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CAS No. : | 366789-02-8 | MDL No. : | MFCD11974010 |
Formula : | C19H18ClN3O5S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 435.88 | Pubchem ID : | - |
Synonyms : |
BAY 59-7939
|
Signal Word: | Danger | Class: | 9 |
Precautionary Statements: | P280-P305+P351+P338+P310 | UN#: | 3077 |
Hazard Statements: | H318-H411 | Packing Group: | Ⅲ |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In tetrahydrofuran; at 20℃; for 3h;Product distribution / selectivity; | b3.b)Dissolve 0.175 g of (S)-4-[4-(5-aminomethyl-2-oxo-oxazolidine-3- yl)phenyl]morpholin-3-one (5) (0.6 mmol) in 5 mL of THF. Add 0.13 mL of triethylamine (0.9 mmol) and then 0.12 g of 5-chlorothiophene-2-carbonyl chloride (7) (0.66 mmol) dissolved in 1 mL of THF. Stir at room temperature for 3 h. Add 10 mL of water and 10 mL of dichloromethane, separate the organic phase and extract again the aqueous phase with other 10 mL of dichloromethane. Join the organic phases, dry with anhydrous Na2SO4, filter and remove the solvent at reduced pressure. 262 mg (100% yield) of a whitish solid are obtained corresponding to the intended product. |
100% | With triethylamine; In tetrahydrofuran; at 20℃; for 3h; | [0072] Dissolve 0.175 g of (S)-4-[4-(5-aminomethyl-2-oxo-oxazolidine-3-yl)phenyl]morpholin-3-one (5) (0.6 mmol) in 5 mL of THF. Add 0.13 mL of triethylamine (0.9 mmol) and then 0.12 g of 5-chlorothiophene-2-carbonyl chloride (7) (0.66 mmol) dissolved in 1 mL of THF. Stir at room temperature for 3 h. Add 10 mL of water and 10 mL of dichloromethane, separate the organic phase and extract again the aqueous phase with other 10 mL of dichloromethane. Join the organic phases, dry with anhydrous Na2SO4, filter and remove the solvent at reduced pressure. 262 mg (100% yield) of a whitish solid are obtained corresponding to the intended product. |
94.3% | With triethylamine; In ethyl acetate; at 0 - 5℃; for 2h; | 1200ml of ethyl acetate was added 100g (0.31mol) (S) -4- (4- (5- (aminomethyl) -2-oxo-oxazolidin-3-yl) phenyl) morpholin-3-one (), 75.3g (0.74mol) of triethylamine, 67.0g was added dropwise with stirring at 0 (0.37mol) 5- chloro-thiophene-2-carbonyl chloride, dropwise Bi 5 stirred for 2 hours, the reaction was complete after TLC , filtration, the filter cake successively ethyl acetate, ethanol, washed with water and dried to give 125.3g rivaroxaban, a yield of 94.3%. |
93.1% | With triethylamine; at 0 - 20℃; for 5h; | 27.5 g (94.4 mmol) of the key intermediate of the synthetic rivaroxaban shown in Formula I prepared in Example 5 and 150 mL of triethylamine were added to the reaction flask, and the solution was added dropwise at 0 C.5-Chloro-2-acylchlorothiophene 22.1 g (122.1 mmol), dripped, warmed to room temperature for 5 hours, added 300 mL of water, stirred for 30 minutes, extracted three times with dichloromethane (450 mL × 3), and the organic layer was saturated with salt It was washed twice with water (400 ml × 2), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain 38.3 g of a white solid with a yield of 93.1%. |
92.8% | With pyridine; In dichloromethane; at 30 - 40℃; for 5h; | The reaction flask was charged with 32.9 g of the compound 7 (0.1 mol) prepared in Example 5-2, 300 mL of dichloromethane, 15.8 g (0.2 mol) of pyridine, 25.3 g of compound 8 (0.14 mol), the mixture was stirred at 30 C to 40 C for 5 hours. The reaction was monitored by TLC. The solvent was removed by distillation under reduced pressure. The residue was washed with 200 mL of purified water, and then recrystallized from a mixture of methylene chloride and ethyl acetate in a volume ratio of 5: 1 and dried under reduced pressure to obtain rivaroxaban 40.4 g, a molar yield of 92.8%, an HPLC chemical purity of 99.8% and an optical purity of 100.0%. |
92.9% | With pyridine; In dichloromethane; at 30 - 40℃; for 5h; | S6, (S)-3-[4-(3-oxo-4-morpholino)phenyl]-5-aminomethyl-1,3-oxazolidin-2-one obtained in the step S5 ( 36.2g, 0.11mol),pyridine (17.4 g, 0.22 mol)and 5-chloro-2-acylchlorothiophene (27.8 g, 0.15 mol) add to dichloromethane (330ml), stir evenly, heat to 30 ~ 40 C, reaction for 5h,The solvent was evaporated under reduced pressure and the obtained residue was washed with purified waterThe crude product was obtained as a white solid. The crude solid was obtained from methylene chloride: ethyl acetate (5:1) (1000 ml), and the mixture was heated to 40 C to dissolve all the solids, and the temperature was lowered to 0 C for 2 h, and the obtained solid was dried at 30~ 40 C for 2 h under reduced pressure obtained as a white solid (44.45 g, 92.9%); mp 229-231 C, [alpha]D20-39.3(c 0.3,DMSO) purity 99.8% (HPLC normalization). Chiral purity was 99.9% (HPLC normalization). |
91% | 1.5 kg of 4- (4- (5- (aminomethyl) -2-oxyloxazolidin-3-yl) phenyl) morpholino-3-one was put into a 50 L reaction flask,Add 10kg acetone, stirring at 20 ~ 25 10min,Sodium carbonate solution (1 kg of sodium carbonate dissolved in 10 kg of water) was added with stirring,After completion of the addition, the mixture was cooled to 5 to 10 C and a toluene solution of 5-chloro-thiophene-2-carboxylic acid chloride was added dropwise,Containing 5 kg of 5-chloro-thiophene-2-carboxylic acid chloride,Upon completion of the addition,4 kg of acetone was added,After the completion of stirring at room temperature for 60min,The mixture was stirred at 50 to 55 C for 2 hours,Reaction completed,Cooled to 15 C or less,After stirring for 1 hour,filter,The filter cake was washed with 10 kg of water,10 kg of acetone,Drained,Blast-drying for 10 hours gave 1.83 kg of rivaroxaban in a yield of 91%. | |
90% | With triethylamine; at 0 - 5℃; for 3h; | (S)-4-(4-(5-(aminomethyl)-2-oxo-oxazolidine-3-yl) phenyl) morpholinyl-3-ketone solution (0.20mol) add triethylamine (22.2g, 0 . 22mol), cooled to 5 C, dropwise 5-chloro-2-acyl chloride thiophene (36.2g, 0 . 20mol), control the feed liquid temperature is lower than 5 C, 1 hour internal dropping end. Maintain the temperature 0-5 C reaction 2 hours to the reaction is complete. Evaporate solvent 300 ml, solid precipitate in liquid, cooling to 0-5 C stirring 3 hours, filtering, washing, ice-methanol washing, drying the white solid obtained 78.3g, yield 90.0%. |
90% | With sodium carbonate; In water; at 50 - 55℃; for 1h; | 8.25g (0.078mol) sodium carbonate, 90 mL of water, 24g (0.06mol) of compound 8, and 180mL of acetone pointsrespectively into 500mL three-necked flask, the system was cooled to 8-10 , 22.8g (0.12mol) 5 - chloro-thiophene-2-carboxylic acid chloride anda mixed solution of 72mL of toluene was slowly dropwise added to the system dropwise, gradually warmed to 50-55 deg.] C the system was stirred for IH, the system then cooledto room temperature, filtered, the filter cake was dried in vacuo 80 24.6 g of product was obtained and HPLC was 99.64%.The crude product was recrystallized from 200 mL of acetic acidand filtered to give 22.1 g (yield 90%) of white crystalline powder, 99.90% HPLC, mp = 229.2-230.2 C, |
86.1% | With triethylamine; In N,N-dimethyl-formamide; at 30 - 40℃; for 5h; | 131.1 g (0.4 mol) of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl] prepared in Example 10 was added to the reaction flask. Phenyl}morpholin-3-one hydrochloride (Formula VIII), 500 ml of N,N-dimethylformamide, 50.6 g (0.5 mol) of triethylamine, 101.4 g (0.56 mol) of 5-chlorothiophene-2-carbonyl chloride,Stir well and react at 30C to 40C for 5 hours.TLC control (dichloromethane:methanol = 20:1, volume ratio) was completed. 500 ml of purified water was added and a large amount of solids precipitated.Stir for 2 hours, filter and filter cake washed with 200 ml purified water.Decompression drying, 150.1g of rivaroxaban product Molar yield 86.1%, HPLC chemical purity 99.8%,Optical purity 100.0% |
85.7% | With triethylamine; In N,N-dimethyl-formamide; at 20 - 30℃; for 5h; | The reaction flask was prepared in Example 5 was added 20.4g (0.07mol) 4- {4 - [(5S) -5- (aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl} morpholin-3-one (formula VII), 200ml of N, N- dimethylformamide, 10g triethylamine, stir, a solution of 12.6g (0.07mol) at 20 to 30 2- formyl-5-chloro-thiophene chloride, dropwise, reaction was continued incubation at 20 deg.] C to 30 5 h, TLC in the control (dichloromethane: methanol = 20: 1, volume ratio) to complete the reaction, the reaction solution was poured into 500ml purified water, with a large amount of solid precipitates, stirred for 1 hour, filtered, the filter cake was washed with purified water 100ml, drying under reduced pressure, the product enrichment rivaroxaban 26.1g (0.060mol), molar yield 85.7%, HPLC purity 99.6% |
85.7% | With triethylamine; In N,N-dimethyl-formamide; at 20 - 30℃; for 5h; | The reaction flask was charged with 20.4 g (0.07 mol) of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl] prepared in Example 5. Phenyl}morpholin-3-one (formula VII),200 ml of N,N-dimethylformamide and 10 g of triethylamine were stirred well and 12.6 g (0.07 mol) of 2-chlorocarbonyl-5-chlorothiophene was added dropwise at 20C to 30C.After dripping, continue the incubation at 20C to 30C for 5 hours.TLC control (dichloromethane: methanol = 20:1, volume ratio) was completed. The reaction solution was poured into 500 ml of purified water, a large amount of solids precipitated, stirred for 1 hour, filtered, and the filter cake was washed with 100 ml of purified water. drying,26.4g (0.060mol) of derivaroxaban product with a molar yield of 85.7% and HPLC purity of 99.6% |
81% | With triethylamine; In dichloromethane; toluene; at 0 - 20℃; for 0.5h; | In a 250ml reaction flask as in formula II compound (10.56g, 36.25mmol), triethylamine (4.04g, 39.88mmol), in methylene chloride (100 mL) was stirred at 0 clear solution. Was added dropwise a toluene solution of Formula IV as 29% of the compound (23.6g, 38mmol), room temperature 0.5h. Saturated aqueous sodium bicarbonate (90mL) and n-heptane (200mL), filtration and drying pale yellow rivaroxaban crude, crystalline water DMF- benefit rivaroxaban product (12.59g, 81.0%). |
81% | With triethylamine; In dichloromethane; toluene; at 0 - 20℃; for 0.5h; | In 250mL reaction flask as shown in Formula II compound (10.56g, 36.25mmol), Triethylamine (4.04g, 39.88mmol), dichloromethane (100mL) at 0 C stirred solution clear. Dropping As a toluene solution of Formula IV 29% of the compound (23.6g, 38mmol), room temperature 0.5h. Saturated aqueous sodium bicarbonate (90mL) and n-heptane (200mL), filtered and dried to give a crude product of rivaroxaban, which was crystallized from DMF-water to yield a rivaroxaban product (12. 59 g, 81.0%). ESI-MS (m / z): 436 [M + H] +, 438 [M + H] + |
81% | With triethylamine; In dichloromethane; toluene; at 0 - 20℃; for 0.5h; | To a 250 ml reaction flask a compound of formula II (10. 56 g, 36.25 mmol), triethylamine (4. 04 g, 39.88 mmol) and dichloromethane (100 mL) were added and stirred at 0C. 29% toluene solution of the compound of formula IV was added dropwise (containing 38 mmol of the compound of formula IV,The total mass of toluene solution 23. 6g,The percentage is the amount of the compound represented by formula IV as a percentage of the total mass of the toluene solution) and reacted at room temperature for 0.5 h. A saturated aqueous solution of sodium bicarbonate (90 mL) and n-heptane (200 mL) were added, filtered and dried to obtain crude light yellow rivaroxaban. The crude product was crystallized by DMF-water to obtain rivastane products (12.59 g,Yield 81. 0%, HPLC purity 99. 91%). |
67% | With triethylamine; In toluene; at 30℃; for 1.5h; | 10.5 g of the amine prepared according to Example 26 were suspended in 200 ml of dichloromethane and then 5.4 ml of triethylamine dissolved in 50 ml of dichloromethane were added. This was followed by addition of 14.4 ml of a solution of 5-chlorothiophene-2- carboxylic acid chloride in toluene (2.46 M) and 25 ml of dichloromethane. The reaction mixture was stirred and heated at boiling for 1.5 hours and then slowly cooled below 30C. The separated product was filtered off, washed with dichloromethane (15 ml) and ethanol (2 x 15 ml). The crude product was crystallized from a mixture of acetic acid (20 ml) and ethanol (200 ml). 10.5 g (yield 67%) of rivaroxaban was obtained in the form of an off-white powder with the melt, point of 228-230C, HPLC 99.97%, content of the (R)-isomer below 0.03%. The NMR and MS spectra were in accordance with Example 28. |
65.6 g | With potassium carbonate; at 10 - 15℃; for 4h; | Aqueous reaction mass of example 4 containing 4-[4-((S)-5-aminomethyl]-2- oxooxazolidin-3-yl)phenyl]morpholine-3-one (VII) is chilled up to 10- 15C . Charged 49.16 gm (0.3562 moles) potassium carbonate at 10- 15C. The solution of 5-chloro thiophene-2 -carbonyl chloride (VIII) 51.6 gm (0.2850 moles) in 200ml dimethyl carbonate was charged to the reaction mixture at 10- 15C. Precipitated reaction mixture was stirred at 10-15C for 4 hours. The product was filtered and washed with water. The product was dried under vacuum at 65C. It is then further purified by methanol purification at reflux temperature followed by DMSO/MeOH purification to get pure |
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 0 - 30℃; for 2h; | Charge Dichloromethane (250 ml) to reaction mass to obtain solution of compound (VII), which is gradually added at 0-5C to a pre-cooled solution of compound (II) (100 gms), Dichloromethane (700 ml) and Diisopropyl ethyl amine (50 ml). Stirr the reaction mass for 30 mins at same temperature followed by stirring at 25-30C for 30 mins. Cool the reaction mass and stir at 10-15C for 30 mins followed by stirring at 25- 30C for 30 mins. Filtered the solid and dried under vacuum at 45-50C for 5 hrs. | |
3.7 g | With pyridine; In dichloromethane; at 0 - 10℃; for 4h; | (R-1) in dichloromethane was added 1.1 g (13.9 mmol) of pyridine, cooled to 0 C with an ice salt bath, 1.91 g of compound VII (5-chloro-thiophene-2-carboxylic acid chloride) was added dropwise with stirring In 20 ml of methylene chloride solution, the temperature was controlled at 10 C for 4 hours. The organic layer was separated and the organic layer was washed three times with water and dried over anhydrous magnesium sulfate. Distillation of dichloromethane to give a solid residue. To the solid residue was added 150 ml of ethanol, stirred at 50 C for 3 hours, cooled to 10 C, stirred for 1 hour, filtered and the filter cake was washed three times with ethanol. Vacuum drying profit rivaroxaban 3.7g, content of 99.6% (HPLC), The overall yield of compound II to rivaroxaban was 83.4%. |
With potassium carbonate; at 10℃; for 3h; | In the aqueous phase obtained in Example 6,Added 2.54 g (18.4 mmol) of potassium carbonate,Stir and dissolve,Compound VI (1.665 g, 9.2 mmol) was added dropwise.Keep the temperature at 10 C for 3 hours,filter,Filter cake washed,80C blast dryingDerivata Shaban 3.0 grams,The three-step total yield is 75%.Rivaroxaban was confirmed as detected. | |
26.1 g | With triethylamine; In N,N-dimethyl-formamide; at 20 - 30℃; for 5h; | 20.4 g (0.07 mol) prepared in Example 5 was added to the reaction flask4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one (Formula VII),200ml of N,N-dimethylformamide, 10g of triethylamine, stir well,12.6 g (0.07 mol) of 2-chlorocarbonyl-5-chlorothiophene are added dropwise at 20C to 30C.After dripping, continue the incubation at 20C to 30C for 5 hours.TLC control (dichloromethane:methanol = 20:1, volume ratio) reacted completely.The reaction solution was poured into 500 ml of purified water, a large amount of solids precipitated, stirred for 1 hour, and filtered.The cake was washed with 100 ml of purified water and dried under reduced pressure to obtain 26.1 g (0.060 mol) of rivaroxaban product.Molar yield 85.7%, HPLC purity 99.6% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.12% | With sodium carbonate; In water; acetone; toluene; at 8 - 53℃; | Comparative example 1: Synthesis of rivaroxaban (compound I) as is disclosed in '823 patent6.80 g sodium carbonate were mixed with 87.0 mL of water and the suspension was stirred at room temperature until all solid dissolved. The solution was then cooled down to 10 C . 17.00 g (5 1 .9 mmol) of (5)-4-{4-[5-(aminomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one hydrochloride as obtained in reference example 3, 5. 1 mL water and 39.5 mL acetone were then successively added to the solution to give a solution. While keeping the mixture at 8-12 C, 37. 1 5 g of 5-chlorothiophene-2- carbonyl chloride (-30% strength in toluene), as obtained in reference example 4, were added. Following this, 7.7 mL of toluene were added. The mixture so formed was then heated to 50 C. A further 39.6 mL of acetone were added and the mixture was stirred for another 30 minutes at 50-53 C . After cooling down to 26 C the mixture was filtered and washed with 15.0 mL water and 15.0 mL acetone to give 23.62 g of wet, crude rivaroxaban as an off-white solid. Estimated dry mass: 21.06 g. Yield: 93.12%>. HPLC chromatographic purity: Rivaroxaban: 98.378%) (%> area). Compound A: 0.023%) (w/w); Compound B: 0.108% (% area). HPLC chiral purity: 99.998% (% area). |
90% | With sodium carbonate; In water; acetone; toluene; at 10 - 53℃; for 0.5h;High pressure; | 4- {4 - [(5S) -5- (Aminomethyl) -2-oxo-1,3-oxazolidin-3- yl] phenyl} morpholine-3-one hydrochloride (Formula 3), 10 g, 23 ml of water in a solution of sodium carbonate in a 10 C 4 g 51 ml 3 ml water and acetone was added.In 8 C to 12 C, 5-chloro thiophene-2-carbonyl chloride (fluorotoluene solution of 30% concentration) in a high pressure liquid coolant in the embodiment 2 reference number 21. 9g and further toluene 4.5 ml was added .Then add a heated reaction mixture 50 C 23 ml acetone, further 30 minutes stirring mixture 50 C to 53 C-gate.26 C after cooling and filtering the acetone precipitated reaction product under suction after washing, drying in the rock quarter of ribavirin in 4 hours at 50 C 15g obtained.Yield 90.0%, moisture content 0. 3% |
88% | With potassium carbonate; In dichloromethane; at 25 - 30℃; for 5h; | At room temperature, 5-chlorothiophene-2-carbonyl chloride (26.5 gm)) was added drop-wise to a solution of <strong>[898543-06-1]4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride</strong> (41 gm) & potassium carbonate (42 gm) in dichloromethane (200 ml). The reaction mass was stirred at 25 to 30 C for 5 hr. After completion of reaction, water (200 ml) was added to reaction mass followed by addition of hydrochloric acid (10 ml). The precipitated solid was then filtered and washed with water (100 ml) to obtain solid which was then dried under vacuum at 55 to 60 C for 5 to 6 hr to obtain 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide [Yield = 48 gm (88%); Purity (HPLC) 99.0%] |
88% | With potassium carbonate; In dichloromethane; at 25 - 30℃; for 5h; | At room temperature, 5-chlorothiohene-2-carbonyl chloride (26.5 gm)) was added drop-wise to a solution of <strong>[898543-06-1]4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride</strong> (41 gm) & potassium carbonate (42 gm) in dichloromethane (200 ml). The reaction mass was stirred at 25 to 30 C. for 5 hr. After completion of reaction, water (200 ml) was added to reaction mass followed by addition of hydrochloric acid (10 ml). The precipitated solid was then filtered and washed with water (100 ml) to obtain solid which was then dried under vacuum at 55 to 60 C. for 5 to 6 hr to obtain 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide [Yield=48 gm (88%); Purity (HPLC)=99.0%] |
86.1% | With triethylamine; In N,N-dimethyl-formamide; at 30 - 40℃; for 5h; | The reaction flask was charged with 131. lg (0.4 mil) of 4- {4- [(5S) -5- (aminomethyl) -2-oxo1-oxazolidin-3-yl] phenyl} morpholin-3-one hydrochloride (formula VIII), 500 ml of N, N-dimethylformamide, 50.6 g (0.5 mol ) Triethylamine, 101.4 g (0.5 mg) 1-Chloroformyl-5-chlorothiophene, stirred uniformly, reacted at 30 C to 40 C for 5 hours, controlled by TLC (dichloromethane: methanol = 20: 1, volume ratio) complete reaction, adding 500ml of purified water, a large amount of solid precipitation, stirring 2 hours, filtration, filter cake with 200ml of purified water, vacuum drying, rivaca sand products 150. lg, The yield was 86.1%, the HPLC purity was 99.8% and the optical purity was 100.0%. |
86.1% | With triethylamine; In N,N-dimethyl-formamide; at 30 - 40℃; for 5h; | 131.1 g (0.4 mol) of 4-{4-[(5S)-5-(aminomethyl)-2-oxo] prepared in Example 10 was added to the reaction flask.De-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (Formula VIII), 500 ml of N,N-dimethylformamide, 50.6 g (0.5 mol) three Ethylamine, 101.4 g (0.56 mol) of 2-chloromethyl-5-chlorothiophene, stirred uniformly, reacted at 30 C. to 40 C. for 5 hours, controlled by TLC (dichloromethane:methanol=20:1, volume ratio). The reaction was complete, 500 ml of purified water was added, a large amount of solids precipitated, stirred for 2 hours, filtered, and the filter cake was washed with 200 ml of purified water and dried under reduced pressure to obtain 150.1 g of rivaroxaban with a molar yield of 86.1%. HPLC purity 99.8%, optical purity 100.0%. |
82.7% | Example 10: 5-Chlor-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morp oiiny.)pher.y.3-1 s3-oxazofidin- 5-y.}methyl)-2 hiophenecarboxamidUnder an atmosphere of nitrogen to a suspension of 0. 64 g of 4-((S)-5-aminomethyl-2-oxo- oxazolidin-3-yl)-phenyl-morpholin-3-one hydrochloride (MW = 327.77; 1 eq.) in 7 mL of acetonitriie were added 0.101 g of triethylamine (MW = 101 ,12; 2.0 eq.). After stirring for 10 min at room temperature, the suspension was cooled to 0 C and then 0.091 g of 5-chloro- thiophene-2-carbonyi chloride (MW = 181.04; 1.0 eq.) were added. After stirring for 80 min at 0 C, the resulting slurry was filtered and the cake washed with 5 mL of acetonitriie and 5 mL of water. After drying in vacuo at 30 C, 0.180 g of the title compound in the form of a white crystalline powder was isolated. Yield = 82.7%. | |
80% | With sodium carbonate; In water; toluene; at 8 - 20℃; for 2h;Industrial scale; | 3.HCl (1.40 kg, 4.27 mol) was dissolved in 4.85 L water and filtered, to the filtrate was added 6.0 L toluene and Na2CO3 (0.56 kg, 5.28 mol) at room temperature. The mixture was cooled to 8 to 12C, the above solution of 9 in toluene was then added, and the reaction mixture was stirred for 2 hr at room temperature. After completion of reaction, 2.5 L acetone was added and the precipitated solid was filtered and washed with 2 mol/L aq. HCl(1.5 L). The wet solid was dried at 70C under reduced pressure (400 mmHg) to afford 1.76 kg of the crude product 1 with 99.0% purity by HPLC. The crude product was charged into acetic acid (7.8 L) and heated to reflux for 15 min. The clear solution was cooled to 15C and stirred for 2 hr, and the precipitated solid was filtered and washed with 1.5 L acetone. The wet solid was dried at 70C under reduced pressure (400 mmHg) to furnish 1.49 kg (80.0%) of the final product, mp. 228.9-230.1C (lit.2 232-233C,lit.25 227.8-228.5C), with 99.91% chemical purity and 99.93 chiral purity by chiralHPLC analysis. 1H NMR (500 MHz, DMSO) d: 3.61 (t, 2H, J D 5.5 Hz), 3.71 (t, 2H, J D5.5 Hz,), 3.86 (dd, 1H, J1 D 6.0 Hz, J2 D 9.0 Hz), 3.97 (t, 2H, J D 4.5 Hz), 4.20 (t, 3H, JD 6.5 Hz), 4.83-4.86 (m, 1H), 7.20 (d, 1H J D 4.0 Hz), 7.41 (d, 2H, J D 8.5 Hz), 7.56 (d,2H, J D 9.0 Hz), 7.69 (d, 1H, J D 4.0 Hz), 8.97 (t, 1H, J D 5.5 Hz); 13C NMR (125 MHz, DMSO) d: 42.69, 47.92, 49.49, 63.95, 68.20, 71.80, 118.83, 126.41, 128.61,128.92, 133.73, 136.96, 137.56, 138.93, 154.57, 161.28, 166.43. MS m/z 436.0 [MCH]C. |
1160 g of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one (VU) hydrochloride, 350 ml of water and 2.7 l of acetone are successively added to a solution of 464 g of sodium carbonate in 5.95 l of water at 10 C. At 8 to 12 C., 2535 g of 5-chlorothiophene-2-carbonyl chloride (IV) (30% strength solution in toluene) and a further 517 ml of toluene are added. The reaction mixture is then heated to 50 C., 2700 ml of acetone are added, and the mixture is stirred at 50 to 53 C. for a further 30 minutes. After cooling to 26 C., the precipitated reaction product is filtered off with suction and washed with water and acetone. | ||
With sodium acetate; In sulfolane; water; toluene; at 25 - 55℃; | Process for the preparation of Rivaroxaban 3.10 g of 5-chlorothiophene-2-carboxylic acid is suspended in 25 ml Tetrahydrofuran at 25- 30C. At this temperature, 3.77 g Oxalyl chloride is added drop wise, followed by stirring at 25-30C for 2 hours. After the reaction mixture is distilled under reduced pressure at 25- 30C, 12.5 ml toluene is added (approximate 30% strength solution of the acid chloride in Toluene). 5.0 g of 4-{4-[(55)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride is successively added to a solution of 25 ml Water, 20 ml Sulfolane and 3.75 g sodium acetate at 25-30C, and 5-chlorothiophene-2-carbonyl chloride solution in Toluene is added at 10-20C.The reaction mixture is then heated to 50-55C for 8-10 hours. After cooling to 25-30C, the precipitated reaction product is filtered off and washed with water and acetone. | |
150.1 g | With triethylamine; In N,N-dimethyl-formamide; at 30 - 40℃; for 5h; | 131.1 g (0.4 mol) of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl] prepared in Example 10 was added to the reaction flask. Phenyl}morpholin-3-one hydrochloride (Formula VIII), 500 ml of N,N-dimethylformamide, 50.6 g (0.5 mol) of triethylamine, 101.4 g (0.56 mol) of 2-chlorobenzoyl -5-chlorothiophene, Stir evenly, react at 30C to 40C for 5 hours, TLC control (dichloromethane:methanol = 20:1, volume ratio) react completely, add 500 ml of purified water, a lot of solids precipitate, stir After 2 hours, the filter cake was washed with 200 ml of purified water and dried under reduced pressure to obtain 150.1 g of rivaroxaban, the molar yield was 86.1%, the HPLC chemical purity was 99.8%, and the optical purity was 100.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.1% | With dmap; In acetone; at 100℃; for 6h; | Weigh 0.87 g of 5-chlorothiophene-2-{(R)-2-hydroxy-3-[4-(3-oxo-4-morpholinyl)phenylamino]-propyl}amide, then add 0.7 g of N ,N'-carbonyldiimidazole and 0.1 g of 4-dimethylaminopyridine, added with 15 mL of acetone,Start stirring,Heating at 100 C for 6 h,5-Chloro-N-(((5S)-2-oxo-3-(4-(3-oxomorpholin-4-yl)phenyl)-1,3-oxazolin-5-yl) )methyl)thiophene-2-carboxamide,After the reaction, water and ethyl acetate were added for extraction, and the organic phase was combined.Drying with anhydrous sodium sulfate, drying and then steaming.Rivaroxaban was obtained in a yield of 95.1%. |
90% | In 1-methyl-pyrrolidin-2-one; toluene; at 20 - 110℃; for 3.5h;Inert atmosphere; | Example 5: 5-Chioro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophencarboxamide Under an atmosphere of nitrogen to a suspension of 14.85g of 5-chlorothiophen-2-carboxylic acid-{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}amide (MW = 409.89; 1 eq.) in 145mL toluene and 22mL N-methylpyrrolidone were added 7.13g (MW = 162.15; 1.2 eq.) of 1,1'-carbonyldiimidazol. The reaction mixture was heated to 80C. After stirring for 30 minutes the mixture was heated to 110C and stirred at this temperature for 2 hours. Then the mixture was cooled to 22C. After stirring for 1 hour at ambient temperature the product was isolated by filtration and washed with 60mL of toluene and 60mL of water. The wet product was dried at 30C in vacuo to yield 15.99g (MW = 435.89; 1.013 eq.) of the title compound (90 % of theory). |
90% | In 1-methyl-pyrrolidin-2-one; toluene; at 80 - 110℃; for 2.5h;Inert atmosphere; | Under an atmosphere of nitrogen to a suspension of 14.85g of 5-chlorothiophen-2- carboxylic acid-{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}amide (MW = 409.89; 1 eq.) in 145ml_ toluene and 22mL N-methylpyrrolidone were added 7.13g (MW = 162.15; 1.2 eq.) of 1 ,1 '-carbonyldiimidazol. The reaction mixture was heated to 80C. After stirring for 30 minutes the mixture was heated to 110C and stirred at this temperature for 2 hours. Then the mixture was cooled to 22C. After stirring for 1 hour at ambient temperature the product was isolated by filtration and washed with 60ml_ of toluene and 60ml_ of water. The wet product was dried at 30C in vacuo to yield 15.99g (MW = 435.89; 1.013 eq.) of the title compound (90 % of theory). |
85% | In dichloromethane; at 25 - 30℃; for 3h; | 1 , 1 -Carbonyldiimidazole (0.35 g, 0.00216 moles) was added to a solution of 5- chloro-N- [(2R)-2-hydroxy-3 - { [4-(3 -oxomorpholin-4-yl)phenyl] amino }propyl]thiophene- 2-carboxamide (Formula VII - 0.5 g, 0.00121 moles) in dichloromethane (7.5 mL). The mixture was stirred for 3 hours at 25C to 30C. The slurry of the reaction mass was filtered, washed with dichloromethane (2.0 mL), and the wet solid was dried at 40C to 45C under vacuum. Yield = 0.45 g (85%) |
85% | In ethyl acetate; at 25 - 30℃; for 8h; | 5 -Chloro-N-((2R)-2-hydroxy-3 - { [4-(3-oxo-4-morpholinyl)-phenyljamino}propyl)-2-thiophenecarboxamide (Formula II; 100 g) was added to ethyl acetate (1500 mL) at25C to 30C. The seed of crystalline modification I of rivaroxaban (from Example 9; 4 g) and 1,1 -carbonyldiimidazole (71.1 g) were added to the reaction mixture, and the reaction mixture was stirred for 8 hours at 25C to 3 0C. The solid was filtered and suck dried. The solid was washed with ethyl acetate (200 mL), suck dried, and then further dried at 55C to 60C under vacuum to obtain rivaroxaban.Yield: 85% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With hydrogenchloride; water; acetic acid at 70℃; for 5 - 6h; | 1 WORKING EXAMPLESExample 12-({4-[(5S)-5-([(5-Chloro-2-thienyl)carbonyl]amino}methyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}-amino)ethoxy]acetic acid hydrochloride 50 g (115 mmol) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide are suspended in 100 g of acetic acid, 50 g of water and 300 g of 37% strength hydrochloric acid, and the mixture is heated to 70° C. The reaction mixture is stirred at 70° C. for 5-6 h, and after about 2 h a clear solution is formed. The mixture is then cooled to RT, and the resulting suspension is allowed to stand at RT for 15 h. The crystals are filtered off with suction and washed with 40 ml of acetic acid. For further purification, the crystals are twice suspended in each case 150 ml of isopropanol and filtered off with suction and then washed twice with in each case 200 ml of isopropanol. The crystals, which still contain residual moisture, are dried for 15 h at 35° C. and a pressure of <80 mbar.Yield: 43 g (76% of theory)HPLC: Rt=12.74 min;MS (ESI): m/z=454 [M+H]+;1H-NMR (500 MHz, DMSO6): δ=3.39 (m, 2H), 3.60 (m, 2H), 3.71 (m, 2H), 3.85 (m, 1H), 4.10 (s, 2H), 4.15 (m, 1H), 4.82 (m, 1H), 7.20 (d, 1H), 7.27 (br. m, 2H), 7.53 (m, 2H), 7.74 (d, 1H), 9.01 (m, 1H |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
208 g of chlorothiophenecarboxylic acid were suspended in 1100 ml of toluene and heated to 75 to 80 C. 112 ml of thionyl chloride were added dropwise at this temperature in the course of 2 h. The resulting reaction solution was stirred for a further 2 h until the end of evolution of gas. In the course of this, the internal temperature was increased to 100-110 C. in 5 steps. The mixture was cooled and the solution of the acid chloride was concentrated on a rotary evaporator.350 g of oxamine hydrochloride were suspended in 2450 ml of NMP, treated with 385 ml of triethylamine and stirred for 15 min. The mixture was cooled to 10 C., treated with the solution of the acid chloride and 70 ml of toluene and stirred. 350 ml of tap water were added to the suspension and it was heated to 82 C. After filtration, the active substance was precipitated using 3.5 l of water and the mixture was subsequently stirred for 2 h. Drying at 70 C. in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.5% | Stage #1: Rivaroxaban With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 4-Chlorobutanoyl chloride In N,N-dimethyl-formamide at 20℃; for 16h; Stage #3: With water In N,N-dimethyl-formamide Cooling; | 1A 1 g (2.3 mmol) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide [compound (A)] is dissolved in 100 ml of abs. DMF under argon. 110 mg (4.6 mmol) of sodium hydride (98% strength) are added, and the mixture is stirred at RT for 20 min. Then 4.37 g (30.97 mmol) of chlorobutanoyl chloride are added, keeping the reaction temperature at RT. The reaction mixture is stirred at RT for 16 h and is then admixed with 25 ml of water added gradually with cooling. Subsequently, 300 ml of ethyl acetate are added and a further 50 ml of water. The phases are separated and the ethyl acetate phase is concentrated in vacuo. The residue is stirred up with ethyl acetate and filtered. The mother liquor is concentrated and the residue is purified by flash chromatography on silica gel with toluene/ethanol 5:1 as eluent. The appropriate fractions which contain the target compound and also those which contain a bis-acylated compound formed after enolization are combined and the solvent is removed. The residue is admixed with a saturated solution of hydrogen chloride in dichloromethane and stirred at RT overnight. This is followed by concentrating in vacuo and the residue is again purified by flash chromatography on silica gel with toluene/ethanol 6:1 as eluent. The appropriate fractions are concentrated and the residue is lyophilized from dioxane to obtain 94 mg (7.5% of theory) of the target compound.HPLC (method 2): Rt=5.23 min;LC-MS (method 6): Rt=2.13 min; m/z=540 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | Stage #1: Rivaroxaban With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: Benzyl (4-chloro-4-oxobutyl)(4-methoxybenzyl)carbamate In N,N-dimethyl-formamide at 20℃; for 0.25h; | 3A.a 1.33 g (3.06 mmol) of compound (A) are dissolved in 75 ml of abs. DMF and admixed with 220 mg (9.2 mmol) of sodium hydride (98% strength), and the mixture is stirred at RT for 30 min. Then 11.5 g (30.6 mmol) of Example 5A, dissolved in 10 ml of abs. DMF, are added. The batch is stirred at RT for a further 15 min and then admixed with 20 ml of water. Thereafter, the batch is concentrated and the residue is taken up in 300 ml ethyl acetate and extracted three times with 300 ml of 10% sodium carbonate solution. The organic phase is separated off, concentrated and taken up in 50 ml of dichloromethane. Then 25 ml of diethyl ether are added. After brief stirring, undissolved residues are filtered off and the dichloromethane phase is concentrated. The residue is purified by flash chromatography on silica gel with ethyl acetate/toluene 5:1 as eluent. The appropriate fractions, which contain a bis-acylated by-product of mass M=1113, which is formed after enolization of the mono-acyl compound, are concentrated. Subsequently, the residue is stirred up with 10 ml of a saturated solution of hydrogen chloride in dichloromethane for 2 h, the enol ester initially formed being cleaved. This is followed by concentrating, and the remaining residue is purified by flash chromatography on silica gel with ethyl acetate/toluene 5:1 as eluent. The appropriate fractions are concentrated to obtain 151 mg (7% of theory) of the compound fully protected at the amino group.HPLC (method 2): Rt=5.83 minLC-MS (method 6): Rt=2.61 min; m/z=775 (M+H)+. |
7% | Stage #1: Rivaroxaban With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: Benzyl (4-chloro-4-oxobutyl)(4-methoxybenzyl)carbamate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #3: With hydrogenchloride In dichloromethane for 2h; | 19.a Stage a):1.33 g (3.06 mmol) of compound (A) are dissolved in 75 ml of DMF, 220 mg (9.2 mmol) of sodium hydride are added, and the mixture is stirred at RT for 30 min. Then 11.5 g (30.6 mmol) of Intermediate 14A, dissolved in 10 ml of DMF, are added. After stirring at RT for a further 15 min, 20 ml of water are added to the mixture. It is then concentrated and the residue is taken up in 300 ml of ethyl acetate. The solution is extracted three times with 300 ml of a 10% strength sodium carbonate solution. The organic phase is separated off and concentrated, and the residue is taken up in 50 ml of dichloromethane. After brief stirring, insoluble constituents are filtered off, and the dichloromethane phase is concentrated. The residue is purified by flash chromatography on silica gel with ethyl acetate/toluene 5:1 as eluent. The product-containing fractions, which contain a bisacylated by-product (m/z=1113), are concentrated. The residue is then stirred with 10 ml of a saturated solution of hydrogen chloride in dichloromethane for 2 h, during which the initially produced enol ester is cleaved. The mixture is then concentrated, and the remaining residue is again purified by flash chromatography on silica gel with ethyl acetate/toluene 5:1 as eluent. The appropriate fractions are concentrated, and 151 mg (7% of theory) of the diprotected intermediate are obtained.HPLC (method 2): Rt=5.83 min;LC-MS (method 6): Rt=2.61 min; m/z=775 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | Stage #1: Rivaroxaban With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: Benzyl (5-chloro-5-oxopentyl)(4-methoxybenzyl)carbamate In N,N-dimethyl-formamide at 20℃; for 0.25h; | 4A.a 2.83 g (6.5 mmol) of compound (A) are dissolved in 100 ml of abs. DMF under argon. 468 mg (19.5 mmol) of sodium hydride are added, and the mixture is stirred at RT for 30 min. Then 7.6 g (19.5 mmol) of Example 10A, dissolved in 10 ml of DMF, are added. Stirring is continued at RT for a further 15 min and the batch is then admixed with 20 ml of water added gradually. Thereafter the batch is concentrated and the residue is stirred up with 150 ml of saturated solution of hydrogen chloride in dichloromethane for 1 h, during which the bis-acyl compound initially formed after enolization, with mass M=1141, is cleaved. This is followed by concentrating and the residue is taken up in 700 ml of ethyl acetate and extracted twice with 200 ml each time of 10% sodium carbonate solution. The organic phase is separated off, concentrated and taken up in 30 ml of ethyl acetate and then admixed with 30 ml of diethyl ether. After brief stirring, undissolved residues are filtered off and the organic phase is concentrated. The residue is purified by flash chromatography on silica gel with ethyl acetate/toluene 4:1 as eluent. The appropriate fractions are concentrated and the residue is taken up in 10 ml of ethyl acetate. 100 ml of cold diethyl ether are added and the batch is left to stand at 0° C. for 30 min. After filtration, the residue is treated once more with 100 ml of diethyl ether. After renewed filtration, the filter residue is collected and dried to obtain 1 g (20% of theory) of the compound fully protected at the amino group.HPLC (method 2): Rt=5.92 minLC-MS (method 6): Rt=2.68 min; m/z=789 (M+H)+. |
20% | Stage #1: Rivaroxaban With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: Benzyl (5-chloro-5-oxopentyl)(4-methoxybenzyl)carbamate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #3: With hydrogenchloride In dichloromethane for 1h; | 20.a Stage a):2.83 g (6.5 mmol) of compound (A) are dissolved in 100 ml of DMF, 468 mg (19.5 mmol) of sodium hydride are added, and the mixture is stirred at RT for 30 min. Then 7.6 g (19.5 mmol) of Intermediate 12A, dissolved in 10 ml of DMF, are added. After stirring at RT for a further 15 min, 20 ml of water are added to the mixture. It is then concentrated and the residue is stirred with 150 ml of a saturated solution of hydrogen chloride in dichloromethane for 1 h, during which the initially produced enol ester is cleaved. The mixture is then concentrated and the residue is taken up in 700 ml of ethyl acetate. The solution is extracted twice with 200 ml of a 10% strength sodium carbonate solution each time. The organic phase is separated off and concentrated, and the residue is taken up in 30 ml of ethyl acetate and 30 ml of diethyl ether. After brief stirring, insoluble constituents are filtered off and the organic phase is concentrated. The residue is purified by flash chromatography on silica gel with ethyl acetate/toluene 4:1 as eluent. The appropriate fractions are concentrated and the residue is taken up in 10 ml ethyl acetate. 100 ml of cold diethyl ether are added, and the mixture is left to stand at 0° C. for 30 min. The residue after filtration is treated again with 100 ml of diethyl ether. After filtration again, the residue is collected and dried. 1 g (20% of theory) of the diprotected intermediate are obtained.HPLC (method 2): Rt=5.92 min;LC-MS (method 6): Rt=2.68 min; m/z=789 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9.5% | Stage #1: Rivaroxaban With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.333333h; Inert atmosphere; Stage #2: chloroacetyl chloride In N,N-dimethyl-formamide at 20℃; for 0.5h; | 1A Intermediate 1A5-Chloro-N-(chloroacetyl)-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide; 1 g (2.3 mmol) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide [compound (A)] is dissolved in 170 ml of abs. DMF under argon. 110 mg (4.6 mmol) of sodium hydride are added, and the mixture is stirred at RT for 20 min. Then 3.5 g (31 mmol) of chloroacetyl chloride are added, keeping the reaction temperature at RT. After 30 min, 25 ml of water are added while cooling, and the mixture is left to stand at RT for two days. The solvent is then removed in vacuo, during which the temperature should not rise above +25° C. The residue is taken up in 500 ml of dichloromethane and extracted five times with 200 ml of water. The organic phase is dried over magnesium sulphate, filtered and concentrated to a volume of about 50 ml. While stirring, 200 ml of diethyl ether are added, and the precipitate (mostly unreacted starting material) is then filtered off. The mother liquor is concentrated and the residue is purified by flash chromatography on silica gel with toluene/ethanol 10:1 as eluent. The appropriate fractions are combined, and the solvent is removed. The residue is lyophilized from dioxane.Yield: 111 mg (9.5% of theory)HPLC (method 2): Rt=5.09 min;LC-MS (method 4): Rt=2.31 min; m/z=512 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23.5% | Stage #1: Rivaroxaban With sodium hydride In N,N-dimethyl-formamide for 0.5h; Stage #2: Benzyl (5-chloro-5-oxopentyl)methylcarbamate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #3: With hydrogenchloride In dichloromethane for 2h; | 17.a Stage a):1.96 g (4.5 mmol) of compound (A) are dissolved in 70 ml of DMF, 323 mg (13.5 mmol) of sodium hydride are added, and the mixture is stirred for 30 min. Then 5.1 g (18 mmol) of Intermediate 8A, dissolved in 10 ml of DMF, are added. After stirring at RT for a further 15 min, 20 ml of water are added to the mixture. It is then concentrated and the residue is taken up in 500 ml of ethyl acetate. The solution is extracted three times with 300 ml of a 5% strength sodium bicarbonate solution. The ethyl acetate phase is separated off and concentrated. The residue is stirred with 40 ml of a dichloromethane/diethyl ether mixture (2:1) and then filtered. The remaining solution is concentrated in vacuo. The residue is then stirred with 100 ml of a saturated solution of hydrogen chloride in dichloromethane for 2 h, during which the initially produced enol ester is cleaved. The mixture is then concentrated, and the remaining residue is purified by flash chromatography on silica gel with ethyl acetate/toluene 5:1 as eluent. The appropriate fractions are concentrated, and 721 mg (23.5% of theory) of the Z-protected intermediate are obtained.HPLC (method 2): Rt=5.54 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | Stage #1: Rivaroxaban With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: Benzyl (6-chloro-6-oxohexyl)(4-methoxybenzyl)carbamate In N,N-dimethyl-formamide at 20℃; for 0.25h; | 21.a Stage a):1.6 g (3.7 mmol) of compound (A) are dissolved in 50 ml of DMF, 263 mg (11 mmol) of sodium hydride are added, and the mixture is stirred at RT for 30 min. Then 14.1 g (36.6 mmol) of intermediate 13A, dissolved in 10 ml of DMF, are added. After stirring at RT for a further 15 min, 20 ml of water are added to the mixture. It is concentrated and the residue is taken up in 500 ml of ethyl acetate. The solution is extracted three times with 100 ml of a 10% strength sodium carbonate solution each time. The organic phase is separated off and concentrated, and the residue is taken up in 15 ml of dichloromethane/diethyl ether (2:1). After brief stirring, insoluble constituents are filtered off, and the organic phase is concentrated. The residue is purified by flash chromatography on silica gel with ethyl acetate/toluene 5:1 as eluent. 256 mg (9% of theory) of the diprotected intermediate are obtained.HPLC (method 2): Rt=6.07 min;LC-MS (method 5): Rt=2.92 min; m/z=803 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18% | Stage #1: Rivaroxaban With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: benzyl (6-chloro-6-oxohexyl)methylcarbamate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #3: With hydrogenchloride In dichloromethane for 2h; | 18.a Stage a):2 g (4.59 mmol) of compound (A) are dissolved in 70 ml of DMF, 330 mg (13.8 mmol) of sodium hydride are added, and the mixture is stirred at RT for 30 min. Then 5.1 g (18 mmol) of Intermediate 10A, dissolved in 10 ml of DMF, are added. After stirring at RT for a further 15 min, 20 ml of water are added to the mixture. It is then concentrated and the residue is stirred with 100 ml of a saturated solution of hydrogen chloride in dichloromethane for 2 h, during which the initially produced enol ester is cleaved. The mixture is then concentrated, and the residue is taken up in 600 ml of ethyl acetate. The solution is extracted three times with a 10% strength sodium carbonate solution. The ethyl acetate phase is separated off and concentrated. The residue is stirred with 150 ml of a dichloromethane/diethyl ether mixture (2:1) and then filtered. The remaining solution is concentrated in vacuo and the residue is purified by flash chromatography on silica gel with ethyl acetate/toluene 5:1 as eluent. The appropriate fractions are concentrated, resulting in the still slightly impure product. Purification again by flash chromatography on silica gel with acetonitrile/dichloromethane 1:1 as eluent then leads to 572 mg (18% of theory) of the purer Z-protected intermediate.HPLC (method 2): Rt=5.68 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.4% | Stage #1: Rivaroxaban With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: benzyl butyl(4-chloro-4-oxobutyl)carbamate In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #3: With hydrogenchloride In dichloromethane | 22.a Stage a):3.215 g (7.38 mmol) of compound (A) are dissolved in 60 ml of DMF, 531 mg (22.1 mmol) of sodium hydride are added, and the mixture is stirred at RT for 30 min. Then 6.9 g (22.1 mmol) of Intermediate 15A, dissolved in 10 ml of DMF, are added. After stirring at RT for a further 10 min, 10 ml of water are added to the mixture. It is then concentrated, and the residue is stirred with 70 ml of a saturated solution of hydrogen chloride in dichloromethane overnight, during which the initially produced enol ester is cleaved. The mixture is filtered, and the remaining solution is concentrated. The residue is taken up in 600 ml of ethyl acetate and extracted three times with 100 ml of a 10% strength sodium carbonate solution and once with water. The ethyl acetate phase is separated off and concentrated. The residue is purified by flash chromatography on silica gel with acetonitrile/dichloromethane 1:1 as eluent. The appropriate fractions are concentrated. The remaining resinous product is taken up 20 ml of ethyl acetate, and 40 ml of cold diethyl ether are added. The residue remaining after filtration is washed with diethyl ether. Drying under high vacuum results in 1.7 g (32.4% of theory) of the Z-protected intermediate.HPLC (method 2): Rt=6.0 min;LC-MS (method 12): Rt=3.9 min; m/z=711 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | Stage #1: Rivaroxaban With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: benzyl [2-(2-chloro-2-oxoethoxy)ethyl](4-methoxybenzyl)carbamate In N,N-dimethyl-formamide at 20℃; for 0.166667h; Stage #3: With hydrogenchloride In dichloromethane | 23.a Stage a):589.6 mg (1.35 mmol) of compound (A) are dissolved in 25 ml of DMF, 97 mg (4 mmol) of sodium hydride are added, and the mixture is stirred at RT for 30 min. Then 2.65 g (6.76 mmol) of Intermediate 16A, dissolved in 4 ml of DMF, are added. After stirring at RT for a further 10 min, 5 ml of water are added to the mixture. It is then concentrated and the residue is stirred with 150 ml of a saturated solution of hydrogen chloride in dichloromethane overnight. It is then concentrated again, and the residue is taken up in 200 ml of ethyl acetate. The solution is extracted twice with 50 ml of a 10% strength sodium carbonate solution each time. The organic phase is separated off and concentrated and the residue is stirred with 30 ml of ethyl acetate. Insoluble constituents are filtered off, and the organic phase is concentrated. The residue is purified by flash chromatography on silica gel with acetonitrile/dichloromethane 1:1 as eluent. The product-containing fractions are concentrated and the residue is again purified by preparative HPLC (method 1). The appropriate fractions are concentrated and dried. 30 mg (3% of theory) of the diprotected intermediate are obtained.HPLC (method 2): Rt=5.71 min;LC-MS (method 12): Rt=3.74 min; m/z=791 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.2% | With 4-methyl-morpholine; hydrogenchloride; In water; N,N-dimethyl-formamide; at 20℃; for 2.83333h; | A1 L three-necked flask was used, 26.0 g of 5-chlorothiophene-2-carboxylic acid, 50.0 g of the hydrochloride of the compound of the formula (R-1) and 33.0 g of CDMT were suspended in 450 mL of N,N-dimethylformamide, a mixed solution of 40.0 g of NMM and 50.0 mL of N,N-dimethylformamide was added dropwise with stirring under ice bath, after stirring for 20 minutes, stirring was continued for 1 hour, and then heated to room temperature stirring for about 1.5 hours. Stop stirring, the reaction solution was added to the water to beater, ice bath crystal, filter, dried under reduced pressure to a white solid rivaroxaban 63.25g, the yield was 95.2% and the purity was 99.8%. |
85% | With ortho-iodophenylboronic acid; In dichloromethane; at 30℃; for 48h;Dean-Stark; | Example 4: 1.625g (10 mmol) of 5-chloro-thiophene-2-carboxylic acid, (0.248 g, (1 mmol) of 2-iodophenyl boronic acid and 50 ml of dichloromethane were charged into a clean and dry R.B flask. To the resultant clear colourless reaction solution 2.91g (lOmmol) of 4-{4-[(5S)-5- (aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]-phenyl}-morpholin-3-one (chiral purity: 99.9%) was added and stirred at about 30C for about 48 hrs. After the completion of the reaction as indicated by TLC, the solid separated was filtered and washed with dichloromethane and water. Additional material was recovered by evaporation of the filtrate. The wet solid was recrystallized in acetic acid to afford rivaraoxaban (I) as white crystalline solid. Yield: 3.7g (% Yield : 85%); Purity by HPLC: 99.85%; Purity by Chiral HPLC: 99.9%. |
68.9% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 3h; | Add 11.00 g of the white solid, 7.10 g of 5-chlorothiophene-2-carboxylic acid, 8.35 g of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, and 6.76 g of Hydroxybenzotriazole, 13.03 g of N, N diisopropylethylamine, 44 ml of N, N-dimethylformamide were added to a 250 ml three-necked flask, and reacted at room temperature for 3 hours. After the reaction was completed, the reaction solution was added to 176 ml of water. The solid was filtered and dried at 70 C. for 8 h to obtain a white-like solid, which was recrystallized from 200 ml of a glacial acetic acid-acetonitrile mixture with a volume ratio of 5: 1 to obtain a white-like solid, which was then recrystallized from glacial acetic acid to obtain a white-like powdery solid. 10.08 g, yield 68.9%, purity 99.74% (area normalization method). |
N,N-Carbonyldiimidazole (1.444 kg,1.2eq) was added slowly to a suspension of 5-chlorothiophene-2-carboxylic acid( 120Og, 7.430mol ) in DMF ( 8L ) below 0 0C, and stirred for 1 hour at room temperature, then Et3N (90Og , 1.2eq) was added to the mixture at 0 0C , and compound according to f.)(250Og, 1.03eq)was further added within 30 minutes and stirred for 2hours at 25 0C. Ice-water (10kg) was added and the product then precipitated from the solution. The product was filtered off and the crude product (240Og) has been obtained. | ||
Carbonyldiimidazole (12.0 gr, 0.074 mol) was added slowly to a suspension of 5-chlorothiophene-2-carboxylic acid (compound 7b) (10.0 gr, 0.055 mol) in methylenedichloride (60.0 mL) at 0-5C, and stirred for 1.0 hr at room temperature, then triethyl amine (7.5 gr, 0.074 mol) was added to the reaction mixture at 0-5C followed by adding a solution of (5)-4-[4-(5-aminomethyl-2-oxooxazolidin-3-yl)phenyl]morpholin-3-one (compound 6b) (18.0gr, 0.061 mol) in methylenedichloride (100.0 mL) at 0-5C over a period of 30 minutes. The whole reaction mass was stirred at reflux temperature for 3.0 hrs. Water (100.0 mL) was added, stirred for 20 minutes and separated the organic layer and aqueous layer extract with methylenedichloride (100.0 mL). The organic layers were combined and washed with water, distilled off the organic solvent under vacuum, followed by adding methanol and stirred for 30 minutes. The separated product was filtered and washed with methanol to get the Rivaroxaban (compound 8b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: 5-chlorothiophene-2-carbonyl chloride; 4-(4-((S)-5-(tert-butylaminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one With triethylamine In toluene at 120℃; for 2h; Stage #2: With hydrogenchloride In toluene at 55℃; for 4h; Stage #3: With sodium hydroxide In toluene at 20℃; | 13 Example 13: Preparation of rivaroxaban by one pot process(from 4-(4-((S)-5-(tert-butylaminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one (compound III with R1 = tert-butyl)). To a suspension of 4-(4-((S)-5-(tert-butylaminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one (554 mg, 1 .59 mmol) (92.6% HPLC-MS) in toluene (2.1 ml_) were added NEt3 (244 μΙ_, 1 .73 mmol) and, subsequently, a solution of 5-chlorothiophene-2-carbonyl chloride (3.46 ml_ of a solution 0.69 M in toluene). The mixture was stirred at 120°C for 2 h, then was allowed to cool to 55°C and 6 M HCI solution was added (530 μΙ_). The mixture was stirred at 55°C for 4 h, was cooled to room temperature and was basified with 3 M NaOH to pH 9. The solid was filtered and washed with H2O (0.5 ml_) affording 5-Chloro-N-[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl]methyl}thiophene-2-carboxamide (rivaroxaban or compound I) (554 mg, yield 81 %, 93.7% HPLC-MS) as a brownish solid. |
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 24 h / 20 °C 2.1: hydrogenchloride / ethyl acetate / 2 h / 55 °C 2.2: pH 9 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 5-chloro-N-tert-butyl-N-[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl]methyl}thiophene-2-carboxamide With hydrogenchloride In ethyl acetate at 55℃; for 2h; Stage #2: With sodium hydroxide In ethyl acetate | 12 Example 12: Preparation of rivaroxaban by dealkylation of 5-Chloro-N-tert-butyl-N-[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl]methyl)thiophene-2-carboxamide usinq ethyl acetate and hydrochloric acid.To a suspension of 5-chloro-N-tert-butyl-N-({(5S)-2-oxo-3-[4-(3-nnorpholin-4- yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (99 mg, 0.20 mmol) in EtOAc (0.6 ml_) was added 6 M HCI solution (74 μΙ_, 0.4 mmol). The mixture was heated to 55 °C for 2 h, was cooled to room temperature and was basified with 6 M NaOH to approximately pH 9. The solvent was evaporated and the residue was diluted with H2O and extracted with CH2CI2. The organic phases were dried over MgSO4 and concentrated in vacuo, affording 5- Chloro-N-[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl] oxazolidin-5-yl]methyl}thiophene-2-carboxamide (rivaroxaban or compound I) (79 mg, yield 90%, 92% HPLC-MS) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
34% | With hydrogenchloride In tetrahydrofuran at 55℃; for 2.25h; | 18 Example 18: Preparation of rivaroxaban by dealkylation of 5-Chloro-N-tert-octyl-N-[(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl]methyl}thiophene-2-carboxamide using hydrochloric acid andtetrahydrofuran To a solution of 5-Chloro-N-tert-octyl-N-[(5S)-2-oxo-3-[4-(3-oxonnorpholin-4-yl)phenyl]oxazolidin-5-yl]methyl}thiophene-2-carboxannide (37 mg, 0.068 mmol) in THF (1 .0 ml_), HCI 6 M (0.050 ml_, 0.30 mmol) was added. The solution was heated to 55 °C for 2 hours and 15 minutes, cooled, dried over anhydrous Na2SO4 and evaporated in vacuo. The crude was purified by flash cromatography (CH2CI2:MeOH 95:5, Rf 0.17) affording 5-Chloro-N-[(5S)-2- oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-5-yl]methyl}thiophene-2- carboxamide (rivaroxaban or compound of formula I) (10 mg, yield 34%, 100% HPLC-MS, [CC]D -38.9 (c = 1 , DMSO). Ref. Roehring et al., Journal of Medicinal Chemistry, 2005, Vol. 48, pp 5900, [cc]D -38 (c = 0.3, DMSO)) as a white solid. 1H NMR (c/6-DMSO, 400 MHz) δ 8.95 (t, J = 5.6, 1 H), 7.68 (d, J = 4.0, 1 H), 7.54 (d, J = 8.8, 2 H), 7.39 (d, J = 8.8, 2 H), 7.18 (d, J = 4.0, 1 H), 4.86-4.80 (m, 1 H), 4.20-4.16 (m, 1 H), 4.18 (s, 2 H), 3.97-3.94 (m, 2 H), 3.84 (dd, J = 9.2, 6.0, 1 H), 3.71 -3.69 (m, 2 H), 3.59 (t, J = 5.6, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | In toluene for 3h; Inert atmosphere; Reflux; | 9 Under an atmosphere of nitrogen 25mg of LiBr and 63mg of tributylphosphinoxide were added to 5ml_ of toluene and the mixture was heated to reflux. At this temperature 1.09g of 4-(isocyanato-phenyl)-morpholin-3-one (MW = 218.21 ; 1 eq.) and 1.09g 5-chloro- thiophene-2-carboxylic acid ((S)-1-oxiranylmethyl)-amide (MW = 217.68; 1 eq.) were added and the mixture was refluxed for 3 hours. After stirring for 3 hours the product was isolated by filtration and washed with toluene and water. The wet product was dried at 30°C in vacuo to yield 1.20g (MW = 435.89; 1.013 eq.) of the title compound (55% of theory). |
Multi-step reaction with 2 steps 1: Tributylphosphine oxide; lithium bromide / toluene / 3 h / Inert atmosphere; Reflux 2: toluene; 1-methyl-pyrrolidin-2-one / 3.5 h / 20 - 110 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21.1% | Example 11: 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophencarboxamide A mixture of 4.2mL of acetic acid anhydride and 3.0mL of pyridine was cooled to 0C. At this temperature 4.00g of 4-[4-[(5R)-5-(chlorothiopheno-2-carboxylic acid ((S)-2-hydroxy-3-tosyloxy)-propyl)-amide (MW = 389.88; 1 eq.) were added. After stirring for 1 hour at this temperature the reaction mixture was poured into 150mL of methyl-t-butylether and 50mL of water and the pH was adjusted to 2.0 by addition of 6 M hydrochloric acid. After separation of the layers, the aqueous layer was extracted once more with 50mL of methyl-t-butylether. The combined organic layers were washed with 50mL of saturated bicarbonate and brine and dried over sodium sulfate. The solution was concentrated to dryness in vacuo at room temperature. The residue was dissolved in 20mL of acetonitrile and then 2.48g of 4-(3-oxo-morpholin-4-yl)-phenyl]-carbamic acid benzyl ester (MW = 326.36; 0.76 eq.) and 302muL of methanol (MW = 32.04; 0.76 eq.) were added. The mixture was cooled to 0C and 1.22g of lithium tert.-butoxide were added. After stirring for 17 hours at 0C, the resulting suspension was filtered. The filter cake was washed with acetonitrile and water. The wet product was dried at 30C in vacuo to yield 0.94g (MW = 435.89) of the title compound (21.1 % of theory). | |
21.1% | A mixture of 4.2ml_ of acetic acid anhydride and 3.0mL of pyridine was cooled to 0C. At this temperature 4.00g of 4-[4-[(5R)-5-(chlorothiopheno-2-carboxylic acid ((S)-2-hydroxy-3- tosyloxy)-propyl)-amide (MW = 389.88; 1 eq.) were added. After stirring for 1 hour at this temperature the reaction mixture was poured into 150ml_ of methyl-t-butylether and 50mL of water and the pH was adjusted to 2.0 by addition of 6 M hydrochloric acid. After separation of the layers, the aqueous layer was extracted once more with 50ml_ of methyl-t-butylether. The combined organic layers were washed with 50ml_ of saturated bicarbonate and brine and dried over sodium sulfate. The solution was concentrated to dryness in vacuo at room temperature. The residue was dissolved in 20ml_ of acetonitrile and then 2.48g of 4-(3-oxo- morpholin-4-yl)-phenyl]-carbamic acid benzyl ester (MW = 326.36; 0.76 eq.) and 302muIota_ of methanol (MW = 32.04; 0.76 eq.) were added. The mixture was cooled to 0C and 1.22g of lithium tert.-butoxide were added. After stirring for 17 hours at 0C, the resulting suspension was filtered. The filter cake was washed with acetonitrile and water. The wet product was dried at 30C in vacuo to yield 0.94g (MW = 435.89) of the title compound (21.1 % of theory). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.5% | With lithium tert-butoxide In tetrahydrofuran at 0℃; for 1h; | 7 Example 7: 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl )phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophencarboxamide Under an atmosphere of nitrogen a suspension of 1.00g of toluene-4-sulfonic acid (S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-2-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyloxy]-propyl ester (MW = 608.09; 1 eq.) in 25mL tetrahydrofuran was cooled to 0°C. At this temperature 1.6mL of a 1 M solution of lithium t-butoxide in tetrahydrofuran were added dropwise. After stirring at this temperature for 1 hour the resulting slurry was filtered. The cake was rinsed with 14mL of tetrahydrofuran and 14mL of water. The wet product was dried at 30°C in vacuo to yield 0.63g (MW = 435.89; 1.013 eq.) of the title compound (88.5 % of theory). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.5% | With lithium tert-butoxide In tetrahydrofuran at 0℃; for 1h; Inert atmosphere; | 7 Under an atmosphere of nitrogen a suspension of 1.00g of toluene-4-sulfonic acid (S)-3-[(5- chloro-thiophene-2-carbonyl)-amino]-2-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyloxy]- propyl ester (MW = 608.09; 1 eq.) in 25ml_ tetrahydrofuran was cooled to 0°C. At this temperature 1.6ml_ of a 1 M solution of lithium t-butoxide in tetrahydrofuran were added dropwise. After stirring at this temperature for 1 hour the resulting slurry was filtered. The cake was rinsed with 14mL of tetrahydrofuran and 14ml_ of water. The wet product was dried at 30°C in vacuo to yield 0,63g (MW = 435.89; 1.013 eq.) of the title compound (88.5 % of theory). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | Stage #1: 5-Chlorothiophene-2-carboxylic acid; 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine In ethyl acetate at 10 - 25℃; for 12.5h; Stage #2: With water In ethyl acetate for 1h; | 1 Reaction of 5-chlorothiophene-2-carboxylic acid with 4-[4-((S)-4-aminomethyl-2-oxoimidazolidin-1-yl)phenyl]morpholin-3-one (II) to give 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (I) Example 1 Reaction of 5-chlorothiophene-2-carboxylic acid with 4-[4-((S)-4-aminomethyl-2-oxoimidazolidin-1-yl)phenyl]morpholin-3-one (II) to give 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (I) 47.0 g of 4-[4-((S)-5-aminomethyl-2-oxooxazolidin-3-yl)phenyl]morpholin-3-one hydrochloride and 28.0 g of 5-chlorothiophene-2-carboxylic acid are introduced as initial charge together with 75.0 g of ethyldiisopropylamine in 132 g of ethyl acetate and cooled to 10° C. 125 g of a 50% strength solution of propanephosphonic anhydride (T3P) in ethyl acetate are then metered in over a period of ca. 30 minutes. During this, the temperature is kept at 10-15° C. The mixture is further stirred for ca. 12 h and during this time the temperature is slowly increased to 25° C. 210 g of water are then added dropwise over a period of ca. 60 minutes. The multiphase mixture is stirred for a further 60 minutes and then filtered with suction. The crude product is washed with 100 g of water and then with 100 g of acetone and then dried. This gives 58.9 g (94% of theory) of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (I). The purity of the product obtained in this way is >98% area percent (HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide In water at 20℃; for 16h; | 3 0.5 g of Rivaroxaban. Formic acid crystals were suspended in water and stirred for approx. one hour at room temperature. To the obtained suspension 1.25 ml (1.2 equivalents) of a 1 molar aqueous sodium hydroxide solution were added and the mixture was stirred for 16 hours at room temperature. After filtration the solid was washed with water and sucked dry for approx. 15 minutes. The product Rivaroxaban Dihydrate was obtained as a colorless wet crystalline solid. | |
With sodium hydroxide In water at 20℃; for 16h; | 3 0.5 g of Rivaroxaban. Formic acid crystals were suspended in water and stirred for approx. one hour at room temperature. To the obtained suspension 1.25 ml (1.2 equivalents) of a 1 molar aqueous sodium hydroxide solution were added and the mixture was stirred for 16 hours at room temperature. After filtration the solid was washed with water and sucked dry for approx. 15 minutes. The product Rivaroxaban Dihydrate was obtained as a colorless wet crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate; methylamine In water; isopropyl alcohol at 60℃; for 15h; | 8 Example 8:Methylamine (390 mg, 40% in water) in IPA (1 mL) was added to a stirred mixture of 5-Chloro-thiophene-2-carboxylic acid-1 -(1 ,3-dioxo-1 ,3- dihydro-isoindol-2-ylmethyl)-2-{methoxycarbonyl-[4-(3-oxo-morpholin-4-yl)- phenyl]-amino}-ethyl ester (13a) (1 g, 1.672 mmol) and anhydrous K2C03 (12 mg, 0.084 mmol) in IPA (6 mL). The mixture was heated to 60 °C for 15 h and cooled to room temperature. The precipitated solids were filtered, washed with IPA (2 x 1 mL) followed by water (2 x 2 mL), IPA (1 mL) and dried at 50 °C for 10 h to obtain Rivaroxaban (628 mg, 86 %) as a crystalline white solid.1HNMR (300MHz, DMSO-d6) δ 3.59-3.62 (m, 2H), 3.69-3.73 (m, 2H), 3.85 (dd, J=8.9, 6.3 Hz, 1 H), 3.95-3.99 (m, 2H), 4.16-4.22 (m, 1 H), 4.19 (s, 2H), 4.82-4.86 (m, 1 H), 7.19 (d, J=4.2 Hz, 1 H), 7.40 (d, J=8.7 Hz, 2H), 7.56 (d, J=8.7 Hz, 2H), 7.69 (d, J=4.2 Hz, 1 H), 8.97 (t, J=5.5 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium carbonate; acetone In water; toluene at 8 - 53℃; | 33 Example 33Preparation of racemic rivaroxaban of the Formula raclA solution of 0.64 g (0.006 mole) of sodium carbonate in 9 ml of water is cooled to 10 °C under stirring whereupon 1.8 g (0.005 mole) of 4-{4-[5-aminomethyl-2- oxo-l,3-oxazolidine-3-yl]-phenyl}-morpholine-3-one acetate (rac3b) 0.6 ml of water and 1.8 ml of acetone are added. The solution is filtered and at a temperature of 8-12°C 3 ml of a toluene solution of 5-chloro-thiophen-2- carboxylic acid chloride (compound of the Formula 4) having a concentration of 36.1 g/100 ml are added, (this corresponds to 1.07 g, 0.059 mole) of 5-chloro- thiophen-2-carboxylic acid chloride. The reaction mixture is warmed to 50°C, whereupon 5 ml of acetone are added and the mixture is stirred at 50-53°C for a further period of 30 minutes. The reaction mixture is cooled to 25°C.The precipitated product is filtered, washed three times with 5 ml of acetone each, three times with 5ml of water each and again twice with 55 ml of acetone each. Thus 1.75 g (83 %) of the title compound are obtained. Mp.: 229-231°C. The product is recrystallized from a 6.2-fold amount of glacial acetic acid. Thus 1.50 g (86 %) of the title compound are obtained. Mp.: 230-233°C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.2% | With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine; In N,N-dimethyl-formamide; at 20℃; for 2.83333h;Cooling with ice; | Take 1L three-necked flask and 26.0g of 5-chloro-thiophene-2-carboxylic acid,50.0 g of <strong>[898543-06-1]4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride</strong> 33.0 g of CDMT was suspended in 450 mL of N,N-dimethylformamide, and a mixed solution of 40.0 g of NMM and 50.0 mL of N,N-dimethylformamide was added dropwise with stirring in an ice water bath, and the addition was continued within 20 minutes. Stir for 1 hour,Then, the temperature was raised to room temperature and stirred for about 1.5 hours. Stop stirring,The reaction solution was added to water and beaten, crystallized in an ice bath, filtered, and dried under reduced pressure to give a white solid, 63.25 g, yield 95.2%, HPLC 99.82%, ee >99.9%. |
94.7% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 24h;pH 8 - 9;Large scale; | Add rivaroxaban intermediate V 18kg to 180L of dichloromethane,Add 13.4 kg of 5-chlorothiophene-2-carboxylic acid,12 kg of 1-hydroxybenzotriazole (HOBt) and 16.8 kg of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride(EDCl),Triethylamine is added dropwise to a pH of 8-9.After reacting at room temperature for 24 hours, steam down to dryness.The solid viscous material was added to 180 L of absolute ethanol and stirred at room temperature for 1 to 2 hours, and centrifuged.The filter cake is dried to obtain 22.66kg of rivaroxaban.The yield is 94.7%.The purity is 99.85%. |
94.4% | With triethylamine; 1,1'-carbonyldiimidazole; In N,N-dimethyl-formamide; at 0 - 25℃; for 0.0416667h; | 650 g of N,N-dimethylformamide (DMF) was added to the reaction flask at room temperature.The stirring was turned on, the temperature was lowered to 0 C, and then 40 g of the compound (LF-II) and 73 g of the compound (SMI) were sequentially introduced.39.7g CDI, the reaction solution is in suspension state; temperature control is 0-5 C,67.6 g of triethylamine was added dropwise to the reaction solution, and the internal temperature of the reaction solution was controlled to be 0-5 C during the dropwise addition.Stir for 30 minutes with heat and warm to room temperature (20-25 C).The reaction was stirred for 2 hours with heat.After suction filtration, the filter cake was washed with 80 g of DMF, and the filtrate was added to 1200 g of water and stirred for 2 hours at room temperature.Centrifuge the slurry mixture to a cut-off using a centrifuge.The reaction flask was washed with 500 g of purified water.Combine the washing liquid to the flow,Deli Vaasa class crude. |
86% | Example 15Preparation of rivaroxaban (compound of the Formula 1) from thecompound of the Formula 3a1.9 g (11.7 millimoles) of 5-chloro-thiophen-2-carboxylic acid (15) and 1.9 g (11,7 millimoles) of NN'-carbonyl-diimidazole are dissolved in 5o ml of dried acetonitrile. The reaction mixture is stirred at 50-55C for an hour whereupon 0.78 g (9.3 millimoles) of sodium carbonate, 3.27 g (10 millimoles) of 4-{4- [(5S)-5-aminomethyl- 2-oxo-l, 3-oxazolidine-3-yl]-phenyl}-morpholine-3-one hydrochloride and 1 ml of distilled water are added. The reaction mixture is stirred at 50C for an hour, cooled in an icecold bath and stirred for a further 0.5 hours. The precipitated solid is filtered, washed three times with 10 ml of water each and 10 ml of acetone and dried under an infrared lamp to constant weight. Thus 3.9 g (77%) of the title compound are obtained. This crude product is recrystallized from 24 ml of glacial acetic acid. Thus 3.34 g (86 %) of rivaroxaban are obtained in a HPLC purity of 99.0 %. Mp.: 229-230C. | |
16.25 gms of 5-chlorothiophene-2-carboxylic acid and 162.5 ml of dichloromethane were charged into a clean and dry 1 lit. 4 neck R.B. Flask. 12.12 gms of triethyl amine was charged at about 30C followed by stirring for about 15 mins. to get homogenous solution. The resultant reaction solution was cooled to about -5C and 11.935 gms of ethyl chloro formate was added at about -5C over about 15 mins. Then reaction temperature was raised to about 0C and was stirred for about 30mins. After completion of the reaction, a mixture of 32.75 gms of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}-morpholin-3-onehydrochloride, 10.1 gms of triethyl amine and 100ml of dichloromethane was added at about - 5C over about 30mins. The resultant reaction mixture was stirred at about -5C for about 1 hr. The reaction temperature was raised to about 30C and was stirred overnight. After completion of the reaction, the solvent was distilled completely at about 40C to afford 98 gms of the title compound as solid, the solid obtained was recry stall ized from water to afford of the title compound in pure form.Yield : 36 gms.; Purity by HPLC: 99.85%. |
Yield | Reaction Conditions | Operation in experiment |
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at 120℃; for 48h;Inert atmosphere; Heating;Product distribution / selectivity; | 20 gms of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}-morpholin- 3-one, and 12.13 gms of methyl-5-chlorothiophene-2-carboxylic acid were charged into a clean and dry 500ml. 4 neck R.B. Flask. The reaction mixture was heated to about 120C for about 48 hours under nitrogen. After completion of the reaction, the reaction mass was cooled to about 30C, 180ml of acetic acid was added. The resultant reaction suspension was heated to about 110C, 2.5 gms of charcoal carbon was added. The suspension was filtered and the filtrate was cooled to about 20C for about 15 mins. The solid separated was filtered and the solid was washed with water afford the title compound in pure form.Yield : 26gms.; Purity by HPLC: 99.96%. |
Yield | Reaction Conditions | Operation in experiment |
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83% | Stage #1: 4-{4-[(S)-5-[(((4-chlorophenyl)methylene)amino)methyl]-2-oxo-1,3-oxazolidin-3-yl]phenyl}-morpholin-3-one With hydrogenchloride In water; ethyl acetate at 20℃; for 2h; Stage #2: 5-chlorothiophene-2-carbonyl chloride With sodium hydroxide In dichloromethane; water at 20℃; for 4h; | 8.b1 b1 ) Obtaining rivaroxaban from 23a (23, R = 4-CI)Mix 0.25 g of (S)-4-[4-(5-[(4-chlorobenzylidine)-amino]-methyl}-2-oxo- oxazolidine-3-yl)-phenyl]-morpholin-3-one (23a) (0.6 mmol), 19 mL of water, and 19 mL of AcOEt. Then add 0.1 mL of 37% HCI in water (1 .2 mmol) and stir at room temperature for 2 hours. Separate the phases. Extract the aqueous phase with 20 ml_ of AcOEt. Take the aqueous phase to pH 7-8 adding 1 N NaOH. Then add 0.1 1 g of 5-chloro-thiophene-2-carbonyl chloride (7) (0.6 mmol) dissolved in 19 mL of dichloromethane. Stir at roomtemperature for 4 hours, maintaining the pH between 7 and 8 by addition of 1 N NaOH. Separate the phases. Extract the aqueous phase with 20 mL of dichloromethane. Join the organic phases, dry with MgSO4, filter, and remove the solvent at reduced pressure. Suspend the raw matter in hexane (3 mL). Filter the solid obtained and vacuum dry at room temperature, obtaining 0.22 g (83% yield) of a white solid that corresponds to the intended product. Mp = 220-225°C. IR (cm"1): 3351 ; 1754.2, 1645.23, 1630.21 . 1H N MR (500 MHz, CDCIs) δ 7.56 (d, J = 8.9 Hz, 2H), 7.34 (d, J = 8.9 Hz, 2H), 7.29 (d, J = 4.0 Hz, 1 H), 6.90 (d, J = 4.0 Hz, 1 H), 6.49 (t, J = 6.0 Hz, 1 H), 4.85 (ddd, J = 9.4, 7.8, 4.6 Hz, 1 H), 4.34 (s, 2H), 4.10 (t, J = 9.0 Hz, 1 H), 4.06 - 4.01 (m, 2H), 3.92 - 3.87 (m, 1 H), 3.84 (dd, J = 9.3, 6.8 Hz, 1 H), 3.77 - 3.70 (m, 3H). MS: m/z= 458 (M +Na) ,436 (M), 893 (2M +Na), 1330 (3M +Na). [a]D= a/c I = -29.35 +/- 0.93°g"1 mL drn"1 (c=0.295g/100mL in DMSO). b2) Obtaining rivaroxaban from 23b (23, R = H) Mix 87 mg of (S)-4-(4-{5-[(benzylidene-amino)-methyl]-2-oxo-oxazolidine-3-yl}- phenyl)-morpholin-3-one (23b) (0.23 mmol), 7 mL of water, and 7 mL of AcOEt. Then add 0.04 mL of 37% HCI in water (0.46 mmol) and stir at room temperature for 2 hours. Separate the phases. Extract the aqueous phase with 20 mL of AcOEt. Take the aqueous phase to pH 7-8 adding 1 N NaOH. Then add 42 mg of 5-chloro-thiophene-2-carbonyl chloride (7) (0.23 mmol) dissolved in 8 mL of dichloromethane. Stir at room temperature for 2 hours. Separate the phases. Extract the aqueous phase with 20 mL ofdichloromethane. Join the organic phases, dry with MgSO4, filter, and remove the solvent at reduced pressure. Suspend the raw matter in hexane (3 mL). Filter the solid obtained and vacuum dry at room temperature, obtaining 72 mg (72% yield) of a white solid that corresponds to the intended product. |
83% | Stage #1: 4-{4-[(S)-5-[(((4-chlorophenyl)methylene)amino)methyl]-2-oxo-1,3-oxazolidin-3-yl]phenyl}-morpholin-3-one With hydrogenchloride In water; ethyl acetate at 20℃; for 2h; Stage #2: 5-chlorothiophene-2-carbonyl chloride With sodium hydroxide In dichloromethane at 20℃; for 4h; | 8b1 b1) Obtaining Rivaroxaban from 23a (23, R=4-Cl) 0068] Mix 0.25 g of (S)-4-[4-(5-[(4-chlorobenzylidine)-amino]-methyl}-2-oxo-oxazolidine-3-yl)-phenyl]-morpholin-3-one (23a) (0.6 mmol), 19 mL of water, and 19 mL of AcOEt. Then add 0.1 mL of 37% HCl in water (1.2 mmol) and stir at room temperature for 2 hours. Separate the phases. Extract the aqueous phase with 20 mL of AcOEt. Take the aqueous phase to pH 7-8 adding 1N NaOH. Then add 0.11 g of 5-chloro-thiophene-2-carbonyl chloride (7) (0.6 mmol) dissolved in 19 mL of dichloromethane. Stir at room temperature for 4 hours, maintaining the pH between 7 and 8 by addition of 1 N NaOH. Separate the phases. Extract the aqueous phase with 20 mL of dichloromethane. Join the organic phases, dry with MgSO4, filter, and remove the solvent at reduced pressure. Suspend the raw matter in hexane (3 mL). Filter the solid obtained and vacuum dry at room temperature, obtaining 0.22 g (83% yield) of a white solid that corresponds to the intended product. Mp=220-225° C. IR (cm-1): 3351; 1754.2, 1645.23, 1630.21. 1H NMR (500 MHz, CDCl3) δ 7.56 (d, J=8.9 Hz, 2H), 7.34 (d, J=8.9 Hz, 2H), 7.29 (d, J=4.0 Hz, 1H), 6.90 (d, J=4.0 Hz, 1H), 6.49 (t, J=6.0 Hz, 1H), 4.85 (ddd, J=9.4, 7.8, 4.6 Hz, 1H), 4.34 (s, 2H), 4.10 (t, J=9.0 Hz, 1H), 4.06-4.01 (m, 2H), 3.92-3.87 (m, 1H), 3.84 (dd, J=9.3, 6.8 Hz, 1H), 3.77-3.70 (m, 3H). MS: m/z=458 (M+Na), 436 (M), 893 (2M+Na), 1330 (3M+Na). [α]D=α/c I=-29.35±0.93° g-1 mL dm-1 (c=0.295 g/100 mL in DMSO). |
36.0 g | Stage #1: 4-{4-[(S)-5-[(((4-chlorophenyl)methylene)amino)methyl]-2-oxo-1,3-oxazolidin-3-yl]phenyl}-morpholin-3-one With hydrogenchloride; water In dichloromethane for 1.5h; Stage #2: With sodium hydroxide In dichloromethane; water Cooling with ice; Stage #3: 5-chlorothiophene-2-carbonyl chloride In dichloromethane; water at 20℃; for 0.5h; Cooling with ice; | EXAMPLE. 5-Chloro-N-({ (5S)-2-oxo-3-[4-(3-oxomorpholino-4-yl)phenyl]- 1.3-oxazolidine-5-yl}methyl)-thiophene-2-carboxamide (rivaroxaban, 5). To a 3L-3 neck round bottom flask with overhead stirrer was added water (250 ml), 12 N hydrochloric acid (25 ml, 300 mmol), methylene chloride (150 ml) and (S)-(E,Z)-5-((4- chlorobenzylideneamino)methyl)-3-(4-morpholin-3-onephenyl)oxazolidin-2-one (4) (41 g,, 99 mmol) that was washed in with methylene chloride (75 ml). The mixture was rapidly stirred and within 15 minutes a clear light yellow two-phase solution resulted. The reaction was stirred an additional 1 hour 15 minutes and the lower organic layer discarded. The colorless aqueous layer was washed with additional methylene chloride (2 x 75 ml) and the methylene chloride was discarded. Methylene chloride (225 ml) was added to the aqueous layer and the two phase solution was transferred back to the 3L-3neck round bottom flask with overhead stirrer. The reaction was cooled in an ice bath and basified to ca. pH 9 to 10 with ice cold 6 N NaOH. The two phase solution was rapidly stirred and a solution of 5- chloro-2-thiophenecarbonyl chloride (4) (300 mmol) in methylene chloride (150 ml) was added all at once to the rapidly stirring solution and gas evolution/foaming was observed. The reaction mixture was removed from the ice bath and stirred at room temp for 30 minutes. A thick white mass of crystalline solid formed within a few minutes. The crystals of 5 were collected by filtration and washed with cold (- 15° C) methanol (100 ml) and then ether. The product was dried in a vacuum oven at 40° C for 16 hours (40.53 g, 94%). TLC (CH2Cl2:MeOH 9: 1) Rf = 0.5). Recrystallization from glacial acetic acid (350 ml) provided shiny white crystals (36.0 g, 83.7%). mp 229-230° C (Lit2 mp 230° C). LCMS (Method 2) Retention time: 15.79 min (100%) m/e 474 (M+K)+. 1H NMR (500 MHz, DMSO-d6) δ 8.98 (t, 1H, J = 5.8 Hz), 7.69 (d, 1H, J = 4.1 Hz), 7.55 ( d, 2H, J = 9 Hz), 7.40 (d, 2H, J = 9.0 Hz), 7.19 (d, 1H, J=4.1 Hz), 4.84 (m, 1H), 4.19 (s, 2H), 4.188 ( t, 1H, J =10.6 Hz), 3.97 (dd, 2H, J = 4.7 Hz, J = 4.7 Hz), 3.84 (dd, 1H, J = 9.1 Hz, J=6.2 Hz), 3.71 (t, 2H, J =5.1Hz), 3.60 (t, 2H, J =5.4Hz),. [a]23D -38.0° (c = 1.00, DMSO) (Lit.2 [a]D21 -38° (c = 1.00, DMSO). Chiral chromatography: Retention time: 24.19 min (100 %) >98% ee) m/e 436 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
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72% | Stage #1: (S)-4-(4-{5-[(benzylidene-amino)-methyl]-2-oxo-oxazolidine-3-yl}-phenyl)-morpholin-3-one With hydrogenchloride In water; ethyl acetate at 20℃; for 2h; Stage #2: 5-chlorothiophene-2-carbonyl chloride With sodium hydroxide In dichloromethane; water at 20℃; for 2h; | 8.b2 b2) Obtaining rivaroxaban from 23b (23, R = H) Mix 87 mg of (S)-4-(4-{5-[(benzylidene-amino)-methyl]-2-oxo-oxazolidine-3-yl}- phenyl)-morpholin-3-one (23b) (0.23 mmol), 7 mL of water, and 7 mL of AcOEt. Then add 0.04 mL of 37% HCI in water (0.46 mmol) and stir at room temperature for 2 hours. Separate the phases. Extract the aqueous phase with 20 mL of AcOEt. Take the aqueous phase to pH 7-8 adding 1 N NaOH. Then add 42 mg of 5-chloro-thiophene-2-carbonyl chloride (7) (0.23 mmol) dissolved in 8 mL of dichloromethane. Stir at room temperature for 2 hours. Separate the phases. Extract the aqueous phase with 20 mL ofdichloromethane. Join the organic phases, dry with MgSO4, filter, and remove the solvent at reduced pressure. Suspend the raw matter in hexane (3 mL). Filter the solid obtained and vacuum dry at room temperature, obtaining 72 mg (72% yield) of a white solid that corresponds to the intended product. |
72% | Stage #1: (S)-4-(4-{5-[(benzylidene-amino)-methyl]-2-oxo-oxazolidine-3-yl}-phenyl)-morpholin-3-one With hydrogenchloride In water; ethyl acetate at 20℃; for 2h; Stage #2: 5-chlorothiophene-2-carbonyl chloride With sodium hydroxide In dichloromethane at 20℃; for 2h; | 8b2 b2) Obtaining Rivaroxaban from 23b (23, R═H) 0069] Mix 87 mg of (S)-4-(4-{5-[(benzylidene-amino)-methyl]-2-oxo-oxazolidine-3-yl}-phenyl)-morpholin-3-one (23b) (0.23 mmol), 7 mL of water, and 7 mL of AcOEt. Then add 0.04 mL of 37% HCl in water (0.46 mmol) and stir at room temperature for 2 hours. Separate the phases. Extract the aqueous phase with 20 mL of AcOEt. Take the aqueous phase to pH 7-8 adding 1N NaOH. Then add 42 mg of 5-chloro-thiophene-2-carbonyl chloride (7) (0.23 mmol) dissolved in 8 mL of dichloromethane. Stir at room temperature for 2 hours. Separate the phases. Extract the aqueous phase with 20 mL of dichloromethane. Join the organic phases, dry with MgSO4, filter, and remove the solvent at reduced pressure. Suspend the raw matter in hexane (3 mL). Filter the solid obtained and vacuum dry at room temperature, obtaining 72 mg (72% yield) of a white solid that corresponds to the intended product. |
Yield | Reaction Conditions | Operation in experiment |
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69% | In 2,2,2-trifluoroethanol at 20 - 80℃; for 4h; | 1 Example 1Preparation of rivaroxaban - oxalic acid (1:1) co crystal of the Formula 2 Example 1Preparation of rivaroxaban - oxalic acid (1:1) co crystal of the Formula 2A/ 4.50 g /10.32 millimoles/ of polymorph I of rivaroxaban of the Formula 1 /HPLC purity: 99.59 %/ are dissolved in 9,5 ml of 2,2,2-trifluoro-ethanol at 70- 80°C. To the hot solution 1.29 g /10.15 millimoles/ of oxalic acid dihydrate are added. The solution is stirred at this temperature for 5 minutes. The reaction mixture is allowed to cool to room temperature under stirring. After 4 hours the product is filtered and dried under an infrared lamp. Thus 3.66 g /69 %/ of rivaroxaban - oxalic acid co crystals l are obtained in the form of a white solid substance. HPLC purity 99,90 %..Mp.: 168-169°C.IR (KBr): 3347, 1788, 1737, 1630, 1557, 1520 cm'1.1H-NMR (DMSO-d6, 500 MHz): 13.96 (br s, 1H), 8.94 (t, J=5.8 Hz, 1H), 7.68 (d, J=4.1 Hz, 1H), 7.56 (~d, J=9.0 Hz, 2H), 7.41 (~d, J=9.0 Hz, 2H), 7.18 (d, J=4.0 Hz, 1H), 4.84 (m, 1H), 4.19 (m, 1H), 4.19 (s, 2H), 3.97 (m, 2H), 3.86 (m, 1H), 3.72 (m, 2H), 3.61 (~t, J=5.6 Hz, 2H).l3C-NMR (DMSO-d6, 125 MHz): 166.12, 161.08, 160.97, 154.25, 138.61, 137.26, 136.66, 133.42, 128.60, 128.26, 126.08, 118.54, 71.48, 67.90, 63.64, 49.18, 47.62, 42.38. Elemantary analysis for the Formula C21H20ClN3O9S (M: 435,89): calc: C 47,96; H 3,83; N 7,99; S 6,10; CI 6,74 %. Found: C 47,80; H 3,84; N 7,95; S 6,18; CI 6,77 %.The X-ray powder diffractogram of the rivaroxaban - gamma cyclodextrine co crystal /1:1/ of the Formula 2 is shown on Figure 1. The characteristic peaks are summarized in Table 1.B/ 0,75 g /1,72 millimoles/ of the above product are dissolved in 4 ml of hot 2,2,2- trifluoro-ethanol, the solution is stirred for 10 minutes and allowed to cool to room temperature. The product is filtered off. Thus 0.50 g /67 %/ of rivaroxaban - oxalic acid co crystal /l : 1/ is obtained.Elementary analysis for the Formula C21H20ClN3O9S (M: 435,89): calc. C 47,96; H 3,83; N 7,99; S 6,10; CI 6,74 %. Found: C 47,64; H 3,73; N 7,96; S 6,17; CI 6,80 %.DSC: 169,85 °C.The IR and NMR spectral data and the X-ray powder diffractogram of the product obtained are identical with those of the product before recrystallization. /Example 1/A/. |
Yield | Reaction Conditions | Operation in experiment |
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72.57% | With sodium carbonate In water; acetone; toluene at 50 - 55℃; for 1h; | 13 Example 13. Preparation of crude rivaroxaban 25 g (0.0633 mol) of 4-{4-[(5S)-5-(amino methyl)-2-oxo-1 ,3-oxazolidine-3- yl]phenyl}morpholin-3-one malonate, 8.31 g (0.784 mol) of sodium carbonate, 1 12 mL of water and 250 mL of acetone were charged in a 5 L flask. After cooling the reaction mass to 8-10 °C, 17.18 g (0.095 mol) of 5-chlorothiophene-2-carbonyl chloride in 85 mL of toluene were added maintaining the same temperature. Then, the reaction mass was heated to 50-55 °C and stirred for 1 hour. The resulting product was allowed to cool at 25-30 °C, filtered off and dried under vacuum at 80 °C. Yield: 20 g. Molar yield: 72.57%. HPLC purity 98.22%. |
Yield | Reaction Conditions | Operation in experiment |
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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, |
Yield | Reaction Conditions | Operation in experiment |
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89.9% | With sodium carbonate In water; acetone; toluene at 50 - 55℃; for 1h; | 11 Example 11. Preparation of crude rivaroxaban. 8 g (0.021 mol) of 4-{4-[(5S)-5-(amino methyl)-2-oxo-1 ,3-oxazolidine-3- yl]phenyl}morpholin-3-one oxalate, 2.75 g of sodium carbonate (0.026 mol), 35 mL of water and 60 mL of acetone were charged in a 1 L flask. After cooling the reaction mass to 8-10 °C, a solution of 7.60 g of 5-chlorothiophene-2-carbonyl chloride (0.042 mol) in 24 mL of toluene were added maintaining the same temperature. Then, the reaction mass was heated to 50-55 °C and stirred for 1 hour. The resulting product was allowed to cool at 25-30 °C, filtered off and dried under vacuum at 80 °C.Yield: 8.2 g. Molar yield: 89.90%. HPLC purity 98.84%. S.O.R.: [a ]D25 = -39.7° (c=0.2983, DMSO) |
Yield | Reaction Conditions | Operation in experiment |
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With sodium carbonate In dichloromethane; water at 0 - 35℃; | 10 EXAMPLE-10: Preparation of rivaroxaban. Thionyl chloride (10 ml) and 5-chlorothiophene-2-carboxylic acid (5 g) were added at 25°C to 35°C and heated to 65°C to 70°C and maintained for^O minutes. Toluene (25 ml) was added and heated to 110°C to 120°C and excess thionyl chloride and toluene was distilled out. In another RBF formate salt of (S)-4-(4-(5- (aminomethyl)-2-o o-oxazolidin-3-yl)phenyl)mo holin-3-one of Formula (JF) (10 g) was added and water (50 ml) and MDC (100 ml) was added at 25°C to 35°C and cooled to 0°C to 5°C followed by addition of sodium carbonate (4.5 g). To the reaction mass above prepared acid chloride solution was added at 0°C to 5°C and raised to 25 °C to 35°C. The reaction mass was filtered and washed with water (20 ml). The wet cake was treated with MDC (50 ml) and stirred for 15 minutes. To the reaction mass methanol (50 ml) was added and stirred for 30 minutes and washed with mixture of MDC-methanol (1:1) (10 ml). The wet cake was treated with 50% HC1 solution (100 ml) at 50°C to 60°C and stirred for 30 minutes. The reaction mass and washed with water (20 ml) afforded as crude rivaroxaban of Formula ( 1 ). 10 g of crude Rivaroxaban was treated with methanol (100 ml) at 50°C to 55°C and stirred for 30 minutes. The product was filtered and washed with methanol (10 ml) afforded the title compound as pure rivaroxaban. (free of MDC as residual solvent and HPLC purity: 99.98%) | |
With sodium carbonate In dichloromethane; water at 0 - 35℃; | 10 Preparation of Rivaroxaban Thionyl chloride (10 ml) and 5-chlorothiophene-2-carboxylic acid (5 g) were added at 25° C. to 35° C. and heated to 65° C. to 70° C. and maintained for 60 minutes. Toluene (25 ml) was added and heated to 110° C. to 120° C. and excess thionyl chloride and toluene was distilled out. In another RBF formate salt of (S)-4-(4-(5-(aminomethyl)-2-oxo-oxazolidin-3-yl)phenyl)morpholin-3-one of Formula (JF) (10 g) was added and water (50 ml) and MDC (100 ml) was added at 25° C. to 35° C. and cooled to 0° C. to 5° C. followed by addition of sodium carbonate (4.5 g). To the reaction mass above prepared acid chloride solution was added at 0° C. to 5° C. and raised to 25° C. to 35° C. The reaction mass was filtered and washed with water (20 ml). The wet cake was treated with MDC (50 ml) and stirred for 15 minutes. To the reaction mass methanol (50 ml) was added and stirred for 30 minutes and washed with mixture of MDC-methanol (1:1) (10 ml). The wet cake was treated with 50% HCl solution (100 ml) at 50° C. to 60° C. and stirred for 30 minutes. The reaction mass was filtered and washed with water (20 ml) afforded as crude rivaroxaban of Formula (1). 10 g of crude Rivaroxaban was treated with methanol (100 ml) at 50°C. to 55°C. and stirred for30 minutes. The product was filtered and washed with methanol (10 ml) afforded the title compound as pure rivaroxaban. (free of MDC as residual solvent and HPLC purity: 99.98%) |
Yield | Reaction Conditions | Operation in experiment |
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With sodium carbonate In dichloromethane; water at 0 - 35℃; | 20 EXAMPLE-20; Preparation of rivaroxaban: Thionyl chloride (10 ml) and 5-chlorothiophene-2-carboxylic acid (5 g) were added at 25°C to 35°C and heated to 65°C to 70°C and maintained for 60 minutes. Toluene (25 ml) was added and heated to 110°C to 120°C and excess thionyl chloride and toluene was distilled out. In another RBF L (+)-mandelate salt of (S)-4-(4-(5-and toluene was distilled out. In another RBF L (+)-mandelate salt of (S)-4-(4-(5- (aminomethyl)-2-o o-oxazolidin-3-yl)phenyl)mo holin-3-one of Formula (JM) (10 g) was added and water (50 ml) and MDC (100 ml) was added at 25°C to 35°C and cooled to 0°C to 5°C followed by addition of sodium carbonate (4.5 g). To the reaction mass above prepared acid chloride solution was added at 0°C to 5°C and raised to 25°C to 35°C. The reaction mass was filtered and washed with water (20 ml). The reaction mass was treated with 50% HCl solution (100 ml) at 50°C to 60°C and stirred for 30 minutes. The reaction mass was filtered and washed with water (20 ml) afforded as crude rivaroxaban of Formula (1). 10 g of crude rivaroxaban was treated with MDC (50 ml) at 25°C to 35°C and heated to 40°C to 45°C and stirred for 15 minutes. To the reaction mass Methanol (50 ml) was added and stirred for 30 minutes. The product was filtered and washed with mixture of methanol (10 ml) afforded pure rivaroxaban. | |
With sodium carbonate In dichloromethane; water at 0 - 35℃; | 20 Preparation of Rivaroxaban Thionyl chloride (10 ml) and 5-chlorothiophene-2-carboxylic acid (5 g) were added at 25° C. to 35° C. and heated to 65° C. to 70° C. and maintained for 60 minutes. Toluene (25 ml) was added and heated to 110° C. to 120° C. and excess thionyl chloride and toluene was distilled out. In another RBF L (+)-mandelate salt of (S)-4-(4-(5- and toluene was distilled out. In another RBF L (+)-mandelate salt of (S)-4-(4-(5-(aminomethyl)-2-oxo-oxazolidin-3-yl)phenyl)morpholin-3-one of Formula (JM) (10 g) was added and water (50 ml) and MDC (100 ml) was added at 25° C. to 35° C. and cooled to 0° C. to 5° C. followed by addition of sodium carbonate (4.5 g). To the reaction mass above prepared acid chloride solution was added at 0° C. to 5° C. and raised to 25° C. to 35° C. The reaction mass was filtered and washed with water (20 ml). The reaction mass was treated with 50% HCl solution (100 ml) at 50° C. to 60° C. and stirred for 30 minutes. The reaction mass was filtered and washed with water (20 ml) afforded as crude rivaroxaban of Formula (1). 10g of crude rivaroxaban was treated with MDC (50 ml) at 25° C. to 35° C. and heated to 40° C. to 45° C. and stirred for 15 minutes. To the reaction mass methanol (50 ml) was added and stirred for 30 minutes. The product was filtered and washed with mixture of methanol (10 ml) afforded pure |
Yield | Reaction Conditions | Operation in experiment |
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54.3% | With palladium 10% on activated carbon; hydrogen In ethanol at 50 - 55℃; for 18h; | 18.III Step-Ill: Preparation of Rivaroxaban (I): Step-Ill: Preparation of Rivaroxaban (I): To a solution of 5-ο1ι1θΓθ-Ν-[{(58)-2-οχο-3-[4-(3-οχο-4-ηιοφΗοΗη>)ρ1ιεη>]-1,3- oxazolidin-5-yl}methyl]-N'-benzyl-2-thiophene carboxamide (Prepared in Step-II) (5.0 g) in ethanol ( 100 ml) was added 10 % Pd-C( l.Og) and the mixture was hydrogenated at 50-55°C under a hydrogen pressure of 4-5 kgs for about 18 hrs. Filtered the catalyst and concentrated the filtrate and the crude obtained was re-crystallized from acetone to yield the title compound as white crystalline solid. Yield: 2.25g (% Yield: 54.3%). |
2.66 g | With <i>N</i>-methyl-acetamide; N-Bromosuccinimide In chloroform at 30℃; for 18h; Reflux; | 10.II Step II: Debenzylation of 5-Chloro-N-[{(5S)-2-oxo-3-[4-(3-oxo-4-morpholin-4-yl)phenyl]- -oxazolidin-5-yl}methyl]-N1-benzyl-2-h carboxamide Preparation of Rivaroxaban(I)): To a suspension of 5-Chloro N-[{(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3- oxazolidin-5-yl}methyl]-N1-benzyl-2-thiophene carboxamide (prepared in step -I) ( 5.26 gms , 10 mmol) in CHC13 ( 100 ml), N-methylacetamide ( 0.73 gms , 0.2 eq) and N- bromosuccinimide ( 4.45 gms, 2.5eq) were added at about 30°C and the resulting mix.was stirred at reflux for 18 hrs . The solvent was evaporated under vacuum and dichloromethane ( 100 ml) and aq. Sodium hydroxide ( 1M, 50 ml) were added and the phases are separated .The aq. was extracted with dichloromethane ( 25 ml x 3) and the combined organics washed with water ( 20 ml x 2), brine( 1 X 10 ml) and dried over sodium sulphate. The solvent was evaporated under vacuum and the solid obtained was re-crystallized from acetic acid. (Yield = 2.66 gms, 61 % of the theory). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.7% | With triethylamine; In dimethyl sulfoxide; at 35 - 40℃; | <strong>[1450877-56-1]4-nitrophenyl 5-chlorothiophene-2-carboxylate</strong> (9.5 gm) was added to a solution of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (10 gm) in dimethyl sulfoxide (40 ml) and triethyl amine (4.6 gm) at 35 to 40 C. After completion of reaction, acetonitrile (40 ml) was added to the reaction mass. Heat the, reaction mass to reflux or till clear solution appear, added methanol (60 ml), cool the reaction mass to 25 to 30 C, stir the reaction mass for 2 h, filtered the solid and dried at 50 to 55 C for 3 to 5 hr to obtain 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide[Yield = 11.0 gm (82.7 %); Purity (HPLC) = 99.7 %] |
82.7% | With triethylamine; In dimethyl sulfoxide; acetonitrile; at 35 - 40℃; | <strong>[1450877-56-1]4-nitrophenyl 5-chlorothiophene-2-carboxylate</strong> (9.5 gm) was added to a solution of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (10 gm) in dimethyl sulfoxide (40 ml) and triethyl amine (4.6 gm) at 35 to 40 C. After completion of reaction, acetonitrile (40 ml) was added to the reaction mass. Heat the reaction mass to reflux or till clear solution appear, added methanol (60 ml), cool the reaction mass to 25 to 30 C., stir the reaction mass for 2 h, filtered the solid and dried at 50 to 55 C. for 3 to 5 hr to obtain 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide [Yield=11.0 gm (82.7%); Purity (HPLC)=99.7%] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With potassium hydrogencarbonate In ethanol; water; butanone at 20 - 35℃; for 0.75h; Large scale; | Preparation of Rivaroxaban 1 The methanesulfonate salt (S)-12 (2.0 kg) was dissolved in a mixture of 5.0 L methylethyl ketone (MEK) and 10.0 L of water; we then added a solution of KHCO3 (1.55 kgin 5.0 L of water), and the mixture was stirred and cooled to 15 C. This was followedby the addition of a solution of the acid chloride of 5-chlorothiophene-2-carboxylic acid(13.9 L, 2.14 M in toluene) in 6.0 MEK and the reaction mixture was stirred at 20 Cfor 15 minutes. Then ethanol (16.0 L) was added and stirred at 35 C for 30 min. Themixture was stirred, heated to 50 C for 30 min, filtered, the clear filtrate cooled to 5 Cand stirred for 2 hours. The separated product was collected by filtration, washed withhot water (2 x 2.5 L, 60 C), ethanol (2 x 3.0 L) and dried under vacuum. Rivaroxaban(2.16 kg, yield 96%) was obtained in the form of a nearly white powder with m.p. 229.5-231 C, HPLC 99.95%, the content of (R)- isomer was under 0.03%. 1H NMR (DMSOd6),d(ppm): 3.61 (t, 2H, CH2); 3.71 (m, 2H, CH2); 3.85 a 4.19 (m, 2x1H, CH2); 3.97(m, 2H, CH2); 4.19 (s, 2H, CH2); 4.84 (pent, 1H, CH); 7.18 (d, 1H); 7.40 (m, 2H); 7.56(m, 2H); 7.68 (d, 1H); 8.95 (bt, 1H, NH).13C NMR (DMSO-d6), d(ppm): 42.2; 47.4;49.0; 63.4; 67.7; 71.3; 118.3; 125.9; 128.1; 128.4; 133.2; 136.4; 137.0; 138.4; 154.0; 160.8;165.9.MS (m/z): 436.0729 (MH). |
81% | With triethylamine In 1-methyl-pyrrolidin-2-one; toluene at 50 - 60℃; for 0.25h; | 28 (preparation of rivaroxaban) 10 g of the salt prepared according to Example 18 were suspended in 75 ml of N- methylpyrolidone, the suspension was heated at 50°C, then 14 ml of triethylamine was added and the mixture was heated at 60°C. This was followed by addition of 15.7 ml of a solution of 5-chlorothiophene-2-carboxylic acid chloride in toluene (2.46 M) and the reaction mixture was stirred and heated at 55°C for 15 minutes, then slowly cooled below 30°C, 75 ml were added and the turbid solution was filtered. The clear filtrate was stirred at 50°C, which was followed by addition of 15 ml of water and 75 ml of ethanol and stirring for 1 hour under slow cooling. The separated product was filtered off, washed with water (15 ml, 60°C), ethanol (2 x 25 ml) and dried in vacuo. 9.1 g (yield 81%) of rivaroxaban in the form of an off-white powder with the melt, point of 229.5-231°C was obtained, HPLC 99.95%, content of the ( )-isomer below 0.03%. 1H NMR (250 MHz, DMSO-D6), δ (ppm): 3.61 (t, 2H, CH2); 3.71 (m, 2H, CH2); 3.85 and 4.19 (m, 2x1 H, CH2); 3.97 (m, 2H, CH2); 4.19 (s, 2H, CH2); 4.84 (pent, 1H, CH); 7.18 (d, 1H); 7.40 (m, 2H); 7.56 (m, 2H); 7.68 (d, 1H); 8.95 (bt, 1H, NH). 13C NMR (250 MHz, DMSO-D6), δ (ppm): 42.2; 47.4; 49.0; 63.4; 67.7; 71.3; 1 18.3; 125.9; 128.1 ; 128.4; 133.2; 136.4; 137.0; 138.4; 154.0; 160.8; 165.9. MS (m/z): 436.0729 (M+H)+. ation) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3 g | With lithium tert-butoxide; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 44h;Cooling with ice; | To a solution of [4-(3-oxo-morpholin-4-yl) phenyl carbamic acid benzyl ester] (5g,15.3 mmol) (prepared in Ex.2) and N-[(2S)-3-chloro-2-hydroxypropyl]-5-chlorothiophene-2- carboxamide (5.0 gms , 1.28 eq) (prepared in Ex. 3 or 4) in DMF (15 ml) in an icebath was added a solution of lithium tert. Butoxide (3.0 gms, 2.45 eq) in THF (16.5 ml). The resultant mix. was allowed to stand at 20 0 C for 44 hrs. Saturated aq. amm. Chloride (25 ml), water (50 ml) and methylene chloride (60 ml) were added and the phases separated. The aq. was washed with methylene chloride (60 ml) and the combined org. were dried on magnesium sulfate and concentrated to get a crude compound. After re-crystallization from acetic acid, yields a title compound as white crystalline solid (Yield = 3.0 g , corresponds to 45% of the theory). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.34 g | With lithium tert-butoxide; In tetrahydrofuran; methanol; N,N-dimethyl-formamide; at 5 - 21℃; for 21h; | To a solution of [4-(3-oxo-morpholin-4-yl)phenyl carbamic acid benzyl ester (prepared in Ex.2) (5g,15.3 mmol) in N,N - dimethyl formamide (15ml) and methanol (1.0 g, 2 eq) at 20C is added a solution of lithium-t-butoxide (3.6 g, 3 eq) in 20 ml THF while keeping less than 24C with an ice-bath. The solution is cooled to 5 C and N-[(2S)-3-chloro-2-(acetyloxy) propyl]-5-chlorothiophene-2-carboxamide (9 gms, 2 eq) (prepared in Ex.5) is added. The resulting solution is allowed to stand for 21 hrs at 21 C .Saturated, amm. chloride solution (25 ml) is added followed by water (50 ml), sat. Sodium chloride solution (25 ml) and methylene chloride (50 ml).The phases are separated and the aq. Washed with methylene chloride (3 x 25 ml). The organic layers are dried on magnesium sulfate and concentrated in vacuo to yield semi-solid and re-crystallized from ethanol to yield title compound as a white solid (Yield = 3. 34 gms, 50% of theory). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.2 g | In dichloromethane; at 25 - 30℃; | l -Methylimidazole (24.6 g, 0.3 mol) was added to a stirred suspension of 5- chlorothiophene-2-carboxylic acid ( 16.25 g, 0.1 mol) in dichloromethane ( 162 ml) at 0- 5C and the resulting solution was stirred for 10 minutes. A solution of methanesulfonyl chloride ( 12 g, 0.105 mol) in dichloromethane (40 ml) was added to the above solution at -5C. The resulting solution was stirred for 1 hour at -5C to produce a reaction mass containing the sulfonyl ester intermediate, followed by portion wise addition of 4-[4-[(5S)- 5-(aminomethyl)-2-oxo- l ,3-oxazolidin-3-yl]phenyl] morpholine-3-one (29.1 g, 0.1 mol, chiral purity: 99.9%). The reaction mixture was stirred for 2 hours at 25-30C, followed by the addition of water ( 162 ml) and then stirring for 15 minutes. The separated solid was filtered, washed with dichloromethane (50 ml) and water ( 100 ml), and the resulting wet material was dried at 80-85C for 3 to 5 hours to produce 39.2 g of pure rivaroxaban as a white crystalline solid (Theoretical Yield: 90%; Purity by HPLC: 99.9%; and Chiral Purity by HPLC: 99.9%). |
38.5 g | In dichloromethane; at 25 - 30℃; for 2h; | 1-Methylimidazole (20.5 g, 0.25 mol) was added to a stirred suspension of 5-chlorothiophene-2-carboxylic acid (16.25 g, 0.1 mol) in dichloromethane (162 ml) at 0-5 C. and the resulting solution was stirred for 10 minutes. A solution of methanesulfonic anhydride (17.4 g, 0.1 mol) in dichloromethane (40 ml) was added to the above solution at -5 C. The resulting solution was stirred for 1 hour at -5 C. to produce a reaction mass containing the sulfonyl ester intermediate, followed by portion wise addition of 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl], morpholine-3-one (29.1 g, 0.1 mol, chiral purity by HPLC: 99.85%). The reaction mixture was stirred for 2 hours at 25-30 C., followed by the addition of water (162 ml) and then stirring for 15 minutes. The separated solid was filtered, washed with dichloromethane (50 ml) and water (100 ml), and the resulting wet material was dried at 80-85 C. for 3 to 5 hours to produce 38.5 g of pure rivaroxaban as a white crystalline solid (Theoretical Yield: 88.4%; Purity by HPLC: 99.8%; and Chiral Purity by HPLC: 99.85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37.3 g | In dichloromethane; at 25 - 30℃; for 2h; | 4- (N,N-dimethylamino)pyridine (36.6 g, 0.3 mol) was added to a stirred suspension of 5- chlorothiophene-2-carboxylic acid (16.25 g, 0.1 mol) in dichloromethane ( 162 ml) at 0- 5C and the resulting solution was stirred for 10 minutes. A mixture of p-toluenesulfonyl chloride ( 19.05 g, 0.1 mol) and dichloromethane (50 ml) was added to the above solution at -5C. The resulting solution was stirred for 1 hour at -5C to produce a reaction mass containing the sulfonyl ester intermediate, followed by portion wise addition of 4-[4-[(5S)- 5- (aminomethyl)-2-oxo- l ,3-oxazolidin-3-yl]phenyl] morpholine-3-one (29.1 g, 0.1 mol, chiral purity: 99.9%). The reaction mixture was stirred for 2 hours at 25-30C, followed by the addition of water ( 1 62 ml) and then stirring for 15 minutes. The separated solid was filtered, washed with dichloromethane (50 ml) and water ( 100 ml), and the resulting wet material was dried at 80-85C for 3 to 5 hours to produce 37.3 g of pure rivaroxaban as a white crystalline solid (Theoretical Yield: 85.6%; Purity by HPLC: 99.9%; and Chiral Purity by HPLC: 99.9%). ) |
37.3 g | In dichloromethane; at 25 - 30℃; for 2h; | 4-(N,N-dimethylamino)pyridine (36.6 g, 0.3 mol) was added to a stirred suspension of 5-chlorothiophene-2-carboxylic acid (16.25 g, 0.1 mol) in dichloromethane (162 ml) at 0-5 C. and the resulting solution was stirred for 10 minutes. A mixture of p-toluenesulfonyl chloride (19.05 g, 0.1 mol) and dichloromethane (50 ml) was added to the above solution at -5 C. The resulting solution was stirred for 1 hour at -5 C. to produce a reaction mass containing the sulfonyl ester intermediate, followed by portion wise addition of <strong>[446292-10-0]4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholine-3-one</strong> (29.1 g, 0.1 mol, chiral purity: 99.9%). The reaction mixture was stirred for 2 hours at 25-30 C., followed by the addition of water (162 ml) and then stirring for 15 minutes. The separated solid was filtered, washed with dichloromethane (50 ml) and water (100 ml), and the resulting wet material was dried at 80-85 C. for 3 to 5 hours to produce 37.3 g of pure rivaroxaban as a white crystalline solid (Theoretical Yield: 85.6%; Purity by HPLC: 99.9%; and Chiral Purity by HPLC: 99.9%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With potassium carbonate In water-d2; acetone at 25 - 30℃; for 12h; | 4 Example 4: Preparation of rivaroxaban (Formula I) Example 4: Preparation of rivaroxaban (Formula I) Potassium carbonate (0.135 g, 0.000952 moles) was added to a solution of (2S)-1- chloro-3 - { [(5-chlorothiophen-2-yl)carbonyl] amino } propan-2-yl[4-(3 -oxomorpholin-4- yl)phenyl] carbamate (Formula II; 0.3 g, 0.000635 moles) in acetone (6 mL) and deionized water (3 mL) at 25°C to 30°C. The mixture was stirred for 12 hours at 25°C to 30°C. The reaction mixture was extracted with dichloromethane (10 mL). The organic layer was separated and concentrated under vacuum to get an oily product. The oily product was crystallized in ethyl acetate (3 mL) and hexanes (5 mL) at 25°C to 30°C. The slurry obtained was filtered and suck dried. The wet solid was dried under vacuum at 40°C to 45°C. Yield = 0.15 g (56%) |
56% | With potassium carbonate In water; acetone at 25 - 30℃; for 12h; | 4 Preparation of Rivaroxaban (Formula I) Potassium carbonate (0.135 g, 0.000952 moles) was added to a solution of (2S)-1-chloro-3-[(5-chlorothiophen-2-yl)carbonyl]amino}propan-2-yl[4-(3-oxomorpholin-4-yl)phenyl]carbamate (Formula II; 0.3 g, 0.000635 moles) in acetone (6 mL) and deionized water (3 mL) at 25° C. to 30° C. The mixture was stirred for 12 hours at 25° C. to 30° C. The reaction mixture was extracted with dichloromethane (10 mL). The organic layer was separated and concentrated under vacuum to get an oily product. The oily product was crystallized in ethyl acetate (3 mL) and hexanes (5 mL) at 25° C. to 30° C. The slurry obtained was filtered and suck dried. The wet solid was dried under vacuum at 40° C. to 45° C. Yield=0.15 g (56%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l, 3-oxazolidin-3-yl] phenyl} morpholin- 3-one hydrochloride (5.7 g) in ethanol (70 ml) added potassium carbonate (7.1 g) and the mixture was stirred 2 h at 25 to 30C then filtered to obtain 4-{4-[(5S)-5-(aminomethyl)-2- oxo-1, 3-oxazolidin-3-yl] phenyl} morpholin-3-one (free base). In another flask charged solution of 5-chlorothiophene-2-carbonitrile (2.9 g) under nitrogen in ethanolic HCl (12 ml) and stirred for 5 h at room temperature till white precipitate was obtained. Distilled under nitrogen to avoid from moisture and obtained residue added in solution of 4-{4-[(5S)-5- (aminomethyl)-2-oxo-l, 3-oxazolidin-3-yl] phenyl} morpholin-3-one. The mixture was stirred for 16 to 18 h at reflux temperature. Added aq.ethanol (5ml) and again heat the mixture at reflux temperature for 10 tol2 h to obtain 5-chloro-N-({(5S)-2-oxo-3-[4-(3- oxomorpholin-4-yl)phenyl]-L3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (crud material) which further purified by column Chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.67 g | With sodium hydroxide; In dichloromethane; water; at 25 - 30℃; | N-({ (5 S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl] - 1 ,3 -oxazolidin-5 -yl}methyl)formamide (1 g) taken in a dichloromethane(10 ml) and stirred reaction mass at 25 to 30C for 30 minutes. To this mixture added solution of 4-nitrophenyl- 5-chlorothiophene-2-carboxylate (1.06 g) in a dichloromethane (10 ml) and sodium hydroxide (0.38 g) in water (5 ml) simultaneously through addition funnel. Obtained reaction mass then stirred for 1 to 2 h at 25 to 30C. After completion of reaction, Separated organic layer and concentrated under reduced pressure to obtain residue. Added acetic acid and methanol to residue stirred for 30 minutes and obtained solid is filtered off. Washed solid with methanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.6 g | With hydrogenchloride In water; acetic acid at 70 - 80℃; | 8.VI EXAMPLE S [054] Preparation of Rivaroxaban (Stage- VI) 5-chloro-N-formyl-N-({(5S)-2-oxo-3-[4-(3-oxomo holin-4-yl)phenyl]-l,3-oxazolidin-5- yl}methyl)thiophene-2-carboxamide (1.0 g) taken in mixture of acetic acid (5 ml) and cone hydrochloric acid (0.25 ml).Obtained reaction mixture is heated to 70 to 80°C for 3 to 4 h. After completion of reaction, cooled reaction mixture 25 to 30°C and added methanol (5 ml). The precipitated solid is filtered off and washed by methanol (3 ml). Yield 0.6 g |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55.5% | With potassium carbonate; In dichloromethane; at 25 - 30℃; | <strong>[1450877-56-1]4-nitrophenyl 5-chlorothiophene-2-carboxylate</strong> (2.33 gm) was added to a solution of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one (2 gm) and potassium carbonate (1.13 gm) in dichloromethane (20 ml) at 25 to 30 C. After completion of reaction, water and hydrochloric acid was added to the reaction mass & concentrated reaction mass under reduced pressure to obtain crude solid. Methanol was charged to the obtained crude solid and stirred for 30 minutes at 60 C. Finally filtered the solid and dried at 50 to 55 C. for 3 to 5 hr to obtain 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide [Yield=1.5 gm (55.5%); Purity (HPLC)=97.98%] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: (S)-5-chloro-thiophene-2-carboxylic acid (3-{N-benzyl-[4-(3-oxo-morpholin-4-yl)-phenyl]-amino}-2-hydroxy-propyl)-amide With potassium carbonate In dichloromethane at 25 - 35℃; Stage #2: bis(trichloromethyl) carbonate In dichloromethane at 0 - 35℃; for 8.5h; | 10 Preparation of (S)-5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l, 3- oxazolidin-5-yl} methyl)-2-thiophenecarboxamide (Rivaroxaban) (I) To a stirred solution of (S)-5-chloro-thiophene-2-carboxylic acid (3-{N-benzyl-[4-(3-oxo- morpholin-4-yl)-phenyl] -amino }-2-hydroxy-propyl)-amide (IXa) (5 g; 0.01 mol) in dichloromethane (25 ml), potassium carbonate was added (3.3 g; 0.024 mol) at 25-35°C to give a heterogeneous reaction mixture. The mixture was cooled to 0-10°C. A solution of triphosgene (4.75 g; 0.016 mol) in dichloromethane (25 ml) was added to the reaction mixture at 0-10°C within 30 minutes. The reaction was allowed to proceed at 25-35°C for 8 hours. After completion of reaction, the mixture was cooled to 0-10°C and diluted with water (25 ml). The solid was filtered and washed twice with water (2.5 ml) and then twice with dichloromethane (2.5 ml). The solid was dried at 25-35°C to give the title product Rivaroxaban (3.6 g). Yield: 80.0 %. 1H NMR (DMSO)5: 3.60-3.62 (2H, t), 3.70-3.72 (2H, t), 3.84-3.87 (1H, m), 3.96-3.98 (2H, m), 4.17-4.21 (3H, m), 4.81-4.88 (1H, m), 7.19-7.20 (1H, d), 7.39-7.42 (2H, m),7.54-7.58 (2H, m), 7.69-7.70 (1H, d), 8.98-9.01 (1H, t) Mass: 436.1 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.7% | In dichloromethane at 0 - 35℃; for 8.5h; | 11 Preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin- 5-yl} methyl)-2-thiophenecarboxamide (Rivaroxaban) (I) A solution of triphosgene (4.75 g; 0.016 mol) in dichloromethane (25 ml) was added to a mixture of (S)-4-(4-{3-[2-(5-Chloro-thiophen-2-yl)-2-oxo-ethylamino]-2-hydroxy- propylamino}-phenyl)-morpholin-3-one (IX') (5.0 g; 0.01 mol) in dichloromethane (25 ml) and cooled at 0-10°C within 30 minutes. The reaction was allowed to proceed at 25-35°C for 8 hours. After completion of the reaction, the reaction mixture was cooled to 0-10°C and diluted with water (25 ml). An exotherm was observed. The reaction mixture was stirred at 25-35°C for 1 hour. The solid was filtered and washed twice with water (2.5 ml) and then twice with dichloromethane (2.5 ml). The solid was dried at 25-35°C to give the title product Rivaroxaban (I) (3.6 g). Yield: 82.7%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl acetamide; water; at 5 - 10℃; | To the mixture of thioester (as referred as compound hA, 10.7g), 4-{4-[(5S)-5- (aminomethyl)-2-oxo- 1,3 -oxazolidin-3-yl]phenyl } morpholine-3 -one( 1 Og) in tetrahydrofuran (30 ml),water (30 ml) under stirring triethylamine (3.8g) was added The reaction mixture was further stirred at 5-10C for 4-6 hours. After completion of the reaction, it was quenched with water & extracted in methylene chloride (250 ml x 2). The aqueous layer was back extracted using methylene chloride and methylene chloride layers were combined and its pH was adjusted to 6-7 with 2 N hydrochloric acid. Finally, the organic layer was concentrated to get desired product. The product obtained was dried to yield Rivaroxaban.Yield: 11.5Purity: 99.3 %; Exemplified procedure iii example 1 with the replacement thioester of compound hA with S -methyl 5-chlorothiophene-2-carbothioate in N,N-dimethylacetamide and water with potassium carbonate were used iii place of triethylanEe, during workup methylene chloride was used in mixture of N,N dimethyl acetamide and water to extract the Rivaroxaban.; EXAMPLE 4: A process for the preparation of rivaroxabanExemplified procedure iii example 1 with the replacement thioester of compound hA with S -3H- 1,2, 3-triazol-4-yl 5-chlorothiophene-2-carbothioate in dichioromethane with N-methylpiperidine were used to get the Rivaroxaban. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide; In water; acetone; at 5 - 10℃; | To the mixture of thioester (as referred as compound hA, 10.7g), 4-{4-[(5S)-5- (aminomethyl)-2-oxo- 1,3 -oxazolidin-3-yl]phenyl } morpholine-3 -one( 1 Og) in tetrahydrofuran (30 ml),water (30 ml) under stirring triethylamine (3.8g) was added The reaction mixture was further stirred at 5-10C for 4-6 hours. After completion of the reaction, it was quenched with water & extracted in methylene chloride (250 ml x 2). The aqueous layer was back extracted using methylene chloride and methylene chloride layers were combined and its pH was adjusted to 6-7 with 2 N hydrochloric acid. Finally, the organic layer was concentrated to get desired product. The product obtained was dried to yield Rivaroxaban.Yield: 11.5Purity: 99.3 %; Exemplified procedure iii example 1 with the replacement thioester of compound hA with S-benzo[djisoxazol-3-yl 5-chlorothiophene-2-carbothioate in acetone with potassium hydroxide were used and similar workup process of example 2was followed to get the Rivaroxaban. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-methylcyclohexylamine; In dichloromethane; water; at 5 - 10℃; | To the mixture of thioester (as referred as compound hA, 10.7g), 4-{4-[(5S)-5- (aminomethyl)-2-oxo- 1,3 -oxazolidin-3-yl]phenyl } morpholine-3 -one( 1 Og) in tetrahydrofuran (30 ml),water (30 ml) under stirring triethylamine (3.8g) was added The reaction mixture was further stirred at 5-10C for 4-6 hours. After completion of the reaction, it was quenched with water & extracted in methylene chloride (250 ml x 2). The aqueous layer was back extracted using methylene chloride and methylene chloride layers were combined and its pH was adjusted to 6-7 with 2 N hydrochloric acid. Finally, the organic layer was concentrated to get desired product. The product obtained was dried to yield Rivaroxaban.Yield: 11.5Purity: 99.3 %; EXAMPLE 4: A process for the preparation of rivaroxabanExemplified procedure iii example 1 with the replacement thioester of compound hA with S -3H- 1,2, 3-triazol-4-yl 5-chlorothiophene-2-carbothioate in dichioromethane with N-methylpiperidine were used to get the Rivaroxaban. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; water; at 5 - 10℃; | To the mixture of thioester (as referred as compound hA, 10.7g), 4-{4-[(5S)-5- (aminomethyl)-2-oxo- 1,3 -oxazolidin-3-yl]phenyl } morpholine-3 -one( 1 Og) in tetrahydrofuran (30 ml),water (30 ml) under stirring triethylamine (3.8g) was added The reaction mixture was further stirred at 5-10C for 4-6 hours. After completion of the reaction, it was quenched with water & extracted in methylene chloride (250 ml x 2). The aqueous layer was back extracted using methylene chloride and methylene chloride layers were combined and its pH was adjusted to 6-7 with 2 N hydrochloric acid. Finally, the organic layer was concentrated to get desired product. The product obtained was dried to yield Rivaroxaban.Yield: 11.5Purity: 99.3 % |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine In dichloromethane at 10 - 20℃; for 1h; Large scale; | 5; 6 EXAMPLE 5-6 This example relates to the preparation of Rivaroxaban. 1 1 .0 kg of the compound (V) obtained in example 3, 88.0 kg of methylene chloride and 1 1 .0 kg of triethylamine are loaded into an glass-lined reactor. The solution containing the 5-chlorothiophene-2-carbonyl chloride obtained in example 4 is added to the suspension which has been maintained at a temperature between 10-20 °C. The mass, maintained at a temperature of between 10-20 °C, is reacted for about one hour then 55.0 kg of water are added. A suspension is obtained that is centrifuged to separate the solid; this is then washed with 16.5 kg of water. The recovered solid is dried, obtaining 12.2 kg of crude Rivaroxaban, with a yield equal to 90.2%. The 12.2 kg of crude Rivaroxaban obtained in example 5 and 122 Kg of acetic acid are loaded into an glass-lined reactor. The mass is heated to solution at about 90 °C to be filtered and thus allow elimination of any mechanical impurities present, then the solvent used to dissolve the crude product (the acetic acid) is almost completely eliminated by vacuum distillation, without going below 90 °C, thus reobtaining the solid product in the form of almost dry residue. The practically dry residue thus obtained is then dissolved with 50 kg of acetone; the undissolved mass is heated to about 62 °C for about 30' (there is no solubilisation therefore it is not to be considered a crystallization but merely a slurry in acetone), then cooled to 10-20 °C and filtered. The product thus obtained is dried at 80-90 °C. 1 1 .0 kg of pure Rivaroxaban are recovered, with a purification yield equal to 90.0%, having HPLC purity greater than 99.85% and enantiomeric purity greater than 99.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.6 g | To a reaction mixture of 100 gm (0.45 moles) 4-(4-Nitrophenyl) morpholin-3-one in 1000ml of purified water, charged 30 gm Raney nickel and 850 gm (13.49 moles) ammonium formate lot wise at 30C. The reaction mixture was heated to 90C. Reaction mixture was cooled to 25-30C. The reaction mixture was filtered and the filtrate was used in the next step. To the filtrate, charged 185 gm (0.9104 moles) (S)-Glycidyl Phthalimide. The reaction mixture was heated to 70C for 10 hours. The reaction mixture was cooled to room temperature and taken for next stage. 196.49 gm (0.6615 moles) triphosgene and 507.16 ml (3.6455 moles) of triethylamine were charged to above reaction mixture at 0C to 5C. The reaction mixture was heated to 70C for 8 hours. The reaction mixture was cooled to 0C to 5C. 253.58 ml (1.8227 moles) of triethylamine was charged and heated to 70C for 7 hours. The reaction mixture was cooled to 0C to 5C. Inorganics formed during reaction were filtered through the hyflo bed. Filtrate taken for next stage. The filtrate was cooled to 5C tol0C and charged with 38.8 gm (0.3007 moles) N,N- diisopropylethylamine and 146 ml acetone. A solution of 5-chloro thiophene-2-carbonyl chloride 68 gm (0.3757 moles) in dimethyl carbonate was added at 5C to l0C. The reaction mixture was heated to 20C to 25C for one hour. Then the reaction mixture was heated to 50C to 55C for one hour. The reaction mixture was cooled to 20-25C for one hour. The product rivaroxaban was filtered and washed with water and dried at 45C under vacuum for 8- 10 hours. Dried weight = 87.6 gm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.3% | With triethylamine; In water; acetone; toluene; at 30 - 35℃; for 2h; | Compound 12.1g of purified water metering (36.9 mmol), 76.7 g of acetone, triethylamine 12g, 12.1g of formula monohydrochloride was added to the reaction flask dropwise at between 30-35 10% 5-chloro thiophene-2-carboxylic acid chloride in 87g toluene solution, after the addition was complete, the reaction was continued in this temperature range for 2 hours and filtered to give a solid. The solid was washed with 85g of purified water and filtered and dried to benefit rivaroxaban crude 12g, 74.5% yield, 95% purity, a type impurity content of 5%.To the reaction flask was added 80g of glacial acetic acid, stirred open, rivaroxaban resulting crude placed and heated to 95-100 , the solid dissolved, filtered, and the filtrate was cooled to 15-20 , filtration, solid, solid wash 123g of purified water, filtered, profit rivaroxaban influx of goods.The influx of goods above dried profit rivaroxaban 11.2g, a yield of 93.3%. Melting point: 230-231 , purity: 99.5%, type a 0.13% impurity content, type two impurity content of 0.12%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.1% | With dmap In N,N-dimethyl-formamide for 6h; Reflux; | 12 Preparation of Rivaroxaban Weigh 8.7g5- chloro-thiophen -2 - {(R) -2- hydroxy-3- [4- (3-oxo-morpholin-4-yl) phenyl amino - propyl} -amide (VIII) into a reaction flask, followed by addition of 7g carbonyl diimidazole (CDI) and 1g 4- dimethylaminopyridine (of DMAP) and 100ml of DMF anhydrous, open stirring.At 100 reflux 6h.Reaction to complete, to the reaction flask 100ml water, extracted with ethyl acetate, ethyl acetate layer was dried and concentrated to give a yellow solid rivaroxaban 9.3g, melting point 227-229 , the yield of 93.1%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.41 g | To a 250 ml reaction flask was added 5. 37 g of 4- (4-aminophenyl) -3-morpholinone,5. 68 g of S-glycidyl phthalimide,140 ml of ethanol-water (nu: nu = 9: 1), heated to reflux for 12 hours,filter,The filter cake was washed with ethanol,dry,Get solid 7. 50g,The mother liquor is concentrated under reduced pressure,Add 5.68 g of S-glycidyl phthalimide,140 ml of ethanol-water (nu: nu = 9: 1),Heated to reflux for 13 hours. filter,The filter cake was washed with ethanol,Dried to give 2.80 g of solid,A total of 10. 30 g was obtained as a white solid. 5.23 g of the above white solid was added to a 100 ml reaction flask,Further, 20 ml of N, N-dimethylformamide,4. 29 g N, N-carbonyl imidazole ( I),Temperature rise of 100 C agitation, TLC monitoring reaction process,6 hours reaction is complete. Add 100 ml of water,Stirring and filtering,dry,White solid 5. 08g,4.45 g of the 5. 08 g white solid was charged into a 250 ml reaction flask,Add lml of ethanol,10 ml of a 40% aqueous solution of methylamine was added dropwise,Heating up,After 1 hour, the solvent was evaporated under reduced pressure,50 ml of tetrahydrofuran was added,Stir,0-5 C by adding 1. 92 g of triethylamine,A solution of 2.30 g of 5-chlorothiophene-2-carboxylic acid chloride,5 minutes drop finished,Stir at room temperature,TLC monitors the reaction process,2 hours after the reaction is complete. Vacuum drying solvent,A white solid was added, stirred with 50 ml of water,filter,The filter cake was washed with ethanol,dry,A white solid is rivabhaban 3. 41g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95.6% | Stage #1: 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride With sodium carbonate In water; acetone at 8 - 12℃; Stage #2: 5-chlorothiophene-2-carbonyl chloride In water; acetone at 50 - 53℃; for 0.5h; | 5.5-1 Example 5[ Preparation of rivaroxaban[ Example 5-1 At 10 ° C, the hydrochloride of the formula (III) structure is added(75) (^, 230%), 231111 of water and 1881111 of acetone were addedTo 400 ml of a 7.1% aqueous solution of sodium carbonate, stirred at 8 to 12 ° C,Add the structure of (V)5-chlorothiophene-2-carbonylchlorotolueneSolution,The reaction mixture was then heated to 50 ° C, 188 ml of acetone was added and stirred at 50 to 53 ° C for 30 minutes,Cooled to room temperature, filtered, washed with water and acetone, 95.23 g of rivaroxab, the yield of 95.6 |
150.1 g | With triethylamine In N,N-dimethyl-formamide at 30 - 40℃; for 5h; | 11; 12 rivaroxaban The reaction flask was charged with 131.1 g (0.4 mol) of Example 10 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (Formula VIII ), 500ml of N,N-dimethylformamide, 50.6g (0.5mol) of triethylamine, 101.4g (0.56mol) 2-chloro-formyl-5-chlorothiophene, stir at 30 °C to 40 °C, Reaction for 5 hours. TLC in the control (dichloromethane: methanol = 20: 1, volume ratio) reaction is complete, adding 500ml of purified water, a large amount of solid precipitation, stirring 2 hours, filtration, filter cake washed with 200ml of purified water. Decompression drying, rivaroxaban product 150.1 g, molar yield 86.1%, HPLC chemical purity 99.8%, optical purity 100.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.4% | Stage #1: (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one hydrobromide With sodium carbonate In dichloromethane at 20℃; for 1h; Stage #2: 5-chlorothiophene-2-carbonyl chloride In dichloromethane at 0 - 20℃; for 5h; | 18 Example 18 Synthesis of rivaroxaban To a reaction flask, a solution of the compound of formula (6) (53.6 g, 144 mmol), dichloromethane (100 mL), sodium carbonate (45.79 g, 432 mmol), stirred at room temperature for 1 h. Then, 5-chlorothiophene-2-carbonyl chloride (c) (39.09 g, 216 mmol) was added dropwise at 0-5 ° C and the reaction was stirred at room temperature for 5 hours. The reaction was complete, washed three times with purified water (150 mL), washed twice with 100 mL of saturated aqueous sodium carbonate solution, washed three times with purified water (150 mL), dried over anhydrous MgSO4. The desiccant was filtered and concentrated, and isopropyl alcohol was purified to give 58.6 g of a white solid, the yield was 93.4%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.8 kg | In tetrahydrofuran; water; at 30℃; for 8h;Large scale; | 3) temperature control 30 , The CO2 product is fed into the reaction product of (2) Gradually precipitated a large number of solid, After 8 hours of continuous access, Filtered to a white solid, The filter cake was washed with absolute ethanol, After drying, 6.8kg rivaishaban crude. Recrystallization from acetic acid, Respectively, with purified water and ethanol washing, vacuum drying, rivaca Ban boutique about 5.8Kg, The total yield was 62.6% Chemical purity: 99.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: N-(tert-butoxycarbonyl)-4-(3-oxo-morpholinyl)aniline With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 25 - 30℃; for 0.25h; Stage #2: 5-chloro-N-[(2S)-oxiran-2-yl]methyl}thiophene-2-carboxamide In N,N-dimethyl-formamide at 120℃; for 8.5h; | 5 Example 5 Synthesis of rivaroxaban 9.0 g (80 mmol) of potassium tert-butoxide was added to a solution of 12.0 g (41 mmol) of N- (4-tert-butoxycarbonylaminophenyl) -3-morpholinone in DMF (100 mL)Followed by stirring at 25-30 ° C for 15 minutes.A solution of 9.0 g (41.5 mmol) of N- (1,2-epoxypropyl) -5-chlorothiophene-2-carboxamide in DMF (50 mL) was added dropwise for about 30 minutes.The temperature was raised to 120 ° C and the mixture was stirred at this temperature for 8 hours.TLC followed the reaction process, after the completion of the reaction, the water quenching reaction. Most of the DMF was evaporated under reduced pressure and the residue was washed with dichloromethane(3 x 200 mL), and the organic phase was dried over anhydrous sodium sulfate. The solvent is concentrated to dryness. The product was recrystallized from ethyl acetate,12.1 g of rivaroxaban was obtained in a yield of 68%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.5% | With sodium carbonate In water; acetone at 10 - 50℃; for 0.5h; | 3 Example 3 Manufacture of Rivaroxaban 4- {4 - [(5S) -5- (Aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl}Morpholin-3-oneThis phosphate(2) And 1.9 g of sodium carbonate were added 42.4 ml of water and 36.8 ml of acetone, and the mixture was cooled to 10 DEG C with stirring.The 5-chlorothiophene-2-carbonyl chloride prepared in Example 2 was added thereto, and the reaction mixture was stirred at 50 DEG C for 30 minutes. The reaction product was cooled to room temperature and the precipitated reaction product was filtered under suction,After each wash, it was dried at 50 DEG C for 4 hours to obtain 7.0 g of Rivaroxaban.Yield 97.5%, (water content 0.3% or less)Purity 99.2%, morpholine intermediate residue 0.03% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sodium carbonate In water; acetone at 10 - 50℃; for 0.5h; | 2 Example 3 Manufacture of Rivaroxaban 4- {4 - [(5S) -5- (Aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl}Morpholin-3-oneThis phosphate(2) And 1.9 g of sodium carbonate were added 42.4 ml of water and 36.8 ml of acetone, and the mixture was cooled to 10 DEG C with stirring.The 5-chlorothiophene-2-carbonyl chloride prepared in Example 2 was added thereto, and the reaction mixture was stirred at 50 DEG C for 30 minutes. The reaction product was cooled to room temperature and the precipitated reaction product was filtered under suction,After each wash, it was dried at 50 DEG C for 4 hours to obtain 7.0 g of Rivaroxaban.Yield 97.5%, (water content 0.3% or less)Purity 99.2%, morpholine intermediate residue 0.03% |
10 g | With triethylamine In ethyl acetate at 10 - 20℃; for 1h; | 4 Example 4 Preparation of rivaroxaban Add ethyl acetate (100ml), water (80ml) to the reaction flask, add the hydrobromide salt (10g) and triethylamine (3.0g) of the compound of formula 1-5 to the reaction flask with stirring, and lower the temperature to 10 To this, the compound of formula 1-6 (5g) was added dropwise, then warmed to room temperature, reacted for 1 hour, filtered with suction, the solid was rinsed with water (20ml) and dried to obtain 11g of crude product.Add N, N-dimethylformamide (40ml) and crude rivaroxaban (11g) to the reaction flask,Stir and heat to 75 ° C, continue stirring until clear, filter while hot, and the filtrate is heated to 75 ° C,Under stirring conditions, an aqueous ethanol solution (20 ml, volume ratio 1: 3) was added dropwise thereto. After the addition was completed, the crystals were cooled and crystallized under stirring conditions, brought to room temperature, and filtered with suction. The solid aqueous ethanol solution (20 ml, volume ratio 8: 1) Beat for 30 minutes under heating and reflux, filter, and dry the solid. 10g of rivaroxaban was obtained with a purity of 99.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.4% | With sodium carbonate In water; acetone at 10 - 50℃; for 0.5h; | 13 Example 3 Manufacture of Rivaroxaban 4- {4 - [(5S) -5- (Aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl}Morpholin-3-oneThis phosphate(2) And 1.9 g of sodium carbonate were added 42.4 ml of water and 36.8 ml of acetone, and the mixture was cooled to 10 DEG C with stirring.The 5-chlorothiophene-2-carbonyl chloride prepared in Example 2 was added thereto, and the reaction mixture was stirred at 50 DEG C for 30 minutes. The reaction product was cooled to room temperature and the precipitated reaction product was filtered under suction,After each wash, it was dried at 50 DEG C for 4 hours to obtain 7.0 g of Rivaroxaban.Yield 97.5%, (water content 0.3% or less)Purity 99.2%, morpholine intermediate residue 0.03% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75.2% | With sodium carbonate In water; acetone at 10 - 50℃; for 0.5h; | 14 Example 3 Manufacture of Rivaroxaban 4- {4 - [(5S) -5- (Aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl}Morpholin-3-oneThis phosphate(2) And 1.9 g of sodium carbonate were added 42.4 ml of water and 36.8 ml of acetone, and the mixture was cooled to 10 DEG C with stirring.The 5-chlorothiophene-2-carbonyl chloride prepared in Example 2 was added thereto, and the reaction mixture was stirred at 50 DEG C for 30 minutes. The reaction product was cooled to room temperature and the precipitated reaction product was filtered under suction,After each wash, it was dried at 50 DEG C for 4 hours to obtain 7.0 g of Rivaroxaban.Yield 97.5%, (water content 0.3% or less)Purity 99.2%, morpholine intermediate residue 0.03% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.5% | With sodium carbonate In water; acetone at 10 - 50℃; for 0.5h; | 15 Example 3 Manufacture of Rivaroxaban 4- {4 - [(5S) -5- (Aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl}Morpholin-3-oneThis phosphate(2) And 1.9 g of sodium carbonate were added 42.4 ml of water and 36.8 ml of acetone, and the mixture was cooled to 10 DEG C with stirring.The 5-chlorothiophene-2-carbonyl chloride prepared in Example 2 was added thereto, and the reaction mixture was stirred at 50 DEG C for 30 minutes. The reaction product was cooled to room temperature and the precipitated reaction product was filtered under suction,After each wash, it was dried at 50 DEG C for 4 hours to obtain 7.0 g of Rivaroxaban.Yield 97.5%, (water content 0.3% or less)Purity 99.2%, morpholine intermediate residue 0.03% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80.6% | With sodium carbonate In water; acetone at 10 - 50℃; for 0.5h; | 16 Example 3 Manufacture of Rivaroxaban 4- {4 - [(5S) -5- (Aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl}Morpholin-3-oneThis phosphate(2) And 1.9 g of sodium carbonate were added 42.4 ml of water and 36.8 ml of acetone, and the mixture was cooled to 10 DEG C with stirring.The 5-chlorothiophene-2-carbonyl chloride prepared in Example 2 was added thereto, and the reaction mixture was stirred at 50 DEG C for 30 minutes. The reaction product was cooled to room temperature and the precipitated reaction product was filtered under suction,After each wash, it was dried at 50 DEG C for 4 hours to obtain 7.0 g of Rivaroxaban.Yield 97.5%, (water content 0.3% or less)Purity 99.2%, morpholine intermediate residue 0.03% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.6% | With sodium carbonate In water; acetone at 10 - 50℃; for 0.5h; | 17 Example 3 Manufacture of Rivaroxaban 4- {4 - [(5S) -5- (Aminomethyl) -2-oxo-1,3-oxazolidin-3-yl] phenyl}Morpholin-3-oneThis phosphate(2) And 1.9 g of sodium carbonate were added 42.4 ml of water and 36.8 ml of acetone, and the mixture was cooled to 10 DEG C with stirring.The 5-chlorothiophene-2-carbonyl chloride prepared in Example 2 was added thereto, and the reaction mixture was stirred at 50 DEG C for 30 minutes. The reaction product was cooled to room temperature and the precipitated reaction product was filtered under suction,After each wash, it was dried at 50 DEG C for 4 hours to obtain 7.0 g of Rivaroxaban.Yield 97.5%, (water content 0.3% or less)Purity 99.2%, morpholine intermediate residue 0.03% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With trichloroisocyanuric acid In acetic acid at 20 - 40℃; for 2h; | 3.3 (3) 20 g of the compound of Formula 2 and 300 mL of acetic acid were added to a 500 mL reaction flask at room temperature, and the temperature was raised to 35 to 40° C., and 0.5 equivalents of trichloroisocyanuric acid was added in portions below 45° C. After stirring at 35-40°C for 2 hours. Add 2 grams of activated carbon to decolorize. After 60 °C, vacuum concentration to 100 ~ 150mL,Stir at room temperature for 2 hours, filter and dry to obtain the crude compound of Formula 1. The crude product was put into 150 mL of acetic acid and stirred at 60-80°C for half an hour.Stir at room temperature for 2 hours, filter and dry to obtain compound of formula 1The dried product was 19.5g, the yield was 90%, and the structure was consistent with the target. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.8% | 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%), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92.2% | With hydrogenchloride; acetic acid In water at 60℃; for 5h; | 1 (1), Synthesis of compound 3 2-(2-(4-(5-((5-chlorothiophene-2-carboxamido)methyl) 2-oxooxazolidin-3-yl)phenyl)amino)ethoxy)acetic acid 5 g of Compound 2 was placed in a 250 mL two-necked flask equipped with a thermometer and a rotor, and 50 mL of glacial acetic acid, 15 mL of water, and 30 mL of concentrated hydrochloric acid were slowly added in this order. The mixture was heated to 60 ° C with stirring, and the reaction solution was gradually dissolved, and the reaction was kept for 5 hours.Cool to room temperature and filter under reduced pressure. The filter cake was washed twice with 20 mL of isopropanol. The filter cake was then placed in a 50 mL single-mouth bottle and rinsed with 25 mL of isopropanol and filtered under reduced pressure.The filter cake was washed twice with 20 mL of isopropanol to give 4.8 g of Compound 3 as a white solid. Yield 92.2% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate In methanol at 20℃; for 2h; | 1.2.6. (S)-Rivaroxaban (1) To a solution of compound 7 (200 mg; 0.42 mmol) in MeOH (10 mL) was added anhydrous K2CO3 (174 mg; 1.26 mmol) and the mixture was stirred at room temperature for 2 hours. The suspension formed was filtered off, the white crystals of 1 were washed with water (2× 10 mL) and dried in vacuo. Yield: 177 mg (97%); mp: 206-209 °C; [a]D20= -39.5 (c 0.306, DMSO); (Ref.3 [a]D20= -41.0 (c 0.3, DMSO)); 1H NMR (DMSO-d6; 500 MHz): δ 8.96 (bt, 1H), 7.67 (d, J = 4.0 Hz, 1H), 7.55 (m, 2H), 7.39 (m, 2H), 7.17 (d, J = 4.0 Hz, 1H), 4.83 (m, 1H), 4.18 (m, 3H), 3.96 (m, 2H), 3.84 (m, 1H), 3.70 (m, 2H), 3.60 (m, 2H); 13C NMR (CDCl3; 125 MHz): δ 167.1, 161.9, 154.5, 137.6, 136.8, 136.6, 136.4, 128.1, 127.3, 126.5, 119.3, 72.0, 68.8, 64.3, 49.9, 47.9, 42.6; FT-IR (ATR, cm-1): 3336, 3080, 2932, 2873, 1744, 1721, 1661, 1647, 1626, 1518, 1428, 1411, 1327, 1226, 1120 (100%), 1066, 992, 808, 756, 551; HR-MALDI-MS (DHB): m/z calcd. for C19H18ClN3O5S ([M+H]+) 436.07340, found 436.07339 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With potassium hydroxide In tetrahydrofuran at 0 - 80℃; for 7h; | 1 Add rivaroxaban (5.0 g, 11.5 mmol) and tetrahydrofuran (35 mL) to the reaction flask and mix well.The temperature of the reaction solution was lowered to 0 ° C, and an aqueous potassium hydroxide solution (28 mL, 8 mol/L) was added to the reaction mixture.After the addition was completed, the temperature of the reaction solution was raised to 80 ° C for 7 h.After the reaction, the temperature of the reaction product was lowered to 0 ° C, and dilute hydrochloric acid (2 mol/L) was added to the reaction product.The pH of the product was adjusted to 4 to 5, and a large amount of white solid was precipitated, suction filtered, and dried to obtain a crude product.The crude product was beaten with ethanol (30 mL) at room temperature for 2 h, suction filtered, and the filter cake was dried under vacuum at 45 ° C for 12 h to give Compound A.The compound A obtained by the method was a pure product of 4.0 g, a yield of 77.0%, and a purity of 98.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90.3% | With triethylamine; at 10 - 25℃; | To the reaction mixture containing Compound III (obtained in Example 12) was added triethylamine (15.6 g, 154.4 mmol), and mechanical stirring was started. A suspension of Compound II (about 69.6 mmol) was added at 10-15 C. After the addition is completed, the temperature is raised to 20 to 25 C, and the reaction is kept warm. The reaction was followed by TLC until the conversion of the starting compound II was completed. After completion of the reaction, 100 ml of water was added and stirred for 30 minutes. After suction filtration, the filter cake was rinsed with 50 ml of water and dried under reduced pressure at 60 to 65 C. The final yield was 27.4 g of rivaroxaban, and the yield was 90.3%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate In water; acetonitrile at 5 - 40℃; | 8-9 Intermediate VI (10g, 0.024mol, 1 equivalent) was added to acetonitrile (85mL) and water (15mL), stirred well, then potassium carbonate (5.4g, 1.6 equivalent) was added, the mixture was cooled to 5±5, and Sanko Gas solid (3.6g, 0.5 equivalent), stirred at 5±5°C for 1-2 hours, then slowly heated to 40±5°C, continued stirring for 4-6 hours, and the TLC reaction was complete. The reaction solution was cooled to 5±5°C, kept warm and stirred for 1-2 hours, filtered, and the filter cake was rinsed with water and acetonitrile respectively. Collect the wet cake to obtain the crude product. The wet cake was added to acetonitrile/water (1:1, 50mL), the temperature was raised to 60±5°C, and the slurry was stirred for 3±1 hours. Cool down to 25±5°C, keep this temperature, and continue to stir for 1-2 hours. After filtering, the filter cake is rinsed with a small amount of acetonitrile/water mixed solvent. The filter cake was collected and dried at 60±5°C under normal pressure to obtain 10 g of pure rivaroxaban, with a molar yield of 95% and a liquid phase purity of 99.8%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.4% | In ethanol at 36℃; for 7h; | 1.4; 2.4 (4) Weigh 40.0g of compound ,4-(4-aminophenyl)morpholin-3-one() 98.5 g, dissolved in 300 ml of 10% ethanol, turn on the stirring, turn on the heating,The system was heated to 36 and stirred for 7 h.Stop heating, ice-water bath system, and stir for 1 hour.Filter with suction, and rinse the filter cake with 40 ml 10% ethanol.After washing, the solids were collected and dried in a blast drying oven at 50°C.After drying, the white powder obtained is rivaroxaban ().53.8 g of product is obtained,The yield was 96.4%, and the purity was 99.2%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With Tributylphosphine oxide; lithium bromide In toluene for 10h; Inert atmosphere; Reflux; | 1.3; 2.3; 3.3; 4.3 (3) Under nitrogen, heat a toluene (20mL) solution containing lithium bromide (0.1g, 1.0mmol) and tributylphosphorus oxide (0.25g, 1.1mmol) to reflux, and then add Intermediate II (3.18g, 10mmol) and 4-(4-isocyanatophenyl)morpholin-3-one (3.27g, 15mmol). React under reflux conditions for 10 h. Filtering, washing with toluene, washing with water, and drying to obtain 2.84 g of the target product rivaroxaban with a yield of 65%. |