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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