(S)-3-AMINO-2-CBZ-AMINO-PROPIONIC ACID TERT-BUTYL ESTER

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 354 mg (1.7 mmol) of 4-(2-methoxycarbonyl-ethyl)benzoic acid and 500 mg (1.7 mmol) of tert-butyl (2S)-3-amino-2-benzyloxycarbonylaminopropionate were dissolved in 3 ml of dimethylformamide and treated with 557 mg (1.7 mmol) of O-((cyano-(ethoxycarbonyl)-methylidene)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) and 204 mg (1.7 mmol) of diisopropylethylamine, and the mixture was stirred at room temperature for 7 hours at pH 7-8. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate and the solution was washed three times each with KHSO4 solution and NaHCO3 solution until neutral. The organic phase was separated off and dried and the solvent was removed by distillation in vacuo. Yield 770 mg. MS (ES+): m/e=485.2 (M+H+). The solvent was removed in vacuo the residue was dissolved in ethyl acetate the solution was washed three times each with KHSO4 solution and NaHCO3 solution until neutral The organic phase was separated off dried the solvent was removed by distillation in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 10 g (42 mmol) of (2S)-3-amino-2-benzyloxycarbonylaminopropionic acid are shaken in an autoclave for 3 days, at an N2 pressure of 20 atm., in a mixture consisting of 100 ml of dioxane, 100 ml of isobutylene and 8 ml of conc. H2SO4. Excess isobutylene is blown off and 150 ml of diethyl ether and 150 ml of a saturated solution of NaHCO3 are added to the remaining solution. The phases are separated and the aqueous phase is extracted twice with 100 ml of diethyl ether on each occasion. The combined organic phases are washed with 2×100 ml of H2O and dried over Na2SO4. 9.58 g (78%) of (1.6) are obtained as a pale yellow oil after the solvent has been removed in vacuo. The phases are separated the aqueous phase is extracted twice with 100 ml of diethyl ether on each occasion The combined organic phases are washed with 2×100 ml of H2O dried over Na2SO4

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 10 g (42 mmol) of (S)-3-Amino-2-benzyloxycarbonylaminopropionic acid were shaken in an autoclave at an N2 pressure of 20 atm for 3 days in a mixture of 100 ml of dioxane, 100 ml of isobutylene and 8 ml of conc. H2SO4 . Excess isobutylene was blown out and 150 ml of diethyl ether and 150 ml of saturated NaHCO3 solution were added to the remaining solution. The phases were separated and the aqueous phase was extracted 2× with 100 ml of diethyl ether each time. The combined organic phases were washed with 2×100 ml of water and dried over Na2SO4. After removing the solvent in vacuo, 9.58 g (78%) of the title compound were obtained as a pale yellow oil. The phases were separated the aqueous phase was extracted 2× with 100 ml of diethyl ether each time The combined organic phases were washed with 2×100 ml of water dried over Na2SO4 After removing the solvent in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 354 mg (1.7 mmol) of 4-(2-methoxycarbonylethyl)benzoic acid (step b) and 500 mg (1.7 mmol) of tert-butyl (2S)-2-benzyloxycarbonylamino-3-aminopropionate were dissolved in 3 ml of dimethylformamide and treated with 557 mg (1.7 mmol) of O-((cyano(ethoxycarbonyl)methylene)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) and 204 mg (1.7 mmol) of diisopropylethylamine and the solution was stirred at room temperature for 7 h. The solvent was evaporated in vacuo, the residue was dissolved in ethyl acetate and washed three times each with a solution of potassium hydrogen sulfate and a solution of sodium bicarbonate until neutral. The organic phase was separated off and dried, and the solvent was distilled off in vacuo. Yield: 770 mg (93%). The solvent was evaporated in vacuo the residue was dissolved in ethyl acetate washed three times each with a solution of potassium hydrogen sulfate The organic phase was separated off dried the solvent was distilled off in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 10 g (42 mmol) of (2S)-3-amino-2-benzyloxycarbonylaminopropionic acid were shaken for 3 days, in an autoclave and under 20 atm. N2 pressure, in a mixture of 100 ml of dioxane, 100 ml of isobutylene and 8 ml of conc. H2SO4. Excess isobutylene was blown off, and 150 ml of diethyl ether and 150 ml of a saturated solution of NaHCO3 were added to the remaining solution. The phases were separated and the aqueous phase was extracted 2 times with 100 ml of diethyl ether on each occasion. The combined organic phases were washed with 2×100 ml of H2O and dried over Na2SO4. After the solvent had been removed in vacuo, 9.58 g (78%) of (1.6) were obtained as a pale yellow oil. The phases were separated the aqueous phase was extracted 2 times with 100 ml of diethyl ether on each occasion The combined organic phases were washed with 2×100 ml of H2O dried over Na2SO4 After the solvent had been removed in vacuo

反応条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 1000 mg (3.5 mmol) of 4-(4-chloro-2-methyl-pyrrolo[2,3-d]pyrimidin-7-yl)-butyric acid ethyl ester (example 2a) in 7 ml N-methylpyrrolidone were added 1590 mg (5.4 mmol) of (2S)-3-amino-2-benzyloxycarbonylamino-propionic acid tert-butyl ester and 5.9 ml triethylamine and the reaction was stirred at 100° C. for 36 h. The reaction was diluted with 85 ml EE and extracted with water, aqueous citric acid and again with water. The organic phase was dried over MgSO4 filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with DCM/EE (2:1). Yield: 719 mg. The reaction was diluted with 85 ml EE extracted with water, aqueous citric acid and again with water The organic phase was dried over MgSO4 filtered the solvent was removed in vacuo The residue was chromatographed on silica gel eluting with DCM/EE (2:1)

反応条件: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1 g (3.72 mmol) of 4-(6-chloro-purin-9-yl)-butyric acid ethyl ester was dissolved in dimethylformamide (3 ml) and 2.6 ml (14.9 mmol) of N,N-diisopropylethylamine was added. 1.09 g (3.72 mmol) of (2S)-3-amino-2-benzyloxycarbonylamino-propionic acid tert-butyl ester and dimethylformamide (2 ml) were added. The reaction was stirred at 80° C. for 2 days. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with 10% aqueous citric acid solution and three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. Residual amounts of 4-(6-chloro-purin-9-yl)-butyric acid ethyl ester were removed as follows: the residue was dissolved in tetrahydrofuran and 2 g of a macroporous aminomethyl polystyrene resin was added. The suspension was heated at 60° C. for 5 hours, then stirred gently at room temperature for 16 hours. The resin was filtered off, washed with tetrahydrofuran, and the combined organic phase was dried in vacuo. Yield: 908 mg. The solvent was removed in vacuo the residue was dissolved in dichloromethane the solution was washed three times with 10% aqueous citric acid solution and three times with water The organic phase was dried with sodium sulfate filtered the solvent was removed in vacuo Residual amounts of 4-(6-chloro-purin-9-yl)-butyric acid ethyl ester were removed the residue was dissolved in tetrahydrofuran 2 g of a macroporous aminomethyl polystyrene resin was added The suspension was heated at 60° C. for 5 hours stirred gently at room temperature for 16 hours The resin was filtered off washed with tetrahydrofuran the combined organic phase was dried in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 10 g (42 mmol) of (2S)-3-amino-2-benzyloxycarbonylaminopropionic acid were shaken for 3 days, in an autoclave and under 20 atm. N2 pressure, in a mixture of 100 ml of dioxane, 100 ml of isobutylene and 8 ml of conc. H2SO4. Excess isobutylene was blown off, and 150 ml of diethyl ether and 150 ml of a saturated solution of NaHCO3 were added to the remaining solution. The phases were separated and the aqueous phase was extracted 2 times with 100 ml of diethyl ether on each occasion. The combined organic phases were washed with 2×100 ml of H2O and dried over Na2SO4. After the solvent had been removed in vacuo, 9.58 g (78%) of (1.6) were obtained as a pale yellow oil. The phases were separated the aqueous phase was extracted 2 times with 100 ml of diethyl ether on each occasion The combined organic phases were washed with 2×100 ml of H2O dried over Na2SO4 After the solvent had been removed in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2.2 g (6.15 mmoles) of 6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-2,5-dimethyl-4-chloro-pyrimidine and 2.17 g (7.38 mmoles) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176), is heated under reflux for 24 hours in the presence of 1.31 g (8.61 mmoles) of caesium fluoride, 383 mg (0.615 mmoles) of (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 281 mg (0.307 mmoles) of tris-dibenzylideneacetone)dipalladium(o), in 55 ml of 1,2-dimethoxyethane. The reaction mixture is then returned to ambient temperature, 281 mg (0.307 mmoles) of tris-dibenzylideneacetone)dipalladium(o) is added, then the reaction mixture is taken to reflux for another 24 hours. After cooling down the solution is concentrated to dryness under reduced pressure (2 kPa) then taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is decanted and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated to dryness under reduced pressure (2 kPa). The residue is chromatographed on alumina with a gradient of isopropyl ether/ethyl acetate (50/50)-dichloromethane (50-50). The fractions containing the expected product are combined for a second purification on silicagel with a gradient of ethyl acetate-heptane-methanol 50-50-0 to 90-0-10. 550 mg (Yield=15%) of expected product is obtained. is heated is then returned to ambient temperature to reflux for another 24 hours After cooling down the solution is concentrated to dryness under reduced pressure (2 kPa) then taken up in a mixture of water, ethyl acetate The organic phase is decanted the aqueous phase is extracted with ethyl acetate The combined organic phases are dried over magnesium sulphate evaporated to dryness under reduced pressure (2 kPa) The residue is chromatographed on alumina with a gradient of isopropyl ether/ethyl acetate (50/50)-dichloromethane (50-50) The fractions containing the expected product are combined for a second purification on silicagel with a gradient of ethyl acetate-heptane-methanol 50-50-0 to 90-0-10

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2.2 g (6.15 mmoles) of 6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-2,5-dimethyl-4-chloro-pyrimidine and 2.17 g (7.38 mmoles) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176), is heated under reflux for 24 hours in the presence of 1.31 g (8.61 mmoles) of caesium fluoride, 383 mg (0.615 mmoles) of (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 281 mg (0.307 mmoles) of tris-dibenzylideneacetone)dipalladium(o), in 55 ml of 1,2-dimethoxyethane. The reaction mixture is then returned to ambient temperature, 281 mg (0.307 mmoles) of tris-dibenzylideneacetone)dipalladium(o) is added, then the reaction mixture is taken to reflux for another 24 hours. After cooling down the solution is concentrated to dryness under reduced pressure (2 kPa) then taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is decanted and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate and evaporated to dryness under reduced pressure (2 kPa). The residue is chromatographed on alumina with a gradient of isopropyl ether/ethyl acetate (50/50)-dichloromethane (50-50). The fractions containing the expected product are combined for a second purification on silicagel with a gradient of ethyl acetate-heptane-methanol 50-50-0 to 90-0-10. 550 mg (Yield=15%) of expected product is obtained. is heated is then returned to ambient temperature to reflux for another 24 hours After cooling down the solution is concentrated to dryness under reduced pressure (2 kPa) then taken up in a mixture of water, ethyl acetate The organic phase is decanted the aqueous phase is extracted with ethyl acetate The combined organic phases are dried over magnesium sulphate evaporated to dryness under reduced pressure (2 kPa) The residue is chromatographed on alumina with a gradient of isopropyl ether/ethyl acetate (50/50)-dichloromethane (50-50) The fractions containing the expected product are combined for a second purification on silicagel with a gradient of ethyl acetate-heptane-methanol 50-50-0 to 90-0-10

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 280 mg (0.72 mmole) of 4-bromo-5-fluoro-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-pyrimidine, 253 mg (0.86 mmole) of (1,1-dimethylethyl)3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176), 152 mg (1.00 mmole) of caesium fluoride, 33 mg (0.036 mmole) of tris(dibenzylideneacetone)dipalladium(0), 45 mg (0.072 mmole) of 2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl in 50 ml of dioxane is heated under reflux for 6 hours. The reaction medium is cooled down then another 125 mg (0.43 mmole) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate, 152 mg (1.0 mmole) of caesium fluoride, 33 mg (0.036 mmole) of tris(dibenzylideneacetone)dipalladium(0), and 45 mg (0.072 mmole) of 2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl are added and the reaction mixture is heated under reflux for 4 hours, followed by evaporating to dryness under reduced pressure (2 kPa). The residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on silicagel eluting with a gradient of heptane-ethyl acetate-methanol from 100-0-0 to 0-100-0 and finally 0-95-5. The product obtained is chromatographed a second time on alumina eluting with a heptane-methylene chloride mixture 50-50 then with an ethyl acetate-diisopropyl ether mixture 50-50. 300 mg (Yield=70%) of expected product is obtained in the form of a yellow oil. is heated under reflux for 6 hours The reaction medium is cooled down the reaction mixture is heated under reflux for 4 hours by evaporating to dryness under reduced pressure (2 kPa) The organic phase is separated dried over magnesium sulphate the solvent is evaporated off under reduced pressure (2 kPa) The residue is chromatographed on silicagel eluting with a gradient of heptane-ethyl acetate-methanol from 100-0-0 to 0-100-0 and finally 0-95-5 The product obtained is chromatographed a second time on alumina eluting with a heptane-methylene chloride mixture 50-50

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 450 mg (1.17 mmoles) of 4-chloro-5-isobutyl-6-[4-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)-1-piperidinyl]-pyrimidine, 413 mg (1.4 mmoles) of (1,1-dimethylethyl)3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem.(2001), 44(8), 1158-1176), 275 mg (1.81 mmoles) of caesium fluoride, 55 mg (0.060 mmole) of tris(dibenzylideneacetone)dipalladium(0), 75 mg (0.12 mmole) of 2,2′-bis(diphenyl-phosphino)-1,1′-binaphthyl in 35 ml of dioxane is heated under reflux for 20 hours. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and a saturated solution of sodium bicarbonate. The organic phase is separated, dried over magnesium sulphate and the solvent is evaporated off under reduced pressure (2 kPa). The residue is chromatographed on alumina eluting with a gradient of methylene chloride-diisopropyl ether- ethyl acetate-methanol from 50-50-0-0 to 0-50-50-0 then 0-0-100-0 and finally 0-0-90-10. 630 mg (Yield=83%) of expected product is obtained in the form of an amorphous yellow solid. is heated under reflux for 20 hours The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) The organic phase is separated dried over magnesium sulphate the solvent is evaporated off under reduced pressure (2 kPa) The residue is chromatographed on alumina eluting with a gradient of methylene chloride-diisopropyl ether- ethyl acetate-methanol from 50-50-0-0 to 0-50-50-0