N'-(3-aminopropyl)butane-1,4-diamine

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: As an alternative to obtaining a mixture of Schiff bases VI and VI(a) or VI(b), which upon reduction give a mixture of product I the reaction can be conducted stepwise. For example, 1,4-diaminobutane or 4-(2-aminoethyl)piperazine may be converted to a Schiff base with 1,5-di-(4-isopropyl)-phenyl)-3-pentanone, catalytically reduced, then the resulting amine selectively cyanoethylated with acrylonitrile, followed by catalytic hydrogenation to furnish 1-(3-amino-propyl)-4-[1,5-di-(4-isopropylphenyl)-3-pentyl]diaminobutane, a spermidine derivative, or 1-(3-aminopropyl)-4-[2-{(1,5-di-(4-isopropylphenyl)-3-pentylamino}ethyl]piperazine. A primary amine can be dicyanoethylated with excess acrylonitrile, catalytically reduced to the corresponding 3,3'-substituted iminobis(propylamine) and then converted by condensation with a ketone and reduction to the N-alkylated-3,3'-substituted iminobis(propylamine). For example, dicyanoethylation of monoethanolamine followed by catalytic reduction provides 3,3'-(2-hydroxyethylimino)bis(propylamine). Condensation with 1-(2,4-dimethylphenyl)-6-(3-isopropylphenyl)-3-hexanone and subsequent catalytic hydrogenation of the --C=N bond affords 1-[1-(2,4-dimethylphenyl)6-(3-isopropylphenyl)-3-hexyl]-5-(2-hydroxyethyl)-1,5,9-triazanonane.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The scheme for directing nucleic acids to certain sites of the body is based upon the intercalation of a ligand which interacts with a cell surface component into the double stranded DNA. A procedure for selective N4-acylation of spermidine, using N1,N8-bis(t-butoxycarbonyl) spermidine as starting material, has been reported. R. J. Bergeron et al., Synthesis (1982) 689-692. We have used this procedure (FIG. 8) to link the acid functionalized galactosyl derivatives 9(n=1) and 9′(n=4) to the secondary amino group of N1,N8-tBoc-protected spermidine (15) and the resulting galactosylated spermidines 17 and 17′ were, after deprotection, further alkylated with 9-phenoxyacridine by a standard chemical procedure to transform them into bis-intercalator compounds 21 and 21′. The synthesis of the carboxylic acid functionalized galactosyl derivatives is detailed (J. Haensler et al., Biochim Biophys Acta (1988) 946:95-105) and is easily applicable to a wide range of carbohydrate ligands (M. M. Ponpipom et al., J Med Chem (1981) 24:1388-1395). The title compounds were obtained in an overall yield of 30% and the NMR and mass spectrometry data are consistent with the proposed structure. Bergeron et al., Synthesis (1982) 689-692

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 7.5 g of spermidine in water (150 mL) in a 250 mL round bottom flask was added paraformaldehyde (1.6 g). The resulting solution was stirred at room temperature for three hours. TLC (silicon dioxide, ethyl acetate:methanol:ammonium hydroxide=3:6:1) indicated there was no S.M. (Rf-0.01). To the reaction mixture was added toluene (100 mL). The resulting heterogeneous solution was concentrated on a rotovap at 45° C. for 30 minutes. The addition of toluene (100 mL) and concentration at 45° C. was repeated for two more times. The resulting thick oil was washed with tetrahydrofuran:ethanol (10:1)(×3) (220 mL). The combined organic layers were dried with sodium sulfate, filtered and concentrated to give 8.64 g of the title compound as a crude thick oil (yield 103%). The resulting heterogeneous solution was concentrated on a rotovap at 45° C. for 30 minutes The addition of toluene (100 mL) and concentration at 45° C. The resulting thick oil was washed with tetrahydrofuran:ethanol (10:1)(×3) (220 mL) The combined organic layers were dried with sodium sulfate filtered concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: An oven-dried resealable 15 mL Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol), 4-iodotoluene (260 mg, 1.19 mmol), K3PO4 (440 mg, 2.07 mmol), evacuated and backfilled with argon. N-(3-Aminopropyl)-1,4-butanediamine (79 μL, 0.503 mmol), ethylene glycol (115 μL, 2.06 mmol), and isopropyl alcohol (1.0 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred magnetically at 80° C. for 23 h. The resulting thick, gray-brown suspension was allowed to reach room temperature, poured into a solution of 30% aq ammonia (1 mL) in water (20 mL), and extracted with 3×15 mL of CH2Cl2. The organic phase was dried (Na2SO4), concentrated, and the residue was purified by flash chromatography on silica gel (2×15 cm; dichloromethane—dichloromethane saturated with 30% aq ammonia-methanol 30:20:2; 15 mL fractions). Fractions 12-24 were concentrated and the residue was recrystallized from hexanes (2 mL) to give 119 mg (73% yield) of the desired product as fine white crystals. 1H NMR (400 MHz, CDCl3): δ 6.98 (d, J=8.4 Hz, 4H), 6.56-6.50 (m, 4H), 4.04 (br s, 1H), 3.56 (br s, 1H), 3.17 (t, J=6.6 Hz, 2H), 3.11 (t, J=6.6 Hz, 2H), 2.74 (t, J=6.6 Hz, 2H), 2.64 (t, J=6.9 Hz, 2H), 2.23 (s, 6H), 1.79 (quintet, J=6.6 Hz, 2H), 1.70-1.54 (m, 4H), 0.95 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 146.3, 146.1, 129.7, 126.3, 112.89, 112.85, 49.8, 48.5, 44.2, 43.3, 29.6, 27.8, 27.3, 20.4. evacuated The Schlenk tube was sealed with a Teflon valve to reach room temperature extracted with 3×15 mL of CH2Cl2 The organic phase was dried (Na2SO4) concentrated the residue was purified by flash chromatography on silica gel (2×15 cm; dichloromethane—dichloromethane saturated with 30% aq ammonia-methanol 30:20:2; 15 mL fractions) Fractions 12-24 were concentrated the residue was recrystallized from hexanes (2 mL)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The scheme for directing nucleic acids to certain sites of the body is based upon the intercalation of a ligand which interacts with a cell surface component into the double stranded DNA. A procedure for selective N4 -acylation of spermidine, using N1,N8 -bis(t-butoxycarbonyl) spermidine as starting material, has been reported. R. J. Bergeron et al., Synthesis (1982) 689-692. We have used this procedure (FIG. 8) to link the acid functionalized galactosyl derivatives 9 (n=1) and 9' (n=4) to the secondary amino group of N1,N8 -tBOC-protected spermidine (15) and the resulting galactosylated spermidines 17 and 17' were, after deprotection, further alkylated with 9-phenoxyacridine by a standard chemical procedure to transform them into bis-intercalator compounds 21 and 21'. The synthesis of the carboxylic acid functionalized galactosyl derivatives is detailed (J. Haensler et al., Biochim Biophys Acta (1988) 946:95-105) and is easily applicable to a wide range of carbohydrate ligands (M. M. Ponpipom et al., J Med Chem (1981) 24:1388-1395). The title compounds were obtained in an overall yield of 30% and the NMR and mass spectrometry data are consistent with the proposed structure. Bergeron et al., Synthesis (1982) 689-692

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: As an alternative to obtaining a mixture of Schiff bases VI and VI(a) or VI(b), which upon reduction give a mixture of product I the reaction can be conducted stepwise. For example, 1,4-diaminobutane or 4-(2-aminoethyl)piperazine may be converted to a Schiff base with 1,5-di-(4-isopropyl-phenyl)-3-pentanone, catalytically reduced, then the resulting amine selectively cyanoethylated with acrylonitrile, followed by catalytic hydrogenation to furnish 1-(3-aminopropyl)-4-[1,5-di-(4-isopropylphenyl)-3-pentyl]diaminobutane, a spermidine derivative, or 1-(3-aminopropyl)-4-[2{(1,5-di-(4-isopropylphenyl)-3-pentylamino}ethyl]piperazine. A primary amine can be dicyanoethylated with excess acrylonitrile, catalytically reduced to the corresponding 3,3'-substituted iminobis(propylamine) and then converted by condensation with a ketone and reduction to the N-alkylated-3,3'-substituted iminobis(propylamine). For example, dicyanoethylation of monoethanolamine followed by catalytic reduction provides 3,3'-(2-hydroxyethylimino)bis(propylamine). Condensation with 1-(2,4-dimethylphenyl)-6-(3-isopropylphenyl)-3-hexanone and subsequent catalytic hydrogenation of the --C=N bond affords 1-[1-(2,4-dimethylphenyl)-6-(3-isopropylphenyl)-3-hexyl]-5-(2-hydroxyethyl)-1,5,9-triazanonane.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: As an alternative to obtaining a mixture of Schiff bases VI and VI(a) or VI(b), which upon reduction give a mixture of product I the reaction can be conducted stepwise. For example, 1,4-diaminobutane or 4-(2-aminoethyl)piperazine may be converted to a Schiff base with 1,5-di-(4-isopropyl)-phenyl)-3-pentanone, catalytically reduced, then the resulting amine selectively cyanoethylated with acrylonitrile, followed by catalytic hydrogenation to furnish 1-(3-aminopropyl)-4-[1,5-di-(4-isopropylphenyl)-3-pentyl]diaminobutane, a spermidine derivative, or 1-(3-aminopropyl)-4-[2-{(1,5-di-(4-isopropylphenyl)-3-pentylamino}ethyl]piperazine. A primary amine can be dicyanoethylated with excess acrylonitrile, catalytically reduced to the corresponding 3,3'-substituted iminobis(propylamine) and then converted by condensation with a ketone and reduction to the N-alkylated-3,3'-substituted iminobis(propylamine). For example, dicyanoethylation of monoethanolamine followed by catalytic reduction provides 3,3'-(2-hydroxyethylimino)bis(propylamine). Condensation with 1-(2,4-dimethylphenyl)-6-(3-isopropylphenyl)-3-hexanone and subsequent catalytic hydrogenation of the --C=N bond affords 1-[1-(2,4-dimethylphenyl)-6-(3-isopropylphenyl)-3-hexyl]-5-(2-hydroxyethyl)-1,5,9-triazanonane.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: As an alternative to obtaining a mixture of Schiff bases VI and VI(a) or VI(b), which upon reduction give a mixture of product I the reaction can be conducted stepwise. For example, 1,4-diaminobutane or 4-(2-aminoethyl)piperazine may be converted to a Schiff base with 1,5-di-(4-isopropyl)-phenyl)-3-pentanone, catalytically reduced, then the resulting amine selectively cyanoethylated with acrylonitrile, followed by catalytic hydrogenation to furnish 1-(3-amino-propyl)-4-[1,5-di-(4-isopropylphenyl)-3-pentyl]diaminobutane, a spermidine derivative, or 1-(3-aminopropyl)-4-[2-{(1,5-di-(4-isopropylphenyl)-3-pentylamino}ethyl]piperazine. A primary amine can be dicyanoethylated with excess acrylonitrile, catalytically reduced to the corresponding 3,3'-substituted iminobis(propylamine) and then converted by condensation with a ketone and reduction to the N-alkylated-3,3'-substituted iminobis(propylamine). For example, dicyanoethylation of monoethanolamine followed by catalytic reduction provides 3,3'-(2-hydroxyethylimino)bis(propylamine). Condensation with 1-(2,4-dimethylphenyl)-6-(3-isopropylphenyl)-3-hexanone and subsequent catalytic hydrogenation of the --C=N bond affords 1-[1-(2,4-dimethylphenyl)6-(3-isopropylphenyl)-3-hexyl]-5-(2-hydroxyethyl)-1,5,9-triazanonane.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The scheme for directing nucleic acids to certain sites of the body is based upon the intercalation of a ligand which interacts with a cell surface component into the double stranded DNA. A procedure for selective N4-acylation of spermidine, using N1,N8-bis(t-butoxycarbonyl) spermidine as starting material, has been reported. R. J. Bergeron et al., Synthesis (1982) 689-692. We have used this procedure (FIG. 8) to link the acid functionalized galactosyl derivatives 9(n=1) and 9′(n=4) to the secondary amino group of N1,N8-tBoc-protected spermidine (15) and the resulting galactosylated spermidines 17 and 17′ were, after deprotection, further alkylated with 9-phenoxyacridine by a standard chemical procedure to transform them into bis-intercalator compounds 21 and 21′. The synthesis of the carboxylic acid functionalized galactosyl derivatives is detailed (J. Haensler et al., Biochim Biophys Acta (1988) 946:95-105) and is easily applicable to a wide range of carbohydrate ligands (M. M. Ponpipom et al., J Med Chem (1981) 24:1388-1395). The title compounds were obtained in an overall yield of 30% and the NMR and mass spectrometry data are consistent with the proposed structure. Bergeron et al., Synthesis (1982) 689-692

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The scheme for directing nucleic acids to certain sites of the body is based upon the intercalation of a ligand which interacts with a cell surface component into the double stranded DNA. A procedure for selective N4-acylation of spermidine, using N1,N8-bis(t-butoxycarbonyl) spermidine as starting material, has been reported. R. J. Bergeron et al., Synthesis (1982) 689-692. We have used this procedure (FIG. 8) to link the acid functionalized galactosyl derivatives 9(n=1) and 9′(n=4) to the secondary amino group of N1,N8-tBoc-protected spermidine (15) and the resulting galactosylated spermidines 17 and 17′ were, after deprotection, further alkylated with 9-phenoxyacridine by a standard chemical procedure to transform them into bis-intercalator compounds 21 and 21′. The synthesis of the carboxylic acid functionalized galactosyl derivatives is detailed (J. Haensler et al., Biochim Biophys Acta (1988) 946:95-105) and is easily applicable to a wide range of carbohydrate ligands (M. M. Ponpipom et al., J Med Chem (1981) 24:1388-1395). The title compounds were obtained in an overall yield of 30% and the NMR and mass spectrometry data are consistent with the proposed structure. Bergeron et al., Synthesis (1982) 689-692

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 7.5 g of spermidine in water (150 mL) in a 250 mL round bottom flask was added paraformaldehyde (1.6 g). The resulting solution was stirred at room temperature for three hours. TLC (silicon dioxide, ethyl acetate:methanol:ammonium hydroxide=3:6:1) indicated there was no S.M. (Rf-0.01). To the reaction mixture was added toluene (100 mL). The resulting heterogeneous solution was concentrated on a rotovap at 45° C. for 30 minutes. The addition of toluene (100 mL) and concentration at 45° C. was repeated for two more times. The resulting thick oil was washed with tetrahydrofuran:ethanol (10:1)(×3) (220 mL). The combined organic layers were dried with sodium sulfate, filtered and concentrated to give 8.64 g of the title compound as a crude thick oil (yield 103%). The resulting heterogeneous solution was concentrated on a rotovap at 45° C. for 30 minutes The addition of toluene (100 mL) and concentration at 45° C. The resulting thick oil was washed with tetrahydrofuran:ethanol (10:1)(×3) (220 mL) The combined organic layers were dried with sodium sulfate filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 7.5 g of spermidine in water (150 mL) in a 250 mL round bottom flask was added paraformaldehyde (1.6 g). The resulting solution was stirred at room temperature for three hours. TLC (silicon dioxide, ethyl acetate:methanol:ammonium hydroxide=3:6:1) indicated there was no S.M. (Rf-0.01). To the reaction mixture was added toluene (100 mL). The resulting heterogeneous solution was concentrated on a rotovap at 45° C. for 30 minutes. The addition of toluene (100 mL) and concentration at 45° C. was repeated for two more times. The resulting thick oil was washed with tetrahydrofuran:ethanol (10:1)(×3) (220 mL). The combined organic layers were dried with sodium sulfate, filtered and concentrated to give 8.64 g of the title compound as a crude thick oil (yield 103%). The resulting heterogeneous solution was concentrated on a rotovap at 45° C. for 30 minutes The addition of toluene (100 mL) and concentration at 45° C. The resulting thick oil was washed with tetrahydrofuran:ethanol (10:1)(×3) (220 mL) The combined organic layers were dried with sodium sulfate filtered concentrated