3-Amino-4-phenylbutyricacidhydrochloride

General procedure: Into a round bottom flask, the β-lactam 14 or 15 (0.4 mmol) and 10 mL of HCl (6.0 mol L-1) were added. The mixture was submitted to magnetic stirring at reflux for 12 h. Afterwards, evaporation under vacuum leads to the synthesis of the γ-amino acids.The 48.6 g β - phenyl acrylic acid methyl ester by adding 450 g without water in methanol, slowly adding 35 g nitromethane, after thermal insulation 20 °C reaction 9 hours, after the reaction 45 °C dry solid obtained after concentrating under reduced pressure 4 - nitro -3 - phenyl butanoic acid methyl ester 63 g. The 63 g4 - nitro -3 - phenyl butyric acid methyl ester by adding 600 ml in normal butanol, adding 3 g10percent Pd/C, access high-purity [...] 3 mpa, room temperature reaction 18 h, after the reaction the filtrate is concentrated, shall be 4 - amino -3 - phenyl methyl butyrate 55.7 g, the solid by adding 150 ml10percent in the sodium hydroxide solution, water bath to maintain the 60 °C reaction 1 h, reducing the temperature after reacting to 5 °C, slow drop of concentrated hydrochloric acid, to pH 4 continue to control the temperature after stirring 3 h, filtering, drying vested 4 - amino -3 - phenyl butanoic acid hydrochloride 53 g, yield 85.5percent.Example 63 (+/-)-4-{[(6-Bromo-3-methyl-2-phenylquinolin-4-yl)carbonyl]amino}-3-phenylbutanoic Acid (Racemate) HATU (250 mg, 658 mumol) and DIPEA (230 mul, 1.3 mmol) were added to a mixture of 6-bromo-3-methyl-2-phenylquinoline-4-carboxylic Acid (150 mg, 438 mumol, preparable according to WO 2016 146602 A1, p. 51, Example 3A) in DMF (1.5 ml), and the mixture was stirred at RT for 30 min. General procedure: Triethyl orthoformate, 9.73 g (65.7 mmol), and then 1.71 g (26.3 mmol) of sodium azide were added to a stirred solution of the hydrochloride of amino acid 1a-1c or 7a-7c, 21.9 mmol, in 12 mL of acetic acid. The mixture was stirred for 7 h at 100C and then evaporated in a vacuum. Water, 10 mL, was added to the residue and then solid NaOH to pH 9. After treatment with ethyl ether, the aqueous layer was separated and acidified with conc. HCl to pH 2. The precipitate that formed was filtered off and washed with 5 mL of water. 4-(1H-Tetrazol-1-yl)-3-phenylbutanoic acid (8a).Yield 1.58 g (31%), mp 114-117C. IR spectrum, nu, cm-1: 3126 m, 2929 m, 2601 w, 1707 vs, 1489 m, 1443m, 1415 m, 1311 m, 1300 m, 1265 s, 1211 s, 1169 s, 1142 m, 1096 m, 980 m, 926 m, 899 m, 775 m, 733 s, 702 vs, 660 s. 1H NMR spectrum (DMSO-d6), delta, ppm:2.62-2.74 m (2H, CH2COOH), 3.61-3.68 m (1H, CH), 4.62-4.80 m (2H, CH2NH2), 7.13-7.30 m (5Harom), 9.07 s (1Htetrazole), 12.24 br.s (1H, OH). 13C NMRspectrum (DMSO-d6), delta, ppm: 37.9 (CH), 42.4(CH2COOH), 52.3 (CH2NH2), 127.7 (CHarom), 128.2(2CHarom), 129.0 (2CHarom), 140.3 (Carom), 144.6(Ctetrazole), 172.8 (C=O). Found, %: C 56.81; H 5.24; N24.08. C11H12N4O2. Calculated, %: C 56.89; H 5.21; N24.12.General procedure: Sulfonyloxyimide (VIIa-c) (1 mol) was dissolved in methanol (150 mL) and triethylamine (1.2 mol) was added. The reaction mixture was refluxed for 5 h and then evaporated under reduced pressure. To the residue, water was added and the aqueous layer was extracted with toluene. The toluene layer was concentrated under reduced pressure to give crude carbamate. The crude carbamate 15.0 g (1 mol) was mixed with concentrated hydrochloric acid and water. The mixture was refluxed for 8 h and the solvents were distilled off under vacuum to obtain hydrochloride salts. To the hydrochloride salt, water was added and the pH was brought to 6.8-7.0 using 35% sodium hydroxide solution. The solid was again washed with cold water and recrystallized from isopropanol and water (1:1) to give pure racemic compound.The 48.6 g beta - phenyl acrylic acid methyl ester by adding 450 g without water in methanol, slowly adding 35 g nitromethane, after thermal insulation 20 C reaction 9 hours, after the reaction 45 C dry solid obtained after concentrating under reduced pressure 4 - nitro -3 - phenyl butanoic acid methyl ester 63 g. The 63 g4 - nitro -3 - phenyl butyric acid methyl ester by adding 600 ml in normal butanol, adding 3 g10% Pd/C, access high-purity [...] 3 mpa, room temperature reaction 18 h, after the reaction the filtrate is concentrated, shall be 4 - amino -3 - phenyl methyl butyrate 55.7 g, the solid by adding 150 ml10% in the sodium hydroxide solution, water bath to maintain the 60 C reaction 1 h, reducing the temperature after reacting to 5 C, slow drop of concentrated hydrochloric acid, to pH 4 continue to control the temperature after stirring 3 h, filtering, drying vested 4 - amino -3 - phenyl butanoic acid hydrochloride 53 g, yield 85.5%.In a dry high pressure reactor, the addition of the raw material and the methanol ratio of 1: 5 to the addition of MichaelMaterial alpha-Phenyl-beta-benzoyl-gamma-nitrobutyrate, while adding 5% Raney nickel catalyst with a feed weight of 5%Nitrogen 1.5Mpa holding pressure for 15 minutes; holding pressure is completed, the rice with a row of hydrogen 3 times, after the completion of the row in the 38 ~ 42 C conditions through4.OMpa hydrogen reaction 7 hours after the completion of hydrogenation, put it aside for 1 hour, 350 mesh filter out the material was about 700kg, concentrated collectionCatalyst, concentrated methanol to a small volume of crystallization, centrifuged crude.The crude and purified water prepared in Step 3 was added to the clean reactor. Stirring the material to 90 ~ 100 C, After the temperature condition was reached, the hydrochloric acid was added dropwise at a concentration of 37%, and the mixture was stirred for 1 hour and the mixture was cooledTo 30 C below the centrifugal discharge of about 480 ~ 500kg. Concentrated on the centrifugal collection of the mother liquor collected, specifically in the 80 ~ 90 C under the conditions of decompression recovery of hydrochloric acid, until the material is viscous, the temperature dropped to 30 C and centrifugal discharge; the centrifugal discharge of the product using anhydrous BAlcohol recrystallized fine.