1H-ISOINDOLE-1,3(2H)-DIONE, 2-[[(5S)-2-OXO-3-[4-(3-OXO-4-MORPHOLINYL)PHENYL]-5-OXAZOLIDINYL]METHYL]-

White Solid

((S)-2-(oxiran-2-ylmethyl)isoindoline-1, 3-dione (4.56g, 22.46mmol, 1.3eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77g, 17.29mmol) were dissolved in isoamyl acetate (70mL) respectively, and heated to 120°C. Then magnesium chloride (0.12g, 1.28mmol) was added, the mixture was reacted for 4h, white solid was obtained by filtration (6.97g, yield:95.5percent). ESI-MS(m/z): 422(M+H), 444(M+Na); [0048] (S)-2-(oxiran-2-ylmethyl)isoindoline-1, 3-dione (3.87 g, 19.06 mmol, 1.1 eq.) and 4-(4-isocyanatophenyl)morpholin-3-one (3.77 g, 17.29 mmol) were dissolved in chlorobenzene (70 mL) respectively, then heated to 115° C. and lithium iodide (0.23 g, 1.72 mmol) was added. The mixture was reacted for 4 h, white solid was obtained by filtration (6.85 g, yield: 94.09percent). [0049] ESI-MS (m/z): 422 (M+H), 444 (M+Na); [0050] A compound having the structure of formula (I) (106.76 g, 270 mmol) was suspended in 4000 ml of anhydrous tetrahydrofuran(About 40ml / g), stir, gradually heated to 50 ° C, maintained at 50 ° C, A solution of triphosgene (80.2 g, 270 mmol) in tetrahydrofuran (268 ml) was added dropwise over 30 minutes, Heated to 64 ° C reflux, about 10 minutes after the clarification, about 1 hour and precipitation of solid, let cool to room temperature, The filter cake was washed with absolute ethanol (120 ml * 3 times) and air dried at 45 ° C to give 111.4 g of a compound having the structure of formula (II) in a yield of 97.9percentAmino alcohol 170 gm, 0.4293 moles and Triethylamine 41 14.72 gms, 0.9459 moles, was charged to Dichloromethane 2380 ml and cooled reaction mass to 0°C - 5°C. To the cooled reaction mass added triphosgene solution, 51.09 gms in 340 ml MDC, 0.18 moles drop wise at 5°C - 10°C in 60 min, and stirred for 60 - 90 min. Reaction mass quenched with water and distilled out MDC layer atmospherically till thick solid mass obtained. To the thick solid, charged tetrahydrofuran 1360 ml, distilled out 130 ml under vacuum. Cooled slurred mass to 25°C -30°C, stirred for 30 min, filtered. Wet material dried at 55°C -60°C to afford 162 gm dry material. Yield- 89percentTo into a 250 ml three-necked round bottom flask was added (R) -4- [4- (5- hydroxymethyl-2-oxo - oxazole3-yl) - phenyl] - morpholin-3-one compounds (Formula II, 5 g, 17 1 mmol), tetrahydrofuran (75 ml), triphenyl.Phosphine (5. 38g, 20. 5mmol) and phthalimide (3. 02g, 20. 5mmol), the mixture was stirred at room temperature for 5 minutes.30 minutes slowly added isopropyl azodicarboxylate (4. 15g, 20. 5 mmol), continue stirring for 2 to 3 hours.Filtered and dried, to give the compound (Π1) 6. 7g, 93percent yield.The reaction flask was charged with 49.5 g of the compound 4 (0.22 mol) obtained in Example 3-2, CuI (1.9 g, 10 mmol), N, N'-dimethylethylamine (30 mmol, 1.5 mL), potassium carbonate (0.5 mol) and 300 mL of dichloromethane, compound 5 (69.1 g, 0.2 mol) was added with stirring and the reaction flask was sealed and placed in an oil bath at 100 ° C for 15 hours. After the reaction was completed, the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, poured into 500 mL of water and extracted three times with ethyl acetate (3 x 500 mL). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a crude product which was recrystallized from ethyl acetate to give 77.7 g of compound 6 in a yield of 92.2percent and a purity of 99.6percent.Compound I was added to 39.5 g (0.1 mol), N, N-dimethylaniline 19.4 (0.16 mol), trichloromethane 120ml, added to 250ml of three bottles, stir to dissolve the solid. cooling to -20 °C, temperature control at -20°C ~ 10°C slowly into the phosgene about 10.9g (0.11mol), and then heat for 10h. Nitrogen was bubbled through for 15 minutes. The crude product of the compound of formula (II) was obtained by distilling off the trichloromethane under reduced pressure by heating under reduced pressure, Filtration and drying gave 41.1 g of the compound of formula (II) as a white solid in 97.6percent yield. HPLC, the purity was 98.95percent.2641 g of 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1, 3(2H)-dione (V) are suspended in 22 l of toluene and, at 19° C., 1300 g of N, N-carbonyl-diimidazole are added. In a four neck round bottom flask, charged dichloromethane (3400ml), 2-((2R)-2-Hydroxy-3- {[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-lH-isoindole-l, 3(2H)-dione (340 g) and Ν, Ν' -dicarbonyldiimidazole (209.13 g) at 25 to 30°C. The obtained reaction mass then stirred for 8hr. at 25 to 30°C. Reaction mass is concentrated under reduced pressure to obtain residue. Added tetrahydrofuran (1700 ml) to residue. The obtained mixture is heated to 40 to 45°C for 30 minutes followed by cooling to room temperature. Finally obtained solid is filtered off and washed by tetrahydrofuran(170 ml) Yield =93.55percentThis example relates to the preparation of 2-{(S)-2-oxo-3-[4-(3-oxo- morpholine-4-yl)phenyl]-oxazolidine-5-yl-methyl}-isoindol-1 , 3-dione, step b) of the process. 17.0 kg of the compound (III) obtained in , 170 kg of chlorobenzene and 8.5 kg of Ν, Ν-carbonyldiimidazole are loaded into a reactor. The mass is brought to about 100 °C and maintained at this temperature for 4 hours. At the end of the reaction, the mass is cooled to 0-10 °C then filtered by washing it with 34.0 kg of chlorobenzene and lastly oven-dried. 17.0 kg of the desired compound (IV) are obtained, with a reaction yield equal to 93.8percent.To a 2 litre 4 Neck RBF, charge Toluene (830 ml), Compound (IV) (100 gms). Stirr the reaction mass and cool to 10-15°C. Charge N, N-carbonyl-diimidazole (82 gms). Reflux the reaction mass at 105-110°C for 2 hrs. Cool the reaction mass to 55-60°C and charge methanol (170 ml). Cool the reaction mass further to 25-30°C and filter. Wash the residue with Methanol (50 gms). Dry the solid under vacuum. Dry Wt: 100 gms (Theoretical yield: 93.80percent); Purity: 99.78percent142.5 g (0.360 mol) of 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino} propyl)-1 H-isoindole-1 , 3(2H)-dione (I), 175.32 g (1 .082 mol) of N, N- carbonyldiimidazole and 1425 mL of tetrahydrofuran were charged in a 3L flask and the reaction mass was heated to reflux for 4 hours. Then, the reaction mass was cooled down to 0 °C for 1 hour and the resulting solid was filtered off and dried under vacuum at 70 °C.Yield: 137.8 g. Molar yield: 90.73percent. HPLC purity: 99.74percent. M.P.: 223 °C. S.O.R.: [a ]N, N-Carbonyldiimidazole (2.897kg , 1.47eq) was added to a suspension of compound according to d. ) (5.1kg, 12.114mol ) in toluene (49L) . The reaction mixture was refluxed for 3h, then at 60 To suspension of 2-[(2R)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl]-1H-isoindole-1, 3(2H)-dione (170 gm) and potassium carbonate (59.3 gm) in dichloromethane (1500 ml) was added 1, 1’-carbonylbis(1H-imidazole) (153.4 gm) at room temperature. Reaction mass was then stirred for 5 hr at room temperature. After completion of reaction, inorganic base is removed by filtration. The obtained filtrate is concentrated under reduced pressure to yield solid. To this solid tetrahydrofuran (850 ml) was added followed by stirring and filtration. The obtained solid is dried under vacuum for 4 hr at 50 °C to obtain 2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1, 3-oxazolidin-5-yl}methyl)-1H-isoindole-1, 3(2H)-dione. [Yield = 160 gm (88.2 percent); Purity (HPLC) =99.65 percent]To suspension of 2-[(2R)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino}propyl]-1H-isoindole-1, 3(2H)-dione (170 gm) and potassium carbonate (59.3 gm) in dichloromethane (1500 ml) was added 1, 1'-carbonylbis(1H-imidazole) (153.4 gm) at room temperature. : Preparation of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l, 3-oxazolidin- 5-yl}methyl)-lH-isoindol-l, 3(2H)-dione, the compound of formula I(2R)-2-Hydro y-3-[4-(3-oxo-4-moφholinyl)phenyl]amino-propyl-lH-isoindol-l , 3(2H)- dione (10.0 g; 25 mmol), the compound of formula III, containing 1.0 percent of the (2S)-isomer was charged into a flask and tetrahydrofuran (200 ml) was added. NN-carbonyldiimidazole (4.1 g; 25 mmol) was added to the stirred mixture. The mixture was heated up to boil and refluxed for 5 hours.The white suspension was cooled to the temperature of 20°C, stirred for 1.5 hours, aspirated and washed with tetrahydrofuran (50 ml). The product was poured into a flask with 2- methoxyethanol (175 ml). The mixture was heated up to boil and stirred until dissolution. Active carbon (0.5 g) was added to the solution and filtered off while hot after 10 minutes and washed with 2-methoxyethanol (10 ml). The solution was cooled to the laboratory temperature and stirred for 1 hour. The resulting crystals were aspirated and washed with methanol (100 ml). The aspirated product was dried in a vacuum drier at a temperature up to 60°C. 9 g (85 percent of theory) of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l , 3-oxazolidin-5-yl} methyl)- lH-isoindol- l , 3(2H)-dione with the isomeric purity of 99.98percent were obtained, HPLC purity 99.7percent, m. p. = 221 - 223 °C. The polymorphous structure of the compound (I) was also characterized with the X-ray powder diffraction (Fig. 1) with the characteristic 2 theta angles 4.63; 12.00; 13.9; 15.3; 15.87 and 24.55.300 ml of THF were added to 20 g of 2-((2i?)-2-hydroxy-3-{ [4-(3-oxomorpholin-4- yl)phenyl]amino}propyl)- lH-isoindol-l , 3(2H)-dione (14, 0.0506 mol), 16 g of Ι , Γ- carbonyldiimidazole (0.09869 mol) and 0.1 g of 4-dimethylamino)pyridine. The suspension was stirred and heated to boiling for 7 hours, then slightly cooled and another portion of Ι , Γ-carbonyldiimidazole (0, 09869 mol) was added. Then, the suspension was stirred under boiling for 14 hours. After that the mixture was cooled to 25°C, which was followed by filtration, washing of the cake with THF, with an ethanol/water mixture (9: 1) and drying. 15.6kg of an off-white powder was obtained that melted at the temperature of 216 to 217°C; HPLC 99.9percent, content of the (R)- isomer below 0.03percent, yield 73percent.100 gm (0.2531 moles) 2-((2R)-2-Hydroxy-3-{[4-(3-oxo-4-morpholinyl) phenyl] amino} propyl) -lH-isoindole- 1, 3(2H)-dione (V) is added in 700 ml Dimethyl carbonate, 69.9 gm0 (0.4301 moles) Carbonyl diimidazole and 15.4 gm (0.1260 moles) Dimethylaminopyridine. Reaction mass is heated to 80-85°C for 6 hours. It is then cooled, chilled and filtered to get 2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]- l, 3- oxazolidiii-5-yl}methyl)- lH-isoindole- l, 3(2H)-dione. it is washed with dimethyl carbonate followed by water. Wet Wt = 95 gm4-(4-Aminophenyl)morpholin-3-one (100 gm) was added in n-butanol (300 ml) and charged Alumia sulfonic acid at ambient temperature. Cool the mass, added (R)-Epichlorohydrin (72 gm) and maintain the reaction mass at below 20°C. Confirmed the completion of reaction, separated the catalyst. Added sodiumbicarbonate, cool the mass temperature to Q-5°C and added methylchloroformate (56 gm) . After completion of reaction, evaporated the n- butanol and charged N, N-dimethylformamide (500 mi), potassium phthalimide (122 gm). The reaction temperature maintained at 95- 100°C for 3 hours. Cool the mass temperature to ambient temperature, quenched the mass into water. Filtered the mass and washed the product with water. Dried the material up to get constant weight. The obtained 2-({(5Sj-2-Qxo-3-[4-(3-Gxo-4- morpholmyl]phenyl ]-- 1 , 3--oxazol.idm-5--yl}methyl)-- 1 H--isoindole-- 1 , 3(2H)--d.ione was 186 gm (85percent yield) .25 g of 2-((2i?)-2-hydroxy-3-(N-(4-(3-oxomorpholin-4-yl)phenyl)-lH-imidazol-yl-l - carboxamido)propyl)- lH-isoindol-l , 3(2H)-dione (16, 51 mmol) prepared according to Example 4 were suspended in 350 ml of THF, 5.5 ml of a solution of tert-BuOK (20percent by weight, 9.1 mmol) was added dropwise under stirring, which was diluted with 20 ml of THF before adding. The suspension was stirred and heated to boiling for 19 hours, then 400 ml of ethanol were added and the boiling continued for 2 hours. Cooling of the mixture to 35°C was followed by filtration, washing of the cake with ethanol, water and ethanol again. After drying, 16.8 g of an off-white powder that melted at 215-217°C was obtained; HPLC 99.8percent, content of the (R isomer below 0.03percent, yield 78percent, see Fig. 4.60 g (0.25 mol) of compound 6 and 400 mL of toluene were charged into a 500 mL dry three-necked flask, stirred(0.3 mol) of di-tert-butyl dicarbonate (Boc anhydride) and 0.6 g of sodium hydride were added and the system was refluxed for 48 h. TLC was detected until the reaction was complete and the partial solvent was distilled off to give 47.4 g of the white crystals of Compound 7 (93.2percent)To a suspension of (S)-l-phthalimido-2-((phenyloxycarbonyl) oxy)-3-propylchloride (3.595g, 10 mmol) (prepared in Step- I ) and 4-(4-aminophenyl)morpholin-3-one (2.4g, 12.5 mmol, 1.25 eq) in DMF ( 20 ml). Potassium carbonate ( 3.45 gms, 25 mmol, 2.5 eq) and catalytic amount of triethylbenzyl ammonium chloride were added and then stirred for about 18 hrs at 80°C .The reaction mix. is poured into the water ( 50 ml) and then extracted with the DCM ( 25 ml x 3). The combined organics are washed with Dil.HCl (10 ml x2) and water ( 10 ml x 2). Distill off the solvent under reduced pressure to yield a title compound.( (Yield = 0.5 g, 12 percent of the theory).To a solution of [4-(3-oxo-moφholin-4-yl)phenyl]carbamic acid benzyl ester ( 3.26 g, 10 mmol) and (S)-l-phthalimido-3-chloro-propan-2-ol( 3.02 g, 1.26 eq) ( prepared as per US6, 362, 334B1) in DMF ( 10 ml) in an ice-bath was added a solution of Lithium-t-Butoxide ( 1.956 g, 2.4 eq) in THF ( 15 ml) . The resultant solution was allowed to stand at 20° C for 44 hrs. Sat. aq. ammo, chloride ( 25 ml) , water ( 30 ml) and DCM ( 50 ml) was added and the phases are separated . The organics dried on MgS04 and distill off the solvent completely to yield title compound as a off- white crystalline solid. Re-crystallized from acetone to yield a title compound as a white crystalline solid. (Yield = 2.0 g, 48 percent of the theory).To a solution of [4-(3-oxo-morpholin-4-yl)phenyl]carbamic acid benzyl ester ( 3.26 g, lmmol) in DMF ( 10 ml) and methanol ( 0.64 g, 20 mmol) at 20 ° C is added a solution of Lithium-t-butoxide ( 2.4 g, 30 mmol, 3eq) in THF ( 15 ml) while keeping less than 24°C with an ice-bath . The solution is cooled to 5°C, (S)-2-phthalimido-l-(chloromethyl) ethylacetate (5.63 g, 2eq) (prepared in step I) solution is added. The resulting solution is allowed to stand at 21 ° C for 21 hrs. Sat. aq.NCl ( 25 ml), water ( 30 ml) , Sat. NaCl( 25 ml) and DCM ( 50 ml) were added and the phases are separated and the aq. washed with DCM( 20 ml x3 ) . The organics are dried on MgS0The above 17.00g white solid, 12.53g methylamine aqueous solution and 360ml methanol were heated to reflux, reacted for 2h at reflux, cooled to 15 C, adjusted to pH 1-2 with concentrated sulfuric acid, and filtered to obtain 11.24g of white solid Yield: 85.0%.The above 17.00g white solid, 12.53g methylamine aqueous solution and 360ml methanol were heated to reflux, reacted for 2h at reflux, cooled to 15 C, adjusted to pH 1-2 with concentrated sulfuric acid, and filtered to obtain 11.24g of white solid Yield: 85.0%.Add 4 kg of N, N-dimethylacetamide to a 10 L reaction flask.Add 1.0 kg of compound (II), add 1.4 kg of ethylenediamine, stir and heat.The reaction was stirred at 40 C for 4 h. The reaction solution was cooled to 30 ± 5 C, Add about 1.2kg of phosphoric acid, add the reaction, and cool the reaction solution to 10±5C for 1h~1.5h.Filtration, filter cake washed with N, N-dimethylacetamide, ethanol, The wet product was transferred to a blast oven, and the internal temperature of the oven was controlled to dry at 50-55 C for 16 ± 1 hour to obtain a white solid. Yield: 93%, product purity (HPLC): 99.5%.Add 4 kg of N-methylpyrrolidone to a 10 L reaction flask.Add 1.0kg of compound (II), add 0.3kg of 80% hydrazine hydrate, stir and heat.The reaction was stirred at 90 C for 4 h. The reaction solution was cooled to 45 ± 5 C, Add about 0.7kg of sulfuric acid, add the reaction, and cool the reaction solution to 5±5C for 1h~1.5h.Filtration, filter cake washed with N-methylpyrrolidone, ethanol, Transfer the wet product to the blast oven, The internal temperature of the oven was controlled to dry at 50-55 C for 16 ± 1 hour to obtain a white solid.Yield: 92%, product purity (HPLC): 99.5%.Add 28 kg of rivaroxaban intermediate IV to 280 L of absolute ethanol, and add 36.5 kg of 40% methylamine solution.After refluxing for 1 h, the temperature was lowered to 50-60 C.Add 6N hydrochloric acid to adjust the pH to 2~3, Cool down to room temperature, centrifuge, Drying the filter cake to obtain rivaroxaban intermediate V(4-[4-[(5S)-5-(Aminomethyl)-2-oxo-3-oxazolidinyl]phenyl]-3-morpholinone hydrochloride) 19.66kg, The yield is 90.3%, The purity is 99.78%.

1H-isoindole-1,3(2H)-dione, 2-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-5-oxazolidinyl]methyl]- is an important intermediate for the synthesis of rivaroxaban, which is an anticoagulant and the first orally active direct factor Xa inhibitor.
Rivaroxaban intermediate.

Rivaroxaban intermediate.

Molecular Weight:421.4
XLogP3:1.2
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:4
Exact Mass:421.12738533
Monoisotopic Mass:421.12738533
Topological Polar Surface Area:96.5
Heavy Atom Count:31
Complexity:740
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes