4-氨基丁酸甲酯盐酸盐

反应条件: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of 4-amino-butyric acid methyl ester hydrochloride (30 g, 1 eq.) in 360 mL of THF were added TEA (67.7 mL, 2.5 eq.), then 3-chlorobenzaldehyde (19 mL, 0.9 eq.) and MgSO4 (35 g, 1.5 eq.). The reaction was stirred at 20° C. for 15 h under nitrogen. 360 mL of MeOH was added then the reaction was cooled to −20° C. NaBH4 (14.75 g, 2 eq.) was added portionwise. The reaction was stirred for 1 h at 0° C. The crude was partially concentrated under reduced pressure at 20° C., filtered and washed with DCM. The filtrate was washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure at 20° C. The residue, in solution in 1600 mL of Et2O, was treated with 87 mL of HCl 2N in Et2O. A solid was formed, filtrated, washed with Et2O, then pentane and dried to afford 4-(3-chloro-benzylamino)-butyric acid methyl ester hydrochloride (32 g, yield=65%). the reaction was cooled to −20° C The reaction was stirred for 1 h at 0° C The crude was partially concentrated under reduced pressure at 20° C. filtered washed with DCM The filtrate was washed with water and brine The organic layer was dried over MgSO4 filtered concentrated under reduced pressure at 20° C The residue, in solution in 1600 mL of Et2O, was treated with 87 mL of HCl 2N in Et2O A solid was formed filtrated washed with Et2O pentane and dried

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The compound of example 374 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and methyl 4-aminobutanoate hydrochloride.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The compound of example 347 was prepared analogous to compound of example 329 by reaction of the compound of example 328 and methyl 4-aminobutanoate hydrochloride.

反应条件: temp:135.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a suspension of 0.2 g (0.79 mmol) of 10,11-dihydro-10-oxo-5H-dibenz[b,f]azepine-5-carboxamide and 0.1 g (0.67 mmol) of methyl-4-aminobutyrate hydrochloride in 5 mL of xylene was added 0.07 g (0.49 mmol) of boron trifluoride diethyl etherate. The resulting mixture was heated at 135° C. for seven hours and then allowed to cool to room temperature. The mixture was then filtered and the residue was extracted with toluene. The combined extracts were evaporated under reduced pressure and the residue chromatographed on silica gel using a 4:1 mixture of petroleum ether-ethyl acetate. Chromatographically homogenous fractions were pooled and the solvents were removed under reduced pressure to give the desired product as a yellow oil which crystallised on standing to give yellow crystals which decomposed on heating without melting. to cool to room temperature The mixture was then filtered the residue was extracted with toluene The combined extracts were evaporated under reduced pressure the residue chromatographed on silica gel using a 4:1 mixture of petroleum ether-ethyl acetate the solvents were removed under reduced pressure

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The procedure described in Example 1 was repeated, except that dihydropyran (1.37 ml) and methyl 4-aminobutanate hydrochloride (1.69 g) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (2.80 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-methoxycarbonylpropyl)-3-(tetrahydropyran-2-yloxy)propanamide (3.12 g).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The procedure described in Example 1 was repeated, except that dihydropyran (1.37 ml) and methyl 4-aminobutanate hydrochloride (1.69 g) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (2.80 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(3-methoxycarbonylpropyl)-3-(tetrahydropyran-2-yloxy)propanamide (3.12 g).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Dissolve 1,4-dioxaspiro{4.5}decan-8-one (100 g, 640.3 mmol), methyl-4-aminobutyrate hydrochloride (98.5 g, 640.3 mmol), triethylamine (90 mL, 640.3 mmol) and dichloromethane (2 L) and stir at room temperature. Add Sodium triacetoxyborohydride (135.7 g, 640.3 mmol) stir 17 h at room temperature. Quench with water (1 L), separate, wash the aqueous layer with dichloromethane (3×500 mL), combine the organic phases and dry over anhydrous sodium sulfate, filter and concentrate. Purify the material on a 1.5 kg silica column, 6 inches in diameter, and eluted with 8:2 hexanes/ethyl acetate to 95:5 ethyl acetate/methanol to give 73 g of the title compound as a waxy brown solid. 1H NMR (CDCl3) δ 3.99-4.10 (m, 1H), 3.93 (s, 4H), 3.32-3.36 (m, 2H), 2.36-2.40 (m, 2H), 1.94-2.03 (m, 2H), 1.65-1.83 (m, 8H). Quench with water (1 L) separate wash the aqueous layer with dichloromethane (3×500 mL) dry over anhydrous sodium sulfate filter concentrate Purify the material on a 1.5 kg silica column, 6 inches in diameter eluted with 8:2 hexanes/ethyl acetate to 95:5 ethyl acetate/methanol

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To an ice cold solution of 1-benzyl-3,3-dimethyl-piperidin-4-one (0.5 g, 2 mmol) (J. Med. Chem. Lett. 2003, 13, 1627) in CH2Cl2 (10 ml) was added methyl 4-aminobutyrate hydrochloride (0.7 g, 5 mmol), acetic acid (0.4 ml, 7 mmol), triethylamine (0.5 ml, 5 mmol) and sodium triacetoxyborohydride (0.5 g, 3 mmol). The mixture was allowed to reach room temperature and was stirred for 16 h after which time it was washed with saturated sodium hydrogen carbonate solution, dried (Na2SO4) and concentrated. The residue (0.6 g, 2 mmol) was then redissolved in MeOH (10 ml), potassium carbonate (0.3 g, 2 mmol) added and the mixture heated to 70° C. for 2 h. The mixture was then filtered, the methanol evaporated and the residue redissolved in DMF (10 ml) and reacted with EDCl (0.4 g, 2 mmol) at 60° C. for 2 h after which time the DMF was evaporated, the residue taken up in CH2Cl2, washed with saturated sodium hydrogen carbonate solution, dried (Na2SO4) and concentrated. Flash column chromatography (EtOAc:n-heptane 2:1) afforded the title compound (0.4 g, 85%) as yellow oil. MS: 287.4 (MH+). to reach room temperature was washed with saturated sodium hydrogen carbonate solution dried (Na2SO4) concentrated The mixture was then filtered the methanol evaporated the residue redissolved in DMF (10 ml) was evaporated washed with saturated sodium hydrogen carbonate solution dried (Na2SO4) concentrated

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To an ice cold solution of 1-benzyl-3,3-dimethyl-piperidin-4-one (0.5 g, 2 mmol) (J. Med. Chem. Lett. 2003, 13, 1627) in CH2Cl2 (10 ml) was added methyl 4-aminobutyrate hydrochloride (0.7 g, 5 mmol), acetic acid (0.4 ml, 7 mmol), triethylamine (0.5 ml, 5 mmol) and sodium triacetoxyborohydride (0.5 g, 3 mmol). The mixture was allowed to reach room temperature and was stirred for 16 h after which time it was washed with saturated sodium hydrogen carbonate solution, dried (Na2SO4) and concentrated. The residue (0.6 g, 2 mmol) was then redissolved in MeOH (10 ml), potassium carbonate (0.3 g, 2 mmol) added and the mixture heated to 70° C. for 2 h. The mixture was then filtered, the methanol evaporated and the residue redissolved in DMF (10 ml) and reacted with EDCl (0.4 g, 2 mmol) at 60° C. for 2 h after which time the DMF was evaporated, the residue taken up in CH2Cl2, washed with saturated sodium hydrogen carbonate solution, dried (Na2SO4) and concentrated. Flash column chromatography (EtOAc:n-heptane 2:1) afforded the title compound (0.4 g, 85%) as yellow oil. MS: 287.4 (MH+). to reach room temperature was washed with saturated sodium hydrogen carbonate solution dried (Na2SO4) concentrated The mixture was then filtered the methanol evaporated the residue redissolved in DMF (10 ml) was evaporated washed with saturated sodium hydrogen carbonate solution dried (Na2SO4) concentrated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Trifluoromethanesulfonyl chloride (0.23 mL, 2.16 mmol) was added dropwise to a solution of 4-amino-butyric acid methyl ester hydrochloride (0.30 g, 1.96 mmol) and triethylamine (0.68 mL, 4.90 mmol) in dichloromethane and stirred at room temperature for 18 hours. 1N HCl was added and the product was extracted with dichloromethane, dried with magnesium sulfate and evaporated to give the title compound (0.42 g, 85%). 1H-NMR (CDCl3): δ 4.89 (s, 1H), 3.12 (t, 2H, J=7.2 Hz), 2.94 (s, 3H), 2.41 (t, 2H, J=7.2 Hz), 1.84 (m, 2H, J=7.2 Hz). the product was extracted with dichloromethane dried with magnesium sulfate evaporated

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Heat a solution of methyl 4-aminobutanoate hydrochloride (11 g, 71.9 mmol), benzylbromide (25.2 g, 147.3 mmol) and K2CO3 (21.8 g, 158.2 mmol) in MeCN (200 mL) at 40° C. overnight. Concentrate the mixture to dryness, pour the residue into water, extract with EtOAc (3×), wash the combined organics with brine, dry over Na2SO4, concentrate and purify via silica gel chromatography to give the title compound (19.5 g, 91%). 1H NMR (400 MHz, DMSO-d6): δ 7.33-7.18 (m, 10H), 3.57 (s, 3H), 3.52 (s, 4H), 2.43-2.28 (m, 4H), 1.83-1.76 (m, 2H). Concentrate the mixture to dryness pour the residue into water extract with EtOAc (3×) wash the combined organics with brine dry over Na2SO4 concentrate purify via silica gel chromatography

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of triethylamine (3.1 mL, 1.1 equivalent) and methyl 4-aminobutyrate hydrochloride (3.2 g, 1.05 equivalent) in 25 ml of anhydrous N,N-dimethylformamide was stirred at −10° C. under N2 atmosphere for 10 minutes. Sequential addition of Boc-L-alanine (3.8 g, 1.0 equivalent), N-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (4.2 g, 1.1 equivalents), 1-hydroxybezotriazole (1.8 g, 0.6 equivalent), and 15 mL of anhydrous N,N-dimethylformamide was carried out at the same temperature. The final solution was stirred under N2 atmosphere at room temperature overnight and diluted with ethyl acetate. The resulting solution was washed sequentially with 1 M HCl(aq), saturated NaHCO3(aq), and saturated NaCl(aq), followed by a rapid filtration through a pad of silica gel and Na2SO4. The filtrate was concentrated and dried under reduced pressure to give a crude paste (4.8 g). The paste was stirred in a mixture of 50 mL of tetrahydrofuran, 25 mL of methanol, and 20 mL of water with the presence of LiOH (0.45 g, 1.1 equivalents) for 1 hour at room temperature. The solution was acidified with concentrated HCl and extracted with ethyl acetate. The organic extracts were combined and washed with saturated NaCl(aq) and rapidly filtered through a pad of silica gel and Na2SO4. The filtrate was concentrated and dried under reduced pressure to give 4-(2-t-butoxycarbonylamino-propionylamino)butyric acid as a paste (4.0 g, 72% yield); H1-NMR (DMSO-d6), δ=1.1 ppm (d, 3H), 1.3 ppm (s, 9H), 1.6 ppm (p, 2H), 2.2 ppm (t, 2H), 3.0 ppm (m, 2H), 3.8 ppm (m, 1H), 6.8 ppm (d, 1H), 7.8 ppm (t, 1H). The resulting solution was washed sequentially with 1 M HCl(aq), saturated NaHCO3(aq), and saturated NaCl(aq) followed by a rapid filtration through a pad of silica gel and Na2SO4 The filtrate was concentrated dried under reduced pressure to give a crude paste (4.8 g) extracted with ethyl acetate washed with saturated NaCl(aq) rapidly filtered through a pad of silica gel and Na2SO4 The filtrate was concentrated dried under reduced pressure