1,4,8,11-tetrazacyclotetradecane

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

Procedure: A stirred mixture of 4.90 g (30 mmol) of hexamethylphosphorous triamide, 6.00 g (30 mmol) of 1,4,8,11-tetraazacyclotetradecane, and 30 ml of dry toluene is heated to 80°-90°, under nitrogen for 16 hr, then refluxed for 8 hr. The hot solution is filtered under N2 and concentrated, and the residue is sublimed at 60°-70° (0.3 mm) to give 5.45 g (80%) of waxy, white solid 1,4,8,11-tetraaza-15-phosphatetracyclo[6.6.1.04,15.011,15 ]pentadecane. is heated to 80°-90°, under nitrogen for 16 hr refluxed for 8 hr The hot solution is filtered under N2 concentrated is sublimed at 60°-70°

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

Procedure: A stirred mixture of 4.90 g (30 mmol) of hexamethylphosphorous triamide, 6.00 g (30 mmol) of 1,4,8,11-tetraazacyclotetradecane, and 30 ml of dry toluene is heated to 80°-90°, under nitrogen for 16 hr, then refluxed for 8 hr. The hot solution is filtered under N2 and concentrated, and the residue is sublimed at 60°-70° (0.3 mm) to give 5.45 g (80%) of waxy, white solid 1,4,8,11-tetraaza-15-phosphatetracyclo[6.6.1.04,15.011,15 ]pentadecane. is heated to 80°-90°, under nitrogen for 16 hr refluxed for 8 hr The hot solution is filtered under N2 concentrated is sublimed at 60°-70°

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

Procedure: In a first phase, ethyl (1,4,8,11-tetraazacyclotetradec-1-yl)ethanoate is obtained by slowly adding 6.68 g (40.0 mmol) of ethyl bromoacetate onto a solution of 40 g (200.0 mmol) of cyclam and 16 g (116 mmol) of potassium carbonate in 1 L of chloroform. The reaction mixture is maintained under stirring at room temperature for 48 h. After filtration on celite and evaporation of the solvent, the residue is taken up in petroleum ether. The excess cyclam is filtered off, the filtrate is concentrated and ethyl (1,4,8,11-tetraazacyclotetradec-1-yl)ethanoate (so-called compound 5.0) is thereby obtained, as 11.21 g of a slightly yellow oil (yield=98%) which is used without any purification. The reaction mixture is maintained After filtration on celite and evaporation of the solvent The excess cyclam is filtered off the filtrate is concentrated

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

Procedure: 72 g (0.359 mol) of cyclam and 15 g of Na2CO3 (dried at 100° C. under 1 mm Hg for 24 h) are placed in 2.5 l of acetonitrile in a 6 l reactor under a stream of nitrogen. The mixture is brought to reflux, a solution of 24.2 g (0.073 mol) of iodopropyltriethoxysilane in 500 ml of acetonitrile is then added dropwise and then the reaction mixture is maintained at reflux for 48 h. After evaporating the solvent on a rotary evaporator (still under a nitrogen atmosphere), pentane is added to the residue and the excess cyclam is filtered off. This operation is repeated three times, the filtrates are combined, the pentane is evaporated and compound 1 is obtained in the form of a colorless oil (15 g, 50.8%). to reflux the reaction mixture is maintained at reflux for 48 h After evaporating the solvent on a rotary evaporator (still under a nitrogen atmosphere), pentane is added to the residue the excess cyclam is filtered off the pentane is evaporated

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

Procedure: 72 g (0.359 mol) of cyclam and 15 g of Na2CO3 (dried at 100° C. under 1 mm Hg for 24 h) are placed in 2.5 l of acetonitrile in a 6 l reactor under a stream of nitrogen. The mixture is brought to reflux, a solution of 24.2 g (0.073 mol) of iodopropyltriethoxysilane in 500 ml of acetonitrile is then added dropwise and then the reaction mixture is maintained at reflux for 48 h. After evaporating the solvent on a rotary evaporator (still under a nitrogen atmosphere), pentane is added to the residue and the excess cyclam is filtered off. This operation is repeated three times, the filtrates are combined, the pentane is evaporated and compound 1 is obtained in the form of a colorless oil (15 g, 50.8%). to reflux the reaction mixture is maintained at reflux for 48 h After evaporating the solvent on a rotary evaporator (still under a nitrogen atmosphere), pentane is added to the residue the excess cyclam is filtered off the pentane is evaporated

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

Procedure: 1,7-dimethyl-1,4,7,10-tetraazacyclododecane; 1,4,8,11-tetraazacyclotetradecane (cyclam); 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane; 5,7,7,12,14,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane; 1,8-dimethyl-1,4,8,11-tetraazacyclotetradecane; 1,8-diethyl-1,4,8,11-tetraazacyclotetradecane (diethylcyclam); 5,12-dimethyl-1,5,8,12-tetraazabicyclo[6.6.2]hexadecane (dimethyl-Bcyclam), 5,12-diethyl-1,5,8,12-tetraazabicyclo[6.6.2]hexadecane (diethyl-Bcyclam) and 5-N-octyl-12-methyl-1,5,8,12-tetraazabicyclo[6.6.2]hexadecane.

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

Procedure: 1,7-dimethyl-1,4,7,10-tetraazacyclododecane; 1,4,8,11-tetraazacyclotetradecane (cyclam); 1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane; 5,7,7,12,14,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane; 1,8-dimethyl-1,4,8,11-tetraazacyclotetradecane; 1,8-diethyl-1,4,8,11-tetraazacyclotetradecane (diethylcyclam); 5,12-dimethyl-1,5,8,12-tetraazabicyclo[6.6.2]hexadecane (dimethyl-Bcyclam), 5,12-diethyl-1,5,8,12-tetraazabicyclo[6.6.2]hexadecane (diethyl-Bcyclam) and 5-N-octyl-12-methyl-1,5,8,12-tetraazabicyclo[6.6.2]hexadecane.

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

Procedure: To solution of Cyclam (0.913 g, 4.5 mmol) dissolved in a mixture of ethanol:water (5:1 by vol.) (18 ml) was added a solution of 4-chloromethylbenzoic acid (0.157 g, 0.92 mmol) in aqueous LiOH (53 mg in 4 ml of water). This mixture was thereafter refluxed vigorously with stirring for 5 hours. Then the solvent was removed at reduced pressure, and the residue was dissolved in 13 ml of water. The aqueous solution obtained was then extracted with chloroform (10 times 3 ml) and the aqueous layer was concentrated at reduced pressure down to 2 ml. The product as a white solid was precipitated by adding the solution of concentrated HCl and ethanol and purified by recrystallizing from ethanol/water/HCl to yield 0.205 g of the title compound. According to the LC-MS, the assay of 4-(1,4,8,11-tetraazacyclotetradec-1-ylmethyl)-benzoic acid hydrochloride was >95%. This mixture was thereafter refluxed vigorously Then the solvent was removed at reduced pressure the residue was dissolved in 13 ml of water The aqueous solution obtained was then extracted with chloroform (10 times 3 ml) the aqueous layer was concentrated at reduced pressure down to 2 ml The product as a white solid was precipitated by adding the solution of concentrated HCl and ethanol purified by recrystallizing from ethanol/water/HCl

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

Procedure: To solution of Cyclam (0.913 g, 4.5 mmol) dissolved in a mixture of ethanol:water (5:1 by vol.) (18 ml) was added a solution of 4-chloromethylbenzoic acid (0.157 g, 0.92 mmol) in aqueous LiOH (53 mg in 4 ml of water). This mixture was thereafter refluxed vigorously with stirring for 5 hours. Then the solvent was removed at reduced pressure, and the residue was dissolved in 13 ml of water. The aqueous solution obtained was then extracted with chloroform (10 times 3 ml) and the aqueous layer was concentrated at reduced pressure down to 2 ml. The product as a white solid was precipitated by adding the solution of concentrated HCl and ethanol and purified by recrystallizing from ethanol/water/HCl to yield 0.205 g of the title compound. According to the LC-MS, the assay of 4-(1,4,8,11-tetraazacyclotetradec-1-ylmethyl)-benzoic acid hydrochloride was >95%. This mixture was thereafter refluxed vigorously Then the solvent was removed at reduced pressure the residue was dissolved in 13 ml of water The aqueous solution obtained was then extracted with chloroform (10 times 3 ml) the aqueous layer was concentrated at reduced pressure down to 2 ml The product as a white solid was precipitated by adding the solution of concentrated HCl and ethanol purified by recrystallizing from ethanol/water/HCl

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

Procedure: A stirred mixture of 4.90 g (30 mmol) of hexamethylphosphorous triamide, 6.00 g (30 mmol) of 1,4,8,11-tetraazacyclotetradecane, and 30 ml of dry toluene is heated to 80°-90°, under nitrogen for 16 hr, then refluxed for 8 hr. The hot solution is filtered under N2 and concentrated, and the residue is sublimed at 60°-70° (0.3 mm) to give 5.45 g (80%) of waxy, white solid 1,4,8,11-tetraaza-15-phosphatetracyclo[6.6.1.04,15.011,15 ]pentadecane. is heated to 80°-90°, under nitrogen for 16 hr refluxed for 8 hr The hot solution is filtered under N2 concentrated is sublimed at 60°-70°

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

Procedure: Accordingly, the invention provides a method for the synthesis of 1,4,7,10-tetraazacyclododecane N,N',N",N'"-tetraacetic acid (DOTA) and 1,4,8,11-tetraazacyclotetradecane N,N',N",N'"-tetraacetic acid (TETA) (Formula I). For this purpose 1,4,7,10-tetraazacyclododecane and 1,4,8,11-tetraazacyclotetradecane (Formula II) are provided and cyanomethylated using acid, formaldehyde, and cyanide compound yielding a tetranitrile (Formula III) which precipitates upon the addition of base.. The tetranitrile (Formula III) is hydrolyzed followed by acidification, evaporation to dryness, reconstitution and precipitation to give DOTA or TETA. ##STR5## Accordingly, the invention provides a method

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

Procedure: Accordingly, the invention provides a method for the synthesis of 1,4,7,10-tetraazacyclododecane N,N',N",N'"-tetraacetic acid (DOTA) and 1,4,8,11-tetraazacyclotetradecane N,N',N",N'"-tetraacetic acid (TETA) (Formula I). For this purpose 1,4,7,10-tetraazacyclododecane and 1,4,8,11-tetraazacyclotetradecane (Formula II) are provided and cyanomethylated using acid, formaldehyde, and cyanide compound yielding a tetranitrile (Formula III) which precipitates upon the addition of base.. The tetranitrile (Formula III) is hydrolyzed followed by acidification, evaporation to dryness, reconstitution and precipitation to give DOTA or TETA. ##STR5## Accordingly, the invention provides a method