8-13-7-11-10-4-2-1-3-9(10)5-6-14(11)12/h1-4,11,13H,5-8H2/t11-/m1/s1

Resolution of praziquanamine with (-)-di-p-anisoyl-L-tartaric acid to obtain S-(+)-PZQamine (MNR2-1)
Resolution of praziquanamine with (+)-dibenzoyl-D-tartaric acid to obtain S-(+)-PZQamine (MNR2-2)
Resolution of rac-PZQamine with (+)-dibenzoyl-D-tartaric acid to obtain S-PZQamine (MNR2-3)
Resolution of rac-PZQamine with (+)-dibenzoyl-D-tartaric acid to obtain S-PZQamine (MNR2-4)

MNR03.png

InChI=1S/C12H14N2O/c15-12-8-13-7-11-10-4-2-1-3-9(10)5-6-14(11)12/h1-4,11,13H,5-8H2/t11-/m0/s1

Resolution of praziquanamine with (-)-di-p-anisoyl-L-tartaric acid to obtain S-(+)-PZQamine (MNR2-1)
N-Cyclohexanoyl-protection of MNR3-2 to give R-PZQ (MNR9-1)
Resolution of rac-PZQamine with dibenzoyl-L-tartaric acid to obtain R-(-)-PZQamine (MNR3-3)

MNR04.png

InChI=1S/C11H13NO2/c1-12-7-6-9-4-5-10(13-2)11(8-9)14-3/h4-5,8H,6-7H2,2-3H3

Preparation of 2-(3,4-Dimethoxyphenyl)ethyl isocyanide (MNR4-1)
Preparation of 2-(3,4-Dimethoxyphenyl)ethyl isocyanide (MNR4-2)

MNR05.png

InChI=1S/C18H14O8/c19-15(20)13(25-17(23)11-7-3-1-4-8-11)14(16(21)22)26-18(24)12-9-5-2-6-10-12/h1-10,13-14H,(H,19,20)(H,21,22)

Synthesis of (+)-Dibenzoyl-D-tartaric acid (MNR5-1)

MNR06.png

InChI=1S/C18H14O8/c19-15(20)13(25-17(23)11-7-3-1-4-8-11)14(16(21)22)26-18(24)12-9-5-2-6-10-12/h1-10,13-14H,(H,19,20)(H,21,22)

Synthesis of (-)-Dibenzoyl-L-tartaric acid (MNR6-1)

MNR07.png

InChI=1S/C12H14N2O/c15-12-8-13-7-11-10-4-2-1-3-9(10)5-6-14(11)12/h1-4,11,13H,5-8H2

Hydrolysis of rac-PZQ - MNR7-1, MNR7-2, MNR7-3, MNR7-4
Hydrolysis of rac-PZQ - MNR7-5

MNR08.png

InChI=1S/C25H40N2O6/c1-5-32-24(33-6-2)18-27(25(29)20-10-8-7-9-11-20)17-23(28)26-15-14-19-12-13-21(30-3)22(16-19)31-4/h12-13,16,20,24H,5-11,14-15,17-18H2,1-4H3,(H,26,28)

Preparation of the dimethoxy Ugi-intermediate using 2,2-Diethoxyethylamine
Preparation of the dimethoxy Ugi-intermediate (MNR8-2) using 2,2-Diethoxyethylamine
Preparation of the dimethoxy Ugi-intermediate (MNR8-3)

MNR09.png

InChI=1S/C19H24N2O2/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/h4-6,9,15,17H,1-3,7-8,10-13H2/t17-/m0/s1

N-Cyclohexanoyl-protection of MNR3-2 to give R-PZQ (MNR9-1)

MNR10.png

InChI=1S/C25H34N2O6/c1-5-32-24(33-6-2)18-27(25(29)20-10-8-7-9-11-20)17-23(28)26-15-14-19-12-13-21(30-3)22(16-19)31-4/h7-13,16,24H,5-6,14-15,17-18H2,1-4H3,(H,26,28)

Preparation of the dimethoxy Ugi-intermediate (MNR10-1) using 2,2-Diethoxyethylamine

MNR11.png

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

Acid-mediated Pictet-Spengler of MNR8-1 to give dimethoxy PZQ analog MNR11-1
Acid-mediated Pictet-Spengler of MNR8-2 to give dimethoxy PZQ analog MNR11-2
Acid-mediated Pictet-Spengler of MNR8-2 to give dimethoxy PZQ analog MNR11-3
Acid-catalyzed Pictet-Spengler 0f MNR8-2 using binaphthalenedisulfonic acid to give MNR11
Continuation of Acid-catalyzed Pictet-Spengler 0f MNR8-2 using binaphthalenedisulfonic acid to give MNR11
Attempts to imrove the acid-catalyzed Pictet-Spengler of MNR8-2 using binaphthalenedisulfonic acid to give MNR11

MNR12.png

InChI=1S/C21H22N2O4/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/h3-7,10-11,17H,8-9,12-13H2,1-2H3

Acid-mediated Pictet-Spengler of MNR8-2 to give dimethoxy-N-benzoyl-derivative of PZQ MNR12-1
Acid-mediated Pictet-Spengler of MNR8-2 to give dimethoxy-N-benzoyl-derivative of PZQ MNR12-2
Attempts to imrove the acid-catalyzed Pictet-Spengler of MNR10-1 using binaphthalenedisulfonic acid to give MNR12

MNR13.png

InChI=1S/C19H24N2O2/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/h4-6,9,15,17H,1-3,7-8,10-13H2

Acid-mediated Pictet-Spengler of MW29 to give rac-PZQ MNR13-1

MNR14.png

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

Acid-mediated Pictet-Spengler of MW51 to give N-benzoyl-derivative of PZQ MNR14-1
Acid-mediated Pictet-Spengler of MW51 to give N-benzoyl-derivative of PZQ MNR14-1 cont'

MNR15.png

InChI=1S/C26H24N2O2S2/c1-27(2)25(31)29-21-15-13-17-9-5-7-11-19(17)23(21)24-20-12-8-6-10-18(20)14-16-22(24)30-26(32)28(3)4/h5-16H,1-4H3

Preparation of (R)-O,O'-1,1'-binaphthyl-2,2'-diyl bis(dimethylcarbamothioate) (MNR15-1)
Repeat of MNR15-1:- Preparation of (R)-O,O'-1,1'-binaphthyl-2,2'-diyl bis(dimethylcarbamothioate) (MNR15-2)


MNR16.png

InChI=1S/C26H24N2O2S2/c1-27(2)25(31)29-21-15-13-17-9-5-7-11-19(17)23(21)24-20-12-8-6-10-18(20)14-16-22(24)30-26(32)28(3)4/h5-16H,1-4H3

Preparation of (S)-S,S'-1,1'-binaphthyl-2,2'-diyl bis(dimethylcarbamothioate) (MNR18-1) from MNR16-1
Repeat of MNR16-1:- Preparation of (S)-O,O'-1,1'-binaphthyl-2,2'-diyl bis(dimethylcarbamothioate) (MNR16-2)

MNR17.png

InChI=1S/C26H24N2O2S2/c1-27(2)25(29)31-21-15-13-17-9-5-7-11-19(17)23(21)24-20-12-8-6-10-18(20)14-16-22(24)32-26(30)28(3)4/h5-16H,1-4H3

Preparation of (S)-O,O'-1,1'-binaphthyl-2,2'-diyl bis(dimethylcarbamothioate) (MNR16-1)

MNR18.png

InChI=1S/C26H24N2O2S2/c1-27(2)25(29)31-21-15-13-17-9-5-7-11-19(17)23(21)24-20-12-8-6-10-18(20)14-16-22(24)32-26(30)28(3)4/h5-16H,1-4H3

Preparation of (S)-S,S'-1,1'-binaphthyl-2,2'-diyl bis(dimethylcarbamothioate) (MNR18-1) from MNR16-1

MNR19.png

InChI=1S/C26H24N2O2S2/c1-27(2)25(31)29-21-15-13-17-9-5-7-11-19(17)23(21)24-20-12-8-6-10-18(20)14-16-22(24)30-26(32)28(3)4/h5-16H,1-4H3

Preparation of (rac)-S,S'-1,1'-binaphthyl-2,2'-diyl bis(dimethylcarbamothioate) (MNR20) from MNR19-1
Attempts to improve the preparation of (rac)-O,O'-1,1'-binaphthyl-2,2'-diyl bis(dimethylcarbamothioate) (MNR19

MNR20.png

InChI=1S/C26H24N2O2S2/c1-27(2)25(29)31-21-15-13-17-9-5-7-11-19(17)23(21)24-20-12-8-6-10-18(20)14-16-22(24)32-26(30)28(3)4/h5-16H,1-4H3

Preparation of (rac)-S,S'-1,1'-binaphthyl-2,2'-diyl bis(dimethylcarbamothioate) (MNR20) from MNR19-1
Microwave assisited preparation of (rac)-S,S'-1,1'-binaphthyl-2,2'-diyl bis(dimethylcarbamothioate) MNR20 from MNR19-1

MNR21.png

InChI=1S/C9H9N/c1-10-8-7-9-5-3-2-4-6-9/h2-6H,7-8H2

Preparation of (2-isocyanoethyl)benzene (MNR21-1)
Test reaction to try and drive MNR21-1 to complete product.
Preparation of (2-isocyanoethyl)benzene (MNR21-3)


MNR22.png

InChI=1S/C23H30N2O4/c1-3-28-22(29-4-2)18-25(23(27)20-13-9-6-10-14-20)17-21(26)24-16-15-19-11-7-5-8-12-19/h5-14,22H,3-4,15-18H2,1-2H3,(H,24,26)

Preparation of the dimethoxy Ugi-intermediate MNR22-1

MNR23.png

InChI=1S/Cl2HNO4S2/c1-8(4,5)3-9(2,6)7/h3H

Preparation of Imidobis(sulfuryl chloride) (MNR23-1)

MNR24.png

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/t17-/m0/s1

N-benzoyl protection of MNR3-3 to give MNR24-1

MNR25.png

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/t17-/m1/s1

N-benzoyl protection of MNR2-4 to give MNR25-1

MNR26.png

InChI=1S/C14H18N2O3/c1-18-12-5-9-3-4-16-11(7-15-8-14(16)17)10(9)6-13(12)19-2/h5-6,11,15H,3-4,7-8H2,1-2H3

Hydrolysis of rac-MNR12-5 to give MNR26-1

MNR27.png

InChI=1S/C14H18N2O3/c1-18-12-5-9-3-4-16-11(7-15-8-14(16)17)10(9)6-13(12)19-2/h5-6,11,15H,3-4,7-8H2,1-2H3/t11-/m0/s1

Resolution of MNR26-1with (-)-dibenzoyl-L-tartaric acid to obtain R-di-methoxy-PZQamine (MNR27-1)
Resolution of MNR26-1with (-)-dibenzoyl-L-tartaric acid to obtain R-di-methoxy-PZQamine (MNR27-2, MNR27-3, MNR27-4))
Screening conditions for optimum resolution of MNR26-1 to MNR27-X
Screening conditions for optimum resolution of MNR26-1 to MNR27-X

MNR28.png

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/t17-/m0/s1

N-Cyclohexanoyl-protection of MNR27 to give MNR28
N-Cyclohexanoyl-protection of MNR27 to give MNR28-3

mnr29.png

InChI=1S/C18H12Cl2O8/c19-11-5-1-9(2-6-11)17(25)27-13(15(21)22)14(16(23)24)28-18(26)10-3-7-12(20)8-4-10/h1-8,13-14H,(H,21,22)(H,23,24)

Purification of CS-3-1 in toluene (MNR29-1)

MNR30.png

InChI=1S/C14H18N2O3/c1-18-12-5-9-3-4-16-11(7-15-8-14(16)17)10(9)6-13(12)19-2/h5-6,11,15H,3-4,7-8H2,1-2H3/t11-/m1/s1

Resolution of MNR26-1 with (+)-dibenzoyl-D-tartaric acid to obtain S-di-methoxy-PZQamine (MNR30-1)

mnr31.png

InChI=1S/C21H22N2O4/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/h3-7,10-11,17H,8-9,12-13H2,1-2H3/t17-/m0/s1

N-Cyclohexanoyl-protection of MNR27 to give MNR31-1

untitled.png

InChI=1S/C23H36N2O4/c1-3-28-22(29-4-2)18-25(23(27)20-13-9-6-10-14-20)17-21(26)24-16-15-19-11-7-5-8-12-19/h5,7-8,11-12,20,22H,3-4,6,9-10,13-18H2,1-2H3,(H,24,26)

Preparation of the dimethoxy Ugi-intermediate (MNR32-1)

Attached Files
MNR08.png
MNR01.png
MNR10.png
MNR04.png
MNR05.png
MNR09.png
MNR06.png
MNR02.png
MNR07.png
MNR03.png
MNR12.png
MNR13.png
MNR18.png
MNR15.png
MNR14.png
MNR16.png
MNR20.png
MNR11.png
MNR17.png
MNR19.png
MNR26.png
MNR27.png
MNR30.png
mnr31.png
MNR24.png
MNR22.png
MNR21.png
MNR23.png
MNR25.png
mnr29.png
MNR28.png
untitled.png