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[ CAS No. 165800-03-3 ] {[proInfo.proName]}

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Jon Albo ; Shenghao Tan ; Joee D Denis , et al. DOI:

Abstract: Liquid handling is a fundamental capability for many scientific experiments. Previously, we introduced the Surface Patterned Omniphobic Tiles (SPOTs) platform, which enables manipulation of hundreds to thousands of independent experiments without costly equipment or excessive consumable expenses. However, the SPOTs platform requires a custom coating formulation and lacks robustness. To overcome these limitations, we introduce EZ-SPOTs. These devices can be created in an hour with common fabrication tools and just three components - glass, a hydrophobic coating, and acrylic. EZ-SPOTs preserve many of the SPOTs platform’s strengths - ease of use, ability to handle a wide range of volumes, and scalability - and adopt a durable and abrasion resistant coating that enables multiple reuses of each device. Here, we describe the fabrication of EZ-SPOTs and showcase how its reusability allows antibiotic susceptibility testing of many isolates using a single device. These results quantitatively match current gold standard assays and the increased throughput provides substantially more information than standard approaches.

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Canale, Vittorio ; Czekajewska, Joanna ; Klesiewicz, Karolina , et al. DOI: PubMed ID:

Abstract: The alarming increase in the resistance of bacteria to the currently available antibiotics necessitates the development of new effective antimicrobial agents that are active against bacterial pathogens causing major public health problems. For this purpose, our inhouse libraries were screened against a wide panel of clin. relevant Gram-pos. and Gram-neg. bacteria, based on which compound I was selected for further optimization. Synthetic efforts in a group of arylurea derivatives of aryloxy(1-phenylpropyl) alicyclic diamines, followed with an in vitro evaluation of the activity against multidrug-resistant strains identified compound 44 (1-(3-chlorophenyl)-3-(1-{3-phenyl-3-[3-(trifluoromethyl)phenoxy] propyl}piperidin-4-yl)urea). Compound 44 showed antibacterial activity against Gram-pos. bacteria including fatal drug-resistant strains i.e., Staphylococcus aureus (methicillin-resistant, MRSA; vancomycin-intermediate, VISA) and Enterococcus faecium (vancomycin-resistant, VREfm) at low concentrations (0.78-3.125 μg/mL) comparable to last resort antibiotics (i.e., vancomycin and linezolid). It is also potent against biofilm-forming S. aureus and Staphylococcus epidermidis (including linezolid-resistant, LRSE) strains, but with no activity against Gram-neg. bacteria (Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa). Compound 44 showed strong bactericidal properties against susceptible and drug-resistant Gram-pos. bacteria. Depolarization of the bacterial cytoplasmic membrane induced by compound 44 suggests a dissipation of the bacterial membrane potential as its mechanism of antibacterial action. The high antimicrobial activity of compound 44, along with its selectivity over mammalian cells (lung MCR-5 and skin BJ fibroblast cell lines) and no hemolytic properties toward horse erythrocytes, proposes arylurea derivatives of aryloxy(1-phenylpropyl) alicyclic diamines for development of novel antibacterial agents.

Keywords: Arylurea derivatives ; Antibacterial properties ; Anti-MRSA activity ; Anti-VRE activity ; Anti-LRSE activity ; Depolarization of bacterial cell membrane

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Product Details of [ 165800-03-3 ]

CAS No. :165800-03-3 MDL No. :MFCD00937825
Formula : C16H20FN3O4 Boiling Point : -
Linear Structure Formula :OC4H8NC6H3FNCOOCH2CHCH2NHCOCH3 InChI Key :TYZROVQLWOKYKF-ZDUSSCGKSA-N
M.W : 337.35 Pubchem ID :441401
Synonyms :
PNU-100766
Chemical Name :(S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide

Calculated chemistry of [ 165800-03-3 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 24
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.5
Num. rotatable bonds : 5
Num. H-bond acceptors : 5.0
Num. H-bond donors : 1.0
Molar Refractivity : 91.06
TPSA : 71.11 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) : -7.87 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.31
Log Po/w (XLOGP3) : 0.69
Log Po/w (WLOGP) : 0.78
Log Po/w (MLOGP) : 0.99
Log Po/w (SILICOS-IT) : 1.25
Consensus Log Po/w : 1.2

Druglikeness

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

Water Solubility

Log S (ESOL) : -2.22
Solubility : 2.03 mg/ml ; 0.00601 mol/l
Class : Soluble
Log S (Ali) : -1.76
Solubility : 5.86 mg/ml ; 0.0174 mol/l
Class : Very soluble
Log S (SILICOS-IT) : -3.19
Solubility : 0.218 mg/ml ; 0.000647 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 1.0 alert
Brenk : 0.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 3.32

Safety of [ 165800-03-3 ]

Signal Word:Danger Class:9
Precautionary Statements:P501-P273-P260-P270-P264-P280-P391-P314-P337+P313-P305+P351+P338-P301+P312+P330 UN#:3077
Hazard Statements:H302-H319-H372-H410 Packing Group:
GHS Pictogram:

Application In Synthesis of [ 165800-03-3 ]

* 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 [ 165800-03-3 ]

[ 165800-03-3 ] Synthesis Path-Downstream   1~97

  • 1
  • [ 108-24-7 ]
  • [ 168828-90-8 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
88% With triethylamine; In ethyl acetate; at 20 - 40℃; under 608.041 - 912.061 Torr; for 2h;Product distribution / selectivity; Example 17 Preparation of Linezolid (Compound 1) (S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (0.3 g, 1 mmol), acetic anhydride (0.12 g, 1.2 mmol) and triethylamine (0.5 g, 5 mmol) were added to 10 mL ethyl acetate and the reaction mixture was stirred at room temperature for 2 hours. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, most part of the solvent was evaporated, frozen crystallized and filtered to yield the crude product. The crude product was recrystallized with ethyl acetate to provide 0.30 g of linezolid in 88% yield. 1H NMR (300 MHz, CDCl3) delta: 2.02 (s, 3H, CH3CO), 3.05 (t, 4H, CH2CH2N), 3.75 (m, 1H, CHaCHO), 3.67 (m, 2H, CH2NHCO), 3.87 (m, 4H, ArCH2N), 4.02 (m, 1H, CHbNO), 4.76 (m, 1H, CH2CHO), 6.12 (t, 1H, NHCO), 6.93 (t, 1H, ArH), 7.18 (dd, 1H, ArH), 7.46 (dd, ArH).
88% With triethylamine; In ethyl acetate; at 25℃; for 2h;Product distribution / selectivity; (S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (0.3 g, 1 mmol), acetic anhydride (0.12 g, 1.2 mmol) and triethylamine (0.5 g, 5 mmol) were added to 10 mL ethyl acetate and the reaction mixture was stirred at room temperature for 2 hours. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, most part of the solvent was evaporated, frozen crystallized and filtered to yield the crude product. The crude product was recrystallized with ethyl acetate to provide 0.30 g of linezolid in 88% yield. 1H NMR (300MHz, CDCl3) delta: 2.02(s, 3H, CH3CO), 3.05(t, 4H, CH2CH2N), 3.75 (m, 1H, CHaCHO), 3.67(m , 2H , CH2NHCO), 3.87(m, 4H, ArCH2N), 4.02 (m, 1H, CHbNO), 4.76(m, 1H, CH2CHO), 6.12( t, 1H, NHCO), 6.93 (t, 1H, ArH), 7.18 (dd, 1H, ArH), 7.46 (dd, 1H, ArH). HPLC : 99.8%.
88% at 0℃; To a solution of (S)-5-[(4-methoxy-benzylidene)-amino]-methyl}-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazole Alkyl-2-one(186.1 g, 450 mmol, 1.0 equiv)Was added ethyl acetate (900 ml) and water (900 ml).To a heterogeneous mixture was added 12 M aqueous HCI (75 mL, 900 mmol, 2.0 equiv)After a few minutes, the solid was dissolved in the solution and stirring was continued at room temperature for 2 hours,HPLC analysis showed complete hydrolysis.The phases were separated, the organic layer was discarded and the aqueous phase was washed with ethyl acetate (500 ml).To the aqueous phase was added ethyl acetate (900 ml)With 50% sodium hydroxide (about 36 g)The aqueous solution was adjusted to pH 6.7, the organic phase was separated,The aqueous phase was recrystallized from ethyl acetate (500 mL)The organic phase was combined, washed once, dried over anhydrous sodium sulfate (50 g), filtered to remove sodium sulfate,The filtrate was added to acetic anhydride (85 ml, 900 mmol, 2.0 equiv)Concentrated to 900 ml under reduced pressure.The resulting slurry was cooled to 0 C and the precipitate was collected by suction filtration,Dried at 50 C in vacuo to give the title compound, i.e., 133.6 g of the linezolid amine, 88% yield and 99.8% HPLC purity.
88.4% With triethylamine; In dichloromethane; at 20℃; for 1h; (S) - [3- (3-fluoro-4-morpholinophenyl) -2-oxo-5-oxazolidinyl] methylamine (7.2 g, 24.4 mmol) In dichloromethane, acetic anhydride (3.0 g, 29.2 mmol) was added,Triethylamine (4.1 mL, 29.2 mmol), reacted at room temperature for 1 hour, and monitored by TLC.After the reaction was complete, the mixture was washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated,To give the crude product as a milky white which was recrystallized from ethyl acetate,To give linezolid 7.27g,Yield: 88.4%, chemical purity: 99.9%; optical purity: 99.96%.
87% In ethyl acetate; at 20℃; for 1h; General procedure: A solution of acetic anhydride andpropionic anhydride (0.020 mol) was added dropwise to a stirred solution of (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (6) (2.5 g, 0.008 mol) inethyl acetate (20 mL) at ambient temperature andthe reaction mixture was allowed to stirred for 1 h.The reaction mixture was cooled to 0-5C. Theprecipitated solid was filtered off and re-crystallized from methanol (20 ml-) to give the correspondingcompounds (7a-b).
86.9% With triethylamine; In ethyl acetate; at 20℃; for 2h; Amino-methyl-3- (3-fluoro-4-morpholinophenyl) oxazolin-2-one obtained in Example 4-1 was added to a reaction flask (7,23.7 g, 0.08 mol), acetic anhydride (10.2 g, 0.1 mol), triethylamine (40.5 g, 0.4 mol) was added 500 mL of ethyl acetate at room temperature for 2 hours until the reaction was complete. Add water, the organic layer, saturated brine washing, anhydrous magnesium sulfate drying, filtration, evaporation of most of the solvent, frozen crystals, filtered crude. The crude product was recrystallized from ethyl acetate to give nicotinamide 23.5 g, molar yield 86.9%, HPLC chemical purity 99.8%, optical purity 99.9%.
80% With triethylamine; at 25℃; for 0.5h; 2) The compound (intermediate 3) in dichloromethane was suction filtered to take the filtrate, which was added to the reaction vessel and cooled to 0 C, and added.570g of triethylamine, slowly adding 345g acetic anhydride; after the addition is completed, the system is heated to 25 C for 0.5h, then added 2.4L hydrochloric acid aqueous solution, stirred for 10min;Wash again with water 3 times, combine the organic phases, dry over anhydrous sodium sulfate,The mixture was suction filtered, and the solvent was evaporated under reduced pressure.Cool down to 10 C for suction filtration, dry at 40 C,Obtained 758.85g of white solid.The yield was 80%.
77% With triethylamine; In toluene; at 20℃; for 5.5h;Product distribution / selectivity; To a suspension of (S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (III) (452 mg, 1.53 mmol) in toluene (2.3 mL) was added triethylamine (215 muL, 1.54 mmol, 1 eq) and acetic anhydride (146 muL, 1.54 mL, 1 eq) and the mixture was stirred at room temperature for 5.5 h. The suspension was cooled in an ice bath for 30 min, was filtered and the collected solids were washed with cold toluene (2 x 0.5 mL) and were dried in vacuo to give N-(((S)-3-(3-fluoro-4-morpholinophenyl)-2-oxazolidin-5-yl)methyl)acetamide, linezolid (390 mg, 77%, HPLC 99.1%, 99.9% ee) as an off-white solid. For characterization, see Example 11.
75% In dichloromethane; at 25 - 30℃; for 1h; Example-9: (0148) Preparation of N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-2-oxo-l, 3- oxazolidin-5-yl} methyl) acetamide (Linezolid) (0149) To the mixture of Methanol (100 ml) ,DM water (400 ml) and (S) 2-[3-(3-Fluoro-4- morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl] -isoindole-1, 3-Dione (100 g 0.212 moles ) were added Methyl amine solution (47 g) to the reaction mixture at 25- 30C, stirred and the temperature was slowly raised to 80-85C and stirred for 2-3 hours at 80-85C. The reaction mixture was cooled to 25-30C and dichloromethane (500 ml) was added to it and stirred the reaction mixture for 15 min and separated the two layers. MDC was distilled out by atmospheric pressure completely to get the residual product (5S)-5-(amino methyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-l,3-oxazolidin-2-one. Dichloromethane (400 ml) was added to the residue and acetic anhydride (25 g) was slowly added at 25-30C over a period of 60 min. After completion, 5% aqueous sodium bicarbonate solution was slowly added to reaction mixture, stirred for 15 min and the two layers were separated. The dichloromethane layer was washed with DM Water (200 ml). The dichloromethane layer was filtered through hyflo and distilled out dichloromethane completely under vacuum below 40C. Cyclohexane (500 ml) was added to the residue and heated to 45-50C. The slurry obtained was cooled to 20-25C, stirred for 60 min, filtered the solid, washed with cyclohexane (200 ml) and dried the solid at 45-55C to furnish pure crystalline N-({(5S)-3-[3-fluoro-4-(morpholin-4- yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (Linezolid) (53 g 75% ).
68% Example- 7: Preparation of (5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl acetamide (Form II)(5S)-(N)-[[3- fluoro-(4-mophiholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine (20 gms) was added in water (200 ml) and ethyl acetate (80 ml) and the mixture was stirred at 25C-30C followed by the addition of acetic anhydride (19.2 ml, 3 eq.) at the same time. The reaction mixture was neutralized to 6-8 pH with aqueous ammonia and stirred for 2 hours. The reaction mixture was then filtered, to give (5S)-(N)-[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (Yield: 68%)
60% With triethylamine; In dichloromethane; at 5 - 20℃; for 4h; Example-14: Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl acetamide, Linezolid (I) starting from (S)-[[N-3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine(S)-[[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine (3 g) obtained in example 11 and triethylamine (1.54 g) were dissolved in DCM (15 ml). The solution was cooled to 5C and acetic anhydride (1.25 g) was added. The resulting reaction mixture was warmed to room temperature and stirred for 4h. After completion of reaction, water (50 ml) was added in reaction mixture and stirred for 30 min. Separation of DCM and aqueous layers was carried out. Aqueous layer was extracted with DCM. The combined DCM layers were washed with 10% sodium bicarbonate solution followed by washing with water. DCM layer was concentrated under vacuum at 35-40C. Toluene (20 ml) was added into the residue and heated to 70C. The suspended solution was stirred at 65-70C for 30 min and further at room temperature for lh. The solid mass was filtered, washed with toluene and dried to obtain the titled compound (2.1 g) with 60% yield.
In ethyl acetate; at 20℃; for 1h;Product distribution / selectivity; Example 5; To the mixture of (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5- oxazolidinyl] methyl] amine (10 gm) and ethylacetate (100 ml), acetic anhydride (10 ml) is slowly added at ambient temperature, then stirred at ambient temperature for 1 hour. The separated solid is filtered and dried under reduced pressure at 50C to give 9.5 gm of linezolid form 111.
With ammonium hydroxide; triethylamine; In water; toluene; at 3 - 25℃;Product distribution / selectivity; Example 1 - preparation of crystalline linezolid Form IVA flask containing 5.5 g of (S)-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine and 20 ml ammonium hydroxide in 200 ml toluene wasmixed at 25 C. Triethyl amine (2 equivalents) was added. The mixture was cooled to3 C and acetic anhydride (2.5 equivalents) was added dropwise. The reaction mixturewas brought to RT. Linezolid that precipitated from the reaction mixture was filtered.The wet crystals were analyzed by PXRD and shown to be crystalline linezolid FormIV.Example 2 - Procedure for the preparation of crystalline linezolid Form IVThis example was carried out on a Buchi Mini Spray Dryer B-290. 5 g of linezolid was dissolved in methanol (300 ml) at room temperature. Theobtained solution was pumped into the spray dryer. The nitrogen was at an inlettemperature of 50 C. The evaporated solvent and nitrogen exited the spray dryer at35 C. The obtained sample was analyzed by PXRD and shown to be linezolid FormIV.
In toluene; at 20℃; for 1h; S-N-[[3-[3-Fluoro4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] amine (20 gm) is stirred in toluene (200 ml) for 15 minutes, acetic anhydride (20 gm) is added drop wise at ambient temperature and stirred for 1 hour. The reaction mixture is cooled to 0-5C, filtered the solid and re-crystallized from methanol (200 ml) to give 16 gm of N-[[(5S)-3-[3-fluoro-4-(4-morphblinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
In ethyl acetate; at 20℃; for 1h; Example 5; S-N-[[3-[3-Fluoro4-[morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (20 gm) is dissolved in Ethyl acetate (200 ml), Acetic anhydride (20 gm) is added drop wise at ambient temperature and stirred for 1 hour. The reaction mixture is then cooled to 0-5 C., filtered the solid and re-crystallized from Isopropyl alcohol (400 ml) to give 16 gm of N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
With triethylamine; In ethyl acetate; at 25 - 30℃;Product distribution / selectivity; [139] Example 6: Synthesis of Linezolid Crude.[140] Ethyl acetate (3500ml) and 10% palladium on carbon catalyst (6.0g) are added in autoclave having (R)- [N- 3 - (3 -Fluoro-4-morpholinylphenyl) -2-oxo- 5 -oxazolidinyl] methyl azide (lOOg) at 20-30C. Cool the reaction mass & maintain 2-3kg hydrogen pressure at 15-20C for 6-7 hrs. Filter it & wash the hyflo bed by Ethyl acetate(100mlx2). Then add the Triethyl amine (35. lg) & Acetic anhydride (29.9g) slowly at 25-30C under stirring. Cool the mix, filter it and wash the solid with chilled (0-5C) Ethyl acetate (100 ml) followed by water (100mlx2). Finally product is dried at 55-60 C. Yield: 0.85.: Percentage 81%w/w.
EXAMPLE 25. Scale-up of synthesis of (S)-N-[{ 3-[3-fluoro-4- (morpholinyl)phenyl]-oxo-5-oxazolidyl]methyl]acetamide: Linezolid (9). To a 2 L 3 neck round bottom flask with overhead stirrer was added water (425 ml), 12 N hydrochloric acid (34 ml, 408 mmol), methylene chloride (340 ml) and (S)-(E,Z)-5-((4- chlorobenzylideneamino)methyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one (17) (85 g, 203.4 mmol) rinsed in with methylene chloride (85 ml). The mixture was rapidly stirred at room temp and within 30 minutes a two-phase clear homogenous solution formed. The reaction was stirred for 1 hour and the orange yellow lower organic layer was discarded. The lemon yellow aqueous layer was washed with additional methylene chloride (200 ml) and the methylene chloride was discarded. Methylene chloride (425 ml) was added to the aqueous layer and the two phase solution was transferred to a 2 L Erlenmeyer flask, cooled in an ice bath and neutralized to ca. pH 7 with ice cold 6 N NaOH (ca. 45 ml) while stirring the reaction in the ice bath. The reaction changed in color from yellow to colorless and a white precipitate formed. The ice bath was removed from the reaction flask and acetic anhydride (72 ml, 720 mmol) was added all at once to the rapidly stirring mixture. The mixture was vigorously stirred at room temp for 1 hour yielding a light yellow clear 2-layer solution. The solution was cooled in an ice bath and made basic (ca. pH 9) with 6 N sodium hydroxide. The lower organic layer was separated and the aqueous layer was extracted with additional methylene chloride (3 x 100 ml). The combined organic layers were dried (MgS04) and evaporated (bath temp 25 C) to a volume of ca. 400 ml. The light yellow solution
In ethyl acetate; at 20℃; for 1h; (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methylamine ( 15 gr) is dissolved in ethylacetate (1 50 ml); acetic anhydride ( 1 5 gr) is added dropwise at ambient temperature and stirred for 1 hr. The reaction mixture is then cooled to 0-5 C. Filtered the solid to give 12 gr of (S)-3-(3-fluoro-4-morpholinophenyl) -2-oxo-5-oxazolidinyl methyl acetamide.
60 g at 0 - 25℃; ExampIe-5: ; (SMN-[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyllmethyll- acetamide (Linezolid)Methanol (500 mL) and aqueous methylamine (500 mL of 40%) were added to a flask containing the 100 g phthalimido oxazolidinone of Example-4. The suspension was heated at 65C for 3 hours and cooled to room temperature. 500 mL methylene dichloride and 500 mL water were added to the reaction mixture and stirred for 30 minutes. The separated aqueous layer was extracted with 1 L of methylene dichloride and allowed to settle. The combined organic layer was washed with brine solution and distilled to remove 2 times of methylene dichloride under vacuum below 50C. The reaction mixture was cooled to 0C and 72 g acetic anhydride was added to it. The reaction mixture was stirred at 25C and treated with 10% sodium bicarbonate solution (280 mL, 28g). The separated organic layer was washed with water and allowed to settle for 30 minutes. The organic layer was treated with 5 g activated carbon and stirred for 30 minutes. The reaction mixture was filtered and methylene dichloride was completely removed under vacuum below 50C. The residue (linezolid oil) was co- distilled with 100 mL toluene to obtain 83 g Linezolid as a residue. The residue was cooled to room temperature and 300 mL toluene was added to it. The reaction mixture was heated at 50C to 55C for 3 hours and cooled to room temperature. The solid was filtered and washed with 100 mL toluene to obtain 64.8 g wet-cake. The wet-cake was taken in another RBF and 1.5 L ethyl acetate was added. The reaction mixture was heated below 78C and 5 g activated carbon was added to the clear solution. The reaction mixture was fine filtered and washed with 100 mL ethyl acetate. Approx. 700 mL ethyl acetate was distilled below 78C and reaction mixture was cooled to room temperature. Finally, the reaction mixture was cooled to 18C to 20C and stirred for 1 hour. The product was filtered and washed with 100 mL ethyl acetate. The wet-cake was dried at 65C to 70C to obtain 60 g (69%) Linezolid.
21.5 g With triethylamine; In dichloromethane; at 10 - 30℃; Triethyl amine (12.32 ml) and methylene chloride (220 ml) were added to (S)-N-[[3-[3- fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (22 g) at 25-30C, the resulting solution was cooled to 10-15C, followed by slow addition of acetic anhydride at 12-14C for 10 to 15 minutes. During the addition process, the temperature of the reaction mass raised up to 22C. The resulting mass was stirred for 10 to 15 minutes at 10-15C, followed by raising the temperature to 25-30C and then stirring the mass for 1 hour at the same temperature. The reaction mass was washed with water (50 ml x 2), followed by separation of the organic layer and subsequently stirring the organic layer with activated carbon (2.5 g) for 5 minutes at 25-30C. The resulting mixture was filtered through hyflo bed and the bed was washed with methylene chloride (20 ml), followed by removal of solvent by ordinary distillation at 55-60C to produce a solid. The resulting solid was co-distilled two times with ethyl acetate (35 ml x 2) under vacuum at 65-75C. Water (1 10 ml) was added to the resulting solid, followed by heating the mixture at 60- 65C and then stirring for 20 to 25 minutes at the same temperature. The resulting mass was cooled to 25-30C and then stirred for 10 minutes at the same temperature, followed by cooling the mass to 10C and then stirring for 10 to 15 minutes at the same temperature. The separated solid was filtered, washed with water (50 ml) and then dried the material at 80-85C for 4 hours to produce 21.5 g of highly pure linezolid crystalline Form III [Purity by HPLC: 99.95%; Chiral Purity by HPLC: (S)-isomer = 99.989%; (R)-isomer = 0.01 1%; and Melting Point: 177.8C - 178.5C].
12 g In ethyl acetate; at 20℃; for 1h; (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methylamine (15 gr) is dissolved in ethylacetate (150 ml); acetic anhydride (15 gr) is added dropwise at ambient temperature and stirred for 1 hr. The reaction mixture is then cooled to 0-5 C. Filtered the solid to give 12 gr of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl acetamide.
8.5 g In dichloromethane; at 0 - 5℃;Reflux; To a solution of (5)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (compound 6a) ( 10.0 gr, 0.033 mol) in methylene dichloride (25.0 mL), acetic anhydride (compound 7a) (6.0 mL) was added at 0-5C. Slowly temperature was raised to room temperature and heated reflux temperature and stirred for 1 -2 hrs. The reaction mass was distilled and add methanol (20.0 mL) then stirred at room temperature for 10- 1 min, filtered and wash with methanol to get crude Linezolid. The crude compound was crystallized in methanol to get pure Linezolid (compound 8a) (8.5 gr).
50 g With sodium hydroxide; In water; at 20 - 25℃; for 1h;pH 6.2-6.4; Example 4: Preparations of linezolid form-I from the reaction To a solution of azide of formula II (100 gm), ethanol (800 ml) and water (200 ml), NH4CI (55.8gm) was added at 25-30 C under stirring. Zinc powder (39.0 gm) was charged in one-lot to the reaction mixture, raised the temperature to reflux and stirred for 2 hours. The reaction mixture was cooled to 25-30 C and 23% of aqueous ammonia (200ml) was charged. The reaction mixture was filtered through hyflow bed and washed the bed with water (100 ml) and dichloromethane (100 ml). Dichloromethane (900 ml) and water (300 ml) were charged to the filtrate and stirred for 10-15 minutes. The layers were separated and the aqueous layer was stirred with dichloromethane (2x500ml). The total organic layer was collected and combined with water (500 ml) and subjected for pH adjustment of 1.5-2.0 with 15% aqueous HC1 solution (180-200.0ml) at 25-30C. The resultant two layers were separated and then the aqueous layer was stirred with dichloromethane (2x300 ml). The aqueous layer was separated, treated with ceca carbon (10 gm) at 25-30 C, filtered through hyflow bed and then washed the bed with water (200 ml). The filtrate was cooled to 20-25 C and then adjusted pH 6.5-6.8 by 25% aqueous NaOH solution (5-7 ml). Acetic anhydride (68.4gm) was added in single lot (pH drops to 2.0-3.0) at 20-25 C followed by 25% aqueous NaOH solution (-180.0-190.0 ml) was added to adjust pH 6.2- 6.4 at 20-25 C to the reaction solution and stirred for 1 hour. After the completion of the reaction, the reaction mixture was subjected for pH adjustment to 7.5-8.0 with 25% aqueous solution of sodium hydroxide at 25-30C to extract the reaction mixture into dichloromethane. The organic layer was charcoalized, filtered through hyflow bed and washed with dichloromethane (200 ml). The filtrate was distilled out completely to obtain crude Linezolid at 30 C under vacuum.Water (350 ml) was added to the crude and raised the temperature to 95-100 C. Dimethyl formamide (8.4 ml) was added drop wise to the reaction mixture at 98-100C and maintained for 30 minutes at 100C. The reaction mixture was cooled slowly up to 90C and maintained for 5 hours at the same temperature. The resultant obtained solid was filtered and dried in oven at 75-80 C for 10 hours to afford titled compound.Dried weight: 50 gm.XRPD pattern: Matches with the Fig. 1.Purity by HPLC: 99.9%; Chiral purity: greater than 99.9% and R-isomer: not detected. Residual content: DMF (Below detection limit); ethanol (below detection limit); dichloromethane (below detection limit).Loss on Drying (%w/w):0.36.
62.1 g at 20℃; for 0.25h; General procedure: To a 2L 3 neck round bottom flask with overhead stirrer was added water (500 ml), 12N hydrochloric acid (40 ml, 480 mmol), methylene chloride (400 ml) and(S)-(E,Z)-5-((4-chlorobenzylideneamino)methyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one(12) (100 g, 239 mmol) rinsed inwith methylene chloride (100 ml) The mixture was rapidly stirred at room tempand within 30 minutes a two-phase clear homogenous solution formed. Thereaction was stirred for 1 hour and the orange yellow lower organic layer wasdiscarded. The lemon yellow aqueous layer was washed with additional methylenechloride (250 ml) and the methylene chloride was discarded. Methylene chloride(500 ml) was added to the aqueous layer and the two phase solution wastransferred to a 2 L Erlenmeyer flask, cooled in an ice bath and neutralized toca. pH 7 with ice cold 6 NNaOH (ca. 50 ml) while stirring the reaction in an ice bath. Thereaction changed in color from yellow to colorless and a whiteprecipitateformed that went back into solution with continued strirring. The ice bath wasremovedfrom the reaction flask and acetic anhydride (72 ml, 720 mmol) was added all atonceto the rapidly stirring solution. The mixture was stirred at room temp for 15minutes, cooled in an ice bath and made basic (ca. pH 9) with 6 N sodiumhydroxide (ca. 350 ml). The lower organic layer was separated and the aqueouslayer was extracted with additional methylene chloride (3 x 150 ml). Thecombined organic layers were dried (MgSO4) and evaporated (bath temp 25oC) to a volume of ca. 400 ml. The light yellow solution was slowly added to astirring refluxing solution of ethyl acetate (800 ml) and refluxed down to avolume of 800 ml. Hoy ethyl acetate was added to a volume of 1800 ml and themilky solution was treated with Celite (caution to avoid foaming) filtered andconcentrated by refluxing to a volume of 1100 ml with stirring. Crystalsstarted forming in the refluxing solution at a volume of ca. 1250 ml. The flaskwas stirred at room temp overnight and cooled in an ice bath for 30 minutes beforethe white crystals of 1 werecollected by filtration, air dried and dried in vacuo at room temp (62.1 g, 77%) homogenous by TLC (CH2Cl2:MeOH 9:1, Rf = 0.54; 1HNMR ( 500 MHz, CDCl3) delta 7.44 (dd, 1H, J = 13.8 Hz, J = 2.6 Hz), 7.08 (dd, 1H, J= 8.8Hz, J = 2.6 Hz), 6.93 ( t, 1H, J = 9 Hz), 6.1 (bt, 1H, J = 6.1 Hz), 4.8(m, 1H), 4.0 (t, 1H. J =8.9 Hz), 3.87 (t, 4H, J = 4.5 Hz), 3.75 ( dd, 1H, J =9.1 Hz, 6.8 Hz), 3.70 (ddd, 1H, J = 11.6Hz, J = 5.9 Hz, J = 3.1 Hz), 3.62 (dt,1H, J = 14.7. J = 6.0 Hz), 3.05 (t, 4H, 5 J = 4.5 Hz), 2.02(s, 3H); [alpha]25D-13.6o (c = 1.00, EtOH). Lit.3i [alpha]25D-16o (c = 1.05, EtOH).
2.25 g In methanol; dichloromethane; water; 25 g of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl methyl) - isoindoline-1, 3- dione (III)was taken into a clean round bottom flask. To this 100 mL ofdemineralized water, 25 mL methanol and 20 g of mono -methylamine were added at 35C and the temperature wasraised to 85C, stirred for 3 h at 85C and washed withmethylene dichloride 3 times. The compound was extractedwith methylene dichloride and to this acetic anhydride wasadded slowly drop-wise over the period of 45 minutes. Thenmethylene dichloride layer was washed 3 times with demineralizedwater (70mL x 3) and the layer was separated.Methylene dichloride layer was dried over Na2SO4 and distilledout completely at 50C and then stripping with 35 mLof methanol at 60C to remove methylene dichloride traces.70 mL of methanol was added and the temperature wasraised to 65C for refluxing it to get a clear solution. To this3 g of activated carbon was added and filtered through thehyflowbed and washed with 5 mL of methanol. The filtratewas cooled to 35C and stirred for 30 minutes at the sametemperature to obtain (S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl) methyl) acetamide (or) Linezolid(formula- I) product. The product was filtered and purifiedby recrystallization from methanol to obtain 22.5 g ofpure Linezolid. Yield: 90%. 13C NMR (CDCl3): delta 23.4 (C1), 42.1 (C3), 45.7 (C5), 46.3 (C13, C16), 66.4 (C14, C15), 84.3(C4), 111 (C8), 116.1 (C11), 118.1 (C12), 130.2 (C7, C-N),132.9 (C10), 153 (C6, C=O), 155.9 (C9, C-F); 170.8(C2,C=O); 1H NMR (DMSO) ppm: 9.52 (s, 1H), 7.49-7.53(dd, 1H), 7.484-7.490 (d, 1H), 7.20-7.23 (dd, 1H), 7.04-7.15(t, 1H), 4.85-4.95 (m, 1H), 4.00-4.05 (t, 1H :diastereotopicproton), 3.80-3.82 (q, 1H: diastereotopic proton), 3.72-3.75(t, 4H), 2.95-2.97 (t, 2H), 2.85-2.87 (t, 4H), 2.70-2.83(s,3H). IR (KBr, cm-1): 3393 (N-H stretching), 3014, 2994(aromatic C-H stretching), 2915, 2883, 2821 (aliphatic C-Hstretching), 1749, 1720 (C=O stretching), 1580, 1528 (aromaticC=C stretching), 1455, 1407 (N-H bending), 1300,1323 (aliphatic C-H bending), 1203 (C-N stretching), 1156(C-F stretching), 1124, 1112 (C-O stretching), 1012, 958 (CCstretching). MS: 338 (M++H).
55 g In dichloromethane; at 25 - 30℃; for 1h; To a mixture of methanol (100 ml), DM water (400 ml) and (S) 2-[3-(3-fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-1,3-dione (100 g, 0.212 moles) a methyl amine solution (47 g) was added at a temperature of 25-30 C. The reaction mixture was stirred and the temperature was slowly raised to 80-85 C. and maintained for 2-3 hours. The reaction mixture was cooled to 25-30 C. and dichloromethane (500 ml) was added. The reaction mixture was stirred for 15 min and the layers were separated. MDC was distilled out completely under atmospheric pressure to get the residual product <strong>[168828-90-8](5S)-5-(amino methyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-1,3-oxazolidin-2-one</strong>. Dichloromethane (400 ml) was added to the residue and acetic anhydride (25 g) was slowly added at a temperature of 25-30 C. over a period of 60 min. After completion, 5% aqueous sodium bicarbonate solution was slowly added to the reaction mixture. After stirring for 15 min the two layers were separated. The dichloromethane layer was washed with DM Water (200 ml). The dichloromethane layer was filtered through hyflo and the solvent was distilled off completely under vacuum below 40 C. Cyclohexane (500 ml) was added to the residue and heated to 45-50 C. The obtained slurry was cooled to 20-25 C. and stirred for 60 min. filtered the solid, washed with cyclohexane (200 ml) and dried the solid at 45-55 C. to furnish pure crystalline N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (Linezolid)
83.6 g In dichloromethane; for 0.5h; Add to a 2000ml four-necked flask(S,E)-5-((benzylimino)methyl)-3-(3-fluoro-4-morpholinyl)oxazolidin-2-one (100.0 g, 260 mmol) andDichloromethane (600ml), stirring to warm up to 30 C,After adding water, add water(600 ml), then concentrated hydrochloric acid (30 wt%, 63.5 g, 520 mmol) was added for hydrolysis, and the reaction was incubated at 30C for 3 hours. After the reaction was completed, the aqueous layer was separated and the aqueous layer was washed with dichloromethane (100 ml * 2).The aqueous phase was added to dichloromethane (400 mL) and the pH was adjusted to 9 with 2M NaOH solution. The phases were separated, the aqueous layer was discarded, and acetic anhydride (39.8 g, 390 mmol) was added dropwise to the organic layer. After 30 minutes from the completion of the addition, the 2M NaOH solution was adjusted to pH 7, the phases were separated, the organic phase was concentrated to 150 ml, isopropanol (200 ml) was added, and the mixture was concentrated under reduced pressure to 150 ml, and isopropyl alcohol (400 ml) was added and the mixture was stirred and cooled. To 0C, drying under vacuum at a temperature of 50C to obtain the target compound linezolid 83.6g, the yield was 95.3%
With triethylamine; In ethyl acetate; at 20℃; for 3h; Add 484.8 mg of triethylamine and 1.26 g of acetic anhydride to the ethyl acetate solution of the compound VI, stir at room temperature for 3 h, dilute with ethyl acetate, and wash it with water and saturated brine several times, anhydrous sulfuric acid Sodium is dried, petroleum ether-ethyl acetate is recrystallized,The white solid was 1.12 g, and the total yield of catalytic hydrogenation and acetylation was 83%, mp 178.8 -179.0 C.

Reference: [1]Patent: US2011/275805,2011,A1 .Location in patent: Page/Page column 9
[2]Patent: EP2388251,2011,A1 .Location in patent: Page/Page column 11
[3]Patent: CN103626712,2016,B .Location in patent: Paragraph 0066-0069
[4]Patent: CN102617500,2016,B .Location in patent: Paragraph 0052; 0055; 0056
[5]Oriental Journal of Chemistry,2013,vol. 29,p. 1015 - 1019
[6]Patent: CN106749073,2017,A .Location in patent: Paragraph 0035; 0065; 0066
[7]Patent: CN109232457,2019,A .Location in patent: Paragraph 0021
[8]Patent: EP2163547,2010,A1 .Location in patent: Page/Page column 11
[9]Patent: WO2017/182853,2017,A1 .Location in patent: Page/Page column 20
[10]Patent: WO2010/84514,2010,A2 .Location in patent: Page/Page column 17
[11]Patent: WO2011/114210,2011,A2 .Location in patent: Page/Page column 26
[12]Journal of Medicinal Chemistry,1996,vol. 39,p. 673 - 679
[13]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 857 - 859
[14]Tetrahedron Letters,2006,vol. 47,p. 6799 - 6802
[15]Patent: WO2005/35530,2005,A1 .Location in patent: Page/Page column 7
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[21]Patent: WO2011/77310,2011,A1 .Location in patent: Page/Page column 13
[22]Patent: WO2011/137222,2011,A1 .Location in patent: Example 25
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[34]Patent: CN107698533,2018,A .Location in patent: Paragraph 0017; 0061; 0062; 0065; 0066
[35]Patent: CN109721561,2019,A .Location in patent: Paragraph 0009
  • 2
  • [ 165800-03-3 ]
  • <i>N</i>-(3-{4-[formyl-(2-hydroxy-ethyl)-amino]-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide [ No CAS ]
  • 3
  • [ 165800-03-3 ]
  • Formic acid 2-({4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-phenyl}-formyl-amino)-ethyl ester [ No CAS ]
  • 4
  • [ 168828-84-0 ]
  • [ 507-09-5 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
90% at 23℃; for 7h;Inert atmosphere; Linezolid (4). A solution of azide 11 (87.0 mg, 0.247 mmol, 1 equiv) in thioacetic acid (0.17 mL, 2.487 mmol, 10 equiv) was stirred at 23 C. After 7 h, the reaction was quenched by the addition of a KOH solution (5.0 mL, 1 M aqueous). The aqueous layer was saturated by the addition of NaCl, and then extracted sequentially with EtOAc (3 x 5 mL), CH2C12 (3 x 5 mL), and CHC13 (3 x 5 mL) at pH = 14. The aqueous layer was then acidified with HC1 (1 M aqueous) to pH = 5 and extracted with EtOAc (3 x 5 mL). The combined organic layers were dried over Na2S04, and then concentrated under reduced pressure. The crude product was purified by flash chromatography (100% EtOAc? 9: 1 EtOAc:MeOH) to afford linezolid (4) as an off- white solid (75.3 mg, 90% yield). Rf 0.38 (100% EtOAc). 19F NMR (400 MHz, CDC13): delta -120.7. Spectral data match those previously reported (Mallesham et al., Org. Lett. 2003, 5, 963-965).
  • 5
  • [ 108-24-7 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
Example 3; Preparation of (S)~N-[3-(3-fiuoro~4~morpholin-4-yI-rhohenyI)~2-oxo- oxazolidin-5~ylmethyl]-acetarnide (Linezo.id); Method A; To (S)-5-[(4-chloro-benzylidene)-amino]-methyl}-3-(3-fluoro-4-morpholin-4-yl- phenyl)-oxazolidin-2-one (129.5g, 31 mmol, 1.0 eq.) is added ethyl acetate (935 mL) and water (935 mL). To the heterogeneous mixture is added 12M aq. HCl (51.58 mL, 620 mmol, 2.0 eq.). Within minutes, the solid went into solution and the reaction mixture is biphasic. After stirring the emulsion at ambient temperature for 2 hours, HPLC assay showed the hydrolysis reaction to be complete (HPLC conditions: YMC 5mu ODS-AM 150 nm X 4.6 nm column, eluting with CH3CN /water + 0.1% TFA from 20% CH3CN to 80% CH3CN in 8 min at 0.5 mL/min, detecting at 254nm, Retention time of (S)-N-[3-(3-fluoro-4-morpholin-4-yl- phenyl)-2-oxo-oxazolidin-5-ylmethyl]-amine is 3.2 min). The phases are separated, the organic layer is discarded, and the aqueous layer is washed with ethyl acetate (500 mL). <n="12"/>CH2Cl2 (900 mL) is added and the pH is adjusted to 6.7 with ~ 25 mL aq. 50% aq. NaOH. With constant stirring, Ac2O (58.49 mL, 620 mmol, 2.0 eq.) is added in one portion and the pH dropped to 2. The pH is then readjusted to 6 using 50% aq. NaOH. The pH is adjusted to ca. 7.1 with 50% aq. NaOH and the phases separated. The aqueous phase is extracted with CHiCl2 (800 mL) and the organics are combined and concentrated to ~1L in volume. Ethyl acetate (IL) is added and the volume is reduced to 1.5 L under vacuum. Another IL of ethyl acetate is added and volume is reduced again to IL under vacuum. The resultant slurry is cooled to 00C and the precipitate collected by vacuum filtration. The resulting solid is washed with ethyl acetate (250 mL). The crude product is dried under vacuum at 500C for 2 hours to give the title compound as Hnezolid crystalline Form I.Following the general procedure of method A and making non-critical variations, but substituting (S)-5- { [2,4-dichloro-benzylidene)-amino]-methyl } -3-(3-fluoro-4-morphoIin-4-yl- phenyl)-oxazolidin-2-one (example 11) for (S)-5-[(4-chloro-benzylidene)-amino]- methyl}-3-(3-fluoro-4-morrhoholin-4-yl-phenyl)-oxazolidin-2-one, the title compound is obtained.Following the general procedure of method B and making non-critical variations, but substituting (S)-5-{ [4-bromo-benzylidene)-amino] -methyl }-3-(3-fluoro-4-morpholin-4-yl~ phenyl)-oxazolidin-2-one (example 9) for (S)-5-[(4-chloro-benzylidene)-amino]- methyl}-3-(3-fluoro-4-morph.olin-4-yl-phenyl)-oxazoIidin-2-one, the title compound is obtained.
  • 6
  • [ 73921-38-7 ]
  • [ 165800-03-3 ]
  • C21H28FN3O6S [ No CAS ]
  • 7
  • [ 165800-03-3 ]
  • [ 931-59-9 ]
  • (R)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)-N-(phenylthio)acetamide [ No CAS ]
  • 8
  • 3-(3-fluoro-4-morpholin-4-yl-phenylamino)-propan-1-ol [ No CAS ]
  • [ 165800-03-3 ]
  • 9
  • [ 912552-55-7 ]
  • [ 165800-03-3 ]
  • 10
  • [ 912552-54-6 ]
  • [ 165800-03-3 ]
  • 11
  • [ 912552-56-8 ]
  • [ 165800-03-3 ]
  • 12
  • [ 93246-53-8 ]
  • [ 165800-03-3 ]
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[2]Journal of Medicinal Chemistry,1996,vol. 39,p. 673 - 679
[3]Patent: WO2011/77310,2011,A1
[4]Patent: WO2011/114210,2011,A2
[5]Patent: WO2011/114210,2011,A2
[6]Patent: WO2011/114210,2011,A2
[7]Patent: WO2011/114210,2011,A2
[8]Patent: WO2011/114210,2011,A2
[9]Patent: WO2011/114210,2011,A2
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[42]Patent: CN103420933,2016,B
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  • [ 2689-39-6 ]
  • [ 165800-03-3 ]
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  • 19
  • [ 198410-26-3 ]
  • [ 165800-03-3 ]
  • 20
  • (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-carbaldehyde-2-oxazolidinone [ No CAS ]
  • [ 165800-03-3 ]
  • 21
  • [ 905945-96-2 ]
  • [ 165800-03-3 ]
  • 22
  • [ 239438-43-8 ]
  • [ 165800-03-3 ]
  • 23
  • [ 239438-39-2 ]
  • [ 165800-03-3 ]
  • 24
  • [ 165800-03-3 ]
  • [ 216868-57-4 ]
YieldReaction ConditionsOperation in experiment
With Lawessons reagent; In 1,4-dioxane; at 20℃; for 20.5h;Heating / reflux; A stirred mixture of II (PCT/US94/08904, 3.37 g, 10.0 mmol) in dry dioxane (100 mL), under nitrogen was treated with Lawesson's Reagent (4.04 g, 10.0 mml), warmed to reflux during 1 h and refluxed for 1.5 h. The reaction was complete by TLC on silica gel with 10% MeOH-CHCl3. It was kept at ambient temperature for 18 h and concentrated in vacuo. Chromatography of the residue on silica gel with mixtures of acetone-methylene chloride containing 10-15% acetone gave the product which was crystallized from acetone-hexane to give 1: mp 157.5-158.5 C.; HRMS theory for C16H20FN3O3S (M+): 353.1209; found: 353.1212. Anal. calcd for C16H20FN3O3S: C, 54.38; H, 5.38; N, 11.89; S, 9.07. Found: C, 54.21; H 5.58; N, 11.78; S, 8.93.
  • 25
  • [ 212325-40-1 ]
  • [ 183805-10-9 ]
  • [ 165800-03-3 ]
  • 26
  • [ 224323-48-2 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
90% With triethylamine; In dichloromethane; ethyl acetate; at 20℃; for 2h;Cooling with ice; General procedure: To a reaction flask were added 6.53 mmol of dihydrochloride of 3-(3-fluoro-4-morpholinylphenyl-5-aminomethyl-1,3-oxazolidin-2-one (5a), 100 ml of dichloromethane and 2.95 ml (21.2 mmol) of triethylamine. Then 0.8 ml (8.45 mmol) of acetic anhydride was added while being stirred in an ice-bath. The mixture was then allowed to react at room temperature for 2 hours before being washed successively with 5% aqueous NaOH solution and saturated aqueous NaCl solution. The organic layer was then dried by anhydrous sodium sulfate and filtered, and subsequently put under reduced pressure for solvent removal. The residue was then subjected to recrystallization using ethyl acetate to give white needle crystals at a yield of 85%, HR-TOF-MS (+Q) m/z: 338.1520 (Calculated [C16H20FN3O4+H]+: 338.1516).
claim 1 , where the Oxazolidinone is: (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, or [4(S)-cis]-(-)-N-[[3-[3-fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
where the antibacterial oxazolidinone is selected from the group consisting of (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, (S)-N-[[3-[3-fluoro-4-(tetrahydro-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide S,S-dioxide.
Example 2 Linezolid IV Solution (300 mL) Following the general procedure of EXAMPLE 1 and making non-critical variations but using 300 times the amount of each ingredient, 600 mg of linezolid, the title IV solution is prepared.
where the OXAZOLIDINONE is selected from the group consisting of: (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]-phenyl]-2-oxo-5oxazolidinyl]methyl]acetamide, (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, [4(S)-cis]-(-)-N-[[3-[3-fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, N-((5S)-3-(3-fluoro-4-(4-(2-fluoroethyl)-3-oxopiperazin-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide, (S)-N-[[3-[5-(3-pyridyl)thiophen-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide and (S)-N-[[3-[5-(4-pyridyl)pyrid-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide hydrochloride.
where the OXAZOLIDINONE is selected from the group consisting of: (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide and [4(S)-cis]-(-)-N-[[3-[3-fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
Example 18 (S)-[[N-3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide (VIII) (S)-[N-3-[3-Fluoro-4-morpholinylphenyl]-2-oxo-5-oxazolidinyl]methylamine salicylaldehyde imine (EXAMPLE 17, 1.0068 g, 2.521 mmol) Is slurried in water (10 ml) and 37% aqueous hydrochloric acid (0.417 ml, 5.04 mmol) and stirred at 20-25 for 15 hrs. Toluene (10 ml) is added and the phases separated; then, the organic phase is washed with hydrochloric acid (1M, 5 ml) and the combined aqueous phases are washed with toluene (10 ml). The toluene wash is back-extracted with hydrochloric acid (1M, 5 ml). The combined aqueous phases are then adjusted to pH 13.0 with aqueous sodium hydroxide (50%, 1.83 g, 22.9 mmol). To the resultant slurry is then added methylene chloride (10 ml) and sodium chloride (1 g) and the phases separated. The aqueous phase is then washed with methylene chloride (10 ml). To the combined organic phases is then added acetic anhydride (0.472 ml, 5.00 mmol) while maintaining 24-27. The mixture is stirred 40 min, then water is added (5 ml). The phases are separated and the aqueous phase is washed with methylene chloride (5 ml). The combined organic phases are concentrated and ethyl acetate (25 ml) is added. The mixture is warmed to 70 and then the resultant mixture is slowly cooled to -25. The precipitate is collected by vacuum filtration, washed with -25 ethyl acetate (5 ml) and dried to give the title compound, HPLC major component (99.93 area % at 254 nm detection) retention time=0.97 min, column=Zorbax RX-C8, 250*4.6 mm, mobile phase=650 ml acetonitrile, 1.85 ml triethylamine, 1.30 ml acetic acid and sufficient water to make 1000 ml; flow rate=3 ml/min.
Disclosed is the use of an effective amount of an oxazolidinone selected from the group consisting of: (S)-N-[[3-[3-fluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, [4(S)-cis]-(-)-N-[[3-[3-Fluoro-4-(tetrahydro-1-oxido-2H-thiopyran-4-yl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, N-((5S)-3-(3-fluoro-4-(4-(2-fluoroethyl)-3-oxopiperazin-1-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide, (S)-N-[[3-[5-(3-pyridyl)thiophen-2-yl]-2-oxo-5-oxazolidinyl]methyl]acetamide and
Another solution consisting of 45% sorbitol and 25% fructose gave a linezolid solubility result of 0.582 mg/ml.

  • 28
  • [ 108-24-7 ]
  • [ 168828-84-0 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
80% With hydrogen;palladium 10% on activated carbon; In dichloromethane; under 1103.36 Torr; for 6h; Example-15: Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl acetamide, Linezolid (I) starting from (S)-N-3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl azide(S^-N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl azide (10 g) obtained in example 12, and acetic anhydride (4.8 g) were dissolved in DCM (100 ml). To the resulting solution, 10% Pd/C (50% wet, 1.0 g) was added. The reaction mixture was hydrogenated under 1.5 kg/cm2 hydrogen pressure for 6h. After the completion of reaction, catalyst was removed by filtration. The filtrate was washed with water. The DCM layer was concentrated completely under vacuum at 35-40C. To the resulting residue toluene (50 ml) was added and heated to 80C. The suspended solution was stirred at 80-85C for lh and further at room temperature for next lh. The solid mass was filtered, washed with toluene and dried to obtain the titled compound (8.0 g) with 80% yield.
78% 80 g (R)-N-[[3-[3-fluoro-4-morpholinylrhohenyl]-2-oxo-5-oxazolidinyl]methylazide and 6 g 10% Pd/C (50% moist) was suspended in 1.6 L ethyl acetate, 24 ml acetic acid and 56 ml acetic anhydride mixture. The mixture was then hydrogenated in hydrogen gas at 30 psi at temperature of 25 to 35 C for 3 hr. After the completion of the reaction, IL of 5% sodium carbonate solution was added to the mixture and stirred for 10 min. The catalyst was then filtered off. The separated aqueous layer was washed with IL ethyl acetate and the combined ethyl acetate layer was evaporated under reduced pressure at temperature of 50 to 55 C to get the residue. The obtained residue was stirred in 640 ml 1,4-dioxane and the reaction mixture was cooled to 10 to 15 C. 640 ml diisopropyl ether ( precooled) was added to the above reaction mixture at temperature 10 to 150C and filtered. The solid obtained was washed with 200 ml diisopropyl ether and dried at 60 to 70 C to get Linezolid crude. Yield: 65.5 g ; Percentage: 78% Purity: > 99.5%; Example 960 g of Linezolid obtained from Example 7 was suspended in 1.20 L 1,4-dioxane. The obtained reaction mass was warmed at 45 to 550C and filtered at 45 to 550C. The filtrate was cooled to 10 to 150C3 diisopropyl ether (1.20 L, previously cooled) was added to this at temperature 10 to 150C and stirred for 1 hour. The solid obtained was filtered, washed with 250 ml diisopropyl ether and dried at 1000C for 2 hrs and then at 140C for 3 to 4 hr to get pure Linezolid. Yield: 55.8 g.; Percentage: 93% Purity: > 99.9%Example 1050 g Linezolid was dissolved in 2L ethyl acetate at 70-750C. The clear solution was filtered to remove any suspended solid. The obtained clear hot solution was subjected to rapid cooling at -5 to 5C and stirred at same temperature for 2 hr. The separated solid was filtered and dried at 70-800C. Yield: 43 g.; Percentage: 86% Purity: > 99.9%
70% (R)-N-[[3-[3-Fluoro-4-morpholinylphenyl]-2-oxo-5-oxazolidinyl]methylazide 10.0 g and 0.75 g 10% Pd/C (50% moist) were suspended in 200 ml ethyl acetate, 3 ml acetic acid and 7 ml acetic anhydride mixture. The mixture was then hydrogenated in hydrogen gas at 30 psi at 25-35 C for 5 hr. After the completion of the reaction, 100 ml of 5% sodium bicarbonate solution was added to the mixture and stirred for 10 min. The catalyst was then filtered off, ethyl acetate layer was separated. The aqueous layer was washed with 100 ml ethyl acetate and the combined ethyl acetate layers were removed under reduced pressure at 50-55 C. The obtained residue was stirred in 25 ml ethyl acetate, filtered, washed with 20 ml ethyl acetate and the product was dried at 60-70 C. Yield: 7.35 g; 70% Purity: 99.5 ++
2 g of (5Lambda)-5-(azidomethyl)-3-[3-fluoro-4-(4-mo holinyl)phenyl]-l ,3-oxazolidin-2-one was dissolved in 130 ml of ethylacetate. The flask was evacuated and filled with nitrogen, then 150 mg of 10 % Pd/C was added and the mixture hydrogenated at 1 bar of hydrogen pressure, using a Parr apparatus, during 7 hours, then 100 mg of Pd/C was added and hydrogenation was continued over night . The flask was filled with nitrogen and 4.2 ml of pyridine and 2.6 ml of acetic anhydride were added. The mixture was stirred at RT for 3.5 hours. The mixture was filtered over a celite path.
18 g With triphenylphosphine; In toluene; at 0 - 5℃; (R)-5-azidomethy]-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazol idin-2-one (5a) (25.0 gr, 0.077 moo was dissolved in toluene (100.0 mL) and cooled to 0-5C then slowly triphenyl phosphine (20.05 gr, 0.077 mol) and acetic anhydride (25.0 rnL) was added and stirred for 45-50 minutes at the same temperature. Slowly temperature was brought to room temperature and stirred for 2-3 hrs. The progress of the reaction was monitored by TLC. After completion of reaction, separated solid was filtered and washed with toluene and water, followed by drying at 60-70C. The crude compound was crystallized in methanol to get pure Linezolid(8a)(17.5gr)

  • 29
  • [ 75-36-5 ]
  • [ 168828-90-8 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
92.8% With triethylamine; In ethyl acetate; at 20℃; for 2h; A solution of (S)-5- (aminomethyl)-3-(3-fluoro-4-morpholinophenyl) oxazolin-2-one obtained in Example 4-2 (compound 7, 23.7 g , 08.8 mol), acetyl chloride (6.3 g, 0.80 mol) Triethylamine (40.5 g, 0.4 mol) was added to 500 mL of ethyl acetate and allowed to react at room temperature for 2 hours until the reaction was complete. Add water, the organic layer, saturated brine washing, anhydrous magnesium sulfate drying, filtration, evaporation of most of the solvent, Frozen crystal, filtered crude. The crude product was recrystallized from ethyl acetate linezolid 25. 1 g, molar yield 92.8%, HPLC chemical purity 99.8%, optical purity 100.0%.
85% With triethylamine; In dichloromethane; at 0 - 20℃; for 1h; (S)-N-((3-(3-Fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (1): A mixture of 2.95 g (10 mmol) of 11 and 2 g (20 mmol) of triethylamine in 50 mL methylene dichloride was added slowly 0.95 g (12 mmol) of acetyl chloride at 0 C, the reaction remove the room temperature for 1 h. The mixture was washed with water (50 mL) and dried (Na2SO4). The concentrate was purified by chromatography on silica gel column (ethyl acetate:methanol = 10:1) to give 2.86 g (85%) of 1 as a white solid, mp 181-183 C. 1H NMR (300 MHz, CDCl3): delta 2.02 (s, 3H), 3.05 (t, 4H, J = 3.4 Hz), 3.59-3.69 (m, 2H), 3.75 (dd, 1H, J = 6.7 Hz, J = 1.7 Hz), 3.87 (t, 4H, J = 3.4 Hz), 4.02 (t, J = 6.7 Hz, 1H), 4.48 (m, 1H), 6.36 (t, 1H, J = 4.6 Hz), 6.92 (t, 1H, J = 6.8 Hz), 7.06 (dd, 1H, J1 = 6.8 Hz, J2 = 1.8 Hz), 7.42 (dd, 1H, J1 = 10.7 Hz, J2 = 1.8 Hz). 13C NMR (75 MHz, CDCl3): delta 23.1, 41.9, 47.7, 51.0, 67.1, 72.1, 107.6 (d, J = 20.2 Hz), 114.0 (d, J = 3 Hz), 118.9 (d, J = 3.7 Hz), 133.0 (d, J = 7.5 Hz), 136.6 (d, J = 6.7 Hz), 154.4, 155.5 (d, J = 183.8 Hz), 171.4.
  • 30
  • [ 165800-03-3 ]
  • [(S)-N-[[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide dihydrochloride [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In water; acetone; at 20 - 30℃; for 4.5h;Heating / reflux;Product distribution / selectivity; EXAMPLE 1; <strong>[165800-03-3]Linezolid</strong> Dihydrochloride20 g of <strong>[165800-03-3]linezolid</strong> are dissolved in 750 ml of acetone at about 30 C. The solution is kept at about 30 C. and 8 ml of concentrated hydrochloric acid (37% w/w aqueous solution) are added, thus immediately causing <strong>[165800-03-3]linezolid</strong> dihydrochloride to precipitate as a white solid. The mixture is kept under stirring at about 30 C. for approximately 30 minutes, then refluxed under stirring for about 2 hours. The mixture is left to cool to room temperature, then cooled on ice-water bath, under stirring, for about 2 hours. A white solid precipitates which is filtered with suction, washed with 30 ml of acetone and dried under vacuum at about 50 C.A solid water-soluble crystalline product is obtained, characterized by an XRPD spectrum substantially as reported in FIG. 3, wherein the most intense diffraction peaks fall at 13.9; 18.2; 19.1; 19.7; 22.2; 22.9; 23.6; 25.3; 27.1; 28.4+/-0.2 in 2theta; and by a DSC thermogram substantially as reported in FIG. 4, characterized by an exothermic peak around 178+/-2 C. The acid-base potentiometric titre is double while the argentimetric one is 17.71% (theor. dihydrochloride 17.77%). Purity 99.8% as determined by HPLC.1H NMR (300 MHz, DMSO-d6), ppm: 8.37 (bt, 1H), 7.50 (dd, 1H, J=15.3 Hz, J=2.7 Hz), 7.10 (m, 2H), 4.68 (m, 1H), 4.05 (t, 1H, J=9.0 Hz), 3.70 (m, 5H), 3.36 (t, 2H, J=5.1 Hz), 3.07 (t, 4H, J=4.5 Hz), 1.80 (s, 3H).
With hydrogenchloride; In tetrahydrofuran; water; at 20 - 30℃; for 4.5h;Heating / reflux;Product distribution / selectivity; EXAMPLE 2; <strong>[165800-03-3]Linezolid</strong> Dihydrochloride20 g of <strong>[165800-03-3]linezolid</strong> are dissolved in 750 ml of tetrahydrofuran at about 30 C. The solution is treated as described in Example 1, to obtain a <strong>[165800-03-3]linezolid</strong> dihydrochloride precipitate as a white solid, which is filtered with suction, washed with 30 ml of tetrahydrofuran and dried under vacuum at about 50 C.<strong>[165800-03-3]Linezolid</strong> dihydrochloride is obtained in a crystalline form, having the same characteristics as reported for the product obtained in Example 1.
With hydrogenchloride; In water; acetone; at 30℃; for 4.5h;Heating / reflux;Product distribution / selectivity; Example 1. <strong>[165800-03-3]Linezolid</strong> dihydrochloride 20 g of <strong>[165800-03-3]linezolid</strong> are dissolved in 750 ml of acetone at about 30C. The solution is kept at about 30C and 8 ml of concentrated hydrochloric acid (37% w/w aqueous solution) are added, thus immediately causing <strong>[165800-03-3]linezolid</strong> dihydrochloride to precipitate as a white solid. The mixture is kept under stirring at about 30C for approximately 30 minutes, then refluxed under stirring for about 2 hours. The mixture is left to cool to room temperature, then cooled on ice-water bath, under stirring, for about 2 hours. A white solid precipitates which is filtered with suction, washed with 30 ml of acetone and dried under vacuum at about 50C. A solid water-soluble crystalline product is obtained, characterized by an XRPD spectrum substantially as reported in , wherein the most intense diffraction peaks fall at 13.9; 18.2; 19.1; 19.7; 22.2; 22.9; 23.6; 25.3; 27.1; 28.4 +- 0.2 in 2theta; and by a DSC thermogram substantially as reported in , characterized by an exothermic peak around 178 +- 2C. The acid-base potentiometric titre is double while the argentimetric one is 17.71% (theor. dihydrochloride 17.77%). Purity 99.8% as determined by HPLC. 1H NMR (300 MHz, DMSO-d6), ppm: 8.37 (bt, 1 H), 7.50 (dd, 1 H, J=15.3 Hz, J=2.7 Hz), 7.10 (m, 2H), 4.68 (m, 1 H), 4.05 (t, 1 H, J=9.0 Hz), 3.70 (m, 5H), 3.36 (t, 2H, J=5.1 Hz), 3.07 (t, 4H, J=4.5 Hz), 1.80 (s, 3H).
With hydrogenchloride; In tetrahydrofuran; water;Product distribution / selectivity; Example 2. <strong>[165800-03-3]Linezolid</strong> dihydrochloride 20 g of <strong>[165800-03-3]linezolid</strong> are dissolved in 750 ml of tetrahydrofuran at about 30C. The solution is treated as described in Example 1, to obtain a <strong>[165800-03-3]linezolid</strong> dihydrochloride precipitate as a white solid, which is filtered with suction, washed with 30 ml of tetrahydrofuran and dried under vacuum at about 50C. <strong>[165800-03-3]Linezolid</strong> dihydrochloride is obtained in a crystalline form, having the same characteristics as reported for the product obtained in Example 1.

  • 31
  • [ 165800-03-3 ]
  • [(S)-N-[[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide sulfate [ No CAS ]
YieldReaction ConditionsOperation in experiment
With sulfuric acid; In tetrahydrofuran; at 20 - 40℃; for 1h; EXAMPLE 3<strong>[165800-03-3]Linezolid</strong> Sulfate5 g of <strong>[165800-03-3]linezolid</strong> are dissolved at about 40 C. in 150 ml of THF. The solution is kept at about 40 C. and 0.85 ml of concentrated sulfuric acid (98% w/w H2SO4) are added, thus immediately causing <strong>[165800-03-3]linezolid</strong> sulfate to precipitate as a white solid. The mixture is refluxed, under stirring, for about 30 minutes, then left to cool first to room temperature then on an ice-water bath, stirring for about 30 minutes. A white solid precipitates, which is filtered with suction, washed with 5 ml of THF and dried under vacuum at about 50 C.An amorphous, water-soluble solid product is obtained, characterized by an XRPD spectrum substantially as reported in FIG. 5.1H NMR (300 MHz, DMSO-d6), ppm: 8.21 (bt, 1H), 7.47 (dd, 1H, J=15.3 Hz, J=2.7 Hz), 7.10 (m, 2H), 4.68 (m, 1H), 4.05 (t, 1H, J=9.0 Hz), 3.70 (m, 5H), 3.45 (m, 2H), 2.97 (t, 4H, J=4.5 Hz), 1.81 (s, 3H).Purity 99.7% as determined by HPLC.
With sulfuric acid; In tetrahydrofuran; at 0 - 40℃; for 1h;Heating / reflux; Example 3. <strong>[165800-03-3]Linezolid</strong> sulfate 5 g of <strong>[165800-03-3]linezolid</strong> are dissolved at about 40C in 150 ml of THF. The solution is kept at about 40C and 0.85 ml of concentrated sulfuric acid (98% w/w H2SO4) are added, thus immediately causing <strong>[165800-03-3]linezolid</strong> sulfate to precipitate as a white solid. The mixture is refluxed, under stirring, for about 30 minutes, then left to cool first to room temperature then on an ice-water bath, stirring for about 30 minutes. A white solid precipitates, which is filtered with suction, washed with 5 ml of THF and dried under vacuum at about 50C. An amorphous, water-soluble solid product is obtained, characterized by an XRPD spectrum substantially as reported in . 1H NMR (300 MHz, DMSO-d6), ppm: 8.21(bt, 1 H), 7.47 (dd, 1 H, J=15.3 Hz, J=2.7 Hz), 7.10 (m, 2H), 4.68 (m, 1H), 4.05 (t, 1H, J=9.0 Hz), 3.70 (m, 5H), 3.45 (m, 2H), 2.97 (t, 4H, J=4.5 Hz), 1.81 (s, 3H).
  • 32
  • [(S)-N-[[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide dihydrochloride [ No CAS ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
92% With water; potassium carbonate; In ethyl acetate; at 60 - 65℃; EXAMPLE 5; Linezolid Form III Starting from Linezolid DihydrochlorideLinezolid dihydrochloride (40 g, 97.5 mmoles) is suspended in water (40 ml) and ethyl acetate (480 ml). The mixture is heated to a temperature ranging from 60-65 C. to complete dissolution of the solids, then a potassium carbonate solution (20 g) in water (40 ml) is slowly dropwise added. The reaction mixture is kept under stirring to obtain two clear phases which are separated while hot. The organic phase is washed with water then diluted with toluene. Ethyl acetate is distilled off and the mixture is heated to a temperature around 100 C., until Linezolid Form III starts crystallizing. The distillation is stopped and the mixture is left to slowly cool down to room temperature. The solid is filtered and then dried to obtain 30.0 g of crystalline linezolid, in 92% yield. The resulting crystalline product is characterized by the same XRPD spectrum as that reported for the crystalline Form III, described in WO 2005/035530; and a purity of 99.9% as determined by HPLC.
92% Example 5. Linezolid Form III starting from linezolid dihydrochloride Linezolid dihydrochloride (40 g, 97.5 mmoles) is suspended in water (40 ml) and ethyl acetate (480 ml). The mixture is heated to a temperature ranging from 60-65C to complete dissolution of the solids, then a potassium carbonate solution (20 g) in water (40 ml) is slowly dropwise added. The reaction mixture is kept under stirring to obtain two clear phases which are separated while hot. The organic phase is washed with water then diluted with toluene. Ethyl acetate is distilled off and the mixture is heated to a temperature around 100C, until Linezolid Form III starts crystallizing. The distillation is stopped and the mixture is left to slowly cool down to room temperature. The solid is filtered and then dried to obtain 30.0 g of crystalline linezolid, in 92% yield. The resulting crystalline product is characterized by the same XRPD spectrum as that reported for the crystalline Form III, described in; and a purity of 99.9% as determined by HPLC.
With sodium hydroxide; In water; at 0 - 2℃; Example 4. Linezolid hemihydrate starting from linezolid dihydrochloride; 4 g of linezolid dihydrochloride are dissolved at room temperature in 20 ml of water. The solution is cooled to a temperature of about 0-2C, and 2.5 g of a NaOH 50% w/w aqueous solution are added, thus immediately causing linezolid hemihydrate to precipitate. A white solid is obtained which is filtered with suction, thoroughly washed with water and dried under vacuum at about 35-40C. The obtained crystalline solid is characterized by an XRPD spectrum substantially as reported in Figure 1, wherein the most intense diffraction peaks fall at 5.4; 14.5; 14.8; 16.3; 17.6; 18.3; 19.2; 19.9; 23.2; 24.0 and 25.1 +/- 0.2 in 2theta and a DSC thermogram substantially as reported in Figure 2, characterized by two exothermic peaks at 94 and 181 +/- 2C. Purity 99.8% as determined by HPLC. 1H NMR (300 MHz, DMSO-d6), ppm: 8.20 (bt, 1 H), 7.45 (dd, 1 H, J=15.0 Hz, J=2.7 Hz), 7.10 (dd, 1H, J1=9.0Hz, J2=2.4Hz), 7.00 (t, 1H, J=9,3 Hz), 4.68 (m, 1 H), 4.05 (t, 1 H, J=9.0 Hz), 3.70 (m, 5H), 3.40 (m, 2H), 2.93 (t, 4H, J=4.6 Hz), 1.81 (s, 3H).
  • 33
  • [ 1088111-01-6 ]
  • [ 165800-03-3 ]
  • 34
  • [ 67-56-1 ]
  • [ 165800-03-3 ]
  • [ 1097835-43-2 ]
  • (S)-3-(4'-N-morpholinophenyl)-5-(N-acetamidomethyl)-oxazolidin-2-one [ No CAS ]
  • 35
  • [ 109-97-7 ]
  • [ 165800-03-3 ]
  • [ 1097835-47-6 ]
  • 36
  • [ 165800-03-3 ]
  • [ 1097835-42-1 ]
  • (S)-3-(4'-N-morpholinophenyl)-5-(N-acetamidomethyl)-oxazolidin-2-one [ No CAS ]
  • <i>N</i>-{3-[4-(2-hydroxy-ethylamino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide [ No CAS ]
  • <i>N</i>-(3-{4-[formyl-(2-hydroxy-ethyl)-amino]-phenyl}-2-oxo-oxazolidin-5-ylmethyl)-acetamide [ No CAS ]
  • Formic acid 2-({4-[(S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-phenyl}-formyl-amino)-ethyl ester [ No CAS ]
  • 37
  • [ 165800-03-3 ]
  • [ 1097835-49-8 ]
  • 38
  • [ 165800-03-3 ]
  • [ 1097835-45-4 ]
  • (S)-3-(4'-N-morpholinophenyl)-5-(N-acetamidomethyl)-oxazolidin-2-one [ No CAS ]
  • 39
  • [ 165800-03-3 ]
  • [ 556801-28-6 ]
  • (S)-3-(4'-N-morpholinophenyl)-5-(N-acetamidomethyl)-oxazolidin-2-one [ No CAS ]
  • 40
  • [ 65-85-0 ]
  • [ 165800-03-3 ]
  • linezolid-benzoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
at 100 - 160℃;Product distribution / selectivity; EXAMPLE 3: PREPARATION OF LINEZOLID-BENZOIC ACID CO-CRYSTALS <strong>[165800-03-3]Linezolid</strong> (200 mg) and benzoic acid (72.32 mg) are mixed and heated to 100-1600C. The mass is maintained for 15 minutes at 120-1600C and then is cooled to room temperature, to afford 140 mg of co-crystals.
  • 41
  • [ 165800-03-3 ]
  • [ 99-96-7 ]
  • linezolid-4-hydroxybenzoic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
With methanol; EXAMPLE 8: PREPARATION OF LINEZOLID^-HYDROXYBENZOIC ACID CO- CRYSTALS<strong>[165800-03-3]Linezolid</strong> (400 mg) and 4-hydroxybenzoic acid (165.3 mg) are charged in to a mortar and pestle and subjected to grinding for 20 minutes, adding 4-5 drops of methanol in the first 15 minutes, to afford 550 mg of co-crystals.Analysis of the co-crystal product gives the powder X-ray diffraction pattern of Fig. 4, the differential scanning calorimetry curve of Fig. 5, and the infrared absorption spectrum of Fig. 6.Powder X-ray diffraction patterns of the co-crystal product, 4- hydroxybenzoic acid, <strong>[165800-03-3]linezolid</strong> crystalline Form II, and <strong>[165800-03-3]linezolid</strong> crystalline Form IV are shown in Fig. 14.
  • 42
  • [ 165800-03-3 ]
  • [ 69-72-7 ]
  • linezolid-salicylic acid [ No CAS ]
YieldReaction ConditionsOperation in experiment
With methanol; EXAMPLE 10: PREPARATION OF LINEZOLID-SALICYLIC ACID CO- CRYSTALS<strong>[165800-03-3]Linezolid</strong> (400 mg) and salicylic acid (162 mg) are subjected to grinding in a mortar and pestle for 30 minutes, adding methanol (1 mL) within the first 15 minutes, to afford 510 mg of co-crystals.Analysis of the co-crystal product gives the powder X-ray diffraction pattern of Fig. 10, the differential scanning calorimetry curve of Fig. 11 , and the thermogravimetric analysis curve of Fig. 12.Powder X-ray diffraction patterns of the co-crystal product, salicylic acid, <strong>[165800-03-3]linezolid</strong> crystalline Form II, and <strong>[165800-03-3]linezolid</strong> crystalline Form IV are shown in Fig. 16.
  • 43
  • [ 81-04-9 ]
  • [ 165800-03-3 ]
  • [ 1274590-70-3 ]
YieldReaction ConditionsOperation in experiment
With methanol; EXAMPLE 9: PREPARATION OF LINEZOLID-1 ,5-NAPHTHALENE- DISULPHONIC ACID CO-CRYSTALS<strong>[165800-03-3]Linezolid</strong> (300 mg) and 1 ,5-naphthalenedisulphonic acid (227.8 mg) are and subjected to grinding with a mortar and pestle for 30 minutes, adding 7 drops of methanol within the first 15 minutes, to afford 520.7 mg of co-crystals.Analysis of the co-crystal product gives the powder X-ray diffraction pattern of Fig. 7, the differential scanning calorimetry curve of Fig. 8, and the thermogravimetric analysis curve of Fig. 9.Powder X-ray diffraction patterns of the co-crystal product, 1 ,5- naphthalenedisolphonic acid, <strong>[165800-03-3]linezolid</strong> crystalline Form II, and <strong>[165800-03-3]linezolid</strong> crystalline Form IV are shown in Fig. 15.
In water; acetone; at 20℃; for 1.5h;Product distribution / selectivity; Example 4 <strong>[165800-03-3]Linezolid</strong> (1:1) naphthalene-l,5-disulfonate1.0 g of <strong>[165800-03-3]linezolid</strong> base was dissolved in 50 ml of acetone at R.T. To the solution, 1.5 g of naphthalene- 1,5-disulfonic acid (> 1 eq.) dissolved in 3 ml of demi-water was added dropwise, while stirring at R.T. Initially, some oiling was observed, followed by rapid formation of a solid. To the suspension, an additional 50 ml of acetone was added. The solution was stirred at R.T. in an open flask for about 1.5 hours. The solid was isolated by filtration over a P3-glass filter (reduced pressure), washed with acetone and air-dried overnight at R.T. An off-white powder with soft lumps was obtained. The yield was 1.93 g.
  • 44
  • [ 67-56-1 ]
  • [ 165800-03-3 ]
  • [ 1097835-42-1 ]
  • [ 1097835-43-2 ]
  • (S)-3-(4'-N-morpholinophenyl)-5-(N-acetamidomethyl)-oxazolidin-2-one [ No CAS ]
  • 45
  • [ 1215006-10-2 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
14% With sodium acetate; acetic acid;palladium dichloride; In water; at 20℃; for 120h;Product distribution / selectivity; To a solution of N-allyl-N-(((S)-3-(3-fluoro-4-morpholinophenyl)-2-oxazolidin-5-yl)methyl)acetamide (239 mg, 0.63 mmol) in acetic acid (4 mL) and water (1 mL) was added palladium(II) chloride (112 mg, 0.63 mmol, 1 eq) and sodium acetate (104 mg, 1.27 mmol, 2 eq) and the mixture was stirred at room temperature for 5 d. The suspension was filtered through celite, the resulting phases were decanted and the aqueous layer was extracted with dichloromethane (3 x 5 mL). The combined dichloromethane layers were dried over magnesium sulfate, were concentrated in vacuo and were purified by column chromatography (silica, dichloromethane/methanol 0-3%) to give N-(((S)-3-(3-fluoro-4-morpholinophenyl)-2-oxazolidin-5-yl)methyl)acetamide, linezolid (30 mg, 14%) as an oil. 1H NMR (400 MHz, CDCl3): delta 7.43 (dd, 1H, ArH, J 2 and 14 Hz), 7.07 (db, 1H, ArH), 6.92 (t, 1H, ArH, J 9Hz), 6.33 (b, 1H, NH), 4.80-4.75 (m, 1H, CH), 4.02 (t, 1H, CH, J 9 Hz), 3.88-3.86 (m, 4H, CH2), 3.77-3.60 (m, 3H, CH, CH2), 3.06-3.04 (m, 4H, CH2), 2.02 (s, 3H, CH3) ppm. Mp 177.5 - 178.1 C [alpha]D -13.0 (c 0.99, CHCl3)
  • 46
  • [ 1215006-11-3 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
78% To a suspension of N-tert-butyl-N-(((S)-3-(3-fluoro-4-morpholinophenyl)-2-oxazolidin-5-yl)methyl)acetamide (496 mg, 1.26 mmol) in dioxane (1 mL) was added 4 M hydrogen chloride in dioxane (630 muL, 2.52 mmol, 2 eq) and the mixture was heated to 70 C for 7 h. On cooling to room temperature, water (0.5 mL) was added and the mixture was basified with 2 M aqueous sodium hydroxide to pH 9. The resulting solution was concentrated to dryness and the resulting residue was resuspended in water (0.5 mL), was filtered and was washed with water (2 x 0.5 mL) to give N-(((S)-3-(3-fluoro-4-morpholinophenyl)-2-oxazolidin-5-yl)methyl)acetamide, linezolid (330 mg, 78%, HPLC 99.1%, 99.9% ee) as an off-white solid. 1H NMR (400 MHz, CDCl3): delta 7.43 (dd, 1H, ArH, J 2 and 14 Hz), 7.07 (db, 1H, ArH), 6.92 (t, 1H, ArH, J 9Hz), 6.33 (b, 1H, NH), 4.80-4.75 (m, 1H, CH), 4.02 (t, 1H, CH, J 9 Hz), 3.88-3.86 (m, 4H, CH2), 3.77-3.60 (m, 3H, CH, CH2), 3.06-3.04 (m, 4H, CH2), 2.02 (s, 3H, CH3) ppm. Mp 177.5 - 178.3 C [alpha]D-11.1 (c 1.02, CHCl3)
  • 47
  • [ 1215006-12-4 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
87% Example 13 Preparation of linezolid by deprotection of N-tert-octyl-N-(((S)-3-(3-fluoro-4-morpholinophenyl)-2-oxazolidin-5-yl)methyl)acetamide using aqueous hydrochloric acid / ethyl acetate To a suspension of N-tert-octyl-N-(((S)-3-(3-fluoro-4-morpholinophenyl)-2-oxazolidin-5-yl)methyl)acetamide (160 mg, 0.36 mmol) in ethyl acetate (0.8 mL, 5 vol) was added hydrochloric acid (6 M, 120 muL, 0.712 mmol) and the mixture was heated at 55 C for 2 h._6 M aqueous sodium hydroxide solution was added to pH 10 and the ethyl acetate was distilled. The resulting suspension was stirred at 0 C for 1 h and was filtered. The collected solids were washed with water (2 x 0.2 mL) and dried in vacuo to give N-(((S)-3-(3-fluoro-4-morpholinophenyl)-2-oxazolidin-5-yl)methyl)acetamide, linezolid (104 mg, 87%, HPLC 86.6%) as an off-white solid. For characterization, see Example 11.
  • 48
  • [ 104-15-4 ]
  • [ 165800-03-3 ]
  • [ 1274590-76-9 ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; water; at 20℃; for 1h;Product distribution / selectivity; Example 5 <strong>[165800-03-3]Linezolid</strong> (1 : 1) p-toluene sulfonate (Form A)10.0 g of <strong>[165800-03-3]linezolid</strong> base was dissolved in 400 ml of tetrahydrofuran (THF) by means of stirring and heating (no reflux). To the solution, about 5.7 g of /?-toluenesulfonic acidmonohydrate dissolved in about 25 ml of THF was added dropwise, while stirring at R.T. During acid addition, 20-40 mg of <strong>[165800-03-3]linezolid</strong> tosylate was added as seeds. As a result, oiling took place. To the mixture, 5 ml of demi-water and an additional 20 mg of <strong>[165800-03-3]linezolid</strong> tosylate seeds were added. The formed suspension was stirred at R.T. for about 1 hour and stirred at 0 C for about 45 minutes. The solid was isolated by filtration over a P3-glass filter (reduced pressure), washed with acetone and air-dried overnight at R.T. The yield was 13.34 g.
  • 49
  • [ 81-04-9 ]
  • [ 165800-03-3 ]
  • linezolid hemi-naphthalene-1,5-disulfonate [ No CAS ]
YieldReaction ConditionsOperation in experiment
In water; acetone; at 20℃; Example 6 <strong>[165800-03-3]Linezolid</strong> (2:1) naphthalene-l,5-disulfonate0.5 g of <strong>[165800-03-3]linezolid</strong> base was dissolved in 25 ml of acetone at R.T. To the solution, 300 mg of naphthalene- 1,5-disulfonic acid dissolved in 3 ml of demi-water was added dropwise, while stirring at R.T. Initially, some opalescence was observed, followed by formation of a white solid. The suspension was stirred at R.T. for 10-15 minutes. The solid was isolated by filtration over a P3-glass filter, washed with acetone and air-dried overnight at R.T. A white, fine powder with lumps was obtained. The yield was 0.48 g.
  • 52
  • [ 66950-63-8 ]
  • [ 165800-03-3 ]
  • 53
  • N-(2-fluorophenyl)-morpholine [ No CAS ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
90% In propan-1-ol; at 95 - 100℃; for 0.5h;Purification / work up; Example 9: Synthesis of <strong>[165800-03-3]Linezolid</strong> Form I[149] Reflux n-propanol (400ml) and <strong>[165800-03-3]Linezolid</strong> (lOOg) at 95-100C till all solid getsdissolved. Add activated charcoal (2.0g) and heat for 30 mins. Filter thro hyflo bed. Heat the filtrate and concentrate the solution by partially removing n-propanol. Cool to 0-5C and filter the solid and dry it at 55-60C under vacuum. Yield: 0.9. : Percentage 90 w/w.
In ethanol; n-heptane; at -10℃;Reflux;Purification / work up; <strong>[165800-03-3]Linezolid</strong> Form II (0.5 g) is dissolved in 20 ml of ethanol at reflux. The hot solution is dropwise added, through a funnel preheated to 100C, into 100 ml of n-heptane stirred at -10C and containing 50 mg of <strong>[165800-03-3]linezolid</strong> Form A seeds. After 10 minutes of stirring at a temperature between -10 and 0 C, the suspension is filtered. The solid is washed with n-heptane and dried on air at room temperature. Yield : 0.50 g.
In n-heptane; butan-1-ol; at 90℃;Reflux;Purification / work up; 100 g of <strong>[165800-03-3]Linezolid</strong> Form III was dissolved in 250 ml of 1-butanol at reflux. The hot solution was added slowly to 500 ml of hot n-heptane, mechanically stirred at 90 C (200 rpm). The anti-solvent was not seeded prior to mixing. The suspension was cooled down to 20 C using a water bath and stirred at 20 C for 30-60 min (150 rpm). The solid was isolated by filtration over a P3-glass filter (reduced pressure), washed with n-heptane and vacuum-dried overnight at 40 C. The yield was 97.32 g (97%).XRPD showed only peaks of form A.DSC showed only melting of form A around 178-179 C.
In methanol; at 20 - 65℃; for 2.5h;Product distribution / selectivity; Example-16(b): Purification of <strong>[165800-03-3]Linezolid</strong><strong>[165800-03-3]Linezolid</strong> (I) (10. Og) was dissolved in methanol (100 ml) and heated to 65C, further, was stirred at 60-65C for 30 min. The resulting solution was cooled to room temperature and stirred for 2h. The solid mass was filtered, washed with methanol (10 ml) and dried to obtain pure <strong>[165800-03-3]linezolid</strong> (8 g) with 80% yield.
In hexane; ethyl acetate;Reflux;Purification / work up; EXAMPLE 36. Recrystallization of <strong>[165800-03-3]linezolid</strong> (9) from ethyl acetate and hexane. <strong>[165800-03-3]Linezolid</strong> was recrystallized using a procedure similar to the one described by Brickner, S. J., et al, J. Med. Chem., 1996, 39, 673-679. Thus, <strong>[165800-03-3]linezolid</strong> (1.05 g) was dissolved in refluxing ethyl acetate (utilizing a boiling stick) (25 ml) (required this amount of solvent to obtain a homogeneous clear colorless solution) and refluxing hexane (12 ml) was added all at once yielding a clear gently boiling solution. Within 30 seconds shiny white crystals started to form in the refluxing solution. The mixture was stirred and the Erlenmeyer flask filled with white fluffy crystals over ca. a minute or two. The flask was allowed to stand and slowly cool to room temperature over 30 minutes. The crystals were collected by filtration, washed with room temperature ethyl acetate:hexane (1: 1) (10 ml), air dried in the Buchner funnel for 15 minutes and then in the vacuum oven for 1.5 hour at 35 C (0.96 g).

  • 56
  • [ 1334229-25-2 ]
  • [ 108-24-7 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
80% With triethylamine; In dichloromethane; at 5 - 20℃; for 5h;Product distribution / selectivity; Example-13(a): Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl acetamide, Linezolid (I) starting from (S)-[[N-3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinylJmethyl]amine p-TSA salt (S)-[P^-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine -TSA salt (5 g) obtained in example 9 and triethylamine (2.56 g) were dissolved in DCM (25 ml). The solution was cooled to 5C and acetic anhydride (2.07 g) was added. The resulting reaction mixture was warmed to room temperature and stirred for 5h. After completion of reaction, water (50 ml) was added in reaction mixture and stirred for 30 min. Separation of DCM and aqueous layers was carried out. Aqueous layer was extracted with DCM. The combined DCM layers were washed with 10% sodium bicarbonate solution followed by washing with water. DCM layer was concentrated under vacuum at 35-40C. Toluene (30 ml) was added into the residue and heated to 70C. The suspended solution was stirred at 65-70C for 30 min and further at room temperature for lh. The solid mass was filtered, washed with toluene and dried to obtain the titled compound (3 g) with 80% yield.
80% To a suspension of (S -[[N-3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl] amine p-TSA salt (60 g, 0.128 mol) in water (600 mL) was added 6N hydrochloric acid (60 mL) at room temperature to adjust its pH to -0.5. Ethyl acetate (600 mL) was added in the above solution and then readjusted its pH to 4.5-4.7 using 10% sodium hydroxide solution (130 mL). After separating ethyl acetate layer aqueous layer was washed with ethyl acetate (2 x 300 mL). To the acidic aqueous layer were added DCM (600 mL) and acetic anhydride (26.1 1 g, 0.256 mol). The biphasic reaction mixture was adjusted its pH to 4.5-4.7 using 10% sodium hydroxide solution (130 mL) and stirred at room temperature for 3 h at this pH. After completion of reaction pH of the reaction mixture was raised to -7-7.5 using 10% sodium hydroxide solution (100 mL). Separating DCM layer, aqueous layer was extracted with DCM (600 mL). The combined DCM layer was washed with water (2 x 300 mL). DCM layer was concentrated under vacuum at 35-40C completely and kept under vacuum at 35-40C for 1 h. The obtained solid mass was dissolved in ethyl acetate (1020 mL) at 70-75C and cooled to 60C. The resulting solution was filtered through hyflo bed and washed with ethyl acetate (180 mL). To a cold (- 15C) ethyl acetate (175 mL) was added the above combined ethyl acetate solution of crude linezolid at - 15 to 10C in 5- 10 min and stirred for 10 min without further cooling. The suspended solution was then cooled down to - 15C and stirred at - 15 to - 10C for 2 h. The solid mass was filtered, kept under suction for 1 h and then dried under vacuum at 50-55C for overnight to obtain the title compound (34.5 g) with 80% yield. Yield : 80% Polymorph : Form-I Polymorphic impurity : Below detection limit (slow scan count 629) Enantiomer Purity : R-isomer 0.04%
80% [0151] To a suspension of (S)-[[N-3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine p-TSA salt (60 g, 0.128 mol) in water (600 mL) was added 6N hydrochloric acid (60 mL) at room temperature to adjust its pH to 0.5. Ethyl acetate (600 mL) was added in the above solution and then readjusted its pH to 4.5-4.7 using 10% sodium hydroxide solution (130 mL). After separating ethyl acetate layer aqueous layer was washed with ethyl acetate (2×300 mL). To the acidic aqueous layer were added DCM (600 mL) and acetic anhydride (26.11 g, 0.256 mol). The biphasic reaction mixture was adjusted its pH to 4.5-4.7 using 10% sodium hydroxide solution (130 mL) and stirred at room temperature for 3 h at this pH. After completion of reaction pH of the reaction mixture was raised to 7-7.5 using 10% sodium hydroxide solution (100 mL). Separating DCM layer, aqueous layer was extracted with DCM (600 mL). The combined DCM layer was washed with water (2×300 mL). DCM layer was concentrated under vacuum at 35-40 C. completely and kept under vacuum at 35-40 C. for 1 h. The obtained solid mass was dissolved in ethyl acetate (1020 mL) at 70-75 C. and cooled to 60 C. The resulting solution was filtered through hyflo bed and washed with ethyl acetate (180 mL). To a cold (-15 C.) ethyl acetate (175 mL) was added the above combined ethyl acetate solution of crude linezolid at -15 to 10 C. in 5-10 min and stirred for 10 min without further cooling. The suspended solution was then cooled down to -15 C. and stirred at -15 to -10 C. for 2 h. The solid mass was filtered, kept under suction for 1 h and then dried under vacuum at 50-55 C. for overnight to obtain the title compound (34.5 g) with 80% yield. [0152] Yield: 80% [0153] Polymorph: Form-I [0154] Polymorphic impurity: Below detection limit (slow scan count 629) [0155] Enantiomer Purity: R-isomer 0.04%
  • 57
  • [ 1236077-61-4 ]
  • [ 165800-03-3 ]
  • 60
  • [ 168828-90-8 ]
  • [ 165800-03-3 ]
  • 62
  • [ 168828-81-7 ]
  • [ 183805-10-9 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
67% Under an argon atmosphere, 25mL of dry dioxane was added 0.33g (1.0mmol) compound I ,0.05g(1.3mmol) of lithium chloride, 0.30g (2.7mmol) potassium t-butoxide, 0.16g trimethylchlorosilane (1.5mmol), after stirring 50min, cooled to 0 deg.C. 5mL dioxane was added dropwise to dissolve 0.34g (3.0mmol) compound II, and after stirring at 0 deg.C 40min, the reaction temperature wasraised to 25 deg.C and reacted for 15h. added acetic acid and to a pH of 6-7,then add 50mL of dichloromethane, 30 mL of water, and the aqueous phase extracted with 3 × 30mL dichloromethane, The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to an oil with ethylacetate to crystallization, cooled to room temperature and then at -15 crystallization, filtration, washing the filter cake with ice splashed with ethyl acetate, to give 0.23g vacuum dried white powder, purity> 98%, yield 67%.
EXAMPLE 2. Fluorination of 4-chloronitrobenzene with fluorine gas in sulfuric acid provided 4-chloro-3-fluoronitrobenzene as a crystalline solid on aqueous workup of the reaction. This was followed by displacement of the chloro group with morpholine (neat) in quantative yield, isolated as a crystalline solid on dilution of the reaction with methanol. Reduction of the nitro group with ammonium formate under an argon or nitrogen atmosphere provided 3-fluoro-4-morpholinoaniline as a crystalline solid which was converted to the isocyanate and treated with the chiral epoxide (S) N- (oxiranylmethyl)acetamide in xylene with lithium bromide and tributylphosphine oxide to yield linezolid. Alternatively, the intermediate 3-fluoro-4-morpholinoaniline was converted to the benzylcarbamate with benzyl chloroformate in aq. sodium bicarbonate, and subsequently treated with w-butyl lithium to form the anion and treated with (S) N- oxiranylmethyl)acetamide to provide linezolid.
  • 63
  • [ 224323-51-7 ]
  • [ 183805-10-9 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
Tributylphosphine oxide; lithium bromide; In o-xylene; EXAMPLE 2. Fluorination of 4-chloronitrobenzene with fluorine gas in sulfuric acid provided 4-chloro-3-fluoronitrobenzene as a crystalline solid on aqueous workup of the reaction. This was followed by displacement of the chloro group with morpholine (neat) in quantative yield, isolated as a crystalline solid on dilution of the reaction with methanol. Reduction of the nitro group with ammonium formate under an argon or nitrogen atmosphere provided 3-fluoro-4-morpholinoaniline as a crystalline solid which was converted to the isocyanate and treated with the chiral epoxide (S) N- (oxiranylmethyl)acetamide in xylene with lithium bromide and tributylphosphine oxide to yield linezolid. Alternatively, the intermediate 3-fluoro-4-morpholinoaniline was converted to the benzylcarbamate with benzyl chloroformate in aq. sodium bicarbonate, and subsequently treated with w-butyl lithium to form the anion and treated with (S) N- oxiranylmethyl)acetamide to provide linezolid.
  • 66
  • [ 1330034-71-3 ]
  • [ 165800-03-3 ]
  • 68
  • [ 565176-85-4 ]
  • [ 165800-03-3 ]
  • 69
  • (S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one acetate [ No CAS ]
  • [ 108-24-7 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
88% In water; at 50℃; under 608.041 - 912.061 Torr; for 2h; Example 35 Preparation of Linezolid (Compound 1) (S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one acetate (3.5 g, 10 mmol) was dissolved in 20 mL of water. The solution was heated to 50 C. and then acetic anhydride (0.72 g, 12 mmol) was added dropwise and stirred at 50 C. for 2 hours. The mixture was cooled down to 0 C. to crystallize, filtered, washed with water, dried and recrystallized with ethyl acetate to provide 3.0 g of Linezolid in 88% yield. 1H NMR (300 MHz, CDCl3) delta: 2.02 (s, 3H, CH3CO), 3.05 (t, 4H, CH2CH2N), 3.75 (m, 1H, CHaCHO), 3.67 (m, 2H, CH2NHCO), 3.87 (m, 4H, ArCH2N), 4.02 (m, 1H, CHbNO), 4.76 (m, 1H, CH2CHO), 6.12 (t, 1H, NHCO), 6.93 (t, 1H, ArH), 7.18 (dd, 1H, ArH), 7.46 (dd, 1H, ArH).
  • 71
  • [ 1373348-81-2 ]
  • [ 165800-03-3 ]
  • 72
  • [ 1373348-82-3 ]
  • [ 165800-03-3 ]
  • 73
  • [ 1352030-06-8 ]
  • [ 108-24-7 ]
  • linezolid [ No CAS ]
  • [ 165800-03-3 ]
  • 74
  • [ 952680-48-7 ]
  • linezolid [ No CAS ]
  • [ 165800-03-3 ]
  • 75
  • [ 1385053-40-6 ]
  • linezolid [ No CAS ]
  • [ 165800-03-3 ]
  • 76
  • [ 93246-53-8 ]
  • linezolid [ No CAS ]
  • [ 165800-03-3 ]
  • 77
  • [ 513068-96-7 ]
  • linezolid [ No CAS ]
  • [ 165800-03-3 ]
  • 78
  • 5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one [ No CAS ]
  • linezolid [ No CAS ]
  • [ 165800-03-3 ]
  • 79
  • [ 858344-36-2 ]
  • linezolid [ No CAS ]
  • [ 165800-03-3 ]
  • 80
  • [ 367-12-4 ]
  • [ 165800-03-3 ]
  • 81
  • [ 459408-52-7 ]
  • [ 165800-03-3 ]
  • 84
  • [ 496031-56-2 ]
  • [ 165800-03-3 ]
  • 85
  • [ 168828-81-7 ]
  • [ 183905-31-9 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
In a 300L enamel reactor, 15.2 Kg of N-benzyloxycarbonyl-3-fluoro-4-morpholinylaniline was added.Lithium tert-butoxide 11Kg,Tetrahydrofuran 54Kg,Stir well (30min).After that, the reaction solution is cooled to 10 to 16C.A certain amount of anhydrous methanol is added dropwise within 1.5 to 2.5 hours (keeping the temperature of the reaction system 10 to 25C),After the addition is complete, continue stirring for 25 to 30 minutes.Then the reaction solution was cooled to 2-8C.Add (S)-N-(2-acetoxy-3-chloropropyl)acetamide,The temperature of the reaction solution was controlled for a period of time (the reaction time and reaction temperature are shown in Table 1).The reaction solution was transferred to a 500-liter enamel reactor.A saturated aqueous solution of ammonium chloride (12.2 Kg/31 Kg) is added,After stirring for 20 Min, add 84Kg of dichloromethane and 61Kg of water.Continue stirring 20Min, stand still,The organic layer was separated and the aqueous layer was extracted with 46 Kg dichloromethane.Combine organic layers and wash twice (61Kg x 2)The first washed water layer was back-extracted with 31 Kg methylene chloride.The organic layer was separated, washed once, and the combined organic phases were dried over anhydrous sodium sulfate for more than 2 hours.The desiccant was removed by filtration, and the filtrate was transferred to a 300L enamel reactor at 40-50C and concentrated under reduced pressure.Add tetrahydrofuran and beat two times (28Kg × 2).The rejection filter was dried at 40-50C for 15 hours to obtain the finished product of linezolid.
83 g With lithium tert-butoxide; In tetrahydrofuran; methanol; at 20℃; for 16h; The intermediate (S)-1-acetamido-2-acetoxy-3-chloropropane 100g, compound VIII was added to the reaction flask.120g, add 200ml of tetrahydrofuran and 25ml of methanol, cool to 5 C, add LiOtBu 72g of THF solution 200ml, room temperatureReaction for 16 hours. Cool to 0-10 C, add 35 mL of glacial acetic acid dropwise, add 400 ml of water and 400 mL of dichloromethane, separate the liquid, waterThe layer was extracted with 200 mL of dichloromethane. The organic phases were combined, dried and filtered. The filtrate was concentrated under reduced pressure to recover the solvent to obtain 83 g of linezolid.The purity of the HPLC was 99.9%, the optical purity was 100.0%,
In the reactor IV,Add tetrahydrofuran (THF) and lithium t-butoxide,Stirring and mixing; adding the N-benzyloxycarbonyl-3-fluoro-4-(4-morpholinyl)aniline solid obtained in the step S2,Stir for 2 hours; the reaction solution is cooled to 0 to 5 C;Add N, N-dimethylformamide (DMF) and methanol, and stir at 0 to 5 C for 2 hours;(S)-N-(2-acetoxy-3-chloropropyl)acetamide (LN-9) was slowly added to carry out a stepwise temperature increase reaction.The reaction was stirred at 0 to 5 C for 15 hours.Slowly heat up to 15 C ± 3 C,The reaction was stirred for 15 hours and slowly warmed to 20 ± 3 C.After stirring the reaction for 16 hours,TLC thin layer monitoring reaction;After the reaction is completed, the reaction solution is transferred to the reaction vessel V.Adding saturated ammonium chloride solution, saturated sodium chloride solution, purified water, dichloromethane, stirring and separating the organic layer; transferring the organic layer to the reaction vessel VI,Concentrated to produce a semi-solid state product,Add ethyl acetate to the reactor VI,Heating to reflux, then cooling and stirring, centrifuging, centrifugal filtration,Dry, get the crude line of linezolid.
  • 87
  • [ 1402550-23-5 ]
  • [ 93246-53-8 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
74.7% In N,N-dimethyl acetamide; at 160℃; 0.98 g (0.005 mol) Fl and 5 ml solvent (the type and quantity of the solvent are shown in Table 2) were added into a 100 ml four-necked bottle equipped with thermometer, reflux condenser and dripping funnel, stirred, and a mixed liquid of F2 (R is methyl, the content is shown in Table 2) and certain amount of the above-mentioned solvent under certain temperature (the temperature is shown in Table 2); and was continued to react for 34 hours afier the completion of thedropwise adding. The solvent was evaporated under reduced pressure, and 30 ml chloroform and 50 ml water were added into the residue, and stirred to dissolve, and rested to stratify. The organic layer was washed by water, and the dried solvent was recovered to obtain crude product, which is recrystallized from ethyl acetate to obtain white solid; and the NMR spectrum is the same as Example 7.
  • 88
  • [ 1402550-24-6 ]
  • [ 93246-53-8 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
74.5% In N,N-dimethyl-formamide; at 145 - 155℃; for 5h; 1.96 g (0.01 mol) Fl and 10 ml DMF were added into a 250 ml four-necked bottle equipped with thermometer, reflux condenser and dripping funnel A mixed solution of 2.68 g F2 (R is ethyl, 0.012 mol) and 5 ml DMF was placed into the dripping flannel, stirred, and dripped at 145-155 C. After the completion of the dropwise adding about 1 hour later, it was continued for heat preservation under stirring for 4 hours. Afier the completion ofthe reaction analyzed by TLC (developing solvent: ethyl acetate : petroleum ether=1:1), the solvent DMF was evaporated under reduced pressure, and 30 ml chloroform and 50 ml water were added into the residue, and stirred to dissolve, and rested to stratiFy. The organic layer was washed by water and the dried solvent was recovered to obtain 2.73 g crude product, which was recrystallized from ethyl acetate to obtain 2.52 g white solid (yield 74.5%); the NMR spectrum is the same as Example 7.
  • 89
  • [ 1402550-26-8 ]
  • [ 93246-53-8 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
67.6% In N,N-dimethyl-formamide; at 145 - 155℃; for 5h; 1.96 g (0.01 mol) Fl and 12 ml DMF were added into a 250 ml four-necked bottle equipped with thermometer, reflux condenser and dripping funnel A mixed solution of 3.43 g F2 (R is benzyl, 0.012 mol) and 5 ml DMF was placed into the dripping thnnel, stirred, and dripped at 145-155 C. After the completion of the dropwise adding about 1 hour later, it was continued for heat preservation under stirring for 4 hours. Afier the completion ofthe reaction analyzed by TLC (developing solvent:ethyl acetate:petroleum ether=l :1), the solvent DMF was evaporated under reduced pressure, and 30 ml chloroform and 50 ml water were added into the residue, and stirred to dissolve, and rested to stratiFy. The organic layer was washed by water and the dried solvent was recovered to obtain 2.43 g crude product, which was recrystallized from ethyl acetate to obtain 2.19 g white solid (yield 67.6%); the NMR spectrum is the same as Example 7.
  • 90
  • [ 123-86-4 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
Preparation of Anhydrous Linezolid Crystalline Form-II Example-1 Linezolid having an enantiomeric impurity less than 0.5% (10 gr) is suspended with n-butyl acetate (200 ml). Heated the suspension to 85-90 C. and the mixture is stirred for 40-45 min. Slowly cool the mixture to 25-30 C. and stirred for 30 min and then the mixture is cooled to 0-5 C., and stirred for 60 min. The precipitated solids are filtered to give anhydrous Linezolid crystal form-II. The resulting crystalline form-II, complies the water content <0.5% and it is characterized by XRPD spectrum and IR spectrum.
  • 91
  • [ 75-65-0 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
Example-3 Linezolid having an enantiomeric impurity less than 0.5% (10 gr) is suspended with tertiary butanol (200 ml). Heated the suspension to 85-90 C. and the mixture is stirred for 40-45 min. Slowly cool the mixture to 25-30 C. and stirred for 60 min. The precipitated solids are filtered to give anhydrous Linezolid crystalline form-II. The resulting crystalline form-II complies the water content <0.5% and it is characterized by XRPD spectrum and IR spectrum.
  • 92
  • [ 1609632-44-1 ]
  • [ 108-24-7 ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
97% In dichloromethane; at 20 - 24℃; 3.600 g of the benzoate salt (II-D) was suspended in 30.00 g of dichloromethane and the temperature was set up to 24C (thick suspension). Then 1.145 g of acetanhydride was dropped in the course of 15 min. (clear solution). The mixture was stirred at RT. HPLC sample after 60 minutes confirmed complete conversion. The solution was neutralized with a solution of 0.92 g of sodium hydroxide in 4.40 ml of deionized water at 20 - 30C and the mixture was diluted with 2.60 ml of water. The layers were separated, the organic one was washed with 2x 7.0 ml of water. The organic solution was filtered with 100 mg of charcoal and the cake was washed with 3.4 ml of dichloromethane. The filtrate was evaporated (70C, 100 mbar). Yield: 2.825 g (97% of theoretical yield) of white crystals of linezolid.
  • 93
  • (R)-1-azido-3-(3-fluoro-4-(morpholin-4-yl)phenylamino)propan-2-ol [ No CAS ]
  • [ 165800-03-3 ]
  • 94
  • N-[3-phthalimido-2-(R)-acetyloxypropyl]-N-[3-fluoro-4-(4-morpholinyl)phenyl]carbamic acid ethyl ester [ No CAS ]
  • [ 165800-03-3 ]
YieldReaction ConditionsOperation in experiment
86% With potassium carbonate; methylamine; In methanol;Reflux; Potassium carbonate (12.7 g, 0.092 mol) and 40% monomethyl amine (28.5 g, 0.37 mol) were added to a solution of N-[3-phthalimido-2-(R)-acetyloxypropyl]-N-[3-fluoro-4-(4- morpholinyl) phenyl] -carbamic acid ethyl ester (47.2 g, 0.092 mol) in methanol (200 ml) and the mixture was heated to reflux, followed by maintaining the resulting mass at reflux temperature for 4 to 6 hours. After completion of the reaction, the reaction mass was cooled to room temperature (25-30C), followed by the addition of water (200 ml) and then stirring the mass for 1 hour at the same temperature. The separated solid was filtered, washed with methanol (50 ml) and then dried at 70-75C to produce 26.7 g of pure Linezolid as a white crystalline solid (Yield: 86%; Purity by HPLC: 99.9%).
  • 95
  • [ 165800-03-3 ]
  • [ 168828-90-8 ]
YieldReaction ConditionsOperation in experiment
99% With hydrogenchloride; In methanol;Reflux; 50 mg of linezolid were dissolved in MeOH (1 mL), then conc. HCl (1 mL) was added and the reaction was heated to reflux for ON. Solvent was evaporated to dryness under vacuum, and then the product was purified by reverse phase column chromatography on prep-HPLC using gradient of (water/acetonitrile/ 0.1 %TFA). Those fractions containing pure product were pooled and lyophilized to give the pure product yellow solid, 99% yield. RP-HPLC (C18): 2 to 50% (ACN/ Water/ 0.1%TFA) in 30 min, tR = 9.391 min, purity of 95%; 1H NMR (399 MHz, Acetone-d6) delta 7.54 (dd, J = 15.0, 2.6 Hz, 1H), 7.20 (ddd, J = 8.9, 2.6, 1.1 Hz, 1H), 7.14 - 6.95 (m, 1H), 5.25 (q, J = 8.9, 8.5 Hz, 1H), 4.44 - 4.23 (m, 2H), 4.09 (dd, J = 9.4, 6.1 Hz, 1H), 3.82 - 3.72 (m, 4H), 3.08 - 2.94 (m, 4H); 19F NMR (376 MHz, Acetone) delta -122.71; LCMS(ESI) C14H18FN3O3, [M+H]+: m/z calcd; 296.1, found; 296.1.
With pyridine; hydroxylamine hydrochloride; In ethanol; for 48h;Sealed tube; Title compound was synthesized by deacetylation of commercially available Linezolid by heating with hydroxyl amine hydrochloride (4 eq.), pyridine (35 vol) & ethanol (10 vol) in a sealed tube for 48 hrs. Solvents were then distilled and residue was diluted with dichloromethane. Inorganics were filtered and dichloromethane layer was washed with saturated sodium bicarbonate followed by brine. Concentration of dichloromethane extract resulted in crude product containing 20% unreacted Linezolid which was purified by crystallization from diethyl ether to get pure de-acetyl Linezolid which was sufficient pure (>95%) to use for next
  • 96
  • [ 165800-03-3 ]
  • C17H22FN3O5S [ No CAS ]
  • 97
  • [ 165800-03-3 ]
  • (S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acrylamide [ No CAS ]
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