H-β-丙氨酸-OEt盐酸盐

反应条件: temp:45.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Solid HATU (127 mg, 0.34 mmol) was added to a THF solution (3 mL) of 5-(5-chloro-2-(((4′-chloro-[1,1′-biphenyl]-4-yl)(methyl)amino)methyl)phenyl)picolinic acid (155 mg, 0.34 mmol), i-Pr2NEt (0.29 mL, 1.67 mmol), and β-alanine ethyl ester hydrochloride (54 mg, 0.35) and the resulting mixture was warmed to 45° C. After 16 h the resulting mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound. washed with water and brine dried (Na2SO4) concentrated purified via column chromatography

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

实验步骤: The compound of example 377 was prepared analogous to compound of example 359 by reaction of the compound of example 358 and ethyl 3-aminopropanoate hydrochloride.

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

实验步骤: To a solution of 1.5 g of ethyl 3-aminopropionate monohydrochloride and 1.7 g of 2-{(tert-butoxycarbonyl)amino}acetic acid in 50 ml of chloroform, 1.6 g of 1-hydroxybenzotriazole monohydrate, 2.3 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride and 1.4 ml of triethylamine were added at room temperature by the order stated, and stirred for 2 hours at the same temperature. The reaction liquid was diluted with chloroform, and washed successively with saturated aqueous sodium bicarbonate solution, 10% aqueous citric acid solution and saturated saline solution, by the order stated, and dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by means of silica gel column chromatography (eluting solvent: hexane/ethyl acetate=1/4) to provide 2.0 g of the title compound. The reaction liquid washed successively with saturated aqueous sodium bicarbonate solution, 10% aqueous citric acid solution and saturated saline solution, by the order dried on anhydrous magnesium sulfate The solvent was distilled off under reduced pressure the resultant residue was purified by means of silica gel column chromatography (eluting solvent: hexane/ethyl acetate=1/4)

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

实验步骤: A solution of 3-amino benzoic acid (5.0 g, 36.5 mmol) in THF (250 ml)/DCM (250 ml) was cooled to 0° C. and treated with triphosgene (3.79 g, 12.76 mmol) followed by TEA (12.70 ml, 91 mmol). After 5 min, a suspension of beta-alanine ethyl ester hydrochloride (11.20 g, 72.9 mmol) and TEA (12.70 ml, 91.00 mmol) in THF (10 ml)/DCM (10 ml) were added and the resulting mixture was allowed to warm to RT and stirred overnight. The reaction mixture was diluted with DCM (100 ml) and the pH was adjusted to 8 by addition of sat. aq. NaHCO3. The mixture was extracted with water (2×250 ml). The combined aqueous extracts were acidified to pH 1 by addition of 2N HCl, extracted with DCM and the combined organic portions were washed with brine, dried over MgSO4 and concentrated in vacuo to afford the title product as an off-white solid; LC-MS Rt 0.84 mins; 281.2 [M+H]+, Method 2minLC_v003. were added The mixture was extracted with water (2×250 ml) The combined aqueous extracts were acidified to pH 1 by addition of 2N HCl extracted with DCM the combined organic portions were washed with brine dried over MgSO4 concentrated in vacuo

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

实验步骤: A solution of N-(tert-butoxycarbonyl)-L-methionine (6.2 g) in DMF (25 ml) and pyridine (25 ml) was treated with DSC (9.6 g) and a catalytic amount of DMAP. After 4 hours, a solution of β-alanine ethyl ester HCl (3.8 g) and K2CO3 (3.5 g) in saturated aqueous NaHCO3 (25 ml) was added. The reaction mixture was stirred overnight at room temperature. The excess solvent was removed under reduced pressure and purified by HPLC (RP--CH3CN/H2O). N-[2-[[(1,1-dimethylethoxy)carbonyl]-amino]-4-(methylthio)-1-oxobutyl]-β-alanine, ethyl ester (7.0 g) as a colorless oil was obtained. The oil was confirmed as the desired product by MS and used without further purification. The excess solvent was removed under reduced pressure purified by HPLC (RP--CH3CN/H2O)

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

实验步骤: N,N'-Disuccinimidyl carbonate (14 g, 5.5 mmol) was added to 3-nitrobenzoyl glycine (10 g, 4.5 mmol) of Example BB in dry dimethylformamide (30 mL) followed by N,N-dimethylaminopyridine (200 mg). After a period of 1 hour beta-alanine ethyl ester hydrochloride (7 g, 4.6 mmol) in 20% aqueous potassium carbonate (50 mL) was added in one portion. After complete reaction the product was collected by filtration (14 g, 97% yield). 1H-NMR (d6 -DMSO) δ, 1.18 (t, 3H, J=7.2 Hz), 2.46 (t, 2H, J=7.0), 3.34 (q, 2H, J1 =6.7 Hz, J2 =12.6 Hz), 3.87 (d, 2H, J=5.9 Hz), 4.05 (q, 2H, J1 =7.4 Hz, J2 =14.2 Hz), 7.8 (t, 1H, J=8.0 Hz), 8.1 (t, 1H, J=5.6 Hz), 8.35 (m, 2H), 8.71 (s, 1H), 9.22 (bs, 1H). After complete reaction the product was collected by filtration (14 g, 97% yield)

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

实验步骤: A solution of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (1.0 g), β-alanine ethyl ester hydrochloride (1.10 g) and triethylamine (0.73 g) in dichloromethane (20 ml) was stirred at ambient temperature for 2.5 hours. The reaction mixture was extracted with dilute hydrochloric acid (20 ml) then water (10 ml), and the extracts back washed with dichloromethane (10 ml). The combined organic extracts were dried (magnesium sulphate) and evaporated under reduced pressure to yield a crude product which was recrystallised from ethanol: water to yield the title compound, 0.83 g, m.p. 142°-3° C. The reaction mixture was extracted with dilute hydrochloric acid (20 ml) water (10 ml), and the extracts back washed with dichloromethane (10 ml) The combined organic extracts were dried (magnesium sulphate) evaporated under reduced pressure to yield a crude product which was recrystallised from ethanol

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

实验步骤: A solution of 5 g (28.6 mmol) of lH-indazol-6-yl isothiocyanate, 5.3 g (34.3 mmol) of beta-alanine ethyl ester hydrochloride and 4.8 ml (34.3 mmol) of triethylamine in 50 ml of chloroform is left at room temperature under agitation for one hour. The chloroform phase is washed with water (2 × 10 ml) and with a 1 N hydrochloric acid solution (2 × 10 ml). It is dried and concentrated to dryness. The residue (8 g) is triturated in ethyl ether (3 × 20 ml). There is obtained 3.1 g of (lH-indazol-6-yl)thiocarbamoyl-beta-alanine ethyl ester (yield 28%, melting point 145° C.). The chloroform phase is washed with water (2 × 10 ml) and with a 1 N hydrochloric acid solution (2 × 10 ml) It is dried concentrated to dryness The residue (8 g) is triturated in ethyl ether (3 × 20 ml)

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

实验步骤: About 7.23 g of ethyl 3-aminopropionate hydrochloride, 15.71 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 23.00 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was stirred at room temperature for 39 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding ethyl 3-[bis(trimethylsilyl)amino]propionate (3-BTMSAEP) as a colorless oil (11.03 g, 90% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 3.91 (quartet, 2 H, OCH2 protons), 3.21 (multiplet, 2 H, NCH2CH2 protons), 2.36 (multiplet, 2 H, NCH2CH2 protons), 0.91 (triplet, 3 H, CH3 protons), 0.07 (singlet, 18 H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows: cooled with an ice bath To this mixture was added, in a dropwise fashion to give a biphasic mixture The top layer was transferred to another flask the bottom layer was extracted with 40 ml of toluene The combined toluene solution was evaporated under vacuum The residue was extracted with 100 ml of hexane the hexane layer was evaporated under vacuum

反应条件: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Ethyl 3-aminopropionate hydrochloride (10 g) was dissolved in a mixture of tetrahydrofuran (100 ml) and water, which was cooled at 0 to 5° C. in an ice bath and adjusted to pH 8.2 with 30% aqueous sodium hydroxide solution. To a resulting solution was added with care benzyloxycarbonyl chloride (10.3 ml), with maintaining the pH from pH 8.0 to 9.0 with 30% aqueous sodium hydroxide solution at 0 to 5° C. The reaction mixture was extracted with ethyl acetate (300 ml) and organic layer was separated, which was washed two times with saturated sodium chloride in water and dried over magnesium sulfate. Solvent was removed under reduced pressure to give ethyl 3-(benzyloxycarbonylamino)-propionate (15.3 g). The reaction mixture was extracted with ethyl acetate (300 ml) and organic layer was separated which was washed two times with saturated sodium chloride in water dried over magnesium sulfate Solvent was removed under reduced pressure

反应条件: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Ethyl 3-aminopropionate hydrochloride (10 g) was dissolved in a mixture of tetrahydrofuran (100 ml) and water, which was cooled at 0 to 5° C. in an ice bath and adjusted to pH 8.2 with 30% aqueous sodium hydroxide solution. To a resulting solution was added with care benzyloxycarbonyl chloride (10.3 ml), with maintaining the pH from pH 8.0 to 9.0 with 30% aqueous sodium hydroxide solution at 0 to 5° C. The reaction mixture was extracted with ethyl acetate (300 ml) and organic layer was separated, which was washed two times with saturated sodium chloride in water and dried over magnesium sulfate. Solvent was removed under reduced pressure to give ethyl 3-(benzyloxycarbonylamino)-propionate (15.3 g). The reaction mixture was extracted with ethyl acetate (300 ml) and organic layer was separated which was washed two times with saturated sodium chloride in water dried over magnesium sulfate Solvent was removed under reduced pressure

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

实验步骤: A mixture of β-alanine ethyl ester hydrochloride (1.6 g), 3-ethoxy-4-methoxybenzaldehyde (1.8 g), sodium cyanoborohydride (0.42 g) and powdered 3Å molecular seives (2.5 g) in ethanol (25 ml) was stirred at ambient temperature for 24 hours. A further aliquot of sodium cyanoborohydride (0.42 g) was added and stirring was continued for a further 24 hours. The reaction mixture was filtered and the filtrate was evaporated. The residue was treated with ethyl acetate (100 ml) and the solution was washed with 10% aqueous potassium carbonate (50 ml), then twice with water (25 ml), then with brine (25 ml), then dried over magnesium sulphate and then evaporated. The residual oil was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (95:5, v/v) to give the title compound as a colourless oil (1.1 g). stirring was continued for a further 24 hours The reaction mixture was filtered the filtrate was evaporated The residue was treated with ethyl acetate (100 ml) the solution was washed with 10% aqueous potassium carbonate (50 ml) twice with water (25 ml), then with brine (25 ml), then dried over magnesium sulphate evaporated The residual oil was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (95:5