4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: The known method by T. Inaba, A. G. Birchler, Y. Yamada, S. Sagawa, K. Yokata, K. Ando and I. Uchida, J. Org. Chem., 1998, 63, 7582 for the preparation of the enantiomer of the title compound was followed. (S)-1-Phenylethanamine (30.4 ml, 236 mmol) and 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (34 g, 236 mmol) were dissolved in iPrOH (16 ml) and heated under reflux for 16 h. The mixture was stirred and cooled in an ice bath. Hexanes (90 ml) was added. After 1 h the colourless crystalline solid was filtered off, washed with hexanes and dried to give (5S,6R)-2,2-dimethyl-6-((S)-1-phenylethylamino)-1,3-dioxepan-5-ol (21.9 g, 35%). The 1H NMR was in agreement with that described for the enantiomer of the title compound by T. Inaba, A. G. Birchler, Y. Yamada, S. Sagawa, K. Yokata, K. Ando and I. Uchida, J. Org. Chem., 1998, 63, 7582. [α]D 20 −96.6 (c, 1.01, MeOH). Lit. (T. Inaba, A. G. Birchler, Y. Yamada, S. Sagawa, K. Yokata, K. Ando and I. Uchida, J. Org. Chem., 1998, 63, 7582) [α]D 25 +96.2 (c 1.00, MeOH) for the enantiomer. heated under reflux for 16 h cooled in an ice bath After 1 h the colourless crystalline solid was filtered off washed with hexanes dried

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

Procedure: The solution of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid sodium salt is directly reacted, as described in EP 448191, with 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane to give the alkylated product, which can easily be complexed with gadolinium to give the final Gadobutrol. to give the alkylated product, which

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

Procedure: The solution of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid sodium salt is directly reacted, as described in EP 448191, with 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane to give the alkylated product, which can, easily be complexed with gadolinium to give the final Gadobutrol. to give the alkylated product, which can,

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

Procedure: The solution of 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid sodium salt is directly reacted, as described in EP 448191, with 4,4-dimethyl-3,5, 8-trioxabicyclo[5.1.0]octane to give the alkylated product, which can easily be complexed with gadolinium to give the final Gadobutrol. to give the alkylated product, which

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

Procedure: 50 g (78.76 mmol) of 4,7,10-tris(p-toluenesulfonyl)-1,4,7,10-tetraazacyclododecane and 13.63 g (94.51 mmol) of 4,4-dimethyl-3,5,8-trioxabicyclo-[5.1.0]-octane are dissolved in 300 ml of dimethylformamide and heated in an autoclave for 24 hours to 170° C. It is evaporated to dryness and the residue is chromatographed on silica gel (mobile solvent: methylene chloride/hexane/acetone: 10/5/1). The main fractions are concentrated by evaporation and recrystallized from methyl tert-butyl ether/methanol. Yield: 52.76 g (86% of theory) of a cream-colored powder. heated in an autoclave for 24 hours to 170° C It is evaporated to dryness the residue is chromatographed on silica gel (mobile solvent: methylene chloride/hexane/acetone: 10/5/1) The main fractions are concentrated by evaporation recrystallized from methyl tert-butyl ether/methanol

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

Procedure: 50 g (78.76 mmol) of 4,7,10-tris(p-toluenesulfonyl)-1,4,7,10-tetraazacyclododecane and 13.63 g (94.51 mmol) of 4,4-dimethyl-3,5,8-trioxabicyclo-[5.1.0]-octane are dissolved in 300 ml of dimethylformamide and heated in an autoclave for 24 hours to 170° C. It is evaporated to dryness and the residue is chromatographed on silica gel (mobile solvent: methylene chloride/hexane/acetone: 10/5/1). The main fractions are concentrated by evaporation and recrystallized from methyl tert-butyl ether/methanol. Yield: 52.76 g (86% of theory) of a cream-colored powder. heated in an autoclave for 24 hours to 170° C It is evaporated to dryness the residue is chromatographed on silica gel (mobile solvent: methylene chloride/hexane/acetone: 10/5/1) The main fractions are concentrated by evaporation recrystallized from methyl tert-butyl ether/methanol

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The amine of Example 5 (500 mg, 0.70mmol) was dissolved in water (20 mL), and the pH was adjusted to 11.5 with 1M LiOH. The reaction mixture was heated at 60° C., and three aliquots of 4,4-dimethyl-3,5,8-trioxabicyclo[5.1.0]octane (see J. Org. Chem. 41: 2469 (1976)) (180 μL) were added at 8 hour intervals. Heating was continued for 48 hours. After cooling, the mixture was treated with 10% HCl, refluxed for 2 hours, and loaded on an AG1-X8 cation exchange column [40 mL (OAc form)]. The column was washed with water (500 mL), and the product was eluted with 1M CH2COOH. The fractions containing the product were combined and evaporated to a white powder (420 mg (81.4%)). 1H NMR (D2O, 355° K) δ 1.6-2.0 (br mult., 4H), 2.7-3.8 (br mult. 54H). 13C NMR (D2O): 23.5, 25.2, 25.5, 44.5, 44.9, 49.8, 50.3, 54.9, 55.1, 57.2, 58.0, 58.7, 59.5, 61.6, 62.2, 62.9, 68.6, 69.1, 169.6, 170.2, 174.0. MS (FAB): m/e 927.5 (MH+). Anal. Calcd for C38H70N8O18 8H2O: C, 43.92; H, 8.34; N, 10.78. Found C, 43.94; H, 7.65; N, 10.78. Heating After cooling refluxed for 2 hours The column was washed with water (500 mL) the product was eluted with 1M CH2COOH The fractions containing the product evaporated to a white powder (420 mg (81.4%))