1,4,7-trioxa-10-azacyclododecane

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

Procedure: In the mamner of Example 103, 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide and 1,4,7-trioxa-10-aza cyclododecane was converted to 37.5 mg of the title compound(free base) and mass spectrum (electrospray, m/e): M+H 584.1, 17.1 mg of the title compound as the bis-trifluoroacetate salt); mass spectrum (electrospray, m/e): M+H 584.1.

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

Procedure: A quantity of the 1-benzyl-1-aza-4,7,10-trioxacyclododecane compound (3) prepared in Example 3 (45.1 g, 0.17 mol), ethanol (7 g), and 10% palladium on carbon (0.5 g) were shaken in hydrogen atmosphere at more than 50 psi (1 psi= 6.9×103Pa=0.07 kg cm-2). Hydrogen gas was recharged several times into the reaction chamber to keep the pressure elevated. Shaking was continued until the pressure lowering stopped (4 days). After the palladium carbon was filtered, the solvent was evaporated. The pure compound (4) was sublimed from the residue with gentle heating using a water bath (75°-77° C.; crude material melted at this temperature). The sublimate was white needles and was hygroscopic. Yield 60%; 1HNMR (D2O): δ 2.53-2.70 (t, 4H, N--CH2), 3.5-3.75 (m, 12H, O--CH2), no signal at 7.1 (Ar--H of benzyl group, possible contaminant). (4 days) After the palladium carbon was filtered the solvent was evaporated with gentle heating 75°-77° C.

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

Procedure: In the mamner of Example 103, 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide and 1,4,7-trioxa-10-aza cyclododecane was converted to 37.5 mg of the title compound(free base) and mass spectrum (electrospray, m/e): M+H 584.1, 17.1 mg of the title compound as the bis-trifluoroacetate salt); mass spectrum (electrospray, m/e): M+H 584.1.

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

Procedure: A quantity of the 1-benzyl-1-aza-4,7,10-trioxacyclododecane compound (3) prepared in Example 3 (45.1 g, 0.17 mol), ethanol (7 g), and 10% palladium on carbon (0.5 g) were shaken in hydrogen atmosphere at more than 50 psi (1 psi=6.9×103 Pa=0.07 kg cm-2). Hydrogen gas was recharged several times into the reaction chamber to keep the pressure elevated. Shaking was continued until the pressure lowering stopped (4 days). After the palladium carbon was filtered, the solvent was evaporated. The pure compound (4) was sublimed from the residue with gentle heating using a water bath (75°-77° C.; crude material melted at this temperature). The sublimate was white needles and was hygroscopic. Yield 60%; 1HNMR (D2O): δ 2.53-2.70 (t, 4H, N--CH2), 3.5-3.75 (m, 12H, O--CH2), no signal at 7.1 (Ar--H of benzyl group, possible contaminant). (4 days) After the palladium carbon was filtered the solvent was evaporated with gentle heating 75°-77° C.

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

Procedure: In the mamner of Example 103, 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide and 1,4,7-trioxa-10-aza cyclododecane was converted to 37.5 mg of the title compound(free base) and mass spectrum (electrospray, m/e): M+H 584.1, 17.1 mg of the title compound as the bis-trifluoroacetate salt); mass spectrum (electrospray, m/e): M+H 584.1.

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

Procedure: In the mamner of Example 103, 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide and 1,4,7-trioxa-10-aza cyclododecane was converted to 37.5 mg of the title compound(free base) and mass spectrum (electrospray, m/e): M+H 584.1, 17.1 mg of the title compound as the bis-trifluoroacetate salt); mass spectrum (electrospray, m/e): M+H 584.1.

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

Procedure: Analogously to Example 14 from 1-aza-4,7,10-trioxacyclododecane and 3,3-dimethylbutyryl chloride.

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

Procedure: Analogously to Example 14 from 1-aza-4,7,10-trioxacyclododecane and 2,2-dimethylbutyryl chloride.

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

Procedure: Analogously to Example 14 from 1-aza-4,7,10-trioxacyclododecane and (1-adamantyl)acetyl chloride.

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

Procedure: Analogously to Example 14 from 1-aza-4,7,10-trioxacyclododecane and 1-adamantylcarbonyl chloride.

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

Procedure: 3.81 mmol of 1-aza-4,7,10-trioxacyclododecane are dissolved in 50 ml of CH2Cl2. 0.6 ml of triethylamine are added and 0.1 g of DMAP (=4-dimethylaminopyridine) is added as catalyst 3.82 mmol of pivalyl chloride are subsequently added, and the mixture is stirred at room temperature for 18 hours. are subsequently added

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

Procedure: A quantity of the 1-benzyl-1-aza-4,7,10-trioxacyclododecane compound (3) prepared in Example 3 (45.1 g, 0.17 mol), ethanol (7 g), and 10% palladium on carbon (0.5 g) were shaken in hydrogen atmosphere at more than 50 psi (1 psi= 6.9×103Pa=0.07 kg cm-2). Hydrogen gas was recharged several times into the reaction chamber to keep the pressure elevated. Shaking was continued until the pressure lowering stopped (4 days). After the palladium carbon was filtered, the solvent was evaporated. The pure compound (4) was sublimed from the residue with gentle heating using a water bath (75°-77° C.; crude material melted at this temperature). The sublimate was white needles and was hygroscopic. Yield 60%; 1HNMR (D2O): δ 2.53-2.70 (t, 4H, N--CH2), 3.5-3.75 (m, 12H, O--CH2), no signal at 7.1 (Ar--H of benzyl group, possible contaminant). (4 days) After the palladium carbon was filtered the solvent was evaporated with gentle heating 75°-77° C.