* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With ammonium acetate In ethanol at 75 - 80℃; for 8 h;
To 150 mL of ethanol were added 28.5 g (0.21 mol) of 4-methoxybenzaldehyde, 21.8 g (0.21 mol) of malonic acid and 32.3 g (0.42 mol) of ammonium acetate, and the mixture was reacted while stirring under reflux (75 to 80°C) for 8 hours. After completion of the reaction, the obtained reaction mixture was stirred at room temperature for 20 hours, and filtered at room temperature to give 23.6 g of 3-amino-3-(4-methoxyphenyl)propionic acid (racemic mixtures) (isolation yield based on 4-methoxybenzaldehyde: 82.3percent) as white powder. Incidentally, physical properties of the 3-amino-3-(4-methoxyphenyl)propionic acid (racemic mixtures) were as follows. 1H-NMR (δ (ppm), D2O) : 2.50 (dd, 1H, J=17.1, 6.8Hz), 2.65 (dd, 1H, J=17.1, 7.8Hz), 3.24 (s, 3H), 6.46 (s, 1H), 6.48 (s, 1H), 6.86 (s, 1H), 6.88 (s, 1H) 13C-NMR (δ (ppm), D2O) : 37.1, 50.7, 55.1, 114.3, 126.9, 128.2, 159.1, 172.7 MS (EI) m/z: 195 (M+) MS (CI, i-C4H10) m/z: 196 (MH+)
70%
With ammonium acetate In butan-1-olReflux
General procedure: A mixture of appropriate aldehyde 2.40 g (1-15), 2.44 g ofmalonic acid and 3.54 g of ammonium acetate (1:1.1:2.3), in 200mLof the 1-butanol was refluxed for 1.5-2 h until the evolution of CO2ceased. The precipitate formed was filtered and washed withboiling 1-butanol (2 x 50 mL), boiling ethanol (2 x 50 mL) and100mL of water. Precipitates were dried at 80-100 °C for 8-10 h.Purity of product was checked by TLC, and yield obtained about65-80percent in each reaction. 4.1.1.1. 3-Amino-3-(4-methoxyphenyl)propanoic acid (A-1).Yield: 70percent, mp 236-8 °C, FT IR ( cm1): 3250-2900 (NH3), 3050 (CHsp2), 1613asym (CO), 1255 (C-O), 1156 (C-N). 1H NMR (500 MHz,DMSO‑d6): d 7.11 (d, 2H, C6H4), 6.77 (d, 2H, C6H4), 4.12 (q, 1H, CHN),3.61 (s, 3H, OCH3), 2.32-2.41 (d, 2H, CHCH2). 13C NMR (126 MHz,DMSO‑d6): d 179.3, 161.8, 137.5, 129.7, 118.4, 59.8, 53.3, 49.1.
Reference：
[1] Patent: EP1621529, 2006, A1, . Location in patent: Page/Page column 40
[2] Chemical Communications, 2011, vol. 47, # 20, p. 5894 - 5896
[3] Journal of Medicinal Chemistry, 2001, vol. 44, # 12, p. 1938 - 1950
[4] Advanced Synthesis and Catalysis, 2010, vol. 352, # 2-3, p. 395 - 406
[5] European Journal of Medicinal Chemistry, 2018, vol. 156, p. 252 - 268
[6] Preparative Biochemistry and Biotechnology, 2013, vol. 43, # 2, p. 207 - 216
[7] Journal of the Chemical Society. Perkin Transactions 1, 2001, # 14, p. 1673 - 1695
[8] Journal of Organic Chemistry, 1985, vol. 50, # 13, p. 2259 - 2263
[9] Advanced Synthesis and Catalysis, 2017, vol. 359, # 9, p. 1570 - 1576
[10] Heterocycles, 1989, vol. 28, # 2, p. 1015 - 1035
[11] Journal fuer Praktische Chemie (Leipzig), 1965, vol. 30, p. 18 - 38
[12] Bulletin de la Societe Chimique de France, 1987, # 6, p. 1079 - 1083
[13] Journal of Medicinal Chemistry, 1996, vol. 39, # 17, p. 3238 - 3240
[14] Synthesis, 2002, # 14, p. 2023 - 2036
[15] Angewandte Chemie - International Edition, 2005, vol. 44, # 45, p. 7466 - 7469
[16] Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 6, p. 1356 - 1365
2
[ 123-11-5 ]
[ 5678-45-5 ]
Yield
Reaction Conditions
Operation in experiment
53%
With ammonium acetate; malonic acid In water ethanol
EXAMPLE 18 Preparation of N-(4-Cyanophenyl)-N--[3-(3-(4--methoxyphenyl)propionic acid)]urea To a solution of p-anisaldehyde (40.8 g, 300 mmol) in 100 mL of 95:5 ethanol-water was added ammonium acetate (46.2 g, 600 mmol). The reaction mixture was warmed to 45 °C, and then treated with malonic acid (31.2 g, 300 mmol) in one portion. The resulting suspension was heated at reflux for 18 h, allowed to cool to room temperature, and filtered. The precipitate was recrystallized from 3:1 ethanol-water to give 30.9 g (53percent) of a white solid 3-amino-3-(4--methoxyphenyl)propionic acid: mp 234-235 °C; 1H NMR (300 MHz; HOAc-d4) δ 7.45-6.95 (AB, 4 H, JAB=8.6 Hz), 4.76 (dd, 1 H, J=9.1, 5.2 Hz), 3.79 (s, 3 H), 3.24 (dd, 1 H, J=17.3, 9.1 Hz), and 2.97 (dd, 1 H, J=17.3, 5.2 Hz); 13C NMR(75.5 MHz; HOAc-d4) δ 176.2, 161.2, 129.7, 128.4, 115.1, 55.1, 52.8, and 38.9; IR (KBr): 3424, 2937, 2616, 1613, 1535, 1518, 1407, 1251, 1184, 1027, and 838 cmmin1. Analysis Calculated for C10H13NO3: C, 61.53, H, 6.71; N, 7.18. Found: C, 61.86; H, 6.56; N, 7.10.
Reference：
[1] Patent: EP355819, 1990, A1,
3
[ 141-82-2 ]
[ 123-11-5 ]
[ 943-89-5 ]
[ 5678-45-5 ]
Reference：
[1] Tetrahedron, 2002, vol. 58, # 37, p. 7449 - 7461
[2] Russian Journal of General Chemistry, 2005, vol. 75, # 7, p. 1113 - 1124
4
[ 830-09-1 ]
[ 5678-45-5 ]
Reference：
[1] Justus Liebigs Annalen der Chemie, 1912, vol. 389, p. 36,111
[2] Synthetic Communications, 1979, vol. 9, p. 705 - 712
With ammonium acetate In ethanol at 75 - 80℃; for 8h;
24
To 150 mL of ethanol were added 28.5 g (0.21 mol) of 4-methoxybenzaldehyde, 21.8 g (0.21 mol) of malonic acid and 32.3 g (0.42 mol) of ammonium acetate, and the mixture was reacted while stirring under reflux (75 to 80°C) for 8 hours. After completion of the reaction, the obtained reaction mixture was stirred at room temperature for 20 hours, and filtered at room temperature to give 23.6 g of 3-amino-3-(4-methoxyphenyl)propionic acid (racemic mixtures) (isolation yield based on 4-methoxybenzaldehyde: 82.3%) as white powder. Incidentally, physical properties of the 3-amino-3-(4-methoxyphenyl)propionic acid (racemic mixtures) were as follows. 1H-NMR (δ (ppm), D2O) : 2.50 (dd, 1H, J=17.1, 6.8Hz), 2.65 (dd, 1H, J=17.1, 7.8Hz), 3.24 (s, 3H), 6.46 (s, 1H), 6.48 (s, 1H), 6.86 (s, 1H), 6.88 (s, 1H) 13C-NMR (δ (ppm), D2O) : 37.1, 50.7, 55.1, 114.3, 126.9, 128.2, 159.1, 172.7 MS (EI) m/z: 195 (M+) MS (CI, i-C4H10) m/z: 196 (MH+)
81%
With ammonium formate In ethanol for 6h; Reflux;
78%
With ammonium acetate In ethanol for 6h; Heating;
70%
With ammonium acetate In ethanol for 20h; Reflux;
70%
With ammonium acetate In butan-1-ol Reflux;
4.1.1. General procedure for preparation series A compounds A-1 to A-15
General procedure: A mixture of appropriate aldehyde 2.40 g (1-15), 2.44 g ofmalonic acid and 3.54 g of ammonium acetate (1:1.1:2.3), in 200mLof the 1-butanol was refluxed for 1.5-2 h until the evolution of CO2ceased. The precipitate formed was filtered and washed withboiling 1-butanol (2 x 50 mL), boiling ethanol (2 x 50 mL) and100mL of water. Precipitates were dried at 80-100 °C for 8-10 h.Purity of product was checked by TLC, and yield obtained about65-80% in each reaction. 4.1.1.1. 3-Amino-3-(4-methoxyphenyl)propanoic acid (A-1).Yield: 70%, mp 236-8 °C, FT IR ( cm1): 3250-2900 (NH3), 3050 (CHsp2), 1613asym (CO), 1255 (C-O), 1156 (C-N). 1H NMR (500 MHz,DMSO-d6): d 7.11 (d, 2H, C6H4), 6.77 (d, 2H, C6H4), 4.12 (q, 1H, CHN),3.61 (s, 3H, OCH3), 2.32-2.41 (d, 2H, CHCH2). 13C NMR (126 MHz,DMSO-d6): d 179.3, 161.8, 137.5, 129.7, 118.4, 59.8, 53.3, 49.1.
61%
With ammonium acetate In ethanol for 6h; Reflux;
57%
With ammonium acetate In methanol for 6h; Heating;
51%
With ammonium acetate In ethanol; water for 13h; Heating;
51%
With ammonium formate In ethanol for 4h; Reflux;
43.24%
With ammonium formate In ethanol for 8h; Reflux;
20 Example 20: Methyl 3-(4-methoxyphenyl)-3-(4-sulfonamidobenzamido)propanoate (D20)
General procedure: 4-Methoxybenzaldehyde (3.00g, 22.06mmol), malonic acid (2.35g, 22.06mmol, 1eq), ammonium formate (2.81g, 44.12mmol, 2eq), and 40mL of ethanol were added to a 100mL eggplant-shaped flask. Under stirring, the reaction was refluxed for 8h. After suction filtration, washing with ethanol, washing with n-hexane, and drying, a white solid was obtained. The yield was 1.86 g and the yield was 43.24%.
38%
With ammonium acetate In ethanol at 87℃; for 16h;
33%
With ammonium acetate
With ammonium acetate In ethanol
With ammonium acetate In ethanol for 6h; Heating;
With ammonium acetate In ethanol Heating;
With ammonium acetate In ethanol for 6h; Heating;
With ammonium acetate In ethanol for 8h; Heating;
With ammonium acetate In ethanol at 78℃;
General procedure for preparation of β phenylalanine (9a-9l)
General procedure: Benzaldehyde (1 equiv), propanedioic acid (2 equiv) and ammonium acetate (2 equiv) were added to the solution of anhydrous ethanol (30 mL) and heated to 78 °C for 17 h. A lot of precipitated solid was filtered and dried in vacuo at 40 °C for 24 h to give a light white solid.
With ammonium acetate In ethanol at 78℃; for 24h;
3 Example 3: Preparation of target product LL-(13-17)
P-methoxybenzaldehyde(0.90 g, 6.6 mmo 1), malonic acid (0.69 g, 6.6 mmo 1) and ammonium acetate (1.02 g, 13.2 mmol) were dissolved in 30 mL of absolute ethanol and refluxed for 24 h. Filtration, methanol washing 3 times, drying in a vacuum drying oven to obtain a crude yellow solid, which is compound 10c, yield 69%,
With ammonium acetate In ethanol for 16h; Inert atmosphere; Reflux;
3-(Benzoyloxy)-N-(2-(tert-butoxy)-2-oxoethyl)-1-(4-chlorophenyl)-N,N-dimethylpropan-1-aminiumbromide (1j)
General procedure: (Step 1) A mixture of 4-chlorobenzaldehyde (850 mg, 6.05 mmol), NH4OAc (624 mg, 8.10 mmol), and malonic acid (628 mg, 6.03 mmol) in EtOH (12 mL) was refluxed for 16 h under an Ar atmosphere. The resulting mixture was cooled to room temperature and filtered. The filtracts were washed with EtOH and dried under reduced pressure to obtain 3-amino-3-(4-chlorophenyl)propanoic acid (22) (629 mg, 52% yield) as awhite solid.
With ammonium acetate In ethanol Reflux;
With ammonium formate In ethanol Schlenk technique; Inert atmosphere; Reflux;
With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 5.5h; Inert atmosphere; Reflux;
3-(Benzoyloxy)-N-(2-(tert-butoxy)-2-oxoethyl)-1-(4-chlorophenyl)-N,N-dimethylpropan-1-aminiumbromide (1j)
General procedure: (Step 2) 22 (613 mg, 3.07 mmol) was added slowly to a suspension of LiAlH4 (0.18 g, 4.7 mmol)in THF (10 mL) at 0 °C under an Ar atmosphere. The mixture was stirred for 30 min at 0 °C and refluxed for5 h. The resulting mixture was cooled to 0 °C, diluted with Et2O, and quenched with H2O (0.18 mL). The mixture was treated with 15 wt.% NaOH in H2O (0.18 mL) followed by H2O (0.54 mL) and stirred for over30 min at room temperature. The mixture was filtered through a pad of Celite and the filtrate was evaporated.The residue was recrystallized from toluene to obtain 3-amino-3-(4-chlorophenyl)propan-1-ol (23) (291 mg,51% yield) as a white solid
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