3-Morpholinone, 4-[4-[(5S)-5-(aminomethyl)-2-oxo-3-oxazolidinyl]phenyl]-, hydrochloride (1:1)

In a four neck round bottom flask, charged methanol (2900 ml), 2-([(5S)-2- Oxo-3-[4-(3-oxo- 4-morpholinyl)phenyl]-l, 3-oxazolidin-5-yl}methyl)-lH-isoindole-l, 3(2H)-dione (290 g), and 40percent aqueous methylamine (265 g) at 25 to 30°C. Reaction mass is stirred for 1 h at 25 to 30°C and then heated to 60 to 65°C, and maintained at same temperature for 4 h. Reaction mixture then cooled to 25 to 30°C and added cone, hydrochloric acid (290 ml, pH should be 1 to 2) and stirred for 30 minutes. Obtained solid is filtered off and washed by chilled methanol (290ml). Yield= 92.0percentThe reaction flask was charged with 210.7 g (0.5 mol) of the compound prepared in Example 7, (S) -2- {[2-oxo-3- (4- (3-oxorpholine) phenyl) oxazolidin-5-yl] methyl} isoindole- VII), 1500ml of anhydrous ethanol, 500ml of 30percent aqueous solution of methylamine, stirring evenly, The temperature was raised to 40 ° C to 60 ° C for 8 hours, TLC in the control (dichloromethane: methanol = 20: 1, volume ratio) reaction is complete, With 10percent hydrochloric acid to adjust the pH to 1-2 between the precipitation of a large number of white solid, cooling to about 15 ° C, Stirring for 2 hours, filtering, filter cake with 300ml anhydrous ethanol washing, vacuum drying, A mixture of 147.0 g of the white solid (compound of formula VIII) was obtained in a molar yield of 89.7percent, and 1 ^ (purity: 98.7percent).210.7 g (0.5 mol) of (S)-2-{[2-oxo-3-(4-(3-oxomorpholine)benzene] prepared in Example 7 was added to the reaction flask.Based on oxazolidine-5-yl]methyl}isoindole-1, 3-dione (formula VII), 1500 ml of anhydrous ethanol, 500 ml of a 30percent aqueous solution of methylamine was stirred and heated to 40°C to 60°C for 8 hours.TLC control (dichloromethane:methanol = 20:1, volume ratio) reaction is complete, with 10percent hydrochloric acid to adjust the pH to between 1-2, precipitated a lot of white solids, cooled to about 15 °C, stirred for 2 hours, filtered The filter cake was washed with 300 ml of anhydrous ethanol and dried under reduced pressure to obtain 147.0 g of a white solid (compound of formula VIII) with a molar yield of 89.7percent and an HPLC purity of 98.7percent.Reference Synthesis of (S)-4-{4-[5-(aminomethyl)-2-oxo-l, 3-oxazolidin- 3-yl]phenyl}morpholin-3-one hydrochloride (compound IV-hydrochloride)26.00 g (79.3 mmol) of (5)-2-({2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l, 3- oxazolidin-5-yl}methyl)-lH-isoindole-l, 3(2H)-dione (compound III, obtained from compound II following the process disclosed in the ' 823 patent) were suspended in 95.0 mL of ethanol. 21.1 mL (271.6 mmol) of 40percent w/w aqueous methylamine were added to the suspension, and the resulting mixture was heated to 60-63 °C and maintained at this temperature for about 2 hours. The content of unreacted compound III was checked to be below 5percent by TLC. After cooling to 55-60 °C, a total of 31.45 g (172.3 mmol) of 20percent w/w aqueous hydrochloric acid were added over the reaction mixture until the pH was 2.65. Precipitation was observed during the addition. The resulting suspension was cooled down to 20 °C and subsequently filtered. The collected solid was washed with1 5.0 mL of methanol to give 20.01 g of wet (, S)-4-{4-[5-(aminomethyl)-2-oxo-l, 3- oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride as a white solid. After drying at 60 °C, 17.49 g of dry product were obtained. Yield: 86.5percent.Methyl amine (40 percent strength, 153.2 ml) is added to suspension of 2- ({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1, 3-oxazolidin-5-yl}methyl)-1H-isoindole-1, 3(2H)-dione (150 gm) in methanol (1500 ml) at 25 to 30 °C. The reaction mass was then refluxed for 6 hr. After completion of reaction, the reaction mass was cooled to 25-30 °C, the pH of reaction mass was adjusted to 2-3 using cone. HCl. Reaction mass was stirred for 1 hr & filtered off the solid. The solid obtained was washed with methanol (50 ml) Obtained solid was dissolved in mixture of methanol (500 ml) and methylene dichloride (750 ml) by adjusting pH of reaction mass to 7-8 using triethylamine at 25-30 °C and stirred till clear solution was obtained, pH of reaction mass was adjusted to 4-5 by using acetic acid at 25-30 °C. Reaction mass was stirred for 1 h at 25-30 °C and filtered off the solid. The solid obtained was washed with methanol (50 ml) and dried under vacuum at 50 to 55 °C for 5 hr to obtain 4-{4-[(5S)-5-(aminomethyl)-2-oxo- 1 , 3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride. [Yield = 92.4 gm (80 percent); Purity (HPLC) = 98.0 percent]Methylamine (40percent strength, 153.2 ml) was added to suspension of 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1, 3-oxazolidin-5-yl}methyl)-1H-isoindole-1, 3(2H)-dione (150 gm) in methanol (1500 ml) at 25 to 30° C. 2 - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -1, 3-oxazolidin-5- yl} methyl) -1, 3 (2H) -dione (Formula 5) Were suspended in 150 ml of ethanol at 22 °C , 16.2 g of a methylamine solution (concentration in water of 40percent) was added.The reaction mixture is then heated to 60-63 °C, The resulting solution was stirred at this temperature for 2 hours.55 ° C to 60 ° C After cooling, A total of 33.5 g of a hydrochloric acid solution (20percent in water concentration) was added until the pH reached 2.7.After confirming that the crystallization of the product has commenced, After cooling, The precipitated reaction product was filtered under suction, washed with methanol and then dried to give 12.5 g of the desired product. (Yield: 80.5percent)210.7 g (0.5 mol) of (S)-2-{[2-oxo-3-(4-(3-oxomorpholine)phenyl]oxazolidine-5-yl] prepared in Example 7 was added to the reaction flask. Methyl isonon-1, 3-dione (formula VII), 1500 ml of anhydrous ethanol, and 500 ml of a 30percent aqueous solution of methylamine were stirred well and heated to 40° C. to 60° C. for 8 hours. TLC control (2) Chloroethane:methanol = 20:1, volume ratio) The reaction is complete. Adjust the pH to between 1-2 with 10percent hydrochloric acid, precipitate a large amount of white solid, cool down to about 15°C, stir for 2 hours, filter and filter cake with 300ml The mixture was washed with anhydrous ethanol and dried under reduced pressure to obtain 147.0 g of a white solid (the compound of Formula VIII) in a molar yield of 89.7percent. The HPLC purity was 98.7percent.With reference to the method of Example 6, Hydrogen is used instead of formic acid amineAs a reducing agent, Reducing pressure for 6 hours, 15.6 g of compound 4 were obtained in a yield of 90.2percent. The resulting reaction flask was added 39.9g (0.101mol) of Intermediate VI, 100ml of tetrahydrofuran, 63.2g (0.39mol) N, N'- carbonyldiimidazole was stirred uniformly, added 5.0g of 4-dimethylaminopyridine (of DMAP), heated under reflux for 10 hours, TLC in the control (dichloromethane: methanol = 20: 1, volume ratio) reaction was complete, the reaction was stopped, cooled to room temperature after stirring for 1 hour, filtered, the filter cake was washed with 40ml of tetrahydrofuran and 70ml of 95percent ethanol washing, the resulting wet product directly into the reaction flask, and the aqueous solution was added 400ml of ethanol and 80ml of 95percent 30-33percent methylamine, stir, heated under reflux for 8 hours, TLC in the control (dichloromethane: methanol = 20: 1 , volume ratio) to complete the reaction, cooled to room temperature, treated with 37percent hydrochloric acid (V / V) to adjust to pH 1-2, to precipitate large amount of white solid was filtered, the filter cake was rinsed with 40ml of 95percent ethanol.Drying under reduced pressure, the obtained 29.3g (0.09mol) of an off-white solid hydrochloride salt of intermediate VII, prepared in molar yield intermediate VII VI hydrochloride thereof in between about 89.1percent, HPLC purity 99.4percentExample 19: [4-({S)-5-Aminomeihyl-2-oxo-oxazoiidm-3-yI)-pheriyl]-morphoiin-3-one; hydrochlorideUnder an atmosphere of nitrogen to a suspension of 2.00 g of 4-[4-((R)-3-amino-2-hydroxy- propylamino)-phenyi]-morphoiin-3-one hydrochloride (MW = 301.78; 1 eq.) in 100 mL of methylisobutylketone were added 3.85 g of potassium carbonate (MW = 138.21 ; 4.2 eq.) and the suspension was heated to reflux. The formed water was removed by azeotropic distillation. After refiuxing for 4 h and removing water by azeotropic distillation, the reaction mixture was cooled to room temperature and then 1.61 g of Ν, Ν'-carbonyidiimidazoi (MW = 162.15; 1.5 eq.) were added. After stirring at ambient temperature for 15 h, the reaction mixture was filtered. To the clear filtrate were added 5 mL of 6 M hydrochloric acid (1.5 eq.) and 50 mL of water and stirring was continued for 1 h. Then the mixture was concentrated in vacuo. To the solid residue were added 5.5 mL of water and 22 mL of 2-propanol. The resulting siurry was stirred for 1 h at ambient temperature and then cooled to 0 °C. After stirring in an ice bath for at least 2 h, the crystals were isolated by filtration, washed with 10 mL of 2-propanol and the wet product was dried in vacuo at 30 °C. The yield of isolated crystalline hydrochloride ( was 1.74 g (80.1percent).H-NMR (DMSO-dB, 300Mz) δ (ppm) = 3.21-3.26 (m, NCH[4-((S)-5-Aminomethy.-2-oxo-oxazolidin-3-yi)-phenyi]-rnorphoiin-3-one; hydrochlorideUnder an atmosphere of nitrogen to a suspension of 100 mg of 1-{(R)-2-oxo-3-[4-(3-oxo- morpholtn^-yl)-phenyl]-oxazodecane iodide (MW = 542.38; 1 eq.) in 2 mL of ethano. were added 100 mg of cone, hydrochloric acid (MW = 36.46; 5 eq.) and 950 mg of water. The reaction mixture was warmed to 50 °C and stirring was continued for 2 h. Then the reaction mixture was cooled to 0 °C. After stirring for 1 h at 0 °C, the crystals were isolated by filtration, washed with 10 mL of ethanol and the wet product was dried in vacuo at 30 °C. The yield of isolated crystalline hydrochloride of the title compound was 20 mg (approx. 33.1 percent). mp: 210-220 °C39.2 gms (0.1 mol) of tert-butyl-{(5S)-3-[4-[3-oxo-morpholin-4-yl)phenyl]-2-oxo-l, 3- oxazolidin-5-yl} methyl carbamate (prepared in the above examples ) added 300 ml of methanolic hydrochloric acid ( having 8-12 percent assay) and stirred for about 1 hr at R.T Distill off the solvent completely under the reduced pressure and to the white solid added 50 ml dichloromethane and stirred for about 20 min and filtered to get title compound as a white- crystalline solid. (Yield = 26.5 gms, 80.6percent of the theory).

Molecular Weight:327.76
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:3
Exact Mass:327.0985838
Monoisotopic Mass:327.0985838
Topological Polar Surface Area:85.1
Heavy Atom Count:22
Complexity:409
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes