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The starting material was prepared as follows: Potassium hydroxide (485 mg, 8.6mmol) was added to a solution of methyl 3-morpholinopropionate (1 g, 5.7 mmol) in ethanol (20 ml) and the mixture stirred for 2 hours at 80° C. The solution was allowed to cool and adjusted to pH1 with 6M hydrochloric acid. Insoluble material was removed by filtration and the volatiles removed from the filtrate by evaporation. The resulting oil was triturated with ether, the solid product collected by filtration, washed with methylene chloride and dried under vacuum to give 3-morpholinopropionic acid (993 mg, 89percent) as a white solid. 1H NMR Spectrum: (DMSOd6; CF3COOD) 2.83(t, 2H); 3.13(t, 2H); 3.36(t, 2H); 3.46(d, 2H); 3.73(t, 2H); 3.97(d, 2H) MS-ESI: 159 [MH]+
Example 17 Preparation of [3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridin-1-yl]-naphthalen-1-yl-methanone To a solution of methyl 4-morpholinepropionate (5.0 g, 28.9 mmol) in MeOH (25 mL) was added 2N NaOH (17.3 mL, 34.6 mmol). The mixture was stirred for 1 h then concentrated in vacuo. The residue was suspended in dichloromethane (125 mL) and DMF (30 muL) was added followed by oxalylchloride (10 mL, 115.6 mmol). The mixture was allowed to stir for 2 h. then concentrated in vacuo. The resulting solid was added portion-wise to a solution of 2-(aminomethyl)pyridine (2.88 mL, 28.2 mmol) and triethylamine (9.0 mL, 64.86 mmol) in dichloromethane (200 mL). The mixture was stirred at ambient temperature for 1 h. then washed with water (300 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to yield 3-morpholin-4-yl-N-pyridin-2-ylmethyl-propionamide (5.56 g, 77percent).
B. 3-(4-Morpholinyl)propanoic Acid A solution of the resultant compound of Example 202A (8.35 g, 48.3 mmol) in 60 ml of dioxane was treated with 40 ml of water and 19.3 ml (58 mmol) of 3N aqueous NaOH. After being stirred for 4 h, the solution was treated with 58 ml (58 mmol) of 1N aqueous HCl and concentrated in vacuo to provide the crude desired compound.
beta-Morpholino-propionic acid (used for preparing compound No. 32) NMR (60 MHz, delta values in CD3 OD): 2.45 (2H, t, J=6 Hz, --COCH2 --) STR31 3.83 (4H, m, --CH2 OCH2 --)
9
[ 4497-04-5 ]
[ 3282-30-2 ]
C12H21NO4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100%
Example 7; 4-[5-amino- l-(2,6-difluoro-benzoyl)- lH-[ 1 ,2,4]triazol-3- ylamino]-N-(3-morpholin-4-yl-propionyl)-benzenesulfonamide(Cpd 7); 7a; Using the mixed anhydride formation procedure, 1.9 g (100 percent) of Compound7a was generated from morpholinylpropionic acid (1.25 g) and pivaloyl chloride (1.05 g). 1H NMR (300 MHz, CDCl3) delta 3.68 (m, 4 H), 2.75 (t, 2 H), 2.65 (t, 2 H), 2.45 (m, 4 H), 1.21 (s, 9 H).
N-(5-chloro-3-(4-(2-chloro-5-(trifluoromethyl)phenyl)-5-cyano-6-oxo-1,6-dihydropyridin-2-yl)-2-hydroxybenzyl)-N-methyl-3-(4-morpholinyl)propanamide[ No CAS ]
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