* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
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 97.9percent
89%
With triethylamine In dichloromethane at 0 - 10℃;
Amino 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- 89percent
Stage #1: With triphenylphosphine In tetrahydrofuran at 20℃; for 0.0833333 h; Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran
To 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.
Reference：
[1] Patent: CN105777734, 2016, A, . Location in patent: Paragraph 0014
4
[ 634905-12-7 ]
[ 446292-08-6 ]
Yield
Reaction Conditions
Operation in experiment
92.2%
With copper(l) iodide; N,N-dimethyl-ethanamine; potassium carbonate In dichloromethane at 100℃; for 15 h; Sealed tube
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.
Reference：
[1] Patent: CN105801572, 2016, A, . Location in patent: Paragraph 0073; 0074
5
[ 446292-07-5 ]
[ 75-44-5 ]
[ 446292-08-6 ]
Yield
Reaction Conditions
Operation in experiment
97.6%
With <i>N</i>,<i>N</i>-dimethyl-aniline In chloroform at -20 - 10℃; for 10 h; Inert atmosphere
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.
Reference：
[1] Patent: CN106588905, 2017, A, . Location in patent: Paragraph 0074-0075
6
[ 446292-07-5 ]
[ 530-62-1 ]
[ 446292-08-6 ]
Yield
Reaction Conditions
Operation in experiment
97.9%
at 19 - 60℃; for 1 h; Heating / reflux
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. The reaction mixture is subsequently heated under reflux for one hour and then, at 60° C., 4.5 l of ethanol are added. After cooling to 25 to 30° C., the precipitated reaction product is filtered off with suction, washed with ethanol and then dried. Yield: 2756 g; equivalent to 97.9percent of theory. Melting point: 220.5° C.
93.55%
at 25 - 30℃; for 8 h;
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 =93.55percent
93.8%
at 0 - 100℃; for 4 h; Large scale
This 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 example 1 , 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.
93.8%
at 10 - 110℃; for 2 h;
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: 99.78percent
90.73%
for 4 h; Reflux
142.5 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 ]D25 = -75.26° (c = 1 ,DMSO)
88.3%
for 3 h; Industry scale; Reflux
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 0C, ethanol (14L) was added. After cooling to 25 0C, the precipitate was filtered and 4.8 kg of (S) -2- ( (2-oxo-3- (4- (3- oxomorpholino) phenyl) oxazolidin-5-yl) methyl) isoindoline- 1, 3-dione was obtained as a colorless solid (Yield 88,3 percent)
88.2%
With potassium carbonate In dichloromethane at 20℃; for 5 h;
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]
88.2%
With potassium carbonate In dichloromethane at 20℃; for 5 h;
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 (88.2percent); Purity (HPLC)=99.65percent]
85%
for 5 h; Reflux
Example 1 : 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.
73%
With dmap In tetrahydrofuran for 21 h; Reflux; Industrial scale
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.
95 g
at 80 - 85℃; for 6 h;
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 gm
Stage #1: at 20℃; Cooling Stage #2: With sodium hydrogencarbonate In butan-1-ol at 0 - 5℃; Stage #3: at 95 - 100℃; for 3 h;
4-(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) .
With potassium <i>tert</i>-butylate In tetrahydrofuran for 19 h; Reflux
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)
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate In N,N-dimethyl-formamide at 80℃; for 18 h;
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).
With lithium tert-butoxide In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 44 h; Cooling with ice
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).
With lithium tert-butoxide In tetrahydrofuran; methanol; N,N-dimethyl-formamide at 5 - 24℃; for 21 h;
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 MgS04 and concentrated to get crude compound .Re-crystallize from acetone to yield a title compound as a white - crystalline solid (Yield= 0.92 g, 22 percent of the theory).
Stage #1: With methylamine In methanol; water at 25 - 65℃; for 5 h; Stage #2: With hydrogenchloride In methanol; water at 25 - 30℃; for 0.5 h;
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= 92.0percent
89.7%
Stage #1: With methylamine In ethanol; water at 40 - 60℃; for 8 h; Stage #2: With hydrogenchloride In water at 15℃; for 2 h;
The 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).
89.7%
Stage #1: With methylamine In ethanol; water at 40 - 60℃; for 8 h; Stage #2: With hydrogenchloride In ethanol; water at 15℃; for 2 h;
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.
86.5%
Stage #1: With methylamine In ethanol; water at 60 - 63℃; for 2 h; Stage #2: With hydrogenchloride In ethanol; water at 55 - 60℃;
Reference example 3: 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.
80%
Stage #1: With methylamine In methanol at 25℃; for 6 h; Reflux Stage #2: With hydrogenchloride In methanol; water at 25 - 30℃; for 1 h;
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]
80%
Stage #1: With methylamine In methanol at 25℃; for 6 h; Reflux Stage #2: With hydrogenchloride In methanol; water at 25 - 30℃; for 1 h;
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. The reaction mass was refluxed for 6 hr, cooled to 25-30° C., followed by slow addition of acetic acid (300 ml) reaction mass. Thereaction mass was stirred for 30 min at 25-30° C. pH of the reaction mass was adjusted to 2-3 using conc. HCl. Reaction mass was stirred for 1 hr & filtered off the solid. The solid obtained was washed with methanol (50 ml) Obtained solid 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, then adjusted the pH of reaction mass 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 (80percent); Purity (HPLC)=98.0percent]
80.5%
Stage #1: With methylamine In ethanol; water at 55 - 63℃; for 2 h; Stage #2: With hydrogenchloride In ethanol; water
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)
147 g
Stage #1: With methylamine In ethanol; water at 40 - 60℃; for 8 h; Stage #2: With hydrogenchloride In water at 15℃;
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 ethanolamine; In toluene; at 75 - 85℃; for 2h;
5L three neck flask was added to the raw material A (100.0g, 240mmol) and toluene 700ml (7ml / g), being stirred suspension was heated to 80-85 , and then at 75-80 deg.] C, the 145ml (2.4mol ) ethanolamine was added to the suspension, and the mixture was stirred at 80-85 2 hours, and during this time the solid gradually dissolved.After completion of the reaction, the separation layer alkanolamines, alkanolamine layer was washed with toluene twice, each time 100ml, toluene layers were combined and concentrated to give an oily object.Recrystallization from methanol was added powdery crystals, 30 dried under reduced pressure for 10 hours to obtain a solid of about 66.99g, i.e. intermediate B.Yield was about 95.87%, Ms as 291.30, HPLC 99.92%.Intermediate B HPLC chromatogram see figure 7.
95.4%
With hydrazine hydrate; In ethanol; for 2h;Reflux;
63.5 g of the compound 6 (0.15 mol) prepared in Example 4-2 was added to the reaction flask, ethanol (1000 mL), 80% hydrazine hydrate (0.825 mmol) was added dropwise at room temperature, then heated to reflux 2h, the reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. 1000 mL of water was added and the mixture was extracted twice with dichloromethane (500 mL x 2). The dichloromethane phase was dried over anhydrous sodium sulfate and filtered through suction. The filtrate was evaporated to dryness to give a white solid which was dried in vacuo to give compound 7 (45.9 g); the yield was 95.4% and the purity was 99.7%.
95.1%
4 (^ (0.09111001) Compound 7,36.7840% (0.42111001) of the methylamine solution was added to methanol 2L of the three-necked flask, The temperature of the system was increased to 65 C for 1 h, and 62.2 g (0.49 mil) of oxalic acid and 200 mL of methanol was added dropwise to the system until the pH of the system was stopped at 2-3, At this point the system has a large amount of solid precipitation, the system heated reflux lh, cooled to room temperature, filtration, filter cake with methanol, 50 C vacuum drying to get 34.2g compound 8 (95.1%), 250 C above decomposition
95%
With potassium sulfide; In ethanol; at 0 - 60℃;
(1) 40 g of the compound of Formula 4 and 200 mL of ethanol are mixed at room temperature.Stir at room temperature. The temperature was raised to 40 C., a 200 mL aqueous solution of 12.0 potassium sulfide was dropped at 60 C. or lower, and the reaction was carried out at 40 to 40 C. for 4 to 5 hours. After 50 C, vacuum concentration to 150 ~ 200mL, 0 ~ 10 C stirring for 2 hours,Filtration and drying gave 26.3 g of a dry product of the compound of formula 3 in a yield of 95%.
95.6%
With hydrazine hydrate; In ethanol; for 2h;Reflux;
S5, At room temperature 2-[[(S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidine-5-yl]methyl]- 1H-isoindole-1,3(2H)-dione(69.9 g, 0.165 mol) Obtained in step S4 was added to ethanol (1 L),80% hydrazine hydrate (0.044 g, 0.908 mmol) was added dropwise, and the mixture was heated to reflux for 2 h, then cooled to room temperature. The solvent was evaporated under reduced pressure. Water (1L) was evaporated. It was dried over anhydrous sodium sulfate, suction filtered, and then evaporated.The obtained residue was dried under reduced pressure to give a white solid(50.5g, 95.6%); Mp 149 ~ 152 C, [alpha]D25-42.6(c 0.1,DMSO) Chiral purity was 99.9% (HPLC normalization).
89.7%
With water; methylamine; In ethanol; at 40 - 60℃; for 8h;
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 30% aqueous solution of methylamine were stirred well.The reaction was heated to 40C to 60C for 8 hours, and TLC control (dichloromethane:methanol = 20:1, volume ratio) was completed.Adjust pH to 1-2 with 10% hydrochloric acid.A large amount of white solids precipitated and cooled to about 15C.Stir for 2 hours, filter and filter cake washed with 300 ml absolute ethanol.Drying under reduced pressure gave 147.0 g of a white solid (formula VIII) in a molar yield of 89.7%. The HPLC purity was 98.7%.
83.7%
Methylamine (35% in ethanol, 5kg) was added to a suspension of compound according to e.) (4.79kg) in ethanol (36kg) . The reaction mixture was heated to 65 0C for 4 hours. After cooling to 58-60 0C, a total of 7L of 5M hydrochloric acid solution is added until the pH is 2.7, after which the product starts to crystallize. After cooling to 20 0C, the precipitated reaction product is filtered off with suction, washed with CH2Cl2 (8L*2) and then dried to obtain 3.11kg of the product (Yield 83.7%)
82.7%
1360 g of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-iso-indole-1,3(2H)-dione (VI) are suspended in 10.2 l of ethanol at 22 C., and 1103 g of methylamine solution (40% strength in water) are added. The reaction mixture is then heated to 60 to 63 C., and the resulting solution is stirred at this temperature for 2 hours. After cooling to 55 to 60 C., a total of 2348 g of hydrochloric acid solution (20% strength in water) is added until the pH is 2.7, after which the product starts to crystallize. After cooling to 20 C., the precipitated reaction product is filtered off with suction, washed with methanol and then dried. Yield: 875 g; equivalent to 82.7% of theory. Melting point: decomposition above 280 C. 1H NMR (300 MHz, d6-DMSO): 3.25 (m, 2H), 3.72 (m, 2H), 3.98 (m, 3H), 4.42 (m, 3H), 4.97 (m, 1H), 7.42 (d, 2H, J=9.0 Hz), 7.57 (d, 2H, J=9.0 Hz), 8.44 (s (br.), 3H) ppm.
80%
With N-butylamine; In ethanol; at 75 - 80℃;Green chemistry;
Put the compound of formula II (42.1g), ethanol (252mL), and n-butylamine (47.2g, 8eq) into the reaction flask, warm the temperature to 75-80 C, and hold the reaction for 8-12 hours. After the reaction is completed, cool the reaction solution to 0 to 5 C, heat and stir for 1 hour, filter the obtained solid,The filter cake was rinsed with ethanol (20 mL) and dried to obtain the intermediate compound of formula I (23.3 g), purity (HPLC) 99.57%, and yield 80%.
79.60%
With methylamine; In methanol; isopropyl alcohol; at 25 - 60℃; for 6h;
To a 2000 ml 4 neck RBF, charge Isopropanol (1000 ml), Methyl amine 33% solution in methanol (1000 ml) and 100 gms compound (III). Stirr the reaction mass at 55-60C for 5 hrs. Cool the reaction mass at 25-30C and stirr for 1 hr. Filter the reaction mass and wash with Isopropanol (50 ml). Dry the solid at 45-50C under vacuum. Dry Wt: 55 gms (Theoretical yield: 79.60%); Purity: 97.70%
With hydrazine hydrate; In methanol; for 1h;Reflux;
Example 4: Preparation of 4-{4-[5(S)-(amino methyl)-2-oxo-l,3-oxazolidin-3- yI]phenyl}morpholin-3-one (II)Methanol (240 ml) and Hydrazine hydrate (26 g) were added to a flask containing the (2-{2-Oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-ylmethyl}-isoindole-l ,3-dione (40 g), heated for 1 hour at reflux temperature and cooled to room temperature. After completion of the reaction, 500ml of water was added to the reaction mass and was extracted with methylene dichloride (300 ml). The combined extractions were washed with water (100 ml) and the solvent was distilled completely to give 20 gms of the title compound.
With methylamine; In water; at 35℃; for 5h;
4- [4-((S)-5-aminomethyl]-2-oxooxazolidin-3-yl)phenyl]morpholine-3-one (VII) 100 gm (wet) (0.2375 moles) 2-({(5S)-2-Oxo-3-[4-{3-oxo-4-morpholmyl)phenyl]- l,3- oxazolidin-5-yl}methyl)- lH-isoindole- l,3(2H)-dione (VI) is added in 500 ml water and (46.02 gm, 1,4845 moles) methyl amine solution (40% Aqueous). Reaction mass is stirred at 35C for 5 hours to get 4-[4-((S)-5-aminomethyl]-2-oxooxazolidin-3-yl) phenyl]morpholine-3-one (VII). Reaction mass is subjected for degassing (i. e. kept under vacuum) for 1 hour to remove excess methyl amine. This aqueous reaction mass is used as such for the preparation of Rivaroxaban without isolation.
With methylamine; In ethanol; water; for 2h;Reflux;
4.45 g (10.6 mmol) of the structural compound of formula (II) was suspended in 100 ml of ethanol, 40 ml of a methylamine aqueous solution (10.2 ml, 142 mmol) was added, reflux for 2 hours, concentrate to dryness under reduced pressure. Add 100 ml of ethanol, continue to concentrate under reduced pressure to dry. The residue was cooled to room temperature, adding 90 ml of methylene chloride, and the mixture was stirred to obtain a dichloromethane solution of the compound of the formula (R-1) go directly to the next step.
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. The reaction mixture is subsequently heated under reflux for one hour and then, at 60 C., 4.5 l of ethanol are added. After cooling to 25 to 30 C., the precipitated reaction product is filtered off with suction, washed with ethanol and then dried. Yield: 2756 g; equivalent to 97.9% of theory. Melting point: 220.5 C.
93.55%
In dichloromethane; at 25 - 30℃; for 8h;
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 Nu,Nu' -dicarbonyldiimidazole (209.13 g) at 25 to 30C. The obtained reaction mass then stirred for 8hr. at 25 to 30C. Reaction mass is concentrated under reduced pressure to obtain residue. Added tetrahydrofuran (1700 ml) to residue. The obtained mixture is heated to 40 to 45C for 30 minutes followed by cooling to room temperature. Finally obtained solid is filtered off and washed by tetrahydrofuran(170 ml) Yield =93.55%
93.8%
In chlorobenzene; at 0 - 100℃; for 4h;Large scale;
This 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 example 1 , 170 kg of chlorobenzene and 8.5 kg of Nu,Nu-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 93.8%.
93.80%
In toluene; at 10 - 110℃; for 2h;
To a 2 litre 4 Neck RBF, charge Toluene (830 ml), Compound (IV) (100 gms). Stirr the reaction mass and cool to 10-15C. Charge N,N-carbonyl-diimidazole (82 gms). Reflux the reaction mass at 105-110C for 2 hrs. Cool the reaction mass to 55-60C and charge methanol (170 ml). Cool the reaction mass further to 25-30C and filter. Wash the residue with Methanol (50 gms). Dry the solid under vacuum. Dry Wt: 100 gms (Theoretical yield: 93.80%); Purity: 99.78%
91.08%
With dmap; In tetrahydrofuran; for 25h;Reflux; Large scale;
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%.
90.73%
In tetrahydrofuran; for 4h;Reflux;
142.5 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: 90.73%. HPLC purity: 99.74%. M.P.: 223 C. S.O.R.: [a ]D25 = -75.26 (c = 1 ,DMSO)
90%
In tetrahydrofuran; for 4h;Reflux;
Add 18.30 g of the white solid, 30.01 g of N, N-carbonyldiimidazole, and 220 ml of tetrahydrofuran to a 500 ml three-necked flask, heat to reflux, and reflux for 4 h. The system was cooled to room temperature, filtered, the solid was washed with 20 ml of tetrahydrofuran, and dried at 60 C. for 8 h to obtain 17.55 g of off-white solid with a yield of 90.0%.
88.3%
In toluene; for 3h;Industry scale; Reflux;
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 0C, ethanol (14L) was added. After cooling to 25 0C, the precipitate was filtered and 4.8 kg of (S) -2- ( (2-oxo-3- (4- (3- oxomorpholino) phenyl) oxazolidin-5-yl) methyl) isoindoline- 1, 3-dione was obtained as a colorless solid (Yield 88,3 %)
88.2%
With potassium carbonate; In dichloromethane; at 20℃; for 5h;
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 %); Purity (HPLC) =99.65 %]
88.2%
With potassium carbonate; In dichloromethane; at 20℃; for 5h;
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%); Purity (HPLC)=99.65%]
85%
In tetrahydrofuran; for 5h;Reflux;Product distribution / selectivity;
Example 1 : 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-mophiholinyl)phenyl]amino-propyl-lH-isoindol-l ,3(2H)- dione (10.0 g; 25 mmol), the compound of formula III, containing 1.0 % 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 20C, 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 60C. 9 g (85 % 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 99.98% were obtained, HPLC purity 99.7%, 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.
73%
With dmap; In tetrahydrofuran; for 21h;Reflux; Industrial scale;
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 Iota , Gamma- 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 Iota , Gamma-carbonyldiimidazole (0,09869 mol) was added. Then, the suspension was stirred under boiling for 14 hours. After that the mixture was cooled to 25C, 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 217C; HPLC 99.9%, content of the (R)- isomer below 0.03%, yield 73%.
In dichloromethane; at 30℃; for 20h;Product distribution / selectivity;
Example - 6: Preparation of 2-5(S)-{2-Oxo-3-[4-(3-oxo-morpholin-4-yl) phenyl]- oxazolidin-5-ylmethyl}-isoindoIe-l,3-dione (III)60 gms of 2-{2-Hydroxy-3-[4-(3-oxo-mo holin-4-yl)phenylamino]-propyl}-isoindole- 1 ,3-dione and 180 ml of methylene chloride were charged into a clean and dry 4 neck R.B. flask. 29 gms of carbonyl diimidazole was added at about 30C and the resultant reaction mixture was stirred at about 30C for about 20 hours. After completion of the reaction, the reaction mixture was washed with water and the solvent was distilled completely to give 55gms of the title compound.
With dmap; In dichloromethane; at 40 - 45℃;
100 g (i?)-2-(2-hydroxy-3-(4-(3-oxo-morpholino) phenyl amino) propyl) isoindoline-l,3-dione of Formula (F) and MDC (1000 ml) were added to RBF at 25C to 35C and heated to 40C to 45C. Further, 61 g Nu,Nu-Carbonyl diimidazole (CDI) and 0.5 g DMAP were added and stirred for 3-4 hours. Excess MDC was evaporated under reduced pressure. The reaction mass was cooled to 25C to 35C followed by addition of dilute HCl solution and stirred for 1 hour and finally filtered and washed with 2 x 200 ml water to afford title compound as (S)-2-((2-oxo 3-(4-(3-oxo- mo holno)phenyl)oxazolidin-5-yl)methyl)isoindoline-l,3-dione of Formula (I).
With dmap; In dichloromethane; at 40 - 45℃;
100 g (R)-2-(2-hydroxy-3-(4-(3-oxo-morpholino) phenyl amino) propyl) isoindoline-i ,3-dione of Formula (F) and MDC (i000 ml) were added to REF at 25 C. to 35 C. and heated to 40 C. to 45 C. Further, 6i g N,N-Carbonyl diimidazole (CDI) and 0.5 g DMAP were added and stirred for 3-4 hours. Excess MDC was evaporated under, reduced pressure. The reaction mass was cooled to 25 C. to 35 C. followed by addition of dilute HC1 solution and stirred for i hour and finally filtered and washed with 2x200 ml water to afford title compound as (S)-2-((2-oxo-3-(4-(3-oxo-mor- pholino)phenyl)oxazolidin-5-yl)methyl)isoindoline- i ,3-di- one of Formula (I).Excess MDC was evaporated under, reduced pressure. The reaction mass was cooled to 25 C. to 35 C. followed by addition of dilute HCl solution and stirred for 1 hour and finally filtered and washed with 2*200 ml water to afford title compound as (S)-2-((2-oxo-3-(4-(3-oxo-morpholino)phenyl)oxazolidin-5-yl)methyl)isoindoline-1,3-dione of Formula (I).
95 g
With dmap; at 80 - 85℃; for 6h;
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 80-85C 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 gm
b) 2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione N,N'-Carbonyldiimidazole (2.94 g, 18.1 mmol) and dimethylaminopyridine (catalytic amount) are added to a suspension of the amino alcohol (3.58 g, 9.05 mmol) in tetrahydrofuran (90 ml) under argon at room temperature. The reaction suspension is stirred at 60 C. for 12 h (the precipitate dissolves and, after some time, there is renewed formation of a precipitate), a second portion of N,N'-carbonyldiimidazole (2.94 g, 18.1 mmol) is added, and the mixture is stirred at 60 C. for a further 12 h.
b) 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione N,N'-Carbonyldiimidazole (2.94 g, 18.1 mmol) and dimethylaminopyridine (catalytic amount) are added at room temperature to a suspension of the amino alcohol (3.58 g, 9.05 mmol) in tetrahydrofuran (90 ml) under argon. The reaction suspension is stirred at 60 C. for 12 h (the precipitate goes into solution, after some time fresh formation of a precipitate), treated with a second portion of N,N'-carbonyldiimidazole (2.94 g, 18.1 mmol) and stirred for a further 12 h at 60 C.
Example 3: Preparation of 2-5 (S){2-oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl)-oxazolidin- 5-ylmethyI}-isoindole-l,3-dione (III)60 gms of 4-[4-(5-chloromethyl-2-oxo-oxazolidin-3-yl)-phen l]-mophiholin-3-one , potassium phthalimide (40 g) and Nu,Nu-dimethyl formamide (400 ml) were charged into a clean and dry 4 neck R.B. flask. The resultant reaction mixture was heated to reflux for about 5 hours. After completion of the reaction, the reaction mixture was cooled to about 30C, poured into 2 L of water and the solid separated was filtered to give 50 gms of the title compound
With pyrographite; In N,N-dimethyl-formamide; for 0.0833333h;Heating;Purification / work up;
Purification of intermediate compound of formula III using DMF and acetone50g of crude compound of formula III and 125 ml DMF were charged into a clean and dry 4 neck R.B.flask and heated to about 90C, the clear solution obtained, carbon (5g) was charged. The reaction suspension was stirred for 5 mins and filtered under hot conditions. The filtrate was cooled to about 30C, 150 ml of acetone was added and the solid separated was filtered after 30-45 min and washed with acetone(50ml) to afford 42.5g of pure product as half white colored solid.
Add 4 kg of N,N-dimethylformamide (DMF) to a 10 L reaction flask.Add 1.0 kg of compound (II), add 0.44 kg of methylamine gas, stir and heat.The reaction was stirred at 60-65 C for 5 h. The reaction solution was cooled to 40 ± 5 C,0.9kg of hydrochloric acid gas was introduced, and the reaction solution was cooled to 10±5C for crystallization for 1h~1.5h.Filtration, the filter cake was washed separately with DMF and ethanol, and the wet product was transferred to a 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: 96%, product purity (HPLC): 99.5%.
92%
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 40% aqueous methylamine (265 g) at 25 to 30C. Reaction mass is stirred for 1 h at 25 to 30C and then heated to 60 to 65C, and maintained at same temperature for 4 h. Reaction mixture then cooled to 25 to 30C 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= 92.0%
89.7%
The 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 30% 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 10% 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 89.7%, and 1 ^ (purity: 98.7%).
89.7%
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 30% aqueous solution of methylamine was stirred and heated to 40C to 60C for 8 hours.TLC control (dichloromethane:methanol = 20:1, volume ratio) reaction is complete, with 10% 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 89.7% and an HPLC purity of 98.7%.
86.5%
Reference example 3: 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 40% 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 5% by TLC. After cooling to 55-60 C, a total of 31.45 g (172.3 mmol) of 20% 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: 86.5%.
80%
Methyl amine (40 % 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 %); Purity (HPLC) = 98.0 %]
80%
Methylamine (40% strength, 153.2 ml) was added to suspension of <strong>[446292-08-6]2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione</strong> (150 gm) in methanol (1500 ml) at 25 to 30 C. The reaction mass was refluxed for 6 hr, cooled to 25-30 C., followed by slow addition of acetic acid (300 ml) reaction mass. Thereaction mass was stirred for 30 min at 25-30 C. pH of the reaction mass was adjusted to 2-3 using conc. HCl. Reaction mass was stirred for 1 hr & filtered off the solid. The solid obtained was washed with methanol (50 ml) Obtained solid 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, then adjusted the pH of reaction mass 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%); Purity (HPLC)=98.0%]
80.5%
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 40%) 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 (20% 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: 80.5%)
9 g (0.021 mol) of 2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin-5- yl}methyl)-1 H-isoindole-1 ,3(2H)-dione (II), 8.06 mL of methylamineamine (40% aqueous solution, 0.235 mol) and 80 mL of ethanol were charged in a 100 mL flask and the reaction mixture was heated to 65 C for 2h. Then, 10 mL of a 20% HCI solution was added until the pH of the reaction mass was adjusted to 2.7. The reaction mass was cooled to 30 C and the resulting solid was filtered off, washed with ethanol and dried under vacuum at 60 C.Yield: 5.3 g. Molar yield: 75.7%. HPLC purity: 93.9%
147 g
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 30% 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 10% hydrochloric acid, precipitate a large amount of white solid, cool down to about 15C, 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 89.7%. The HPLC purity was 98.7%.
(S)-4-{4-[5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one sulfate (2:1)[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82.7%
Reference example 1: Synthesis of (S)-4-{4-[5-(aminomethyl)-2-oxo-l,3-oxazolidin- 3-yl]phenyl}morpholin-3-one sulfate (2: 1) [compound IV-sulfate (2: 1)]26.07 g (61.9 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 196 mL of ethanol. 24.0 mL (278.4 mmol) of 40% w/w aqueous methylamine were added to the suspension, and the resulting mixture was heated to 60-65C and maintained at this temperature for about 2.5 hours. The content of unreacted compound III was checked to be below 5% by TLC. At this point, 75.1 g (178.2 mmol) of 20% w/w aqueous sulfuric acid were added over the reaction mixture while keeping the temperature above 60 C. Precipitation was observed during the addition. The resulting suspension was heated to 70-75 C and stirred at this temperature for about 1 hour, then cooled down to 20-25 C and stirred at this temperature for about 1 hour. Subsequently, the suspension was filtered and the collected solid was washed with 26.1 mL of ethanol followed by 26.1 mL of acetone to give 18.4 g of wet (,S)-4-{4-[5-(aminomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one sulfate (2: 1) as a white solid. Estimated dry mass: 17.4 g. Yield: 82.7%.
20.0 g (23.80 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 600 mL of acetonitrile and cooled to 0 C. A solution of 3.6 g (7.20 mmol) of sodium sulfide in 60 mL of water was added dropwise to the suspension over 1 hour. The reaction mixture was then stirred for 30 minutes between 5-10 C. The pH was adjusted to 7 using 1.5 M hydrochloric acid solution whilst maintaining the temperature at 5-10 C. The mixture was filtered and 40.0 g of sodium chloride were added to the filtrate. The aqueous phase was collected and kept aside. The organic phase and the solid obtained from the filtration were loaded into the reactor and cooled to 0 C. A solution of 3.6 g (7.20 mmol) of sodium sulfide in 60 mL of water was added dropwise to the suspension over 1 hour. The reaction mixture was then stirred for 30 minutes between 5-10 C. The pH was adjusted to 7 using 1.5 M hydrochloric acid solution whilst maintaining the temperature at 5-10 C. The mixture was filtered and 40.0 g of sodium chloride were added to the filtrate. The aqueous phase was collected and combined with the previous one which was kept aside. The combined aqueous phase was cooled to 0 C. The pH was adjusted to 4-5 using 1.5 M hydrochloric acid solution whilst maintaining the temperature at 5-10 C. 40.0 g of sodium chloride were added and the solution was extracted twice with 600 mL of acetonitrile. The combined organic phases were dried with 60 g of anhydrous sodium sulfate, filtered and concentrated under vacuum without exceeded 38 C . 1 1 .0 g of (5)-2-[({2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3- oxazolidin-5-yl}methyl)carbamoyl]benzoic acid (compound V) were obtained as a pale yellow foam-like solid. Yield: 56.0 %. HPLC chromatographic purity: 95.29% (% area).
10 g (0.024 mol) of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin-5- yl}methyl)-1 H-isoindole-1 ,3(2H)-dione (II), 7.12 mL of methylamine (40% aqueous solution, 0.083 mol) and 150 mL of methanol were charged in a 1 L autoclave and heated to reflux temperature (65.0C) for 1 hour. Afterwards, the reaction mass was cooled to 25-30C and transferred to another flask. Then, 9.9 g (0.095 mol) of malonic acid in 50 mL of methanol were added dropwise within 30 min. Then, the reaction mass was stirred to 25-30 C for 24 hours. The solid obtained after filtration was stirred in 100 mL of ethanol at 25 C for 1 hour. Finally, the solid obtained was filtered off and dried under vacuum at 50 C.Yield: 5.9 g. Molar yield: 62.89%. HPLC purity: 99.15%. MP.: 189.14 C (DSC).XRD (2Th): 18.0, 20.1 , 21 .6, 23.0, 24.0, 24.1 , 24.3, and 27.6 as shown in figure 5. IR (cm"1): 3473.0, 2912.5, 2691.9, 1745.6, 1661 .6, 1598.7, 1519.5, 1459.3, 1475.5, 1434.8, 1409.9, 1378.0, 1343.0, 1328.9, 131 1.1 , 1288.9, 1263.3, 1227.1 , 1 162.2, 1 136.7, 1 125.3, 1060.4, 1037.9, 1002.6, 982.6, 919.5, 858.4, 833.0, 777.3, 752.5, 710.8, 689.0, 671.8, 597.5, 556.5, 547.3, 526.1 , 516.0, 505.8, 495.9, 486.1 , 475.3, 465.5 and 455.6 as shown in figure 6. Example
25 g (0.012 mol) of 2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin- 5-yl}methyl)-1 H-isoindole-1 ,3(2H)-dione (II), 1 1.2 mL of methylamine (40% aqueous solution, 0.058 mol) and 125 mL of methanol were charged in a 500 mL flask. Then, the reaction mass was heated to reflux for 1 hour and concentrated under reduced pressure. The crude product was slurried in 125 mL of toluene and 16.5 mL of triethylamine were added to the reaction mass at 25 C. Afterwards, 17.81 g (0.098 mol) of 5-chlorothiophene-2-carbonyl chloride in 100 mL of toluene were added dropwise and the reaction mass was stirred for 1 hour at 25 C. At this stage, the reaction mass was heated at 50 C for 1 hour and 75 ml of water was added at the same temperature. Finally, the resulting product was filtered off, washed with water and dried under vacuum at 50 C.Yield: 15 g. Molar yield: 52.63%. HPLC purity 81.82%
2-{{(5S)-2-Oxo-3-(4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-ymethyr|- lH-isoindole- l ,3(2H)-dione ( 100 gm) and ethanol (1500 ml) charged into flask. Added methylamme (40%) solution (230 ml) at ambient temperature. Refluxed for one hour.After completion of reaction distilled off solvent completely. Charged pyridine ( 3,9 L) to the mass, cooled to 5C. Added 5'- chlorothiophene-2-carbonyichloride (51.5 gm) . Raise the. temperature to ambient temperature maintained for one hour and further extracted with, methylene chloride. The organic phase dried with sodium sulphate. Concentrated the organic layer under reduced pressure to obtain Rivaroxaban,
50 g (0.1 10 mol) of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1 ,3-oxazolidin-5- yl}methyl)-1 H-isoindole-1 ,3(2H)-dione (II), 45.81 mL of methylamine (40% aqueous solution, 0.53 mol) and 1250 mL of methanol were charged in a 3 L flask and the reaction mixture was heated to 65 C for 1 hour. Afterwards, 77.81 g (0.610 mol) of oxalic acid dihydrate in 233 mL of methanol were added dropwise until pH 2-3 was reached, at which the solid started to precipitate, and heated the reaction mass to reflux for 1 hour. After cooling to 25 C for 1 h, the product was filtered off, washed with methanol and dried under vacuum at 50 C.Yield: 37 g. Molar yield: 82.22%. HPLC purity: 99.91 %. M.P.: 195.90 C (DSC).
100 g (S)-2-((2-oxo-3-(4-(3-oxo-morpholino)phenyl)oxazolidin-5-yl)methyl)isoindoline-1,3-dione of Formula (I), 1000 ml Methanol and 119 g methyl amine were added to RBF at 25 C. to 35 C. The reaction was heated to 60 C. to 65 C. for 1-2 hours. To the reaction mass oxalic acid (15 g) was added till to pH 5.5 to 6.0 and maintained for 30 minutes. The reaction mass was cooled to 45 to 50 C. and maintained for 30 minutes. The reaction mass was cooled to 25 to 35 C. and maintained for 30 minutes. The product was filtered and washed with methanol (50 ml*2) afforded the oxalate salt of (S)-4-(4-(5-(aminomethyl)-2-oxo-oxazolidin-3-yl)phenyl)morpholin-3-one of Formula (JO).
With potassium carbonate; In N,N-dimethyl-formamide; at 25 - 45℃; for 10h;
500 mL DMF and 30 g Phthalimide, 91.08 g K2C03 and 100 g (7?)-(2-oxo-3-(4- (3-oxo-mo holino) phenyl) oxazolidin-5-yl)methyl 4-methylbenzenesulfonate of Formula (H) were added to RBF at 25C to 35C. The reaction mass was heated to 40C to 45 C and stirred for 10 hours. Further, reaction mass was treated 1000 ml 10% HC1 solution and 500 ml MDC. The MDC layer was washed with 3 x 500 mL 10% HCL solution to afford the title compound as (S)-2-((2-oxo-3-(4-(3-oxo- mophiholino)phenyl)oxazolidin-5-yl)methyl) isoindoline-l,3-dione of Formula (I).
With hydrogenchloride; potassium carbonate; In N,N-dimethyl-formamide; at 25 - 45℃; for 10h;
500 mL DMF and 30 g Phthalimide, 91.08 g K2CO3 and 100 g (R)-(2-oxo-3-(4-(3-oxo-morpholino) phenyl)oxazolidin-5-yl)methyl 4-methylbenzenesulfonate of Formula (H) were added to RBF at 25 C. to 35 C. The reaction mass was heated to 40 C. to 45 C. and stirred for 10 hours. Further, reaction mass was treated 1000 ml 10% HCl solution and 500 ml MDC. The MDC layer was washed with 3*500 mL 10% HCL solution to afford the title compound as (S)-2-((2-oxo-3-(4-(3-oxo-morpholino)phenyl)oxazolidin-5-yl)methyl)isoindoline-1,3-dione of Formula (I).
100 g (S)-2-((2-oxo-3-(4-(3-o o-mo holino)phenyl)oxazol^din-5- yl)methyl)isoindoline-l,3-dione of Formula (I), 1000 ml Methanol and 119 g methyl amine were added to RBF at 25C to 35C. The reaction was heated to 60C to 65C for 1-2 hours. To the reaction mass formic acid (15g) was added till to pH 5.5 to 6.0 and maintained for 30 minutes. The reaction mass was cooled to 45 to 50C and maintained for 30 minutes. The reaction mass was cooled to 25 to 35C andmaintained for 30 minutes. The product was filtered and washed with methanol (50 ml x 2) afforded the formate salt of (S)-4-(4-(5-(Aminomethyl)-2-oxooxazolidin-3- yl)phenyl)morpholin-3 -one of Formula (JF).
100 g (S)-2-((2-oxo-3-(4-(3-oxo-morpholino)phenyl)oxazolidin-5-yl)methyl)isoindoline-1,3-dione of Formula (I), 1000 ml Methanol and 119 g methyl amine were added to RBF at 25 C. to 35 C. The reaction was heated to 60 C. to 65 C. for 1-2 hours. To the reaction mass formic acid (15 g) was added till to pH 5.5 to 6.0 and maintained for 30 minutes. The reaction mass was cooled to 45 to 50 C. and maintained for 30 minutes. The reaction mass was cooled to 25 to 35 C. and maintained for 30 minutes. The product was filtered and washed with methanol (50 ml*2) afforded the formate salt of (S)-4-(4-(5-(Aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one of Formula (JF).
(S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one oxalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100 g (S)-2-((2-oxo-3-(4-(3-oxo-morpholino)phenyl)oxazolidin-5- yl)methyl)isoindoline-l,3-dione of Formula (I), 1000 ml Methanol and 119 g methyl amine were added to RBF at 25C to 35C. The reaction was heated to 60C to 65C for 1-2 hours. To the reaction mass oxalic acid (15g) was added till to pH 5.5 to 6.0 and maintained for 30 minutes. The reaction mass was cooled to 45 to 50C andmaintained for 30 minutes. The reaction mass was cooled to 25 to 35C and maintained for 30 minutes. The product was filtered and washed with methanol (50 ml x 2) afforded the oxalate salt of (S)-4-(4-(5-(aminomethyl)-2-oxo-oxazolidin-3- yl)phenyl)morpholin-3-one of Formula (JO). ^
4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one succinic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61.9%
2-({(5S) -2-oxo-3-[4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5- yl} methyl)-1,3(2H) -dione (Formula 5) were added 75 ml of ethanol and 8.1 ml of a methylamine solution (concentration in water 40%) was added.The reaction mixture was then diluted with 60In Heating, Stir at this temperature for 2 hours.Confirm that the reaction is completed, and while maintaining the temperature, dilute the solution with 50 ml of ethanol and 3.04 ml of phosphoric acid, and slowly add the solution to the reaction solution. After confirming that the crystallization of the product was initiated and cooling to 20 C, the precipitated reaction product was filtered under suction. The resulting solid was dispersed in 110 ml of methanol, refluxed for 30 minutes and stirred, and then cooled to room temperature. The resulting crystals were filtered,And dried at 50 DEG C for 4 hours to obtain 11.1 g of morpholine diphosphate (Formula 2). (Yield: 96.0%)
100 g (S)-2-((2-oxo-3-(4-(3-oxo-morpholino)phenyl)oxazolidin-5- yl)methyl)isoindoline-l,3-dione of Formula (I), 1000 ml methanol and 119 g methyl amine were added to RBF at 25C to 35C. The reaction was heated to 60C to 65C for 1-2 hours. To the reaction mass succinic acid (15g) was added till to pH 5.5 to 6.0 and maintained for 30 minutes. The reaction mass was cooled to 45 to 50C and maintained for 30 minutes. The reaction mass was cooled to 25 to 35C and maintained for 30 minutes. The product was filtered and washed with methanol (50 ml x 2) afforded succinate salt of (S)-4-(4-(5-(aminomethyl)-2-oxo-^xazolidin-3- yl)phenyl)morpholin-3-one of Formula (JS).
10 g (S)-2-((2-oxo-3-(4-(3-oxo-morpholino)phenyl)oxazolidin-5- yl)methyl)isoindoline-l,3-dione of Formula (I), 70 ml methanol and 60 ml monomethyl amine were added to RBF at 25C to 35C. The reaction was heated to 60C to 65C for 1-2 hours. To the reaction mass L (+)-mandelic acid (3.6 g) was added and maintained for 30 minutes. The reaction mass was cooled to 45 to 50C and maintained for 30 minutes. The reaction mass was cooled to 25 to 35C and maintained for 30 minutes. The product was filtered and washed with methanol (50 ml x 2) afforded the L(+)-mandelate salt of (S)-4-(4-(5-(aminomethyl)-2-oxo-oxazolidin- 3-yl)phenyl)morpholin-3-one of Formula (JM).
10 g (S)-2-((2-oxo-3-(4-(3-oxo-morpholino)phe- nyl)oxazolidin-5-yl)methyl)isoindoline- i ,3-dione of Formula (I), 70 ml methanol and 60 ml monomethyl amine were added to REF at 25 C. to 35 C. The reaction was heated to 60 C. to 65 C. for i-2 hours. To the reaction mass L (+)- mandelic acid (3.6 g) was added and maintained for 30 minutes. The reaction mass was cooled to 45 to 50 C. and maintained for 30 minutes. The reaction mass was cooled to 25 to 35 C. and maintained for 30 minutes. The product was filtered and washed with methanol (50 mlx2) afforded the L(+)-mandelate salt of(S)-4-(4-(5-(aminomethyl)-2-oxo-ox- azolidin-3-yl)phenyl)morpholin-3-one of Formula (JM).
With dmap; In tetrahydrofuran; for 0.666667h;Reflux;
200 ml of THF were added to 15.5 g of 2-((2 ?)-2-hydroxy-3-[4-(3-oxomorpholin-4- yl)phenyl]amino}propyl)- l H-isoindol- l ,3(2H)-dione (14, 0.0392 mol), 19.0 g of Iota , Gamma- carbonyldiimidazole (0.1 176 mol) and 0.05 g of 4-dimethylamino)pyridine. The suspension was stirred and heated to boiling. After ca. 20 minutes from the beginning of boiling the suspension got dissolved, and conversely, after another 5 minutes of boiling a solid substance was formed. Then, the mixture was boiled for another 15 minutes and after that cooled to ca. 40C, which was followed by filtration, washing of the cake with THF (25 ml) and drying. 17.8 of an off-white powder that first melts at 165-175C, then re-crystallizes and melts again at 215 to 217C was obtained. According to HPLC the isolated product was a mixture of 39.6% of the compound (15) and 60.4% of the compound (16), see Fig. 2.
With potassium tert-butylate; In tetrahydrofuran; for 19h;Reflux;
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 (20% 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 35C 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 215-217C was obtained; HPLC 99.8%, content of the (R isomer below 0.03%, yield 78%, see Fig. 4.
With hydrazine hydrate; In ethanol; at 65℃; for 3h;
20 g of 2-({(5S) -2-oxo-3-[4-(3-oxomo holin-4-yl) henyl]-1 ,3-oxazolidin-5-yl}methyl)-1H- isoindole-1,3(2H)-dione was suspended in 450 ml of ethanol, which was followed by addition of 6 ml of hydrazinehydrate in 50 ml of ethanol and the mixture was stirred and refluxed for 3 hours. Then, the suspension was cooled down to 65C and filtered and the cake was washed with 2x50 ml of nearly boiling ethanol. After drying 7.2 g of an off-white powder were obtained, which slowly melted at a temperature over 260C (this fraction contained 99.9% of 2,3-dihydrophtalazine-l,4-dione according to HPLC). After cooling of the hot filtrate another solid fraction separated. After its isolation by filtration and drying, 12.5 g of white lumpy powder with the melt, point of 141-144C was obtained (this fraction contained 86.7% of the desired product, 12.7% of 2,3-dihydrophtalazine-l,4-dione, and the rest to 100 % were other unidentifiable impurities according to HPLC). The yield of the isolated amine calculated to the pure substance was 73%.
With N-benzyl-N,N,N-triethylammonium chloride; potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 18h;
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 80C .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 % of the theory).
With lithium tert-butoxide; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 44h;Cooling with ice;
To a solution of [4-(3-oxo-mophiholin-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 % of the theory).
(S)-2-phthalimido-1-(chloromethyl)ethyl acetate[ No CAS ]
[ 1313613-18-1 ]
[ 446292-08-6 ]
Yield
Reaction Conditions
Operation in experiment
0.92 g
With lithium tert-butoxide; In tetrahydrofuran; methanol; N,N-dimethyl-formamide; at 5 - 24℃; for 21h;
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 24C with an ice-bath . The solution is cooled to 5C, (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 MgS04 and concentrated to get crude compound .Re-crystallize from acetone to yield a title compound as a white - crystalline solid (Yield= 0.92 g, 22 % of the theory).
(S)-4-(4-(5-(aminomethyl)-2-oxo-oxazolidin-3-yl)phenyl)morpholin-3-one succinate salt[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
100 g (S)-2-((2-oxo-3-(4-(3-oxo-morpholino)phenyl)oxazolidin-5-yl)methyl)isoindoline-1,3-dione of Formula (I), 1000 ml methanol and 119 g methyl amine were added to RBF at 25 C. to 35 C. The reaction was heated to 60 C. to 65 C. for 1-2 hours. To the reaction mass succinic acid (15 g) was added till to pH 5.5 to 6.0 and maintained for 30 minutes. The reaction mass was cooled to 45 to 50 C. and maintained for 30 minutes. The reaction mass was cooled to 25 to 35 C. and maintained for 30 minutes. The product was filtered and washed with methanol (50 ml*2) afforded succinate salt of (S)-4-(4-(5-(aminomethyl)-2-oxo-oxazolidin-3-yl)phenyl)morpholin-3-one of Formula (JS).
(5S)-4-{4-[5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one nitrate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76.9%
This example relates to preparation of the compound (5S)-4-{4-[5- (aminomethyl)-2-oxo-1 ,3-oxazolidine-3-yl]phenyl}morpholine-3-one nitrate, step c) of the process. 17.0 kg of the compound (IV) obtained in example 2, 170 kg of ethanol and 20.4 kg of methylamine in aqueous solution at 40% by weight, are loaded into a reactor. The temperature of the reactant system is then brought to about 60 C and maintained at this value for 3 hours. At the end of the reaction, the mass obtained is distilled under vacuum until a dense residue is obtained; 170 kg of ethanol and 34.0 kg of water are added to the residue. 4.47 kg of an aqueous solution at 65% by weight of nitric acid, are slowly added to the mixture thus obtained, maintained at a temperature of about 30 C. At the end of the addition of the acid, the precipitate is filtered and washed with 25.5 kg of ethanol and lastly oven-dried. 1 1 .0 kg of the desired compound (V) are obtained, with a reaction yield equal to 76.9%.
To 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 (Pi1) 6. 7g, 93% yield.
4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
With methylamine; In ethanol; water; at 60 - 70℃;
Into a 100ml three-neck round bottom flask was added the compound (III) (3.0g, 7.1mmol), 25% aqueous methylamine solution (3.89 g of the) and ethanol (22.5ml), heated to 60 ~ 70 for 2 to 3 hours, cooling to room temperature, concentrated hydrochloric acid was added to adjust PH 1-2, filtered, Suntory rivaroxaban V intermediate compound hydrochloride salt 1.98g, yield 85%
85%
5L three-necked flask with a compound of formula (II)(100, (^, 24011111101),Anhydrous ethanol 6001111 (6ml / g), stirring, suspended state,Room temperature dropMethylamine solution(40% aqueous solution, 56 g, 720 mmo 1),The reaction system gradually heated to 60 ~ 63 C, keep the temperature stirring for 2 hours,(20 ~ 25 C), suction filter, filter cake methanol washing, drying and drying for 6 hours, to give the formula (20 ~ 25 C), and then cooled to 55 C, III) hydrochloride of the structural compound in a yield of 85%.
147 g
The 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), 1500 ml of absolute ethanol, 500 ml of 30% aqueous methylamine solution, stirred evenly, heated to 40 C to 60 C for 8 hours, TLC in the control (dichloromethane: methanol = 20: 1, volume ratio) reaction is complete, with 10% hydrochloric acid to adjust the pH between 1-2 to precipitate a large number of white solid, cooled to about 15 C, stirring 2 hours, filter. The filter cake was washed with 300 ml of absolute ethanol and dried under reduced pressure to give 147.0 g of a white solid (compound of formula VIII) with a molar yield of 89.7% and an HPLC purity of 98.7%.
(S)-2-[[2-oxo-1,3-oxazolidin-5-yl]methyl]-1H-isoindole-1,3(2H)-dione[ No CAS ]
[ 446292-08-6 ]
Yield
Reaction Conditions
Operation in experiment
92.2%
With copper(l) iodide; N,N-dimethyl-ethanamine; potassium carbonate; In dichloromethane; at 100℃; for 15h;Sealed tube;
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 92.2% and a purity of 99.6%.
92.5%
With copper(l) iodide; N,N-dimethyl-ethanamine; potassium carbonate; In dichloromethane; at 100℃; for 15h;Sealed tube;
S4, (S)-2-[[2-oxo-1,3-oxazolidine-5-yl]methyl]-1H-isoindole-1,3(2H)-dione which is obtained in the step S3 (54.45g, 0.24mol), CuI (2.1g, 11mmol), N,N-dimethylethylamine (1.65ml, 33mmol) and potassium carbonate (76.0g, 0.55mol) were added to dichloromethane (330ml) ), 4-(4-bromophenyl)morpholin-3-one (76.0 g, 0.22 mol) was added under stirring, the reaction flask was sealed, stirred in an oil bath at 100 C for 15 h, cooled to room temperature, and the solvent was evaporated under reduced pressure. , poured into water (550 ml), extracted with ethyl acetate (500 ml × 3), combined with organic phase, with saturated sodium chloride solution (330 ml)×2) Washed, dried over anhydrous sodium sulfate, filtered, and evaporated.Obtained as a white solid (85.5 g, 92.5%);Mp 217 ~ 219 C, [alpha]D25-25.4(c 0.1, dichloromethane).
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 97.9%
89%
With triethylamine; In dichloromethane; at 0 - 10℃;
Amino 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 0C - 5C. To the cooled reaction mass added triphosgene solution, 51.09 gms in 340 ml MDC, 0.18 moles drop wise at 5C - 10C 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 25C -30C, stirred for 30 min, filtered. Wet material dried at 55C -60C to afford 162 gm dry material. Yield- 89%
(S)-{1-(chloroformate)-2-[2-(1,3-dioxoisoindol)yl]ethyl}magnesium chloride[ No CAS ]
4-[4-(methylideneamino)phenyl]morpholin-3-one[ No CAS ]
[ 446292-08-6 ]
Yield
Reaction Conditions
Operation in experiment
91.4%
In tetrahydrofuran; at 0 - 5℃; for 7h;
The reaction flask was charged with 159.3 g (0.78 mol) of 4-(4-methylaminophenyl)-3-morpholinone prepared in Example 1.(Formula III), 300 ml of tetrahydrofuran, stirring uniformly, the temperature was controlled at 0 C. to 5 C., and the intermediate VI prepared in Example 5 was added dropwise. After completion of the dropwise addition, the reaction was incubated for 7 hours. The supernatant in the reaction solution was taken as HPLC control. The intermediate III is completely reacted and filtered. The filter cake is washed successively with 200 ml of tetrahydrofuran and 200 ml of 95% ethanol, and dried under reduced pressure to obtain 300.4 g of a white solid (compound of formula VII) with a molar yield of 91.4% and an HPLC purity of 98.9%.
300.4 g
In tetrahydrofuran; at 0 - 5℃; for 7h;
The reaction flask was charged with 159.38 (0.78 mol) of 4-(4-methylaminophenyl)-3-morpholinone (Formula III) prepared in Example 1,300 ml of tetrahydrofuran, stirred uniformly at a temperature of 0 C to 5 C. The intermediate VI prepared in Example 5 was added dropwise, After the addition was complete the reaction was kept 7 hours, the reaction mixture taken to do the HPLC supernatant control, completion of the reaction intermediate III, The filter cake was washed with 200ml of tetrahydrofuran and 200ml 95% ethanol successively,Dried under reduced pressure to give 300.4 g of a white solid (compound of formula VII) in a molar yield of 91.4% and an HPLC purity of 98.9%.
300.4 g
In tetrahydrofuran; at 0 - 5℃; for 7h;
The reaction flask was charged with 159.3 g (0.78 mol) of 4-(4-methylaminophenyl)-3-morpholinone (Formula III) prepared in Example 1, 300 ml of tetrahydrofuran, and the temperature was controlled at 0 C. The intermediate VI prepared in Example 5 was added dropwise at 5 C. After the addition was complete, the reaction was incubated for 7 hours. The supernatant in the reaction solution was taken as the HPLC control, and the intermediate III was completely reacted and filtered. The filter cake was 200 ml of tetrahydrofuran and 200 ml of The 95% ethanol was washed sequentially and dried under reduced pressure to give 300.4 g of a white solid (compound of formula VII) with a molar yield of 91.4% and an HPLC purity of 98.9%.
4-[4-(methylideneamino)phenyl]morpholin-3-one[ No CAS ]
(S)-1-chloro-2-[2-(1,3-dioxoisoindolyl)ethyl]ethyl chloroformate[ No CAS ]
[ 446292-08-6 ]
Yield
Reaction Conditions
Operation in experiment
91.4%
The reaction flask was charged with 300 ml of THF, 23.1 g (0.95 mol) of the pretreated magnesium residue,Iodine 3.55g (0.014mol), nitrogen under the protection of uniform mixing,Temperature control at 10 to 20 ,And 224.7 g (0.78 mol) of the compound prepared in Example 3 dissolved in 400 ml of THF was slowly added dropwise,(S) -1-halo-2- [2- (1,3-dioxinoindolyl) ethyl] ethyl chloroformate (formula V), the reaction was carried out for 5 hours,(S) - {1- (chloroformate) -2- [2- (1,3-dioxoisoindolyl) ethyl] magnesium chloride (Formula VI) was prepared.Magnesium Chip Pretreatment Method: Wash with 10% hydrochloric acid for 30 minutes, quickly filter, rinse with acetone, vacuum dry, straight Then put into use in the reaction.The reaction flask was charged with 159.38 (0.78111001) prepared in Example 1,4- (4-methylaminophenyl) -3-morpholinone (Formula III), 300 ml of tetrahydrofuran,Temperature Control The intermediate VI prepared in Example 5 was added dropwise at 0 C to 5 C and incubated for 7 hours after the dropwise addition,Take the reaction solution in the liquid clear HPLC control,Intermediate III is complete,The filter cake was washed successively with 200 ml of tetrahydrofuran and 200 ml of 95% ethanol and dried under reduced pressure to give 300 g of a white solid (compound of formula VII) having a molar yield of 91.4% and an HPLC purity of 98.9%.
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 (93.2%)
With N,N-dimethyl-aniline; In chloroform; at -20 - 10℃; for 10h;Inert atmosphere;
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 -20C ~ 10C 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 97.6% yield. HPLC, the purity was 98.95%.
4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one diphosphate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
2-({(5S) -2-oxo-3-[4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5- yl} methyl)-1,3(2H) -dione (Formula 5) were added 75 ml of ethanol and 8.1 ml of a methylamine solution (concentration in water 40%) was added.The reaction mixture was then diluted with 60In Heating, Stir at this temperature for 2 hours.Confirm that the reaction is completed, and while maintaining the temperature, dilute the solution with 50 ml of ethanol and 3.04 ml of phosphoric acid, and slowly add the solution to the reaction solution. After confirming that the crystallization of the product was initiated and cooling to 20 C, the precipitated reaction product was filtered under suction. The resulting solid was dispersed in 110 ml of methanol, refluxed for 30 minutes and stirred, and then cooled to room temperature. The resulting crystals were filtered,And dried at 50 DEG C for 4 hours to obtain 11.1 g of morpholine diphosphate (Formula 2). (Yield: 96.0%)
4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrobromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82.6%
2 - ({(5S) -2-oxo-3- [4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5- yl} methyl) -1,3 (2H) -dione (Formula 5) was suspended in 75 ml of ethanol at 22 , and 8.1 g of a methylamine solution (concentration in water of 40%) was added.The reaction mixture was then heated to 60-63 C and stirred at this temperature for 2 hours.After cooling to 55-60 & lt; 0 & gt; C, a total of 14.6 g of a solution of bromic acid (47% in water) was added until the pH was 2.7. After confirming that the crystallization of the product started, the precipitated reaction product was filtered off under suction, washed with methanol, and then dried at 50 DEG C for 4 hours to obtain 7.3 g of the desired product (Yield: 82.6%).
4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74.6%
2-({(5S) -2-oxo-3-[4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5- yl} methyl)-1,3(2H) -dione (Formula 5) were added 75 ml of ethanol and 8.1 ml of a methylamine solution (concentration in water 40%) was added.The reaction mixture was then diluted with 60In Heating, Stir at this temperature for 2 hours.Confirm that the reaction is completed, and while maintaining the temperature, dilute the solution with 50 ml of ethanol and 3.04 ml of phosphoric acid, and slowly add the solution to the reaction solution. After confirming that the crystallization of the product was initiated and cooling to 20 C, the precipitated reaction product was filtered under suction. The resulting solid was dispersed in 110 ml of methanol, refluxed for 30 minutes and stirred, and then cooled to room temperature. The resulting crystals were filtered,And dried at 50 DEG C for 4 hours to obtain 11.1 g of morpholine diphosphate (Formula 2). (Yield: 96.0%)
4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one citric acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
67.7%
2-({(5S) -2-oxo-3-[4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5- yl} methyl)-1,3(2H) -dione (Formula 5) were added 75 ml of ethanol and 8.1 ml of a methylamine solution (concentration in water 40%) was added.The reaction mixture was then diluted with 60In Heating, Stir at this temperature for 2 hours.Confirm that the reaction is completed, and while maintaining the temperature, dilute the solution with 50 ml of ethanol and 3.04 ml of phosphoric acid, and slowly add the solution to the reaction solution. After confirming that the crystallization of the product was initiated and cooling to 20 C, the precipitated reaction product was filtered under suction. The resulting solid was dispersed in 110 ml of methanol, refluxed for 30 minutes and stirred, and then cooled to room temperature. The resulting crystals were filtered,And dried at 50 DEG C for 4 hours to obtain 11.1 g of morpholine diphosphate (Formula 2). (Yield: 96.0%)
4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one adipic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74.4%
2-({(5S) -2-oxo-3-[4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5- yl} methyl)-1,3(2H) -dione (Formula 5) were added 75 ml of ethanol and 8.1 ml of a methylamine solution (concentration in water 40%) was added.The reaction mixture was then diluted with 60In Heating, Stir at this temperature for 2 hours.Confirm that the reaction is completed, and while maintaining the temperature, dilute the solution with 50 ml of ethanol and 3.04 ml of phosphoric acid, and slowly add the solution to the reaction solution. After confirming that the crystallization of the product was initiated and cooling to 20 C, the precipitated reaction product was filtered under suction. The resulting solid was dispersed in 110 ml of methanol, refluxed for 30 minutes and stirred, and then cooled to room temperature. The resulting crystals were filtered,And dried at 50 DEG C for 4 hours to obtain 11.1 g of morpholine diphosphate (Formula 2). (Yield: 96.0%)
4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one camphoric acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.8%
2-({(5S) -2-oxo-3-[4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5- yl} methyl)-1,3(2H) -dione (Formula 5) were added 75 ml of ethanol and 8.1 ml of a methylamine solution (concentration in water 40%) was added.The reaction mixture was then diluted with 60In Heating, Stir at this temperature for 2 hours.Confirm that the reaction is completed, and while maintaining the temperature, dilute the solution with 50 ml of ethanol and 3.04 ml of phosphoric acid, and slowly add the solution to the reaction solution. After confirming that the crystallization of the product was initiated and cooling to 20 C, the precipitated reaction product was filtered under suction. The resulting solid was dispersed in 110 ml of methanol, refluxed for 30 minutes and stirred, and then cooled to room temperature. The resulting crystals were filtered,And dried at 50 DEG C for 4 hours to obtain 11.1 g of morpholine diphosphate (Formula 2). (Yield: 96.0%)
4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one boric acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37.7%
2-({(5S) -2-oxo-3-[4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5- yl} methyl)-1,3(2H) -dione (Formula 5) were added 75 ml of ethanol and 8.1 ml of a methylamine solution (concentration in water 40%) was added.The reaction mixture was then diluted with 60In Heating, Stir at this temperature for 2 hours.Confirm that the reaction is completed, and while maintaining the temperature, dilute the solution with 50 ml of ethanol and 3.04 ml of phosphoric acid, and slowly add the solution to the reaction solution. After confirming that the crystallization of the product was initiated and cooling to 20 C, the precipitated reaction product was filtered under suction. The resulting solid was dispersed in 110 ml of methanol, refluxed for 30 minutes and stirred, and then cooled to room temperature. The resulting crystals were filtered,And dried at 50 DEG C for 4 hours to obtain 11.1 g of morpholine diphosphate (Formula 2). (Yield: 96.0%)
4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one malic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98.8%
2-({(5S) -2-oxo-3-[4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5- yl} methyl)-1,3(2H) -dione (Formula 5) were added 75 ml of ethanol and 8.1 ml of a methylamine solution (concentration in water 40%) was added.The reaction mixture was then diluted with 60In Heating, Stir at this temperature for 2 hours.Confirm that the reaction is completed, and while maintaining the temperature, dilute the solution with 50 ml of ethanol and 3.04 ml of phosphoric acid, and slowly add the solution to the reaction solution. After confirming that the crystallization of the product was initiated and cooling to 20 C, the precipitated reaction product was filtered under suction. The resulting solid was dispersed in 110 ml of methanol, refluxed for 30 minutes and stirred, and then cooled to room temperature. The resulting crystals were filtered,And dried at 50 DEG C for 4 hours to obtain 11.1 g of morpholine diphosphate (Formula 2). (Yield: 96.0%)
4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one glutaric acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73.5%
2-({(5S) -2-oxo-3-[4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5- yl} methyl)-1,3(2H) -dione (Formula 5) were added 75 ml of ethanol and 8.1 ml of a methylamine solution (concentration in water 40%) was added.The reaction mixture was then diluted with 60In Heating, Stir at this temperature for 2 hours.Confirm that the reaction is completed, and while maintaining the temperature, dilute the solution with 50 ml of ethanol and 3.04 ml of phosphoric acid, and slowly add the solution to the reaction solution. After confirming that the crystallization of the product was initiated and cooling to 20 C, the precipitated reaction product was filtered under suction. The resulting solid was dispersed in 110 ml of methanol, refluxed for 30 minutes and stirred, and then cooled to room temperature. The resulting crystals were filtered,And dried at 50 DEG C for 4 hours to obtain 11.1 g of morpholine diphosphate (Formula 2). (Yield: 96.0%)
4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one malonic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84.5%
2-({(5S) -2-oxo-3-[4- (3-oxo-4-morpholinyl) phenyl] -1,3-oxazolidin-5- yl} methyl)-1,3(2H) -dione (Formula 5) were added 75 ml of ethanol and 8.1 ml of a methylamine solution (concentration in water 40%) was added.The reaction mixture was then diluted with 60In Heating, Stir at this temperature for 2 hours.Confirm that the reaction is completed, and while maintaining the temperature, dilute the solution with 50 ml of ethanol and 3.04 ml of phosphoric acid, and slowly add the solution to the reaction solution. After confirming that the crystallization of the product was initiated and cooling to 20 C, the precipitated reaction product was filtered under suction. The resulting solid was dispersed in 110 ml of methanol, refluxed for 30 minutes and stirred, and then cooled to room temperature. The resulting crystals were filtered,And dried at 50 DEG C for 4 hours to obtain 11.1 g of morpholine diphosphate (Formula 2). (Yield: 96.0%)
4-[4-(methylideneamino)phenyl]morpholin-3-one[ No CAS ]
(S)-2-(2-chloro-2-hydroxyethyl)isoindole-1,3-dione[ No CAS ]
[ 446292-08-6 ]
Yield
Reaction Conditions
Operation in experiment
91.4%
In tetrahydrofuran; at 0 - 5℃; for 7h;
159.3 g (0.78 mol) of 4-(4-methylaminophenyl)-3-morpholinone prepared in Example 1 was added to the reaction flask.(formula III), 300 ml of tetrahydrofuran, stirring uniformly, and the temperature was controlled at 0 C. to 5 C., and the intermediate VI prepared in Example 5 was dropped.After the addition, the reaction was incubated for 7 hours. The supernatant from the reaction solution was taken as the HPLC control, and the intermediate III was completely reacted, filtered and filtered.After washing sequentially with 200 ml of tetrahydrofuran and 200 ml of 95% ethanol and drying under reduced pressure, an off-white solid (compound of formula VII) is obtained.300.4 g, molar yield 91.4%, HPLC purity 98.9%.
4-(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 20C. Confirmed the completion of reaction, separated the catalyst. Added sodiumbicarbonate, cool the mass temperature to Q-5C 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- 100C 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 (85% yield) .
4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one perchlorate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
To the slurry of Formula-4 160 gm, 0.379 moles in 800 ml isopropyl alcohol, Charged 40% methylamine solutionl30 gm, 1.677 moles. Reaction mass was heated up to 45C-50C for 2-3 Hrs. Distilled out IPA under vacuum and charged fresh 800 ml Isopropyl alcohol Cooled reaction mass to 45C-50C and added 70% solution of Perchloric acid 59.6 gm, 0.415 moles. Stirred reaction mass for 1 Hrs at 45-50C. Cooled reaction mass to 0-5 C, filtered and dried at 50C-55C to afford 160 gm crude 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-one perchlorate. The crude 4-{4-[(5S)-5-(Aminomethlyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-mophiholin-3-one perchlorate has a crystalline nature and is in considerably pure form.To Above crude 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]-phenyl}-morpholin-3-one perchlorate charged 640 ml Dichloromethane (4 vol of starting material) and charged 320 ml methanol. Heated the slurry to 38C - 40C and stirred for 30 min. Cooled the slurry to 20C. Filtered and suck dried. Product obtained after drying was 138.7 gm pure crystalline perchlorate salt having purity more than 99.5% (Yield-94%)
42.2g was added to the reaction flask2-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-5-oxazolidinyl]methyl]-1H-isoindole -1,3(2H)-dione,8.6 g of 40% aqueous solution of methylamine and 200 g of absolute ethanol; the temperature was raised to 60 C by stirring, the reaction was kept for 3 hours, the system was cooled to 25 C, 2.8 g of DMTMM was added as a condensing agent, and 17.8 g of 5-chlorothiophene-2-carboxylic acid was dissolved. 35.6g of anhydrous ethanol was added to the system, and the reaction was completed at 25 C for 12 hours. The reaction was completed, and a white solid was obtained by filtration. The mixture was washed with 100 g of anhydrous ethanol and a mixture of water and a mass ratio of 1:1, and filtered to obtain a white solid. Drying at a temperature of 55 C, pressure ? 0.08 MPa for 8 h under reduced pressure, 40.5 g of rivaroxaban dry product (yield: 92.8%; HPLC chiral purity:99.9%),
With potassium permanganate; N-benzyl-N,N,N-triethylammonium chloride; In dichloromethane;Reflux;
In a 1000 ml three-necked flask equipped with a condenser, 22.5 g of the structural formula I prepared in the first step, dissolved in 600 ml of dichloromethane, added with 10.0 g of TEBAC, heated to reflux; and 25.0 g of potassium permanganate powder were added in portions. ,Continue to react until the reaction is completed by TLC;Finally, 100 ml of a saturated solution of sodium sulfite was added, and the mixture was separated after stirring.The organic phase was washed with water and brine, dried over magnesium sulfate and evaporated.Column chromatography gave the compound of formula IV.Product analysis: The obtained product was weighed and the yield was calculated, and as a result, the compound of the formula IV weighed 17.4 g, and the yield was 74%;
(S)-5-chloro-N-((3-(4-((2-(2-(2-(5-chlorothiophene-2-carbonyl)hydrazinyl)-2-oxoethoxy)ethyl)amino)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide[ No CAS ]
(S)-5-chloro-N-(2-(2-(2-(5-chlorothiophene-2-carbonyl)hydrazinyl)-2-oxoethoxy)ethyl)-N-(4-(5-((5-chlorothiophene-2-carboxamido)methyl)-2-oxooxazolidin-3-yl)phenyl)thiophene-2-carboxamide[ No CAS ]
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