Isoserine

White powder

(S)-isoserine 15a (21 g, 0.20 mol) was dissolved in tetrahydrofuran (100 mL)And a mixed solvent of 10percent aqueous sodium hydroxide solution (100 mL), Di-tert-butyl dicarbonate (50 mL, 0.22 mol) was added dropwise.The reaction was carried out at room temperature for 9 hours.The aqueous phase was adjusted to pH 2 with 4 mol/L hydrochloric acid, and extracted with dichloromethane/methanol (v/v = 5/1, 50 mL × 3) and dried over anhydrous sodium sulfate.Filter by suction, concentrate under reduced pressure, The title compound 15b was obtained as a colorless oil (35 g, yield: 85percent).To a stirring solution of S-isoserine (4.0 g, 0.038 mol) in dioxane: H2O (100 mL, 1:1 v/v) at 0° C was added N-methylmorpholine (4.77 mL, 0.043 mol), followed by BoC2O (11.28 mL, 0.049 mol) and the reaction was stirred overnight with gradual warming to room temperature. Glycine (1.0 g, 0.013 mol) was then added and the reaction was stirred for 20 min. The reaction was cooled to O0C and sat aq. NaHCO3 (75 mL) was added. The aqueous layer was washed with ethyl acetate (2 x 60 mL) and then acidified to pH 1 with NaHSO4. This solution was then extracted with ethyl acetate (3 x 70 mL) and these combined organic layers were dried over Na2SO4, filtered and concentrated to dryness to give the desired N-Boc-3-ammo-2(S)-hydroxy- propanoic acid (6.30 g, 0.031 mmol, 81.5 percent yield): 1H NMR (400 MHz, CDC13) delta 7.45 (bs, 1 H), 5.28 (bs, 1 H), 4.26 (m, 1 H), 3.40-3.62 (m, 2 H), 2.09 (s, 1 H), 1.42 (s, 9 H); 13C NMR (IOO MHz, CDC13) delta 174.72, 158.17, 82, 71.85, 44.28, 28.45.To a stirring solution of S-isoserine (4.0 g, 0.038 mol) in dioxane: H20 (100 mL, 1 :1 v/v) at 0° C was added N-methylmorpholine (4.77 mL, 0.043 mol), followed by Boc20 (11.28 mL, 0.049 mol) and the reaction was stirred overnight with gradual warming to room temperature. Glycine (1.0 g, 0.013 mol) was then added and the reaction was stirred for 20 min. The reaction was cooled to 0°C and sat aq. NaHC03 (75 mL) was added. The aqueous layer was washed with ethyl acetate (2 x 60 mL) and then acidified to pH 1 with NaHS04. This solution was then extracted with ethyl acetate (3 x 70 mL) and these combined organic layers were dried over Na2S04, filtered and concentrated to dryness to give the desired N-Boc-3-amino-2(S)-hydroxy- propanoic acid (6.30 g, 0.031 mmol, 81.5 percent yield): 1H NMR (400 MHz, CDC13) delta 7.45 (bs, 1 H), 5.28 (bs, 1 H), 4.26 (m, 1 H), 3.40-3.62 (m, 2 H), 2.09 (s, 1 H), 1.42 (s, 9 H); 13C NMR (100 MHz, CDC13) delta 174.72, 158.17, 82, 71.85, 44.28, 28.45.To a stirring solution of S-isoserine (4.0 g, 0.038 mol) in dioxane: 3/40 (100 mL, 1:1 v/v) at 0° C was added N-methylmorpholine (4.77 mL, 0.043 mol), followed by B0C2O (11.28 mL, 0.049 mol) and the reaction was stirred overnight with gradual warming to room temperature. Glycine (1.0 g, 0.013 mol) was then added and the reaction was stirred for 20 min. The reaction was cooled to 0°C and sat aq. NaHC<3/4 (75 mL) was added. The aqueous layer was washed with ethyl acetate (2 x 60 mL) and then acidified to pH 1 with NaHS04. This solution was then extracted with ethyl acetate (3 x 70 mL) and these combined organic layers were dried over Na2SC filtered and concentrated to dryness to give the desired N-Boc-3-amino-2(5)-hydroxy- propanoic acid (6.30 g, 0.031 mmol, 81.5 percent yield): [H NM (400 MHz, CDC13) delta 7.45 (bs, 1 H), 5.28 (bs, 1 H), 4.26 (m, 1 H), 3.40-3.62 (m, 2 H), 2.09 (s, 1 H), 1.42 (s, 9 H); 13C NMR (100 MHz, CDC13) delta 174.72, 158.17, 82, 71.85, 44.28, 28.45.N-Boc-3-amino-2(S)-hydroxy-propionic acid ; N-Boc-3-amino-2 (^-hydroxy-propionic acid OHTo a stirring solution of S-isoserine (4.0 g, 0.038 mol) in dioxane: H2O (100 mL, 1 :1 v/v) at 0° C was added N-methylmorpholine (4.77 mL, 0.043 mol), followed by BoC2O (11.28 mL, 0.049 mol) and the reaction was stirred overnight with gradual warming to room temperature. Glycine (1.0 g, 0.013 mol) was then added and the reaction was stirred for 20 min. The reaction was cooled to 0°C and sat aq. NaHCO3 (75 mL) was added. The aqueous layer was washed with ethyl acetate (2 x 60 mL) and then acidified to pH 1 with NaHSO4. This solution was then extracted with ethyl acetate (3 x 70 mL) and these combined organic layers were dried over Na2SO4, filtered and concentrated to dryness to give the desired N-Boc-3-amino-2(5)-hydroxy- propanoic acid (6.30 g, 0.031 mmol, 81.5 percent yield): 1H NMR (400 MHz, CDC13) delta 7.45 (bs, 1 H), 5.28 (bs, 1 H), 4.26 (m, 1 H), 3.40-3.62 (m, 2 H), 2.09 (s, 1 H), 1.42 (s, 9 H); 13C NMR (100 MHz, CDC13) delta 174.72, 158.17, 82, 71.85, 44.28, 28.45.N-Boc-3-amino-2(5)-hydroxy-propionic acid To a stirring solution of S-isoserine (4.0 g, 0.038 mol) in dioxane: H2O (100 mL, 1:1 v/v) at 0° C was added N-methylmorpholine (4.77 mL, 0.043 mol), followed by BoC2O (11.28 mL, 0.049 mol) and the reaction was stirred overnight with gradual warming to room temperature. Glycine (1.0 g, 0.013 mol) was then added and the reaction was stirred for 20 min. The reaction was cooled to 0°C and sat aq. NaHCO3 (75 mL) was added. The aqueous layer was washed with ethyl acetate (2 x 60 mL) and then acidified to pH 1 with NaHSO4. This solution was then extracted with ethyl acetate (3 x 70 mL) and these combined organic layers were dried over Na2SO4, filtered and concentrated to dryness to give the desired N-Boc-3-amino-2(5)-hydroxy- propanoic acid (6.30 g, 0.031 mmol, 81.5 percent yield): 1H NMR (400 MHz, CDC13) delta 7.45 (bs, 1 H), 5.28 (bs, 1 H), 4.26 (m, 1 H), 3.40-3.62 (m, 2 H), 2.09 (s, 1 H), 1.42 (s, 9 H); 13C NMR (100 MHz, CDC13) delta 174.72, 158.17, 82, 71.85, 44.28, 28.45.Part I - Synthesis of (S)-3-((ter^butoxycarbonyl)amino)-2-hydroxypropanoic acid [0261] To To a stirring solution of S-isoserine (4.0 g, 0.038 mol) in dioxane: H20 (100 mL, 1 : 1 v/v) at 0° C was added N-methylmorpholine (4.77 mL, 0.043 mol), followed by Boc20 (1 1.28 mL, 0.049 mol) and the reaction was stirred overnight with gradual warming to room temperature. Glycine (1.0 g, 0.013 mol) was then added and the reaction was stirred for 20 min. The reaction was cooled to 0°C and sat aq. NaHC03 (75 mL) was added. The aqueous layer was washed with ethyl acetate (2 x 60 mL) and then acidified to pH 1 with NaHS04. This solution was then extracted with ethyl acetate (3 x 70 mL) and these combined organic layers were dried over Na2S04, filtered and concentrated to dryness to give the desired N-Boc-3-amino-2(5)-hydroxy- propanoic acid (6.30 g, 0.031 mmol, 81.5 percent yield): 1H NMR (400 MHz, CDC13) delta 7.45 (bs, 1 H), 5.28 (bs, 1 H), 4.26 (m, 1 H), 3.40-3.62 (m, 2 H), 2.09 (s, 1 H), 1.42 (s, 9 H); 13C NMR (100 MHz, CDC13) delta 174.72, 158.17, 82, 71.85, 44.28, 28.45.400 g (3.8 mol) of (S)-isoserine, 592 g (4.0 mol) of phthalic anhydride, 40 g (0.40 mol) of triethylamine were added to the four-necked flask.3L petroleum ether and 1L DMF, The mixture was heated to 78 ° C with stirring and refluxed for 18 hours.After the reaction was completed, the reaction system was cooled to 25 ° C.The mixture was allowed to stand for stratification, and the lower layer was added to the reaction flask, and 12 L of water and 2 L of 2N hydrochloric acid were added.The temperature was lowered to 0 ° C, stirred for 1 hour, filtered, and the obtained cake was dried at 70 ° C for 5 hours to obtain 851 g of a white solid.N-substituted phthalic anhydride-(S)-isoserine (compound 3), The yield was 95.2percent, and the purity of the compound 3 was 99.5percent by HPLC, and the content of the impurity compound 4 was 0.09percent.A mixture of L-Isoserine (50 mg, 0.48 mmol) and (R)-1-(3-((3'-(3- bromopropoxy)-2, 2'-dimethyl-[1, 1'-biphenyl]-3-yl)oxy)propyl)pyrrolidin-3-ol (20 mg, 0.043 mmol) in methanol (1.0 mL), DMF (0.1 mL) and N, N-diisopropylethylamine (90 muL, 0.515 mmol) was heated at 60-70 °C for 48 h. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19 x 200 mm, 5-mum particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 5- 45percent B over 20 minutes, then a 5-minute hold at 100percent B; Flow: 20 mL/min. to give the pure title compound: (15.6 mg, 73percent). LC/MS Condition E: ret time 1.09 min; m/e = 487 (M+H)+. LC/MS Condition F: ret time 1.14 min; m/e = 487 (M+H)+.To a 250-ml flask, 20 g (105.7 mmol) of 4-fluoro-2-(trifluoromethyl)benzonitrile was added and 106 ml of dimethylsulfoxideand 46 ml of water were added thereto, followed by stirring. To this reaction solution, 13.34 g (126.9 mmol, 1.2 eq) of (S)-isoserine and 44.6 ml (317.1 mmol, 3.0 eq) of triethylamine were added, followed by stirring at 120 °C for16 hours. After completion of the reaction, the reaction product was diluted with 150 ml of ethyl acetate and washedwith 200 ml of water three times. After separation of layers, the layer was washed with a NaCl aqueous solution, dehydrated and dried over MgSO4, and concentrated under reduced pressure to obtain 28 g (95percent) of a title compound.1H NMR (Acetone-d6, 400MHz) delta 7.66(d, 1H), 7.22(d, 1H), 7.04(dd, 1H), 6.49(s, 1H), 4.43(q, 1H), 3.72~3.575(m, 2H)Mass[M+H] : 275.0650.0 g of S-isoserine (476 mmol) was dissolved in 200 mL of ethanol, and HCl gas was bubbled under cooling with ice water for 5 hours. The reaction was allowed to warm to room temperature overnight, Ethyl ether was removed by filtration and the white solid was dispersed in 250 mL of ethyl acetate. Triethylamine (130 mL, 94.4 g, 935 mmol), Boc anhydride (150 g, 688 mmol) was added under ice-water bath, The reaction was stirred overnight at room temperature. After removal of the solvent by filtration, petroleum ether was added to afford Boc-protected S-isoserine ethyl ester ll (108 g, 463 mmol, 97percent) as a white solid.

Molecular Weight:105.09
XLogP3:-4
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:2
Exact Mass:105.042593085
Monoisotopic Mass:105.042593085
Topological Polar Surface Area:83.6
Heavy Atom Count:7
Complexity:72.6
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes