ChemicalBook CAS DataBase List Landiolol

Landiolol synthesis

8synthesis methods

Product Name:Landiolol
CAS Number:133242-30-5
Molecular formula:C25H39N3O8
Molecular Weight:509.59

Landiolol is prepared by the reaction of 2-(morpholine-4-carboxamido)ethanamino hydrochloride and (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-hydroxyphenyl)propanoate. The steps are as follows:
A suspension of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-((2R)-3-chloro-2-hydroxypropoxy)phenyl)propanoate prepared according Example 3 (0.50 g, 0.00134 mol) in isopropanol (10 ml) is added with 2-(morpholine-4-carboxamido)ethanamino hydrochloride (18) (1.4 g, 0.00670 mol), heated to 30-35°C and dropwise added with 30% NaOH, keeping pH at 10-11. The mixture is left under stirring at 35-40°C, monitoring by UPLC. After completion of the reaction, ethyl acetate (20 ml) and water (20 ml) are added and the phases are separated. The organic phase is added with water (20 ml) and adjusted to pH 3-4 with hydrochloric acid. The phases are separated and the resulting aqueous phase is then adjusted to pH 10-11 with sodium hydroxide and re-extracted with ethyl acetate (20 ml). The solvent is then evaporated off under reduced pressure to obtain 0.38 g (55.6%) of a pale yellow oil which solidifies in time to a pale yellow solid.
Landiolol synthesis

1398109-46-0
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154467-16-0 Synthesis

N-(2-Aminoethyl)morpholine-4-carboxamide oxalate

154467-16-0
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133242-30-5
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Yield:133242-30-5 70.7%

Reaction Conditions:

Stage #1: (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-((2R)-3-chloro-2-hydroxypropoxy)phenyl)propanoatewith potassium carbonate;potassium iodide in acetonitrile; for 2 h;Reflux;
Stage #2: N-(2-aminoethyl)-4-morpholine carboxamide oxalic acid in acetonitrile;Reflux;

Steps:

5 Example 5
Landiolol (1)

Example 5
Landiolol (1)
A solution of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl 3-(4-((2R)-3-chloro-2-hydroxypropoxy)phenyl)propanoate (5) prepared according to Example 3 (0.30 g, 0.805 mmol) in acetonitrile (6.0 ml) is added with potassium carbonate 0.45 g (3.22 mmol), and KI 0.013 g (0.0805 mmol), then refluxed for 2 h and added with 2-(morpholine-4-carboxamido)ethanamino oxalate (6) (0.64 g, 2.42 mmol).
The mixture is refluxed under stirring, monitoring by UPLC.
After completion of the reaction, ethyl acetate (10 ml) and water (10 ml) are added and the phases are separated.
The organic phase is added with water (10 ml) and adjusted to pH 4-5 with hydrochloric acid, the phases are separated and the resulting aqueous phase is then adjusted to pH 11-12 with sodium hydroxide and re-extracted with ethyl acetate (10 ml).
Then the solvent is evaporated off under reduced pressure to obtain 0.29 g (70.7%) of a pale yellow oil which solidifies in time to a pale yellow solid.
LC-MS (ESI+) [M+H]⁺ = 510
¹H-NMR (CDCl₃) (chemical shifts expressed in ppm with respect to TMS) (assigned based on the hetero correlation HSQC spectrum): 1.36 (3H, s, CH₃); 1.42 (3H, s, CH₃); 2.63 (2H, t, J = 7 Hz, CH₂-Ar); 2.75 - 2.93 (8H, m, CH₂-CO, CH-CH₂-NH, CH₂-CH₂-NH, NH and OH); 3.35 (6H, m, 2CH₂-N morpholine and CH₂-NH); 3.65 (4H, m, 2CH₂-O morpholine), 3.68 (1H, m, CH in 4 oxolane); 3.94 (2H, bd, CH₂-OAr); 4.00 - 4.20 (4H, m, CH in 4 oxolane, CH₂-OCO and CH in 5 oxolane); 4.25 (1H, m, CH-OH); 5.21 (1H, bt, NH carbamate); 6.83 and 7.11 (4H, system AA'XX', aromatics).
¹³C-NMR (CDCl₃) (ppm) (multiplicity was assigned by DEPT-135): 25.3 (CH₃); 26.6 (CH₃); 29.9 (CH₂); 35.8 (CH₂); 40.2 (CH₂); 43.8 (CH₂-N morpholine); 49.2 (CH₂); 51.5 (CH₂); 64.6 (CH₂); 66.2 (CH₂); 66.4 (CH₂-O morpholine); 68.3 (CH); 70.3 (CH₂); 73.4 (CH); 109.7; 114.4 (CH); 129.2 (CH); 132.8; 157.0; 158.0; 172.5 (COOR).
FT-IR (UATR, cm^-1): 3350. 2858, 1735, 1626, 1512, 1454, 1371, 1244, 1153, 1115, 1040. 829, 733.