methyl 3-aminopropanoate;hydrochloride

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-chlorobenzaldehyde (1 eq.) in MeOH were added NaHCO3 (1.3 eq.) and (β-alanine methyl ester hydrochloride (1.2 eq.). The reaction was stirred for 15 h at 20° C. under nitrogen, then cooled to 0° C. Sodium triacetoxyborohydride (1.5 eq.) was added portionwise. The reaction was then warmed to 20° C. and stirred for 8 h. The crude was concentrated under reduced pressure then partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The aqueous layer was extracted twice with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/DCM/MeOH: 50/50/0, then 0/100/0, then 0/99/1) to afford 3-(4-chloro-benzylamino)-propionic acid methyl ester. cooled to 0° C The reaction was then warmed to 20° C. stirred for 8 h The crude was concentrated under reduced pressure then partitioned between EtOAc The aqueous layer was extracted twice with EtOAc dried over MgSO4 filtered concentrated under reduced pressure The crude was purified by chromatography on silica gel ( elution with heptane/DCM/MeOH

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

Procedure: A solution of 2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluorophenyl isothiocyanate (6.0 g, 15.8 mmol) and β-alanine, methyl ester, hydrochloride salt (2.65 g, 19.0 mmol) in acetone is cooled to 0° C., treated dropwise with a solution of triethylamine (1.92 g, 19.0 mmol) in methylene chloride, stirred overnight at room temperature, and poured into water. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with 5% hydrochloric acid and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a brown foam. Flash column chromatography of the foam using silica gel and a (9:1) methylene chloride/diethyl ether solution gives the title product as an off-white foam (5.68 g, 74.4% yield, mp 110° C.) which is identified by 1H NMR spectral analysis. The resultant aqueous mixture is extracted with ethyl acetate washed sequentially with 5% hydrochloric acid and brine dried over anhydrous magnesium sulfate concentrated in vacuo to obtain a brown foam

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

Procedure: According to scheme II, β-alanine methyl ester hydrochloride 4 is reacted with acetyl chloride giving N-acetyl-β-alanine methyl ester 5 which is reacted with disulfide cystamine 6 upon heating neat at 80° C. giving the tetraamide disulfide product N, N - (Dithiodi-2, 1-ethanediyl bis [3-(acetylamino) propanamide 7. Reductive cleavage of the disulfide bond of 7 with sodium borohydride in methanol gives the unstable thiol 8 which is reacted in situ with an excess of oleoyl chloride 1, giving the thioester product S-[2-[[3-(acetylamino)-1-oxopropyl]amino]ethyl]-9(Z)-octadecenethioate 9. ##STR11##

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

Procedure: To an ice-bath-cooled solution of 0.45 g (3.2 mmol) of methyl β-alaninate hydrochloride and 1.14 mL of N,N-diisopropylethylamine (DIEA) in 10 mL of dimethylformamide (DMF) was added dropwise a 2 mL DMF solution of 0.51 g (3.2 mmol) of 2-thiopheneacetyl chloride. After 16 hours of stirring at room temperature, the reaction mixture was added to 50 mL of ethyl acetate (EtOAc) and 50 mL of 1M KHSO4, and the resulting layers were separated. The organic layer was washed with 2×50 mL of 1M KHSO4, 2×50 mL of a saturated KHCO3 solution, and 2×50 mL of H2O. The organic layer was then dried over Na2SO4 (anhydrous), filtered, and then concentrated under reduced pressure. the resulting layers were separated The organic layer was washed with 2×50 mL of 1M KHSO4, 2×50 mL of a saturated KHCO3 solution, and 2×50 mL of H2O The organic layer was then dried over Na2SO4 (anhydrous) filtered concentrated under reduced pressure

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

Procedure: To an ice-bath-cooled solution of 0.45 g (3.2 mmol) of methyl β-alaninate hydrochloride and 1.14 mL of N,N-diisopropylethylamine (DIEA) in 10 mL of dimethylformamide (DMF) was added dropwise a 2 mL DMF solution of 0.51 g (3.2 mmol) of 2-thiopheneacetyl chloride. After 16 hours of stirring at room temperature, the reaction mixture was added to 50 mL of ethyl acetate (EtOAc) and 50 mL of 1M KHSO4, and the resulting layers were separated. The organic layer was washed with 2×50 mL of 1M KHSO4, 2×50 mL of a saturated KHCO3 solution, and 2×50 mL of H2O. The organic layer was then dried over Na2SO4 (anhydrous), filtered, and then concentrated under reduced pressure. the resulting layers were separated The organic layer was washed with 2×50 mL of 1M KHSO4, 2×50 mL of a saturated KHCO3 solution, and 2×50 mL of H2O The organic layer was then dried over Na2SO4 (anhydrous) filtered concentrated under reduced pressure

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

Procedure: To a solution of 1-bromo-4-bromomethyl-benzene (1.80 g, 7.2 mmol) in DMSO (15 ml) is added PBu3 (2.18 g, 10.8 mmol). The resulting mixture is stirred at 60° C. for 23 h. The reaction solution is then cooled down to room temperature, and NaH (432 mg, 10.8 mmol) is added, followed by the addition of 4-(3-methyl-butyryl)-benzoic acid methyl ester (Preparation 2) (1.74 g, 7.92 mmol). The reaction mixture is stirred at room temperature for about 48 h, and then diluted with ethyl acetate. The organic portion is washed with 1N HCl, water, brine, dried over MgSO4, and concentrated. The resulting residue is hydrolyzed in THF using 5N NaOH. The reaction is neutralized with 5N HCl, extracted with diethyl ether. The organic phase is washed with water, dried, filter and concentrated. The resulting residue is taken into dichloromethane (150 ml). To the solution is added triethyl amine (6.41 ml, 46 mmol), followed by the addition of DMAP (5 mg), 3-amino-propionic acid methyl ester hydrochloride (3.21 g, 23 mmol) and EDCI (8.83 g, 46 mmol). The reaction mixture is stirred at room temperature for 2 days. The reaction mixture is loaded on a silica gel column and eluted with a gradient from 0-100% ethyl acetate in hexanes to afford 2.60 g of the titled compound. The reaction solution is then cooled down to room temperature The reaction mixture is stirred at room temperature for about 48 h The organic portion is washed with 1N HCl, water, brine dried over MgSO4 concentrated extracted with diethyl ether The organic phase is washed with water dried filter concentrated The reaction mixture is stirred at room temperature for 2 days eluted with a gradient from 0-100% ethyl acetate in hexanes

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

Procedure: To a solution of 1-bromo-4-bromomethyl-benzene (1.80 g, 7.2 mmol) in DMSO (15 ml) is added PBu3 (2.18 g, 10.8 mmol). The resulting mixture is stirred at 60° C. for 23 h. The reaction solution is then cooled down to room temperature, and NaH (432 mg, 10.8 mmol) is added, followed by the addition of 4-(3-methyl-butyryl)-benzoic acid methyl ester (Preparation 2) (1.74 g, 7.92 mmol). The reaction mixture is stirred at room temperature for about 48 h, and then diluted with ethyl acetate. The organic portion is washed with 1N HCl, water, brine, dried over MgSO4, and concentrated. The resulting residue is hydrolyzed in THF using 5N NaOH. The reaction is neutralized with 5N HCl, extracted with diethyl ether. The organic phase is washed with water, dried, filter and concentrated. The resulting residue is taken into dichloromethane (150 ml). To the solution is added triethyl amine (6.41 ml, 46 mmol), followed by the addition of DMAP (5 mg), 3-amino-propionic acid methyl ester hydrochloride (3.21 g, 23 mmol) and EDCI (8.83 g, 46 mmol). The reaction mixture is stirred at room temperature for 2 days. The reaction mixture is loaded on a silica gel column and eluted with a gradient from 0-100% ethyl acetate in hexanes to afford 2.60 g of the titled compound. The reaction solution is then cooled down to room temperature The reaction mixture is stirred at room temperature for about 48 h The organic portion is washed with 1N HCl, water, brine dried over MgSO4 concentrated extracted with diethyl ether The organic phase is washed with water dried filter concentrated The reaction mixture is stirred at room temperature for 2 days eluted with a gradient from 0-100% ethyl acetate in hexanes

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

Procedure: In analogy to Example 26, step 4, 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-benzoic acid (Example 26, step 3) was reacted with beta-alanin-methyl ester hydrochloride and HBTU at 80° C. 2 h to give the title compound as a colorless viscous oil. MS (m/e, ISP neg. ion)=477.0 [M−H+].

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

Procedure: A solution of 5-chloro-2,4-dinitrobenzoic acid (10.0 g, 40 mmol) in SOCl2 (100 mL) containing DMF (2 drops) was heated under reflux for 5 h, and then concentrated to dryness and azeotroped with benzene. A solution of the resulting crude acid chloride in Et2O was added to a vigorously-stirred suspension of methyl 3-aminopropanoate hydrochloride (6.22 g, 44 mmol) and Et3N (13.9 mL, 100 mmol) in Et2O (100 mL). after stirrign for 30 min, the resulting precipitate was filtered off, washed well with water, and recrystallized from EtOAc/petroleum ether to give 5-chloro-N-[2-(methoxycarbonyl)ethyl]-2,4-dinitrobenzamide (6.24 g, 47%), mp 139-141° C. 1H NMR [(CD3)2SO] δ8.98 (t, J=5.6 Hz, 1H, CONH), 8.83 (s, 1H, H-3), 8.09 (s, 1H, H-6), 3.63 (s, 3H, OCH3), 3.47 (dt, J=6.7, 5.6 Hz, 2H, CONCH2), 2.61 (t, J=6.7 Hz, 2H, CH2CO2CH3) Anal. Calcd for C11H10ClN3O7. C, 39.84;H, 3.04; N, 12.67, Cl, 10 69. Found: C, 40.07;H, 2.79; N, 12 55; Cl, 10.92%. was heated under reflux for 5 h concentrated to dryness azeotroped with benzene the resulting precipitate was filtered off washed well with water recrystallized from EtOAc/petroleum ether

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

Procedure: 33.2 g (0.1 mol) of 3-[2-(p-toluenesulphonyloxy)ethyl]chroman, 14.0 g of N-(2-methoxycarbonylethyl)-amine hydrochloride and 39 g of N-ethyl-N,N-diisopropylamine are dissolved under nitrogen in 750 ml of dimethylformamide and the solution is stirred for 16 hours at room temperature. The reaction mixture is subsequently concentrated to approximately 200 ml under reduced pressure, 500 ml of water are then added and the whole is extracted by shaking three times with 150 ml of dichloromethane each time. The combined organic phases are dried over sodium sulphate and concentrated to dryness by evaporation. By adding ethanolic hydrochloric acid and cooling, N-[2-(chroman-3-yl)ethyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride having a melting point of 190°-192° is obtained. The reaction mixture is subsequently concentrated to approximately 200 ml under reduced pressure, 500 ml of water are then added the whole is extracted by shaking three times with 150 ml of dichloromethane each time The combined organic phases are dried over sodium sulphate concentrated to dryness by evaporation By adding ethanolic hydrochloric acid cooling

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

Procedure: A mixture of p-nitrobenzaldehyde (1.51 g), β-alanine methyl ester hydrochloride (1.40 g), triethylamine (1.6 ml) and methanol (20 ml) is stirred at room temperature for 25 minutes. The mixture is ice-cooled, and sodium borohydride (807 mg) is added thereto. The mixture is stirred at the same temperature for 10 minutes. The mixture is acidified with 10% HCl, and extracted with ethyl acetate. The aqueous layer is neutralized with 10% NaOH, and extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then distilled to remove the solvent. The residue is dissolved in ether, and a HCl-ether solution is added thereto. The precipitates are collected and recrystallized from methanol to give N-(p-nitrobenzyl)-β-alanine methyl ester hydrochloride (1.95 g, 71.1%) as pale yellow plates, m.p. 219.5°-220° C. (decomp.). cooled The mixture is stirred at the same temperature for 10 minutes extracted with ethyl acetate extracted with ethyl acetate The extract is washed with a saturated sodium chloride solution dried distilled to remove the solvent The residue is dissolved in ether a HCl-ether solution is added The precipitates are collected recrystallized from methanol

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

Procedure: A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-thiazol-4-yl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (64 mg, 0.14 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. overnight. The mixture was concentrated to approximately one-third of its original volume, and the resulting mixture was acidified to pH about 3-4 and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. To the residue were then added HOBt (30 mg, 0.22 mmol), CH2Cl2 (3 mL), and EDC (47 mg, 0.25 mmol), and the resulting mixture was stirred for 10 min. β-Alanine methyl ester HCl salt (31 mg, 0.22 mmol) and Hunig's base (0.1 mL, 0.49 mmol) were added, and the mixture was stirred for 16 h. EtOAc (30 mL) was added, and the mixture was washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (5-70% EtOAc/hexanes+1% AcOH) to give 24 mg of the title compound. MS: (+) m/z 541.31 (M+1). The mixture was concentrated to approximately one-third of its original volume extracted with EtOAc The organic layer was dried over MgSO4 concentrated were added the mixture was stirred for 16 h the mixture was washed with 0.1 M HCl The organic layer was dried over MgSO4 concentrated The residue was purified by silica gel chromatography (5-70% EtOAc/hexanes+1% AcOH)