1-(2-hydroxypropylamino)propan-2-ol

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

Procedure: A mixture of 250 mg (0.51 mmol) of 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide, and 136 mg (1.02 mmol) of 1,1′-iminodi-2-propanol in 2.25 ml dimethylformamide was stirred at room temperature for 3 hr and at 60° C. for 2 hr. After the mixture was cooled, saturated sodium bicarbonate solution was added and the solution was subsequently extracted with ethyl acetate. The extracts were evaporated to an oil, washed with hexane and dried under reduced pressure. Yield 240.1 mg (87%) tan solid: mp 122-125° C. After the mixture was cooled the solution was subsequently extracted with ethyl acetate The extracts were evaporated to an oil washed with hexane dried under reduced pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of diisopropanolamine (1.13 g) in THF was stirred under nitrogen at −78° C. N-Butillithium (2.5 M in hexanes, 4.3 ml) was added portionwise at −70° C. and the mixture was stirred for 15 minutes. 1-(Diethoxymethyl)-1H-imidazole (1.81 g) dissolved in THF was added dropwise at −70° C. and the mixture was stirred at −70° C. for 1 hour. Compound 4 (5.54 g) dissolved in THF was added dropwise at −70° C. and the mixture was stirred at −70° C. for 1 hour. The mixture was brought till room temperature and it was stirred at room temperature overnight. Acetic acid (5 ml) was added and the mixture was stirred at room temperature for 20 minutes. K2CO3 (5 g) was added and the mixture was evaporated. The residue was taken up in water and DCM and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried, filtered off and the solvent was evaporated, yielding 6.1 g (97%) of 6,11-dihydro-α-(1H-imidazol-2-yl)-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-methanol (compound 46). the mixture was stirred for 15 minutes was added dropwise at −70° C. the mixture was stirred at −70° C. for 1 hour was added dropwise at −70° C. the mixture was stirred at −70° C. for 1 hour was brought till room temperature it was stirred at room temperature overnight the mixture was stirred at room temperature for 20 minutes the mixture was evaporated DCM and the layers were separated The aqueous layer was extracted with DCM The combined organic layers were dried filtered off the solvent was evaporated

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

Procedure: Subsequently, 3-(3-chloromethyl-benzoylamino)-naphthalene-2-carboxylic acid methyl ester (870 mg) was dissolved in anhydrous methylene chloride (15 ml). Pyridine (400 μl) and diisopropanolamine (compound B′) (1.0 g) were added to the solution at room temperature, and the mixture was then stirred at that temperature for 48 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a hexane-acetone system to give 3-(3-{[bis-(2-hydroxy-propyl)-amino]-methyl}-benzoylamino)-naphthalene-2-carboxylic acid methyl ester as a useful intermediate (640 mg). After the completion of the reaction distilled water was added at room temperature, and the mixture was subjected to separatory extraction with chloroform The organic layer was washed with saturated brine was dried over sodium sulfate was then concentrated under the reduced pressure The residue was purified by column chromatography eluted with a hexane-acetone system

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

Procedure: Subsequently, 2-(3-chloromethyl-benzoylamino)-5-(2-oxo-pyrrolidin-1-yl)benzoic acid methyl ester (14 mg) was dissolved in anhydrous methylene chloride (5 ml). Triethylamine (7 mg: dissolved in 2 ml of anhydrous methylene chloride) and diisopropanolamine (compound B′) (10 mg: dissolved in 2 ml of anhydrous methylene chloride) were added dropwise to the solution at 0° C., and the mixture was stirred at room temperature for 24 hr. After the completion of the reaction, distilled water was added thereto at room temperature, and the mixture was subjected to separatory extraction with chloroform. The organic layer was washed with saturated brine, was dried over sodium sulfate, and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 2-(3-{[bis-(2-hydroxy-propyl)-amino]-methyl}-benzoylamino)-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester (8.0 mg, yield 47%). were added dropwise to the solution at 0° C. After the completion of the reaction distilled water was added at room temperature, and the mixture was subjected to separatory extraction with chloroform The organic layer was washed with saturated brine was dried over sodium sulfate was then concentrated under the reduced pressure The residue was purified by column chromatography eluted with a chloroform-methanol system

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of diisopropanolamine (1.13 g) in THF was stirred under nitrogen at −78° C. N-Butillithium (2.5 M in hexanes, 4.3 ml) was added portionwise at −70° C. and the mixture was stirred for 15 minutes. 1-(Diethoxymethyl)-1H-imidazole (1.81 g) dissolved in THF was added dropwise at −70° C. and the mixture was stirred at −70° C. for 1 hour. Compound 4 (5.54 g) dissolved in THF was added dropwise at −70° C. and the mixture was stirred at −70° C. for 1 hour. The mixture was brought till room temperature and it was stirred at room temperature overnight. Acetic acid (5 ml) was added and the mixture was stirred at room temperature for 20 minutes. K2CO3 (5 g) was added and the mixture was evaporated. The residue was taken up in water and DCM and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried, filtered off and the solvent was evaporated, yielding 6.1 g (97%) of 6,11-dihydro-α-(1H-imidazol-2-yl)-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-methanol (compound 46). the mixture was stirred for 15 minutes was added dropwise at −70° C. the mixture was stirred at −70° C. for 1 hour was added dropwise at −70° C. the mixture was stirred at −70° C. for 1 hour was brought till room temperature it was stirred at room temperature overnight the mixture was stirred at room temperature for 20 minutes the mixture was evaporated DCM and the layers were separated The aqueous layer was extracted with DCM The combined organic layers were dried filtered off the solvent was evaporated

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

Procedure: A solution of 53.2 g (0.4 mole) of diiso-propanolamine in 50 cm3 of pyridine is added dropwise with cooling to a solution of 248 g (1.3 mole) of tosyl chloride in 200 cm3 of pyridine at 0° C. so that the temperature is maintained between 0° and 5° C. The mixture is left at this temperature for 72 h. It is then poured into 2 l of water plus ice and 250 cm3 of concentrated hydrochloric acid. is maintained between 0° and 5° C

Conditions: temp:165.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: This Example describes the method used for making a reaction product of di-isopropanolamine, benzoic acid and succinic acid anhydride. A one-liter reaction flask was provided with a mechanical agitator, a thermometer and a DeanStark arrangement. 261.06 g (1.960 mol) of di-isopropanol amine (type S, BASF), 540.88 g (4.429 mol) of benzoic acid (Aldrich) and 69.69 g (0.696 mol) of succinic acid anhydride (Aldrich) were placed in the flask. A small quantity of o-xylene, approximately 60 ml, was added as entraining agent in order to remove the liberated water. The reaction mixture was kept in a nitrogen atmosphere and heated for 1 hour at 165° C., whereafter the reaction temperature was brought to 180° C. After 6 hours the temperature was reduced to 160° C. and the flask was evacuated to remove the o-xylene. After about 1 hour it was possible to tap off the reaction mixture. Analysis showed that the number-averaged molecular weight (Mn) was 583 and the weight-average molecular weight (Mw) was 733. The ratio between Mw and Mn (1.26) is indicative of the fact that a mixture of compounds has formed. In formula 1 below, the compounds that can form during the reaction between di-isopropanol amine, benzoic acid and succinic acid are diagrammatically indicated (it should be noted that formula 1 is the most probable structure of the resulting compounds). The reaction shows the formation of a mono-disperse compound. The ratio of the reactants as shown in the formula is associated with a selected value for n. This ratio need not be equal to the ratio for the overall reaction, which is, in fact, a mixture of compounds with different values for n forms. In the reaction according to this example, a ratio has been selected equal to 2.82:6.36:1 (di-isopropanol amine: benzoic acid: succinic acid anhydride). This means that there are 3×2.82=8.46 mol-equivalents of reactive NH/OH groups in the amine, against 6.36+2×1.00=8.36 mol/equivalents acid groups in the benzoic acid and anhydride. There is therefore a very small excess (about 1%) of di-isopropanol amine. A one-liter reaction flask was provided with a mechanical agitator to remove the liberated water was brought to 180° C the flask was evacuated to remove the o-xylene After about 1 hour it was possible The ratio between Mw and Mn (1.26) is indicative of the fact that a mixture of compounds has formed

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

Procedure: A mixture of 250 mg (0.51 mmol) of 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide, and 136 mg (1.02 mmol) of 1,1′-iminodi-2-propanol in 2.25 ml dimethylformamide was stirred at room temperature for 3 hr and at 60° C. for 2 hr. After the mixture was cooled, saturated sodium bicarbonate solution was added and the solution was subsequently extracted with ethyl acetate. The extracts were evaporated to an oil, washed with hexane and dried under reduced pressure. Yield 240.1 mg (87%) tan solid: mp 122-125° C. After the mixture was cooled the solution was subsequently extracted with ethyl acetate The extracts were evaporated to an oil washed with hexane dried under reduced pressure

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

Procedure: A mixture of 250 mg (0.51 mmol) of 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide, and 136 mg (1.02 mmol) of 1,1′-iminodi-2-propanol in 2.25 ml dimethylformamide was stirred at room temperature for 3 hr and at 60° C. for 2 hr. After the mixture was cooled, saturated sodium bicarbonate solution was added and the solution was subsequently extracted with ethyl acetate. The extracts were evaporated to an oil, washed with hexane and dried under reduced pressure. Yield 240.1 mg (87%) tan solid: mp 122-125° C. After the mixture was cooled the solution was subsequently extracted with ethyl acetate The extracts were evaporated to an oil washed with hexane dried under reduced pressure

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

Procedure: A mixture of 250 mg (0.51 mmol) of 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide, and 136 mg (1.02 mmol) of 1,1′-iminodi-2-propanol in 2.25 ml dimethylformamide was stirred at room temperature for 3 hr and at 60° C. for 2 hr. After the mixture was cooled, saturated sodium bicarbonate solution was added and the solution was subsequently extracted with ethyl acetate. The extracts were evaporated to an oil, washed with hexane and dried under reduced pressure. Yield 240.1 mg (87%) tan solid: mp 122-125° C. After the mixture was cooled the solution was subsequently extracted with ethyl acetate The extracts were evaporated to an oil washed with hexane dried under reduced pressure

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of diisopropanolamine (1.13 g) in THF was stirred under nitrogen at −78° C. N-Butillithium (2.5 M in hexanes, 4.3 ml) was added portionwise at −70° C. and the mixture was stirred for 15 minutes. 1-(Diethoxymethyl)-1H-imidazole (1.81 g) dissolved in THF was added dropwise at −70° C. and the mixture was stirred at −70° C. for 1 hour. Compound 4 (5.54 g) dissolved in THF was added dropwise at −70° C. and the mixture was stirred at −70° C. for 1 hour. The mixture was brought till room temperature and it was stirred at room temperature overnight. Acetic acid (5 ml) was added and the mixture was stirred at room temperature for 20 minutes. K2CO3 (5 g) was added and the mixture was evaporated. The residue was taken up in water and DCM and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried, filtered off and the solvent was evaporated, yielding 6.1 g (97%) of 6,11-dihydro-α-(1H-imidazol-2-yl)-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-methanol (compound 46). the mixture was stirred for 15 minutes was added dropwise at −70° C. the mixture was stirred at −70° C. for 1 hour was added dropwise at −70° C. the mixture was stirred at −70° C. for 1 hour was brought till room temperature it was stirred at room temperature overnight the mixture was stirred at room temperature for 20 minutes the mixture was evaporated DCM and the layers were separated The aqueous layer was extracted with DCM The combined organic layers were dried filtered off the solvent was evaporated

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of diisopropanolamine (1.13 g) in THF was stirred under nitrogen at −78° C. N-Butillithium (2.5 M in hexanes, 4.3 ml) was added portionwise at −70° C. and the mixture was stirred for 15 minutes. 1-(Diethoxymethyl)-1H-imidazole (1.81 g) dissolved in THF was added dropwise at −70° C. and the mixture was stirred at −70° C. for 1 hour. Compound 4 (5.54 g) dissolved in THF was added dropwise at −70° C. and the mixture was stirred at −70° C. for 1 hour. The mixture was brought till room temperature and it was stirred at room temperature overnight. Acetic acid (5 ml) was added and the mixture was stirred at room temperature for 20 minutes. K2CO3 (5 g) was added and the mixture was evaporated. The residue was taken up in water and DCM and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried, filtered off and the solvent was evaporated, yielding 6.1 g (97%) of 6,11-dihydro-α-(1H-imidazol-2-yl)-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-methanol (compound 46). the mixture was stirred for 15 minutes was added dropwise at −70° C. the mixture was stirred at −70° C. for 1 hour was added dropwise at −70° C. the mixture was stirred at −70° C. for 1 hour was brought till room temperature it was stirred at room temperature overnight the mixture was stirred at room temperature for 20 minutes the mixture was evaporated DCM and the layers were separated The aqueous layer was extracted with DCM The combined organic layers were dried filtered off the solvent was evaporated