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Chemical Structure| 446292-10-0
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Product Details of [ 446292-10-0 ]

CAS No. :446292-10-0 MDL No. :MFCD11977666
Formula : C14H17N3O4 Boiling Point : -
Linear Structure Formula :- InChI Key :DEXXSYVEWAYIGZ-LBPRGKRZSA-N
M.W : 291.30 Pubchem ID :11346837
Synonyms :

Calculated chemistry of [ 446292-10-0 ]

Physicochemical Properties

Num. heavy atoms : 21
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.43
Num. rotatable bonds : 3
Num. H-bond acceptors : 5.0
Num. H-bond donors : 1.0
Molar Refractivity : 81.39
TPSA : 85.1 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : No
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -8.36 cm/s

Lipophilicity

Log Po/w (iLOGP) : 1.94
Log Po/w (XLOGP3) : -0.4
Log Po/w (WLOGP) : -0.43
Log Po/w (MLOGP) : 0.09
Log Po/w (SILICOS-IT) : 0.18
Consensus Log Po/w : 0.28

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -1.41
Solubility : 11.4 mg/ml ; 0.0391 mol/l
Class : Very soluble
Log S (Ali) : -0.92
Solubility : 34.8 mg/ml ; 0.119 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -2.08
Solubility : 2.45 mg/ml ; 0.00839 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 2.98

Safety of [ 446292-10-0 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 446292-10-0 ]

* 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.

  • Downstream synthetic route of [ 446292-10-0 ]

[ 446292-10-0 ] Synthesis Path-Downstream   1~93

  • 1
  • [ 446292-10-0 ]
  • [ 1918-79-2 ]
  • rivaroxaban [ No CAS ]
  • 2
  • [ 446292-10-0 ]
  • [ 5326-23-8 ]
  • 6-chloro-<i>N</i>-{2-oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-ylmethyl}-nicotinamide [ No CAS ]
  • 3
  • [ 446292-10-0 ]
  • [ 86873-60-1 ]
  • 5-Chloro-pyridine-2-carboxylic acid {(S)-2-oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-ylmethyl}-amide [ No CAS ]
  • 4
  • [ 446292-10-0 ]
  • [ 585-70-6 ]
  • 5-Bromo-furan-2-carboxylic acid {(S)-2-oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-ylmethyl}-amide [ No CAS ]
  • 5
  • [ 446292-10-0 ]
  • [ 7311-63-9 ]
  • 5-bromo-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide [ No CAS ]
  • 6
  • [ 446292-10-0 ]
  • [ 42518-98-9 ]
  • [ 366789-02-8 ]
YieldReaction ConditionsOperation 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%

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  • 7
  • [ 446292-10-0 ]
  • [ 2766-74-7 ]
  • 5-Chloro-thiophene-2-sulfonic acid {(R)-2-oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-ylmethyl}-amide [ No CAS ]
  • 8
  • [ 446292-10-0 ]
  • [ 89499-41-2 ]
  • 4-Amino-5-chloro-thiophene-2-carboxylic acid {(S)-2-oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-ylmethyl}-amide [ No CAS ]
  • 9
  • [ 446292-10-0 ]
  • [ 122-01-0 ]
  • 4-chloro-<i>N</i>-{2-oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-ylmethyl}-benzamide [ No CAS ]
  • 10
  • [ 446292-10-0 ]
  • [ 535-80-8 ]
  • 3-chloro-<i>N</i>-{2-oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-ylmethyl}-benzamide [ No CAS ]
  • 11
  • [ 446292-10-0 ]
  • [ 118-91-2 ]
  • 2-chloro-<i>N</i>-{2-oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-ylmethyl}-benzamide [ No CAS ]
  • 12
  • [ 446292-10-0 ]
  • 5-chloro-2-thiophene[14C]carboxylic acid [ No CAS ]
  • 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene-[14C]carboxamide [ No CAS ]
  • 13
  • [ 446292-10-0 ]
  • 5-Chloro-thiophene-2-carboxylic acid methyl-{(S)-2-oxo-3-[4-(3-oxo-morpholin-4-yl)-phenyl]-oxazolidin-5-ylmethyl}-amide [ No CAS ]
  • 15
  • [ 438056-69-0 ]
  • [ 446292-10-0 ]
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[45]Patent: CN104974148,2017,B
[46]Patent: CN104974149,2018,B
[47]Journal of Heterocyclic Chemistry,2018,vol. 55,p. 2852 - 2858
[48]Patent: CN110818700,2020,A
  • 16
  • [ 446292-10-0 ]
  • [ 39608-31-6 ]
  • [ 947181-22-8 ]
YieldReaction ConditionsOperation in experiment
92% 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; General Procedure 1 for Acylating the Amino Group in Compound (B):The carboxyl components employed (in most cases suitably protected amino acid or peptide derivatives) are either commercially available or are prepared by standard methods. 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one [compound (B)] is preferably acylated directly with suitably protected peptide derivatives. In an alternative sequential procedure it is also possible firstly to link to an amino acid derivative, subsequently deprotect where appropriate and then react with further suitably protected amino acid or peptide derivatives by standard methods.2.3 mmol of the appropriate carboxyl component are dissolved in 30 ml of DMF, and 2.3 mmol of 1-hydroxy-1H-benzotriazole, 2 mmol of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), 4.5 mmol of N,N-diisopropylethylamine and then 1.5 mmol of the amine component, 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one [compound (B)] are added. The reaction mixture is stirred at room temperature for 3 h and then concentrated, and the residue is taken up in dichloromethane and extracted twice with 5% strength citric acid, twice with 5% strength sodium bicarbonate solution and twice with water. The organic phase is concentrated and the residue is purified by flash chromatography on silica gel with acetonitrile/water 30:1 as eluent. The appropriate fractions are combined and the solvent is removed. The remaining residue is dissolved in dichloromethane/methanol, and the product is precipitated with diethyl ether and dried under high vacuum.; Intermediate 2AN-[(Benzyloxy)carbonyl]-N-methylglycyl-N2-methyl-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)-phenyl]-1,3-oxazolidin-5-yl}methyl)glycinamide In the first step, 511 mg (1.5 mmol) of Z-sarcosine are reacted as carboxyl component by General Procedure 1 with compound (B) (yield: 697 mg, 92% of theory).The benzyloxycarbonyl protective group is then removed from 200 mg (0.4 mmol) of this intermediate by hydrogenolysis over Pd/C by standard methods (yield: 130 mg, 89% of theory).The compound obtained in this way is then linked in a third step again to 120 mg (0.54 mmol) of Z-sarcosine by General Procedure 1 (yield: 201 mg, 98% of theory).HPLC (method 2): Rt=4.21 min;LC-MS (method 6): Rt=1.54 min; m/z=568 (M+H)+.
  • 18
  • [ 446292-10-0 ]
  • [ 24065-33-6 ]
  • [ 366789-02-8 ]
YieldReaction ConditionsOperation 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).

  • 20
  • [ 1349248-79-8 ]
  • [ 446292-10-0 ]
YieldReaction ConditionsOperation in experiment
96% With 5%-palladium/activated carbon; hydrogen; In ethanol; at 40℃; for 24h; 700ml of ethanol was added 110g (0.35mol) (R) -4- (4- (5- (azidomethyl) -2-oxo-oxazolidin-3-yl) phenyl) morpholin-3-one ( ), 5% palladium on carbon 20g, 40 hydrogenated at atmospheric pressure 24 hours, TLC the reaction was complete, the carbon was filtered off, the filter cake was washed twice with 70ml ethanol and palladium. The filtrate and washings were combined, concentrated hydrochloric acid was adjusted to pH = 2 15 After stirring for 30 minutes, the precipitated white solid was suction filtered, the filter cake rinsed with 50ml of ethanol, and dried to give (S) -4- (4- (5- (carbamoyl yl) -2-oxo-oxazolidin-3-yl) phenyl) morpholin-3-one () 109.1g, a yield of 96.0%.
90.9% With palladium 10% on activated carbon; hydrogen; In methanol; under 1500.15 - 3000.3 Torr; for 4h; Step-II: Preparation of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3- To a solution of 4-{4-[(5R)-5-(azidomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}- morpholin-3-one (30 g, 0.095 mol) in methanol (1.0 lit) was added 10 %w/w Pd/C (3.0 g).The reaction mix. was hydrogenated under 2-4 kg/cm2 hydrogen pressure for 4hr. After completion of reaction (as indicated by TLC); catalyst was removed by filtration. The filtrate was concentrated and re-crystallized from methanol. Yield: 25g (% Yield: 90.9% ).
80% With 5%-palladium/activated carbon; hydrogen; In ethyl acetate; at 45℃; under 3750.38 - 6000.6 Torr; for 8h;Autoclave; 24.5 gms of azido compound obtained in above example was dissolved in ethyl acetate (500 ml), 5 gms of 5% w/w of palladium - carbon ( Pd/C) were charged in a clean and dry autoclave followed by heating to about 45C and agitated under ¾ pressure of 5-8 kgs/cm2 for about 8 hrs. After completion of the reaction, the catalyst was separated by filtration of the reaction suspension on a celite. The filtrate obtained was distilled off completely under reduced pressure to yield crude form of title compound. The crude was recrystallize from methanol to yield pure form of the title compound as off-white crystalline solid. Yield: 18 gms (80%).
18 g With water; triphenylphosphine; In tetrahydrofuran; at 10 - 65℃; (R)-4-[4-(5-azidomethyl-2-oxooxazolidin-3-yl)phenyl]morpholin-3-one (compound 5b) (25.0 gr,0.078 mol) in tetrahydrofuran (125.0 mL) and cooled to 10-15C then slowly added triphenyl phosphine (20.66 gr, 0.078 mol) and stirred for 10-15 minutes at same temperature. Slowly temperature was raised to room temperature and stirred for 2-3 hrs followed by water (10.0 mL) was added and stirred for 2-3 hrs at 60-65C. After completion of reaction by TLC analysis, distil out the solvent and co-distilled with isopropyl alcohol. Isopropyl alcohol (100.0 mL) was added to the reaction mass and cooled to 10-15C, followed by IPA.HCl (18.0 mL) was added and stirred for 2-3 hrs at 25-30C. The precipitated solid was filtered and washed with isopropyl alcohol. The wet compound was dissolved in a water (75.0 mL) and methylene dichloride (100.0 mL), and then PH adjusted to 9.0 to 10.0 with lye solution. Organic layer was separated and aqueous layer extracted with methylene dichloride (50.0 mL). Organic layers were combined and washed with water (40.0 mL) and organic layer was dried with anhydrous. Na2SO4 and distilled the solvent completely under vacuum and product isolated in isopropyl ether and dried to obtain compound (6b) (18.0 gr).

  • 23
  • [ 446292-10-0 ]
  • [ 32315-10-9 ]
  • [ 1365267-35-1 ]
YieldReaction ConditionsOperation in experiment
38.8% Example 8: Preparation of N,N'-bis[{(51V)-2-oxo-3-[4-(3-oxomorpholin-4- yl)phenylj-l,3-oxazolidin-5-yl}methyl]urea (Compound A)1.23 g (12.3 mmol) of triethylamine, 4.0 g (12.3 mmol) of 0S)-4-{4-[5-(aminomethyl)-2- oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one (compound IV) and 500 mL of tetrahydrofuran were mixed together in a 1000 mL reactor and cooled down in an ice bath for 10 minutes. 0.60 g (6.1 mmol) of triphosgene were added and the resulting mixture was stirred for 2 hours. Another 1.23 g ( 12.3 mmol) of triethylamine were added and the mixture was stirred overnight at room temperature. 200 mL of saturated sodium carbonate solution were added and two phases separated. The organic phase was collected and stirred with 200 mL of brine. The mixture was filtered and the collected solid was washed with 30 mL of ethyl acetate to give 1.44 g of white solid. Yield: 38.8%. HPLC chromatographic purity: 96.98% (% area).Analytical data: m.p. : 241.0-241.8 C; IR (KBr, cm"1): 3520, 3374, 3308, 3144, 3111, 3066, 3049, 2972, 2943, 2872, 1749, 1726, 1664, 1649, 1607, 1522, 1477, 1435, 1414, 1385, 1346, 1329, 1285, 1265, 1233, 1 163, 1 146, 1 121, 1098, 1061, 1028, 993, 964, 924, 835, 779, 754, 725, 71 1 , 691, 644, 613; 1H NMR (400 MHz, DMSO-d6, ppm): 7.55 (dm, J = 9.0, 4H), 7.39 (dm, J = 9.0, 4H), 6.51 (t, J = 5.9, 2H), 4.62 (m, 2H), 4.17 (s, 4H), 4.07 (t, J = 8.9, 2H), 3.95 (app. t, J = 5.2, 4H), 3.77 (dd, J = 6.2, J = 9.0, 2H), 3.70 (app. t, J = 5.2, 4H), 3.37 (t, J = 5.4, 4H). 13C NMR (101 MHz, DMSO-d6, ppm): 165.9, 158.4, 154.2, 137.0, 136.5, 125.9, 118.3, 72.1, 67.7, 63.5, 49.0, 47.1, 42.2; MS (direct infusion, ESI +), m/z (Da) and relative abundance (%):626 ([M+NH4]+, 6), 609 ([M+H]+, 2), 179 (81), 174 (63), 157 (100).
  • 24
  • [ 446292-10-0 ]
  • [ 1365267-37-3 ]
  • [ 1365267-36-2 ]
YieldReaction ConditionsOperation in experiment
62.8% With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In ethyl acetate; acetonitrile; at 5℃; for 2.16667h;pH 8; 10.0 g (22.8 mmol) of (5)-2-[({2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3- oxazolidin-5-yl}methyl)carbamoyl]benzoic acid (compound V) and 7.3 g (25.0 mmol) of (
  • 26
  • [ 1414932-72-1 ]
  • [ 446292-10-0 ]
YieldReaction ConditionsOperation in experiment
99.7% With isobutylamine; In toluene; for 3h;Reflux;Product distribution / selectivity; 7d)Prepare a solution of 36 g of (S)-4-[4-(5-[(4-chloro-benzylidene)-amino]- methyl}-2-oxo-oxazolidine-3-yl)-phenyl]-morpholin-3-one 23a in 180 mL of toluene and 180 mL of isobutylamine. Heat at reflux and maintain for 3 hours. Cool at room temperature and remove the solvent at reduced pressure. Stir the residue obtained at less than 10C in 108 mL of toluene. Filter and wash with 50 mL of toluene and then with 20 mL of toluene. After drying at 50C in a vacuum oven 25.19 g of the intended product are obtained (yield 99.7%).
99.7% With isobutylamine; In toluene; for 3h;Heating; Reflux; 0066] Prepare a solution of 36 g of (S)-4-[4-(5-[(4-chloro-benzylidene)-amino]-methyl}-2-oxo-oxazolidine-3-yl)-phenyl]-morpholin-3-one 23a in 180 mL of toluene and 180 mL of isobutylamine. Heat at reflux and maintain for 3 hours. Cool at room temperature and remove the solvent at reduced pressure. Stir the residue obtained at less than 10 C. in 108 mL of toluene. Filter and wash with 50 mL of toluene and then with 20 mL of toluene. After drying at 50 C. in a vacuum oven 25.19 g of the intended product are obtained (yield 99.7%).
95% With hydrogenchloride; triethylamine; In ethanol; water; at 22 - 65℃; for 1h; 25 g of 4-{4-[(5 -5-[(((4-chlorophenyl)methylene)amino)methyl]-2-oxo-1 ,3-oxazolidin-3- yl]phenyl}morpholin-3-one was suspended in 200 ml of ethanol with addition of 10 ml of water. Concentrated hydrochloric acid (30 ml) was added to the stirred and heated (65 C) suspension all at once, which produced a turbid solution. 200 ml of ethanol were added and the suspension was stirred in a bath at the temperature of 65 C, then 100 ml of triethylamine were added and the obtained solution was stirred and heated to 65C. The turbid solution was concentrated in vacuo and 400 ml of ethanol was added to the obtained oil. The produced suspension was stirred at 22 C for 1 hour, then the solid product was filtered off, washed with ethanol (2 x 50 ml) and dried in vacuo. 16.7 g (yield 95%) of an off-white powder with the melt, point of 143-144C was obtained, HPLC 99.8%, content of the (i?)-isomer below 0.03%. 1H NMR (250 MHz, DMSO-D6), delta (ppm): 2.76-2.90 (m, 2H, CH2); 3.71 (m, 2H, CH2); 3.88 (m, 2H, CH2); 3.97 (m, 2H, CH2); 4.07 (t, 2H, CH2); 4.20 (s, 2H, CH2); 4.62 (m, 1H, CH); 7.41 (m, 2H); 7.56 (m, 2H). 13C NMR (250 MHz, DMSO-D6), delta (ppm): 44.2; 47.0; 49.0; 63.4; 67.7; 73.9; 1 18.1 ; 125.8; 136.7; 136.8; 154.4; 165.9.
With hydrogenchloride; In water; for 0.333333h; In the system of Example 1,Add 20 ml of hydrochloric acid at a concentration of 3.7%.Stir for 20 minutes,Separate oil phase,The aqueous phase is washed twice with dichloromethane.10 ml each time. Remove the organic phase,Merge the water phase for use.

  • 27
  • [ 1414932-71-0 ]
  • [ 446292-10-0 ]
  • 28
  • [ 1424942-78-8 ]
  • [ 446292-10-0 ]
YieldReaction ConditionsOperation in experiment
15.5 g With 5%-palladium/activated carbon; hydrogen; acetic acid; In methanol; at 45℃; under 3750.38 - 6000.6 Torr; for 8h;Autoclave; 25 gms of 4-{4-[(5S)-5-(N-benzylaminomethyl)-2-oxo-1,3-Oxazolidin-3-yl]phenyl}morpholin-3-one obtained in above example, 4gms of palladium - carbon (Pd/C) (5%)w/w), acetic acid(25ml) and methanol (300ml) were charged into a clean and dry autoclave followed by heating to about 45C and agitated under H2 pressure of 5-8 kgs/cm2 for about 8 hrs. After completion of the reaction, the reaction mixture was filtered and the filtrate was distilled off completely. To the residue 50ml of ethyl acetate was added and stirred for about 30 min at about 30C. The solid separated was filtered and the solid was washed with ethyl acetate to yield white-off white crystalline solid of the title compound. Yield: 15.5 gms.
  • 31
  • [ 1446022-15-6 ]
  • [ 446292-10-0 ]
  • 32
  • [ 1117893-59-0 ]
  • [ 446292-10-0 ]
  • 33
  • [ 1117893-58-9 ]
  • [ 446292-10-0 ]
  • 34
  • [ 1447919-68-7 ]
  • [ 446292-10-0 ]
  • 35
  • [ 1447919-69-8 ]
  • [ 446292-10-0 ]
  • 36
  • [ 1447919-71-2 ]
  • [ 446292-10-0 ]
  • 38
  • [ 1117893-60-3 ]
  • [ 446292-10-0 ]
  • 39
  • [ 1372665-04-7 ]
  • [ 446292-10-0 ]
YieldReaction ConditionsOperation in experiment
100% With palladium on activated charcoal; hydrogen; In methanol; at 40 - 50℃; under 37503.8 Torr; for 20h; (S)-4-(4-(5-( (dibenzyl amino) methyl)-2-oxo-oxazolidine-3-yl) phenyl) morpholinyl-3-one (94.2g, 0 . 20mol) by adding 500 ml methanol, adding 10% Pd/C9 . 4g, 5 MPa hydrogen, 40-50 C reaction under the conditions of 20 hours. Cooling down to room temperature, filtered, the feed liquid directly used for the next step reaction, the yield is 100.0%.
92.6% With palladium 10% on activated carbon; hydrogen; In ethyl acetate; at 50℃; for 18h;Inert atmosphere; Step-II: Preparation of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one: To a solution of 4-{4-[(5S)-5-(dibenzylamino)methyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one (3.5 g,7.4 mmol) in ethyl acetate (50 ml) was added 10 % Pd- C(0.5 g) and the air was replaced with Nitrogen. Hydrogen was passed into the mix. and the mix. was heated to 50C and reacted for 18 hrs. Filtered and the solvent was evaporated to provide title compound as white crystalline solid. Yield: 2.0 g (% Yield: 92.6%).
2.56 g With palladium 10% on activated carbon; hydrogen; acetic acid; In methanol; at 50℃; under 4200.42 Torr; To a solution of 4-{4-[(5S)-5-(dibenzylamino) methyl-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one (4.17g, lOmmol) in methanol (100ml) and acetic acid (5 ml) was added 10% Pd/C (l.Og). Then passed the hydrogen gas of about 5.6 kgs/cm at about 50C until the reaction completes as indicated by TLC. The reaction suspension was filtered on celite and washed with methanol. The filtrate was distilled off to half of the total volume and cooled to about 0C for about 30 mins. The separated solid was filtered and washed with methanol. (Yield = 2.56 g ; 88% of theory).
  • 40
  • [ 898543-06-1 ]
  • [ 446292-10-0 ]
YieldReaction ConditionsOperation in experiment
96.7% In dichloromethane; water;pH 8; The 29.3g (0.09mol) of intermediate VII hydrochloride was added to 150ml of dichloromethane and 150ml of purified water, under stirring, with sodium carbonate to adjust the pH to about 8, liquid separation, the organic layer was evaporated to dryness, yielding intermediate VII oil 25.3g (0.087mol), a salt solution molar yield 96.7%, HPLC purity 98.5%
56% With potassium carbonate; In methanol; at 25 - 30℃; for 0.5h; 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride (5 g) was stirred in the mixture of methanol (25 ml) and potassium carbonate (3.16) for 30 minutes at 25 to 30 C. The inorganic salt was filtered. The obtained filtrate was concentrated under reduced pressure to obtain solid 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one base. Crystalline form of compound of formula (VI) as a free base is characterized by its XPRD pattern as per Figure 3. The IR spectrum of crystalline form of compound of formula (VI) as a free base having characteristic peaks at 552.41 , 756.16, 836.95, 923.73, 993.89, 1 119.95, 1145.85, 1231.17, 1327.88, 1344.26, 1524.30, 1603.46, 1649.19, 1664.36, 1723.87, 1747.07, 3376.74 cm-1 (Figure 4).[Yield = 2.5 gm (56%)]
56% With potassium carbonate; In methanol; at 25 - 30℃; for 0.5h; 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1 ,3-oxazoli- din-3-yl]phenyl}morpholin-3-one hydrochloride (5 g) was stirred in the mixture of methanol (25 ml) and potassium carbonate (3.16) for 30 minutes at 25 to 30 C. The inorganic salt was filtered. The obtained filtrate was concentrated under reduced pressure to obtain solid 4-{4-[(5S)-5-(aminom- ethyl)-2-oxo-1 ,3-oxazolidin-3-yl]phenyl}morpholin-3-one base. Crystalline form of compound of formula (VI) as a free base is characterized by its XPRD pattern as per FIG. 3. The IR spectrum of crystalline form of compound of formula (VI) as a free base having characteristic peaks at552.41, 756.16, 836.95, 923.73, 993.89, 1119.95, 1145.85, 1231.17, 1327.88, 1344.26, 1524.30, 1603.46, 1649.19, 1664.36, 1723.87, 1747.07, 3376.74 cm? (FIG. 4). [Yield=2.5 gm (56%)]
With potassium carbonate; In water; at 20℃; for 2h; in room temperature,Anhydrous potassium carbonate 6.7g added(S)-5-Chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholinyl))Phenyl]-1,3-oxazolidine-5-yl}methyl)-2-carboxamide hydrochloride, 16g100mL aqueous solution,The reaction was performed at room temperature for 2 hours.Concentrate to remove water from the reaction solution.Then wash with 30mL methanol, filter,The filtrate is concentrated,Dry to give (S)-5-chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidine-5- Based on} methyl)-2-carboxamide,Under argon at room temperature,4.5 mL anhydrous triethylamine was added to (S)-5-chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1, 3-oxazolidin-5-yl}methyl)-2-carboxamideIn 600 mL of anhydrous tetrahydrofuran,Add 5 mL of acetyl chloride dropwise,The reaction was performed at room temperature for 2 hours.Traces of TCL (EA/MeOH = 10:1) showed that some of the starting material was still present.Then add anhydrous 2.2mL of triethylamine and 2.2mL of acetyl chloride and continue to react for 2 hours.TCL (EA/MeOH=10/1) monitoring,Raw material spots have basically disappeared. The reaction was quenched with 20 mL of water.The mixture was concentrated and subjected to silica gel column chromatography (EA/MeOH=10:1) to obtain the relevant substance A as a white powder 13.2 g, yield 80.7%.

  • 41
  • 4-{4-[(5S)-5-(2,5-dimethylpyrrol-1-ylmethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one [ No CAS ]
  • [ 446292-10-0 ]
YieldReaction ConditionsOperation in experiment
1.18 g With pyridine; hydroxylamine hydrochloride; In ethanol; for 6h;Reflux; To a solution of 4-{4-[(5S)-5-(2,5-dimethyl pyrrol-lyl methyl)-3-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one (3.69 g, lOmmol) in pyridine (50 ml) and ethanol (7 ml) was added hydroxyl amine HC1 (4.17 g, 6 eq) and refluxed for 6 hrs. After cooled to RT added water (200ml) and extracted with DCM (3X50ml). washed the organic layer with dil.HCl (2x10 ml) followed by water (loml). Organic layer discarded. To the aqeous layer added 50 ml DCM and pH =9-10 adjusted with 10% NaOH solution and separated the phases and washed the aqueous layer with DCM (2X25 ml) and washed the organic layer with water (2x20ml). Distilled off the solvent completely and recrystalized from acetone (Yield=1.18 gms, 42% of theory).
  • 42
  • [ 1429334-18-8 ]
  • [ 446292-10-0 ]
  • 43
  • [ 1429333-96-9 ]
  • [ 446292-10-0 ]
YieldReaction ConditionsOperation in experiment
23 g With hydrogenchloride; In water; ethyl acetate; at 20℃; for 2h; To (S)-5-[(3,4-dimethoxybenzylidene)amino]methyl}-3-[4-(3-oxomorpholin-4-yl)phenyl]oxazolidin-2-one ( prepared in the above examples of 23, 24 or 25 ) (43. 9 gms, 0.1 mol) is added ethylacetate (300 ml) .To the mix. is added 12M aq. HC1( 85 ml) and the R.M is stirred for about 2 hrs at the ambient temperature . The phases are separated, the org. layer is washed with the ethyl acetate ( 100 ml) , Dichloromethane ( 200 ml) is added and adjusted to pH 9-10 with 50% aq. NaOH solution and separated the org. layer and distilled completely to yield pure title compound as a white- crystalline solid. (Yield = 23 g, 68.9% of the theory).
  • 44
  • [ 1429333-99-2 ]
  • [ 446292-10-0 ]
  • 45
  • [ 1429334-00-8 ]
  • [ 446292-10-0 ]
YieldReaction ConditionsOperation in experiment
0.52 g With pyridine; hydroxylamine hydrochloride; In ethanol; for 24h;Reflux; To a solution of(S)-N-[{3-(4-(3-oxo-morpholin-4-yl)phenyl)-2-oxo-5- oxazolidinyl} methyl] acetamide ( 3.38 g, 10 mmol) in pyridine ( 56 ml) and ethanol ( 7 ml) was added hydroxylamine. Hydrochloride ( 4.5 g, 6.5 eq) and refluxed for about 24 hrs . After cooling to R.T, added water ( 200 ml) and then extracted into MDC ( 50 ml x 2).washed the org. layer with dil.HCl ( 10 ml x 2) and the org. layer discarded . Washed the aq. layer with (10 ml ) dichloromethane. To the aq. layer added 50 ml DCM and pH = 9- 10 adjusted with 10 % NaOH solution. Separated the phases and the org. layer washed with the water (10 ml x 1). Distill- off the solvent completely to yield a title compound as a white crystalline solid.
  • 46
  • [ 1429334-02-0 ]
  • [ 446292-10-0 ]
  • 47
  • 4-{4-[(5R)-(5-azidomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one [ No CAS ]
  • [ 446292-10-0 ]
YieldReaction ConditionsOperation in experiment
25.7 g With 5%-palladium/activated carbon; hydrogen; In ethyl acetate; at 45 - 50℃; To a solution of azido compound (prepared in the above examples 35, 36 or 37) (31.8 g) in 400 ml of ethyl acetate, added 2.5 g, of 5% Pd/C and hydrogenated the mix. at 45-50 C at 6-8 kg of Hydrogen pressure for 8 - 12 hrs . After reaction has been completed (as indicated by the TLC), filtered off the catalyst and washed with ethylacetate (50 ml). Distill-off the solvent completely and then re-crystallized from methanol (Yield = 25. 7 g, 88% of the theory).
  • 49
  • [ 1429334-08-6 ]
  • [ 446292-10-0 ]
YieldReaction ConditionsOperation in experiment
1.6 g With hydrogen bromide; acetic acid; at 10℃; for 0.166667h; A solution of 4-{4-[(5S)-5-(aminotrityl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}- morpholin-3-one (5.34g, lOmmol) in 50 ml of acetic acid is prepared by warming on the steam batch. The solution is then cooled to approximately 10C, 5ml of a saturated solution of dry hydrogen bromide in acetic acid was added, and the reaction mixture was stirred for 10 mins. The trityl bromide formed during the reaction was removed by filtration and the filtrate was poured immediately into 250ml of cold water and adjusted the pH to 9-10 with 50% sodium hydroxide solution. The aqeous layer was washed with chloroform (3x50ml) and organic layer was washed with water (2x20ml) and distilled off the solvent completely and recrystallized from methanol (Yield 1.6 g, 55% of theory).
  • 50
  • 4-[4-{(S)-2-hydroxy-3-(tritylamino)propylamino}phenyl]morpholin-3-one [ No CAS ]
  • [ 446292-10-0 ]
  • 51
  • [ 1411775-00-2 ]
  • [ 446292-10-0 ]
  • 52
  • [ 446292-10-0 ]
  • C6H5ClO4S2 [ No CAS ]
  • [ 366789-02-8 ]
YieldReaction ConditionsOperation 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%).
  • 53
  • [ 446292-10-0 ]
  • C12H9ClO4S2 [ No CAS ]
  • [ 366789-02-8 ]
YieldReaction ConditionsOperation 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%).
  • 54
  • [ 446292-10-0 ]
  • (5-fluorothiophen-2-yl)formyl chloride [ No CAS ]
  • (S)-5-fluoro-N-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)thiophene-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% With pyridine; at 0 - 23℃; for 1h;Inert atmosphere; Under nitrogen, to (5)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3- yl)phenyl)morpholin-3-one (189 mg, 0.648 mmol, 1.00 equiv) (commercially available) in pyridine (5.5 mL) at 0 C was added 5-fluorothiophene-2-carbonyl chloride (160 mg, 0.972 mmol, 1.50 equiv). After stirring for 60 min at 23 C, H20 (10 mL) was added to the reaction mixture and extracted with CH2C12 (3 x 10 mL). The combined organic phases were washed with brine (30 mL) and dried (MgS04). The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel eluting with CH2Cl2/MeOH to afford 100 mg of the title compound as colorless solid (37%). NMR Spectroscopy: *H NMR (300 MHz, DMSO- 6, 23 C, delta): 8.93 (t, / = 6.0 Hz, 1H), 7.60-7.52 (m, 3H), 7.41 (d, / = 9.3 Hz, 2H), 6.79 (dd, / = 4.5 Hz, 2.1 Hz, 1H), 4.88-4.79 (m, 1H), 4.24-4.14 (m, 3H), 3.99-3.94 (m, 2H), 3.87-3.81 (m, 1H), 3.75-3.69 (m, 2H), 3.63- 3.58 (m, 2H).
  • 55
  • [ 1252018-07-7 ]
  • [ 446292-10-0 ]
  • 56
  • [ 1416129-92-4 ]
  • [ 446292-10-0 ]
YieldReaction ConditionsOperation in experiment
90% With hydrogenchloride; water; In ethanol; at 20℃; for 24h; [0065] 5.0 g of compound 3 was added to 50 ml of ethanol. 10 ml of 37% (w/w) hydrochloric acid was added with stirring. The reaction mixture was stirred at room temperature for 24 hours. After vacuum filtration, the filter cake was washed with 10 ml of ethanol, and 3.8 g of off-white solid was obtained as product. The yield was 90%.
90% With hydrogenchloride; In ethanol; water; at 20℃; for 24h; Example 8:Preparation of compound 4[0031] 5.0 g of compound 3 was added to 50 ml of ethanol. 10 ml of 37% (w/w) hydrochloric acid was added withstirring. The reaction mixture was stirred at room temperature for 24 hours. After vacuum filtration, the filter cake waswashed with 10 ml of ethanol, and 3.8 g of off-white solid was obtained as product. The yield was 90%.
  • 57
  • [ 635301-86-9 ]
  • [ 446292-10-0 ]
  • 58
  • [ 1414932-73-2 ]
  • [ 446292-10-0 ]
YieldReaction ConditionsOperation in experiment
90% With hydrogenchloride; water; In ethanol; at 20℃; for 24h; [0075] 5.0 g of compound 7 was added to 50 ml of ethanol. 10 ml of 37% (w/w) hydrochloric acid was added with stirring. The reaction mixture was stirred at room temperature for 24 hours. After vacuum filtration, the filter cake was washed with 10 ml of ethanol, and 3.88 g of off-white solid was obtained as product. The yield was 90%.
90% With hydrogenchloride; In ethanol; water; at 20℃; for 24h; Example 13:Preparation of compound 4[0036] 5.0 g of compound 7 was added to 50 ml of ethanol. 10 ml of 37% (w/w) hydrochloric acid was added withstirring. The reaction mixture was stirred at room temperature for 24 hours. After vacuum filtration, the filter cake waswashed with 10 ml of ethanol, and 3.88 g of off-white solid was obtained as product. The yield was 90%.
  • 59
  • [ 446292-10-0 ]
  • [ 1616563-61-1 ]
  • 61
  • [ 446292-10-0 ]
  • [ 64-18-6 ]
  • [ 1616563-62-2 ]
YieldReaction ConditionsOperation in experiment
96% In toluene; at 110 - 120℃; In a four neck round bottom flask charged 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin- 15 3-yl]phenyl}morpholin-3-one free base (50 g) toluene (350 ml) and formic acid (21.63 g). Reaction mass then heated azeotropically to 110-120C employing dean-stark apparatus for 3 to 4 h. (water removed azeotropically) Reaction mass is cooled to 25 to 30C. Obtained solid is filtered off and washed by toluene. Yield 96%
  • 62
  • [ 446292-10-0 ]
  • S-methyl 5-chlorothiophene-2-carbothioate [ No CAS ]
  • [ 366789-02-8 ]
YieldReaction ConditionsOperation 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.
  • 63
  • [ 446292-10-0 ]
  • S-benzo[d]isoxazol-3-yl 5-chlorothiophene-2-carbothioate [ No CAS ]
  • [ 366789-02-8 ]
YieldReaction ConditionsOperation 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.
  • 64
  • [ 446292-10-0 ]
  • S-3H-1,2,3-triazol-4-yl 5-chlorothiophene-2-carbothioate [ No CAS ]
  • [ 366789-02-8 ]
YieldReaction ConditionsOperation 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.
  • 65
  • [ 446292-10-0 ]
  • S-benzo [d]thiazol-2-yl 5-chlorothiophene-2-carbothioate [ No CAS ]
  • [ 366789-02-8 ]
YieldReaction ConditionsOperation 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 %
  • 66
  • [ 446292-10-0 ]
  • [ 527-72-0 ]
  • N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide [ No CAS ]
  • 67
  • [ 446292-10-0 ]
  • [ 4684-94-0 ]
  • 6-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)pyridine-2-carboxamide [ No CAS ]
  • 68
  • [ 446292-10-0 ]
  • (S)-5-chloro-N-((3-(4-((2-(2-(2-(5-chlorothiophene-2-carbonyl)hydrazinyl)-2-oxoethoxy)ethyl)amino)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide [ No CAS ]
  • 69
  • [ 446292-10-0 ]
  • C24H23Cl2N5O6S2*ClH [ No CAS ]
  • 70
  • [ 446292-10-0 ]
  • C24H23Cl2N5O6S2*H2O4S [ No CAS ]
  • 71
  • [ 446292-10-0 ]
  • C24H23Cl2N5O6S2*CH2O2 [ No CAS ]
  • 72
  • [ 446292-10-0 ]
  • C24H23Cl2N5O6S2*C6H8O7 [ No CAS ]
  • 73
  • [ 446292-10-0 ]
  • CH4O3S*C24H23Cl2N5O6S2 [ No CAS ]
  • 74
  • [ 446292-10-0 ]
  • 2-[2-({4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}amino)ethoxy]acetohydrazide [ No CAS ]
YieldReaction ConditionsOperation in experiment
49.5% With hydrazine hydrate; In methanol; at 80℃; for 12h; The compound of formula II as (10g, 34mmol) was added to the reaction flask, followed by adding 50mL of methanol and hydrazine monohydrate (25mL, 424mmol), the reaction temperature was raised to 80 12h. Concentrated under reduced pressure to give a yellow oil which was purified by column chromatography (mobile phase: DCM / MeOH / NH3H2O = 10/1 / 0.05) give an off-white solid (5.5g, 49.5%), HPLC purity: 99.1%.
49.5% With hydrazine hydrate; In methanol; at 80℃; for 12h; The compound of Formula II (10 g, 34 mmol) was added to the reaction flask, 50 mL of methanol and hydrazine hydrate (25 mL, 424 mmol) were added successively. The temperature was raised to 80C for 12 h, concentrated under reduced pressure to give a yellow oil. Column chromatography (mobile phase:DCM / Me0H / NH3H20 = 10/1/0. 05) was carried out to afford the off-white solid (5.5 g, yield 49.5%, HPLC purity: 99.1%).
  • 75
  • [ 446292-10-0 ]
  • (S)-2-(2-[4-(5-aminomethyl-2-oxo-1,3-oxazolidin-3-yl)phenyl]amino}ethoxy)acetohydrazide hydrochloride [ No CAS ]
  • 76
  • N-(tert-butoxycarbonyl)-4-(3-oxo-morpholinyl)aniline [ No CAS ]
  • [ 446292-10-0 ]
  • 77
  • R-2-hydroxy-3-((4-(3-oxo-morpholinyl)phenyl)amino)propyl-4-methylbenzenesulfonate [ No CAS ]
  • [ 446292-10-0 ]
  • 78
  • [ 446292-10-0 ]
  • (S)-4-(4-(((2-oxooxazolidin-5-yl)methyl)amino)phenyl)morpholin-3-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
46% In water; at 130℃; for 12h;Autoclave; Compounds of formula II (10 g, 34 mmol) and 60 mL of water were added to an autoclave and heated to 130 C for 12 h. The filtrate was concentrated under reduced pressure to give a yellow oil which was purified by column chromatography (mobile phase: DCM / Me0H / NH3H20 = 10/1/0. 05) to give an off-white solid (4.6 g, 46%), HPLC purity 98.2%.
  • 79
  • [ 446292-10-0 ]
  • (S)-5-chloro-N-((3-(4-((2-(2-hydrazinyl-2-oxoethoxy)ethyl)amino)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide [ No CAS ]
  • 80
  • [ 446292-10-0 ]
  • C19H22ClN5O5S*ClH [ No CAS ]
  • 81
  • [ 446292-10-0 ]
  • C19H22ClN5O5S*H2O4S [ No CAS ]
  • 82
  • [ 446292-10-0 ]
  • C19H22ClN5O5S*CH2O2 [ No CAS ]
  • 83
  • [ 446292-10-0 ]
  • C19H22ClN5O5S*CH4O3S [ No CAS ]
  • 84
  • [ 446292-10-0 ]
  • 2-[2-({4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}amino)ethoxy]acetohydrazide hydrochloride [ No CAS ]
  • 86
  • N-(4-aminophenyl)-2-(2-chloroethoxy)acetamide [ No CAS ]
  • [ 446292-10-0 ]
  • 87
  • 4-[4-(methylideneamino)phenyl]morpholin-3-one [ No CAS ]
  • [ 446292-10-0 ]
  • 88
  • [ 446292-07-5 ]
  • [ 530-62-1 ]
  • [ 446292-10-0 ]
YieldReaction ConditionsOperation in experiment
25.3 g The reaction flask was charged with the resulting 39.9 g (0.101 mol) of the intermediate VI and 100 ml of tetrahydrofuran.63.2g (0.39mol) of N,N'-carbonyldiimidazole was stirred well,5.0g of 4-dimethylaminopyridine (DMAP) was added and the mixture was heated at reflux for 10 hours.TLC control (dichloromethane:methanol = 20:1, volume ratio) reacted completely and stopped the reaction.After cooling to room temperature, stir for 1 hour and filter.The cake was washed with 40 ml of tetrahydrofuran and 70 ml of 95% ethanol.The resulting wet product is directly put into the reaction flask.Add 400ml of 95% ethanol and 80ml of 30-33% methylamine aqueous solution and stir well.The temperature was refluxed for 8 hours. The reaction was completed by TLC (dichloromethane: methanol = 20:1, volume ratio).At room temperature, adjust the pH to 1-2 with 37% hydrochloric acid (V/V).A large amount of white solid precipitated out and was filtered. The filter cake was rinsed with 40 ml of 95% ethanol.Drying under reduced pressure gave 29.3 g (0.09 mol) of an off-white solid as the hydrochloride salt of Intermediate VII,The molar yield of intermediate VII hydrochloride was approximately 89.1%.HPLC purity 99.4%.29.3 g (0.09 mol) of the intermediate VII hydrochloride was added to 150 ml of purified water and 150 ml of dichloromethane.Under stirring, the pH was adjusted to about 8 with sodium carbonate, the liquid was separated, and the organic layer was evaporated to dryness.Intermediate VII was obtained as an oil 25.3 g (0.087 mol). The yield of the salt in solution was 96.7% and the HPLC purity was 98.5%.
  • 89
  • [ 446292-10-0 ]
  • [ 75-36-5 ]
  • [ 1429334-00-8 ]
YieldReaction ConditionsOperation in experiment
13.2 g With triethylamine; In tetrahydrofuran; at 20℃; for 2h;Inert atmosphere; in room temperature,Anhydrous potassium carbonate 6.7g added(S)-5-Chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholinyl))Phenyl]-1,3-oxazolidine-5-yl}methyl)-2-carboxamide hydrochloride, 16g100mL aqueous solution,The reaction was performed at room temperature for 2 hours.Concentrate to remove water from the reaction solution.Then wash with 30mL methanol, filter,The filtrate is concentrated,Dry to give (S)-5-chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidine-5- Based on} methyl)-2-carboxamide,Under argon at room temperature,4.5 mL anhydrous triethylamine was added to (S)-5-chloro-N-({2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1, 3-oxazolidin-5-yl}methyl)-2-carboxamideIn 600 mL of anhydrous tetrahydrofuran,Add 5 mL of acetyl chloride dropwise,The reaction was performed at room temperature for 2 hours.Traces of TCL (EA/MeOH = 10:1) showed that some of the starting material was still present.Then add anhydrous 2.2mL of triethylamine and 2.2mL of acetyl chloride and continue to react for 2 hours.TCL (EA/MeOH=10/1) monitoring,Raw material spots have basically disappeared. The reaction was quenched with 20 mL of water.The mixture was concentrated and subjected to silica gel column chromatography (EA/MeOH=10:1) to obtain the relevant substance A as a white powder 13.2 g, yield 80.7%.
  • 90
  • [ 446292-07-5 ]
  • [ 74-89-5 ]
  • [ 446292-10-0 ]
YieldReaction ConditionsOperation in experiment
92.2% The obtained reaction flask was charged with the obtained 51.4 g (0.13 mol) of the intermediate VI, 300 ml of tetrahydrofuran, and 84.3 g (0.52 mol)N,N'-carbonyldiimidazole was stirred well, 6.5g of 4-dimethylaminopyridine (DMAP) was added, and the mixture was heated at reflux for 12 hours.The reaction was completed by TLC (dichloromethane:methanol=20:1, volume ratio), the reaction was stopped, the reaction was allowed to stand at room temperature, and the mixture was stirred for 1 hour. The filter cake was washed successively with 50 ml of tetrahydrofuran and 100 ml of 95% ethanol to obtain a wet product. Directly into the reaction flask,500ml of 95% ethanol and 110ml of 30-33% methylamine aqueous solution were added, and the mixture was stirred and heated at reflux for 8 hours.The reaction was completed by TLC (dichloromethane:methanol=20:1, volume ratio), and the reaction was allowed to come to room temperature. The pH was adjusted to 1-2 with 37% hydrochloric acid (V/V). A large amount of white solids precipitated and was filtered and used as a filter cake. Rinse with 50 ml of 95% ethanol.Drying under reduced pressure gave 39.2 g (0.12 mol) of an off-white solid as the hydrochloride salt of Intermediate VII,Intermediate VI produced approximately 92.2% molar yield of Intermediate VII and HPLC purity of 99.3%.
  • 91
  • [ 446292-10-0 ]
  • [ 5271-67-0 ]
  • N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
96% With 4-methyl-morpholine; In water; acetonitrile; at -5 - 20℃; for 2.5h; (2) 20 g of the compound of Formula 3, 100 mL of acetonitrile, and 50 mL of water were added to a 500 mL reaction flask at room temperature, and 40 mL of N-methylmorpholine was added at -5C to 5C. The temperature was controlled at -5 to 5C, and a solution of 12 g of the compound of Formula 5 in 50 mL of acetonitrile was slowly added dropwise, and it was dripped over about 30 minutes. Stir at room temperature for 2 hours,Filtration and drying gave 26.5 g of a dry product of the formula 2 in 96% yield; the 1H NMR spectrum of the compound of formula 2 is shown in FIG. 2 and the structure is consistent with the target.
  • 92
  • [ 446292-10-0 ]
  • [ 5538-51-2 ]
  • C23H23N3O7 [ No CAS ]
YieldReaction ConditionsOperation in experiment
73% With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; Under anhydrous and anaerobic conditions,(S)-2-((2-Oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-ylmethyl)isoindole -The 1,3-diketone (V, 1 mmol) was dissolved in dichloromethane and N,N-diisopropylethylamine (2.0 eq) was added.2-Acetoxy-benzoyl chloride (IV, 1.5 eq) was reacted overnight at room temperature.The reaction was monitored by TLC, and the reaction was completed, washed twice with water, extracted with dichloromethane, and purified by column chromatography.The compound of formula (I) was obtained in a yield of 73% as calculated by (V).
  • 93
  • C11H12N2O3 [ No CAS ]
  • [ 446292-10-0 ]
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