tert-butyl 4-aminobutanoate

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: 85 mmol of N-benzyloxycarbonyl-5-hydroxy-L-tryptophan and 85 mmol of tert.-butyl γ-aminobutyrate are dissolved in 170 ml of acetone and 300 ml of pure chloroform. A solution of 17.7 g (86 mmol) of dicyclohexylcarbodiimide in 80 ml of chloroform is then added and the mixture is stirred at ordinary temperature until the condensation has ended. After evaporation, taking up with ethyl acetate and the customary treatment, 40 g of a crude product are obtained, which are purified by chromatography on a silica column, elution being carried out with a methylene chloride/acetone mixture. This gives 48% of a pure product showing a single spot in TLC on Kieselgel in the system chloroform 20/acetone 6, of Rf=0.45. The NMR spectrum is recorded in solution in CDCl3 : 8.4 ppm (s) (1H) --OH; 7.3 ppm (s) (5H) benzyl; 7.2 to 6.6 ppm (m) (4H) arom; 6.4 ppm (m) (1H) and 5.9 ppm (d) (1H) --NH; 5 ppm (s) (2H) CH2 --Ph; 4.4 ppm (m) (1H) CH(NH)--CO; 3.1 ppm (m) (4H) CH2 --CH(--NH)CO and NH CH2 ; 2.1 to 1.8 ppm (m) 4H: CH2 --CH2 ; 1.4 ppm (s) (9H) tert.-butyl. After evaporation

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

Procedure: 85 mmol of N-benzyloxycarbonyl-5-hydroxy-L-tryptophan and 85 mmol of tert.-butyl γ-aminobutyrate are dissolved in 170 ml of acetone and 300 ml of pure chloroform. A solution of 17.7 g (86 mmol) of dicyclohexylcarbodiimide in 80 ml of chloroform is then added and the mixture is stirred at ordinary temperature until the condensation has ended. After evaporation, taking up with ethyl acetate and the customary treatment, 40 g of a crude product are obtained, which are purified by chromatography on a silica column, elution being carried out with a methylene chloride/acetone mixture. This gives 48% of a pure product showing a single spot in TLC on Kieselgel in the system chloroform 20/acetone 6, of Rf=0.45. The NMR spectrum is recorded in solution in CDCl3 : 8.4 ppm (s) (1H) --OH; 7.3 ppm (s) (5H) benzyl; 7.2 to 6.6 ppm (m) (4H) arom; 6.4 ppm (m) (1H) and 5.9 ppm (d) (1H) --NH; 5 ppm (s) (2H) CH2 --Ph; 4.4 ppm (m) (1H) CH(NH)--CO; 3.1 ppm (m) (4H) CH2 --CH(--NH)CO and NH CH2 ; 2.1 to 1.8 ppm (m) 4H: CH2 --CH2 ; 1.4 ppm (s) (9H) tert.-butyl. After evaporation

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

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (200 mg), potassium carbonate (410 mg) and tetrabutylammonium bromide (2 mg) in N-methylpyrrolidinone (5 mL) was added 4-amino-butanoic acid 1,1-dimethylethyl ester (1 g). The mixture was heated at 130° C. for 72 hours after which it was cooled and poured into water. The mixture was extracted with dichloromethane (3×20 mL) and the combined extracts dried, filtered and evaporated. Purification (SiO2, ethyl acetate:isohexane 3:7 as eluant) gave the sub-title compound (200 mg). was cooled The mixture was extracted with dichloromethane (3×20 mL) the combined extracts dried filtered evaporated Purification (SiO2, ethyl acetate:isohexane 3:7 as eluant)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1 (a)) (200 mg), potassium carbonate (410 mg) and tetrabutylammonium bromide (2 mg) in N-methylpyrrolidinone (5 mL) was added 4-amino-butanoic acid 1,1-dimethylethyl ester (1 g). The mixture was heated at 130° C. for 72 hours after which it was cooled and poured into water. The mixture was extracted with dichloromethane (3×20 mL) and the combined extracts dried, filtered and evaporated. Purification (SiO2, ethyl acetate:isohexane 3:7 as eluant) gave the sub-title compound (200 mg). was cooled The mixture was extracted with dichloromethane (3×20 mL) the combined extracts dried filtered evaporated Purification (SiO2, ethyl acetate:isohexane 3:7 as eluant)

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

Procedure: To a solution of 0.36 ml (4.10 mmol) of oxalyl chloride in 10 ml CH2Cl2 at −50 to −60° C. was added a solution of 0.60 ml (8.50 mmol) dimethylsulfoxide in 2.4 ml of CH2Cl2 within 10 min. The solution was stirred for 5 min and a solution of 0.90 (3.50 mmol) (R)-2-(3-chloro-4-trifluoromethyl-phenylamino)-propan-1-ol (22% ee) in 10 ml of CH2Cl2 was added within 10 min. The mixture was stirred for 15 min and 2.47 ml (17.70 mmol) of triethylamine were added within 20 min. The suspension was stirred for 75 min and slowly warmed to 0° C. (complete oxidation followed by TLC, SiO2, EtOAc:n-heptane 1:1). 0.73 g (3.70 mmol) of 4-aminobutyric acid tert-butyl ester; hydrochlorid was added and 0.41 ml (7.10 mmol) of acetic acid to adjust the pH to 5 followed by 0.85 g (3.90 mmol) of sodium triacetoxyborohydride. After 5 min at 0° C. and 1.5 h at RT, the reaction was poured on a solution of sat. aq. NaHCO3 solution and extracted with EtOAc (3 times). The organic phases were washed with a solution of 10% aq. NaCl solution. The combined organic phases were dried over Na2SO4 and the solvent was removed under vacuum to give 1.31 g (94%) of the title compound as a 61:39 mixture of the (R) and (S) diastereomers as orange oil. MS: 395.17 (MH+, Cl). The mixture was stirred for 15 min The suspension was stirred for 75 min After 5 min at 0° C. extracted with EtOAc (3 times) The organic phases were washed with a solution of 10% aq. NaCl solution The combined organic phases were dried over Na2SO4 the solvent was removed under vacuum

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

Procedure: To a cooled solution (0° C.) of 2.94 g (15.00 mmol) of 4-aminobutyric acid ter-butylester; hydrochloride in 75 ml of MeOH were added 2.51 ml (18.00 mmol) of dimethoxyacetaldehyde (45% solution in TBME), 3.86 ml (15.00 mmol) of triethylamine, 16.75 g (135.00 mmol) of magnesium sulfate, 3.43 ml (60.00 mmol) of AcOH and 1.29 g (19.50 mmol) of sodium cyanoborohydride (1.99 g, 31.6 mmol). The reaction was stirred 2 h at RT, another 0.39 ml (1.50 mmol) of dimethoxyacetaldehyde (45% solution in TBME) was added and after 1.5 h, the reaction mixture was partitioned between aqueous saturated NaHCO3 and EtOAc/Et2O (1:1) (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to yield after evaporation of the solvent 1.87 g (50%) of the titled compound as light yellow oil. MS: 248.18 (MH+). the reaction mixture was partitioned between aqueous saturated NaHCO3 and EtOAc/Et2O (1:1) (3×) The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl dried over Na2SO4 to yield after evaporation of the solvent 1.87 g (50%) of the titled compound as light yellow oil

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 6-fluoro-5-methylnicotinonitrile (10.0 g, 73.4 mmol), tert-butyl 4-aminobutanoate (Bachem F-3755, 17.4 g, 88.1 mmol) and TEA (25.6 mL, 183.6 mmol) was prepared in DMSO (100 mL) under nitrogen, and the heated at 150° C. for 4 hours. The reaction mixture was cooled to 100° C., and then water was added (100 mL) drop wise. The resulting mixture was stirred at RT for 2 hours, and then the precipitate was filtered off, washed with water and dried under reduced pressure to afford the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 8.27 (1H, s), 7.53 (1H, s), 6.95 (1H, m), 3.40 (2H, t), 2.23 (2H, t), 2.03 (3H, s), 1.75 (2H, m), 1.37 (9H, s). The reaction mixture was cooled to 100° C. the precipitate was filtered off washed with water dried under reduced pressure

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

Procedure: To a solution of 5-methyl 1-(4-nitrophenyl) 6-(4-fluorophenyl)-2-methoxy-4-methyl-1,5(6H)-pyrimidinedicarboxylate (88.7 mg, 0.200 mmol) and K2CO3 (41.5 mg, 0.300 mmol) in CH3OH/CH2Cl2 (0.1/2.0 mL) was added tert-butyl 4-aminobutanoate (31.8 mg, 0.200 mmol). After stirring at rt for 1 h, the mixture was washed with saturated Na2CO3 and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (5%-10% 2 M NH3/MeOH in 50% EtOAc/Hexanes) to afford the product (92.2 g, 99%). mp 135-138° C.; 1H NMR (CD3OD) δ 7.29-7.23 (m, 2H), 6.97-6.88 (m, 2H), 6.65 (s, 1H), 3.98 (s, 3H), 3.66 (s, 3H), 3.38-3.30 (m, 2H), 2.43 (s, 3H), 2.28 (t, 2H, J=7.2 Hz), 1.89-1.78 (m, 2H), 1.43 (s, 9H); ESMS m/e: 464.1 (M+H)+. the mixture was washed with saturated Na2CO3 and brine The organic layer was dried over MgSO4 concentrated in vacuo The crude material was purified by flash chromatography (5%-10% 2 M NH3/MeOH in 50% EtOAc/Hexanes)

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

Procedure: 85 mmol of N-benzyloxycarbonyl-5-hydroxy-L-tryptophan and 85 mmol of tert.-butyl γ-aminobutyrate are dissolved in 170 ml of acetone and 300 ml of pure chloroform. A solution of 17.7 g (86 mmol) of dicyclohexylcarbodiimide in 80 ml of chloroform is then added and the mixture is stirred at ordinary temperature until the condensation has ended. After evaporation, taking up with ethyl acetate and the customary treatment, 40 g of a crude product are obtained, which are purified by chromatography on a silica column, elution being carried out with a methylene chloride/acetone mixture. This gives 48% of a pure product showing a single spot in TLC on Kieselgel in the system chloroform 20/acetone 6, of Rf=0.45. The NMR spectrum is recorded in solution in CDCl3 : 8.4 ppm (s) (1H) --OH; 7.3 ppm (s) (5H) benzyl; 7.2 to 6.6 ppm (m) (4H) arom; 6.4 ppm (m) (1H) and 5.9 ppm (d) (1H) --NH; 5 ppm (s) (2H) CH2 --Ph; 4.4 ppm (m) (1H) CH(NH)--CO; 3.1 ppm (m) (4H) CH2 --CH(--NH)CO and NH CH2 ; 2.1 to 1.8 ppm (m) 4H: CH2 --CH2 ; 1.4 ppm (s) (9H) tert.-butyl. After evaporation