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Quality Control of [ 168828-89-5 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 168828-89-5 ]

CAS No. :	168828-89-5	MDL No. :	MFCD18382488
Formula :	C₂₂H₂₀FN₃O₅	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	425.41	Pubchem ID :	-
Synonyms :

Safety of [ 168828-89-5 ]

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:	Ⅲ
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Application In Synthesis of [ 168828-89-5 ]

* 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 [ 168828-89-5 ]

[ 168828-89-5 ] Synthesis Path-Downstream 1~17

1
[ 168828-89-5 ]
[ 168828-90-8 ]

Yield	Reaction Conditions	Operation in experiment
95.4%	With hydrazine hydrate; In ethanol; for 4h;Reflux;	To the reaction flask was added 63.5 g of compound 6 (0. lmol) obtained in Example 3-2, 1000 mL of ethanol, 80% hydrazine hydrate (0.825 mmol) was added dropwise at room temperature and then heated to reflux for 4 h. The TLC monitored the reaction, The reaction solution was cooled to room temperature, the solvent was removed by distillation under reduced pressure, and 10 mL of water was added and extracted twice with methylene chloride (500 mL of X 2). The dichloromethane phase was dried over anhydrous sodium sulfate and suction filtered. The filtrate was steamed to remove the solvent, A solution of (S) -5- (aminomethyl) -3- (3-fluoro-4-morpholinophenyl) oxazolin-2-one (compound 7, 28.3 g) was obtained in vacuo 95.4%, purity 99.7%
90%	With hydrazine hydrate; In methanol; for 1h;Reflux;	Hydrazine hydrate (2.0g, 0.04 mol) was added to a solution of (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] phthalimide (5) (4.0 g, 0.009 mol) in methanol (25 mL).The reaction mixture was heated to reflux and stirred for1h. The mass was cooled to ambient temperature, and diluted with water (50 ml-) andextracted with dichloromethane (30 mLx2). Thecombined organic extracts were washed with water(30 mL) and concentrated to give (6).Yield: 90%. IR(KBr, cm-1):3579, 3377, (N-H stretching), 3293(aromatic C-H stretching), 2954,2893, 2846,(aliphatic C-H stretching), 1734 (C=O stretching),1625, 1572 (aromatic C=C stretching), 1519, 1480(N-H bending), 1381, 1332 (aliphatic C-H bending),1273, 1256, 1231 (C-N stretching), 1194, 1176 (C-0 stretching), 1114 (C-F stretching), 1066, 1048(aromatic C-H bending). 1H NMR (DMSO-d6) 8 ppm:7.51(m,1H),7.20 (m, 1H), 7.05 (t,1H),4.59 (m,1 H), 3.92 (m, 2H), 3.73 (m, 4H), 2.95 (m, 4H), 2.80(m, 2H), 1.63 (s, 2H); MS: 296 (M+ +H).
71%	With hydrazine hydrate; In methanol; for 1h;Reflux;	(S)-5-(Aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazo-lidin-2-one (11): A solution of 8.5 g (0.02 mol) of 10 in 100 mL methanol was added 6.9 g (0.11 mol) of 80% hydrazinium hydroxide, the mixture was heated at reflux temperature for 1 h and cooled to ambient temperature (the reaction produced a large white byproduct). The mixture was filtered and the filtrate removed the methanol in vacuo, extracted with methylene dichloride (3* 30 mL) and water (50 mL). The combined organic layers were dried (Na2SO4) and the concentrate was purified by chromatography on silica gel column (ethyl acetate:methanol = 10:1) to give 4.2 g (71%) of 11. 1H NMR (300 MHz, CDCl3): delta 1.47 (s, 2H), 2.98 (dd, 1H, J1 = 10.3 Hz, J2 = 4.3 Hz), 3.05 (t, 4H, J = 3.5 Hz), 3.11 (dd, 1H, J1 = 10.3 Hz, J2 = 3 Hz), 3.82 (t, 1H, J = 6.1 Hz), 3.87 (t, 4H, J = 3.5 Hz), 4.01 (t, 1H, J = 6.1 Hz), 4.68 (m, 1H), 6.93 (t, 1H, J = 6.8 Hz), 7.14 (dd, 1H, J1 = 6.8 Hz, J2 = 1.8 Hz), 7.45 (dd, 1H, J1 = 10.1 Hz, J2 = 1.8 Hz). 13C NMR (75 MHz, CDCl3): delta 45.1, 47.8, 51.1, 67.1, 73.9, 107.4 (d, J = 20.2 Hz), 113.8 (d, J = 3 Hz), 118.9 (d, J = 3 Hz), 133.5 (d, J = 22.5 Hz), 136.4 (d, J = 3.7 Hz), 154.7, 155.6 (d, J = 183.7 Hz), 171.4.

	With hydrazine; In methanol; for 1h;Heating / reflux;	Methanol (240 ml) and Hydrazine hydrate (26 gm) are added to a flaskcontaining the (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]phthalimide (40 gm), heated for 1 hour at reflux temperature and cooledto ambient temperature, water (500 ml) is added to the reaction mass and extracted with methylene dichloride (300 ml). The combined extractions are washed with water (100 ml) and the solvent is distilled to give 20 gm of S-N-[[3-i3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine.
	With hydrazine; In N,N-dimethyl-formamide; for 1h;Heating / reflux;	Example 4; Methanol (240 ml) and Hydrazine hydrate (26 g) are added to a flask containing the (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]phthalimide (40 g), heated for 1 hour at reflux temperature and cooled to room temperature. Then water (500 ml) is added to the reaction mass and extracted with methylene dichloride (300 ml). The combined extractions were washed with water (100 ml) and the solvent distilled to give 20 gm of S-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]amine.
	With hydrazine hydrate; In methanol; for 1h;Reflux;	Methanol ( 150 ml) and hydrazine hydrate (16.2 gr) are added to flask containing (S)-3-(3- fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl phthalimide (25 gr), heated for 1 hr at reflux temperature and cooled to room temperature. Distill off solvent completely U/vaccum at 45 C. Then water ( 125 ml) is added to the reaction mass and extracted with methylene dichloride (62 ml*2). The combined extractions were washed with water (62 ml) and the solvent is distilled to give 15 gr of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methylamine.
	With methylamine; In methanol; at 65℃; for 3h;	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.
15 g	With hydrazine hydrate; In methanol; for 1h;Reflux;	Methanol (150 ml) and hydrazine hydrate (16.2 gr) are added to flask containing (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl phthalimide (25 gr), heated for 1 hr at reflux temperature and cooled to room temperature. Distill off solvent completely U/vaccum at 45 C. Then water (125 ml) is added to the reaction mass and extracted with methylene dichloride (62 ml*2). The combined extractions were washed with water (62 ml) and the solvent is distilled to give 15 gr of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methylamine.
	With methylamine; In methanol; water; at 35 - 85℃; for 3h;	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.
	With hydrazine hydrate; In methanol; water; at 25 - 75℃;	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 (5S)-5-(amino methyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-1,3-oxazolidin-2-one. 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)
	With methylamine; In methanol; water; at 25 - 85℃;	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% ).
	With hydrazine hydrate; In ethanol; water; at 70℃; for 0.5h;	1) 1200 g of intermediate 2 is added to the reaction kettle,Add 12L of 50% ethanol water and 2160g of 80% hydrazine hydrate.The reaction was heated to 70 C and stirred for 0.5 h; after the reaction was completed,Evaporate the ethanol under reduced pressure, extract with dichloromethane, and combine the organic phases.Dry over anhydrous sodium sulfate,Filtration of the compound (intermediate 3) in dichloromethane;

Reference： [1]Patent: CN106749073,2017,A .Location in patent: Paragraph 0035; 0063; 0064
[2]Oriental Journal of Chemistry,2013,vol. 29,p. 1015 - 1019
[3]Chinese Chemical Letters,2013,vol. 24,p. 230 - 232
[4]Patent: WO2006/8754,2006,A1 .Location in patent: Page/Page column 11-12
[5]Patent: US2007/32472,2007,A1 .Location in patent: Page/Page column 5
[6]ARKIVOC,2012,vol. 2012,p. 45 - 56
[7]Asian Journal of Chemistry,2012,vol. 24,p. 3479 - 3482
[8]Patent: WO2012/114355,2012,A1 .Location in patent: Page/Page column 12
[9]Patent: WO2013/72923,2013,A1 .Location in patent: Page/Page column 17
[10]Patent: US2013/324719,2013,A1 .Location in patent: Paragraph 0022; 0060-0061
[11]Letters in Organic Chemistry,2017,vol. 14,p. 56 - 60
[12]Patent: US9643939,2017,B1 .Location in patent: Page/Page column 19
[13]Patent: WO2017/182853,2017,A1 .Location in patent: Page/Page column 20
[14]Patent: CN109232457,2019,A .Location in patent: Paragraph 0020

2
[ 168828-89-5 ]
[ 165800-03-3 ]

Reference： [1]ARKIVOC,2012,vol. 2012,p. 45 - 56
[2]Chinese Chemical Letters,2013,vol. 24,p. 230 - 232
[3]Patent: US2013/324719,2013,A1
[4]Oriental Journal of Chemistry,2013,vol. 29,p. 1015 - 1019
[5]Patent: CN106749073,2017,A

3
[ 148857-42-5 ]
[ 168828-89-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: triethylamine / tetrahydrofuran / 20 °C / Inert atmosphere 2: potassium carbonate / dichloromethane / 20 °C 3: potassium carbonate / acetone / 8 h / 20 °C
	Multi-step reaction with 2 steps 1: sodium methylate / methanol / 10 - 30 °C 2: lithium tert-butoxide / ethyl acetate / 25 - 75 °C

Reference： [1]Tammana, Rajesh; Vemula, Kiran Kumar; Guruvindapalli, Ramadasu; Yanamandr, Ramesh; Gutta, Madhusudhan [ARKIVOC, 2012, vol. 2012, # 6, p. 45 - 56]
[2]Current Patent Assignee: OPTIMUS DRAGS PVT; OPTIMUS DRUGS PVT - WO2017/182853, 2017, A1

4
[ 93246-53-8 ]
[ 168828-89-5 ]

Reference： [1]Asian Journal of Chemistry,2012,vol. 24,p. 3479 - 3482
[2]Patent: WO2012/114355,2012,A1
[3]Patent: WO2013/72923,2013,A1
[4]Patent: US2013/324719,2013,A1
[5]Oriental Journal of Chemistry,2013,vol. 29,p. 1015 - 1019
[6]Patent: US2016/39803,2016,A1
[7]Patent: CN103420933,2016,B

5
[ 93246-53-8 ]
[ 161596-47-0 ]
[ 168828-89-5 ]

Reference： [1]Asian Journal of Chemistry,2012,vol. 24,p. 3479 - 3482
[2]Patent: CN109232457,2019,A

6
[ 1074-82-4 ]
[ 174649-09-3 ]
[ 168828-89-5 ]

Yield	Reaction Conditions	Operation in experiment
87.7%	In N,N-dimethyl-formamide; at 80℃; for 3h;	Example-4: (R)-[N-f3-(3-fluoro-4-morpholinylphenyl>-2-oxo-5- oxazolidinyll methyil- PhthalimideTo the solution of 100 g (R)-\| H3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]- methyl]methane sulfonate in 1L Nu,Nu-dimethylformamide, was added 74.3 g of potassium phthalimide and the reaction mixture was heated to 80C for 3 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mixture was quenched in 2L water in another RBF and stirred for 1 hour. The precipitated product was filtered and washed with 200 mL water. The product was dried at 60C to 65C to get 100 g (87.7%) of (R) - [N- [3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]Phthalimide.
	In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl me methanesulphonate (30 gr), potassium phthalimide (19.4 gr) and dimethyl formamide (180 is heated for 2 hrs at 120 C temperature. The reaction , mixture is cooled to 0-5 C, slowly added 360 ml of DM water and filtered the solid to give 27 gr of (S)-3-(3-fluoro-4- morpholinophenyl)-2-oxo-5-oxazolidinyl methyl phthalimide.
27 g	In N,N-dimethyl-formamide; at 120℃; for 2h;	The mixture of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl methanesulphonate (30 gr), potassium phthalimide (19.4 gr) and dimethyl formamide (180 ml) is heated for 2 hrs at 120 C. temperature. The reaction mixture is cooled to 0-5 C., slowly added 360 ml of DM water and filtered the solid to give 27 gr of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl phthalimide.

Reference： [1]Patent: WO2013/72923,2013,A1 .Location in patent: Page/Page column 17
[2]Patent: WO2012/114355,2012,A1 .Location in patent: Page/Page column 11-12
[3]Patent: US2013/324719,2013,A1 .Location in patent: Paragraph 0022; 0058-0059

7
[ 2689-39-6 ]
[ 168828-89-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: hydrogen / Raney nickel / methanol / 8 h / 45 - 50 °C / 2942.29 Torr / Autoclave 2: <i>tert</i>-butyl alcohol / 16 h / Reflux 3: 1,1'-carbonyldiimidazole / dichloromethane / 24 h / 20 - 30 °C 4: N,N-dimethyl-formamide / 120 °C 5: water; sodium t-butanolate / tetrahydrofuran / 0.5 h / 0 - 15 °C 6: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C / Cooling with ice 7: N,N-dimethyl-formamide / 2 h / 120 °C
	Multi-step reaction with 5 steps 1.1: hydrogen / methanol / 10 h / 20 °C / 3750.38 Torr / Inert atmosphere; Autoclave 2.1: sodium hydrogencarbonate / water; toluene / 1 h / 0 - 20 °C 3.1: n-butyllithium / tetrahydrofuran; hexane / 2.5 h / -80 - -78 °C / Inert atmosphere 3.2: 20 °C / Cooling 4.1: triethylamine / dichloromethane / 45 °C 5.1: N,N-dimethyl-formamide / 3 h / 80 °C
	Multi-step reaction with 7 steps 1: hydrogen / methanol / 8 h / 45 - 50 °C / 3000.3 Torr / Autoclave; Inert atmosphere 2: <i>tert</i>-butyl alcohol / 16 h / Reflux 3: dichloromethane / 24 h / 25 - 30 °C 4: N,N-dimethyl-formamide / 120 °C 5: sodium t-butanolate; water / tetrahydrofuran / 0.5 h / 0 - 15 °C 6: triethylamine / dichloromethane / 0.5 h / 0 - 5 °C 7: N,N-dimethyl-formamide / 2 h / 120 °C

	Multi-step reaction with 2 steps 1.1: 5%-palladium/activated carbon; hydrogen / methanol / 22 - 35 °C / 225.02 - 1500.15 Torr 2.1: isopropyl alcohol / 28 - 88 °C 2.2: 35 - 38 °C
	Multi-step reaction with 3 steps 1.1: palladium 10% on activated carbon; ammonium formate / acetone / 8 h / 50 °C 2.1: sodium hydrogencarbonate / acetone; water / 0 - 20 °C 3.1: lithium tert-butoxide / N,N-dimethyl-formamide; tetrahydrofuran / 0.5 h / 5 °C / Inert atmosphere 3.2: 24 h / 5 - 20 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: LEE PHARMA LTD. - WO2012/114355, 2012, A1
[2]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - WO2013/72923, 2013, A1
[3]Current Patent Assignee: LEE PHARMA LTD. - US2013/324719, 2013, A1
[4]Current Patent Assignee: VIRDEV INTERMEDIATES PVT - WO2015/162622, 2015, A1
[5]Current Patent Assignee: LUNAN PHARM GROUP - CN103420933, 2016, B

8
[ 168828-82-8 ]
[ 168828-89-5 ]

Reference： [1]Patent: WO2012/114355,2012,A1
[2]Patent: WO2013/72923,2013,A1
[3]Patent: US2013/324719,2013,A1

9
[ 352524-58-4 ]
[ 513068-89-8 ]
[ 168828-89-5 ]

Yield	Reaction Conditions	Operation in experiment
92.8%	With copper(l) iodide; N,N-dimethyl-ethanamine; potassium carbonate In dichloromethane at 110℃; for 20h;	3-2 Example 3-2: Synthesis of Compound 5 44.4 g of compound 4 (0.18 mol), CuI (1.9 g, 10 mmol), N, N '-dimethylethylamine (30 mmol, 1.5 mL), potassium carbonate 69 (0.18 mol) obtained in Example 2-2 were added successively to the reaction flask . 1 g (0.5 mol) and 400 mL of dichloromethane, A solution of 4- (2-fluoro-4-bromophenyl) morpholine (compound 5,39.1 g, 0.15 mol) was added with stirring, In a 110 ° C oil bath for 20 hours; after completion of the reaction, the reaction solution was cooled to room temperature, The solvent was removed by distillation under reduced pressure, poured into 500 mL of water, extracted three times with ethyl acetate (3 x 500 mL) The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, The filtrate was concentrated under reduced pressure to give the crude product which was recrystallized from ethyl acetate to give 59.4 g of compound 6 in a yield of 92.8% Purity 99.5%
76%	With copper(l) iodide; (S,S)-1,2-diaminocyclohexane; potassium carbonate In 1,4-dioxane at 110℃; for 20h; Inert atmosphere;	(S)-2-((3-(3-Fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)isoindoline-1,3-dione (10): (S)-2-((3-(3-Fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)isoindoline-1,3-dione (10): A mixture of 14.8 g (60 mmol) of 9 in 300 mL of anhydrous dioxane under nitrogen was added 13 g (50 mmol) of 4-(4-bromo-2-fluorophenyl)-morpholine, 0.48 g (2.5 mmol) of CuI, 0.58 g (5 mmol) of (+)-trans-1,2-diaminocyclohexane and 13.9 g (0.1 mol) anhydrous potassium carbonate, the mixture was allowed to stir at reflux for 20 h. The solution was cooled to ambient temperature, which was filtered and the filtrate concentrated in vacuo, diluted with water (100 mL) and extracted with ethyl acetate (3* 40 mL), the combined organic layers were dried (Na2SO4) and the concentrate was purified by chromatography on silica gel column (ethyl acetate:hexane = 1:2) to give 16.2 g (76%) of 10, mp 204-206 °C. 1H NMR (300 MHz, CDCl3): δ 3.05 (t, 4H, J = 3.4 Hz), 3.85-3.89 (m, 5H), 3.98 (dd, 1H, J1 = 10.6 Hz, J2 = 4.3 Hz), 4.09 (t, 1H, J = 6.6 Hz), 4.14 (dd, 1H, J1 = 10.6 Hz, J2 = 5.0 Hz), 4.98 (m, 1H), 6.92 (t, 1H, J = 6.8 Hz), 7.11 (dd, 1H, J1 = 6.8 Hz, J2 = 1.9 Hz), 7.41 (dd, 1H, J1 = 10.6 Hz, J2 = 1.9 Hz), 7.78 (m, 2H), 7.88 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 40.8, 48.5, 51.1, 67.1, 69.7, 107.6 (d, J = 19.5 Hz), 114.1 (d, J = 2.3 Hz), 118.9 (d, J = 3 Hz), 123.8, 131.8, 133.1 (d, J = 8.2 Hz), 134.6, 136.6 (d, J = 6.7 Hz), 153.9, 155.5 (d, J = 183.7 Hz), 168.1.

Reference： [1]Current Patent Assignee: LUOXIN PHARMACEUTICALS GROUP STOCK CO LTD - CN106749073, 2017, A Location in patent: Paragraph 0035; 0059; 0060
[2]Li, Yan-Wu; Liu, Yan; Jia, Yun-Can; Yuan, Jian-Yong [Chinese Chemical Letters, 2013, vol. 24, # 3, p. 230 - 232]

10
[ 168828-81-7 ]
[ 168828-89-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 2.5 h / -80 - -78 °C / Inert atmosphere 1.2: 20 °C / Cooling 2.1: triethylamine / dichloromethane / 45 °C 3.1: N,N-dimethyl-formamide / 3 h / 80 °C

Reference： [1]Current Patent Assignee: ZYDUS LIFESCIENCES LTD - WO2013/72923, 2013, A1

11
[ 224323-51-7 ]
[ 161596-47-0 ]
[ 168828-89-5 ]

Yield	Reaction Conditions	Operation in experiment
96.51%	With lithium bromide; at 120℃; for 4h;	Example 11 The preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) methyl)isoindole-1,3-dione. Anhydrous lithium bromide (0.9 g) and (S)-2-(oxiran-2-ylmethylene)isoindole-1,3-dione (3.66 g) were respectively dissolved in isoamyl acetate (30 mL), and the solution of 3-fluoro-4-morpholinophenyl isocyanate in dimethylbenzene (4.0 g, 20 mL) was added. The reaction was performed at 120 C for 4 h. To the reaction solution was added 60 mL of water and filtered. The filter cake was washed with cold petroleum ether (10 mL * 2) and dried to provide a white solid 7.39g with a yield of 96.51 %. ESI-MS (m/z): 426 (M+H), 448 (M+Na); 1HNMR (400MHz, CDCl3) delta: 3.04 (m, 4H), 3.84 (m, 4H), 3.95 (m, 2H), 4.08 (m, 2H), 4.95 (m, 1H), 6.90 (t, 1H), 7.1 (m, 1H), 7.37 (dd, 1H), 7.75 (m, 2H), 7.87 (m, 2H).
90.11%	With lithium bromide; In N,N-dimethyl-formamide; at 60℃; for 4h;	Example 1 The Preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) methyl)isoindole-1,3-dione (I-1) Anhydrous lithium bromide (0.9 g) and (S)-2-(oxiran-2-ylmethylene)isoindole-1,3-dione (3.66 g) were respectively dissolved in N,N-dimethyl formamide (DMF) (30 mL), and the solution of 3-fluoro-4-morpholinophenyl isocyanate in DMF (4.0 g, 20 mL) was added, the reaction was performed at 60 C. for 4 h. To the reaction solution was added 60 mL of water and filtered. The filter cake was washed with cold petroleum ether (10 mL*2) and dried to provide a white solid 6.90 g with a yield of 90.11%. ESI-MS (m/z): 426 (M+H), 448 (M+Na); 1HNMR (400 MHz, CDCl3) delta: 3.04 (m, 4H), 3.84 (m, 4H), 3.95 (m, 2H), 4.08 (m, 2H), 4.95 (m, 1H), 6.90 (t, 1H), 7.1 (m, 1H), 7.37 (dd, 1H), 7.75 (m, 2H), 7.87 (m, 2H).

Reference： [1]Patent: EP2816039,2014,A1 .Location in patent: Paragraph 0031
[2]Patent: US2015/11757,2015,A1 .Location in patent: Paragraph 0030-0033

12
[ 51594-55-9 ]
[ 1074-82-4 ]
[ 68-12-2 ]
[ 93246-53-8 ]
[ 168828-89-5 ]

Yield	Reaction Conditions	Operation in experiment
234 g		Compound-lI (200 gms) was added in a reactor flask containing 4.2 lit of isopropanol and was dissolved under stirring for about 15-20 minutes at 28-30C. R(-)-epichlorohydrin (112 gms) was then gradually added to the reaction mass over a period of 1 hour.The reaction mass was heated to reflux and was maintained for about 20-24 hrs at 80- 88C. The progress of reaction was monitored by TLC at periodic intervals after 16 hrs. Isopropanol was distilled out from the reaction mass after completion of the reaction and then N,N-dimethyl forrmamide (DMF) was gradually added (540 ml). The reaction mass was cooled to 35-38C and stirred for 15-20 minutes. Potassium phthalamide (222 gms) was next added over a period of 1.5 hours under moderate stirring. The reaction mass was maintained further at 35-40C for 15-20 minutes and then slowly heated to 94-98C with careful control on temperature. Heating was stopped and the temperature of reaction mass rose to 122-130C. The reaction progress was quickly monitored by TLC and reaction was completed in 15-30 minutes period. Reaction mass was cooled to 45-50 and then slowly poured in to a vessel containing ice (1.4 kg), water (3.8 lit) and methylene dichioride solvent (1.6 lit), with vigorous stirring. After 15-20 minutes of stirring, the organic layer was separated. The aqueous layer was extracted further with MDC (500 ml x 3 times). Combined MDC layer was repeatedly extracted with water (350 ml x 4 times), dried over anhydrous sodium sulphate, filtered and partially concentrated to remove water azeotropically. Fresh MDC was added equal to the quantity of solvent removed by distillation (approximately 600-700 ml). Moisture content of the reaction mass was observed to be 0.1%. the reaction mass was next cooled to 30C and carbonyl diimidazole (146 gm) was added to it over a period of half an hour. The reaction mass temperature was then raised to 35-37C and maintained for 20-26 hrs under monitoring by TLC. Reaction was completed in 22 hrs. Water (290 ml) was added in the reaction mass and organic layer was separated. The organic layer was re-extracted with water (250 ml x 3 times), all aqueous layer pooled up and extracted with MDC (220 ml x 1), MDC extracts pooled up and dried over anhydrous sodium sulphate and filtered MDC extracts was then treated with active carbon (6 gms), filtered and concentrated to remove solvent in vacuo. The residual mass was added with methanol (70 ml) and solvent was stripped under vacuum. The mass was again added with methanol (380 ml), heated to 60-65C under stirring, maintained for about half an hour, cooled to 25-28C, and maintained for 1 hr. The product mass was filtered and solid obtained was washed with methanol (50 ml). The product mass dried in a tray dryer at 60-65C for 4-5 hrs to obtain compound-Ill (234 gms, moisture content 0.15%, HPLC purity 96.37%, Assay 97.52%, melting point 196-200C, SOR (-) 48.93).

Reference： [1]Patent: WO2015/162622,2015,A1 .Location in patent: Page/Page column 10; 11; 13; 14

13
[ 168828-89-5 ]
[ 108-24-7 ]
[ 165800-03-3 ]

Yield	Reaction Conditions	Operation in experiment
89.1%		Three 3L flask, was added 2-({(5S)-2-oxo-3-[(4-morpholino-3-fluorophenyl)]-4,5-dihydro-1,3-oxazole-5-yl}methyl)-isoindole-1,3-dione 51g (0. 12mol), 1. 5L of methanol and 80% water and hydrazine 75g (l. 2mol), heated 60 C for 1 hour . TLC (methylene chloride: ethyl acetate = 12: 1) showed the reaction was substantially complete, The reaction solution was concentrated to dryness under reduced pressure, water was added and 600mL dichloromethane 1. 8L, sufficiently stirred and dissolved, separated, the organic layer was washed with 600mL water, dried over anhydrous sodium sulfate, filtered, and the filtrate was transferred to three 3L flask, triethylamine 24. 2g (0. 24ml), stirred Cooled to 0 C, was slowly added dropwise acetic anhydride 14. 7g (0. 144mol), insulation 0 C for 1 hour, then warmed to room temperature for 1 hour. TLC (ethyl acetate) showed essentially complete the reaction, stirring was added 600mL of water, liquid separation, the organic layers are washed with saturated sodium bicarbonate solution, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give a white solid with acetic acid ethyl recrystallization, white crystals linezolid 36. lg, a yield of 89.1%
145 g		Methanol (1.28 lit) and compound-Ill (225 gm) were charged in a reaction flask and stirred for 15 minutes at 30-35C. Hydrazine hydrate (138 gms) was introduced in the reactor and mass was gradually heated to 68-70C over a period of 10-15 minutes. It was maintained at 68-70C under mild reflux for a period of 2 hrs. Completion of reaction was confirmed by TLC and methanol was partially removed by distilling out about 750 ml - 800 ml. Reaction mass is cooled to 30-35C, 2.95 lit of water was slowly introduced followed by extraction with MDC (1.25 Lit x 1, 0.45 lit x 2). MDC extract was washed with water (0.45 lit x 2), dried over anhydrous sodium sulphate, filtered and concentrated partially to remove 0.8 lit MDC. The reaction mass was cooled to 10-12C, and acetic anhydride (122 gms) was added in about an hour while maintaining the temperature at l0-12C. Reaction mass temperature was then raised to 28-30C and maintained for 2 hrs. Reaction completion was ascertained by TLC and solvent was distilled off completely. Two lots of IPA were added in succession (60 ml x 2) and the mass was stripped off to remove the solvent completely. Third lot of IPA (235 ml) was added followed by cooling the mass to 25-30C and then to 2-5C. It was maintained under slow stirring for 2 hrs, filtered to isolate the product and washed with IPA (2-5C, 50 ml x 2). Linezolid isolated thus was dried first at 40-45C for 3 hrs followed by at60-70 for 3-4 hrs (Yield 145 gms, HPLC purity above 99.0%, Assay 99.02%, SOR (- )9.99, JR match value with a working standard of Linezolid polymorph form-Il 86.44%).
9 g		Example-7 Preparation of (S)-N-[ [3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-oxazolidin-5-yl]methyl]-acetamide (Linezolid) Mixture of methanol (80 ml) and hydrazine hydrate (13 g) were added to a flask containing (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide (20 g), heated to reflux temperature and maintained at the same temperature for about 1 hour. Cooled the reaction mass to ambient temperature, water (80 ml) was added and extracted with methylene dichloride (240 ml). The combined extractions were washed with water (160 ml) and separated the organic layer. Triethyl amine (10 g) was added to the organic layer, cooled the reaction mixture to 10-15 C. and acetic anhydride (10 g) was added. The temperature of the reaction mass was raised to 25-30 C. and maintained at the same temperature for about 1 hour. The solvent was distilled off completely and ethyl acetate (100 ml) was added, filtered the obtained solid and dried to get (9 g) the title compound as white solid. melting point=181.5-182.5 C.; HPLC purity=99.6%.

Methanol (1000 ml) and hydrazine hydrate ( 1 15 gm) was taken into flask containing (S) -N- [[3 - [3 -Fluoro-4- [4-morpholinyl] phenyl] -2 -oxo-5- oxazolidinyl]methyl]phthalimide obtained in example- 1 and heated to reflux, maintained the reflux for a period of 2 hrs. Evaporated the solvent under reduced pressure. Cool the mass to ambient temperature, water (900 ml) is added to the reaction mass and extracted into methylene chloride ( .1.500 ml) . Dried the organic layer over sodium sulphate. Take the organic layer cool to 0- 10C. Added acetic anhydride (35 gm). After completion of reaction, distil out under reduced pressure. Isolated the Linezolid in toluene. The material was dried at 60C. The Linezolid recrystallized in methanol to get pure Linezolid. IR values matched with Linezolid polymorph Form-II. The obtained Linezolid was having the HPLC purity >99.5% and FTIR in KBrvalues in cm-1 are: 3364, 1748, 1675, 1537, 1517, 1445, 1410, 1400, 1358, 1329, 1287, 1273, 1252, 1237, 122 1 , 1 144, 1 130, 1 123, 1 1 16, 1078, 1065, 1049, 906, 851 and 757.

Reference： [1]Patent: CN103420933,2016,B .Location in patent: Paragraph 0032; 0064-0065
[2]Patent: WO2015/162622,2015,A1 .Location in patent: Page/Page column 11; 12
[3]Patent: US2016/39803,2016,A1 .Location in patent: Paragraph 0049
[4]Patent: WO2018/55499,2018,A1 .Location in patent: Page/Page column 11

14
[ 565176-83-2 ]
[ 161596-47-0 ]
[ 168828-89-5 ]

Yield	Reaction Conditions	Operation in experiment
40 g	With triethylamine; at 90 - 95℃; for 6h;	Example 1 Preparation of (S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide Mixture of N-ethoxycarbonyl 3-fluoro-4-morpholinyl aniline (30 g), (S)-Glycidyl phthalimide (27 g) and triethylamine (1.5 ml) were heated to 90-95 C. and maintained at the same temperature for about 6 hours. The reaction mass was cooled to ambient temperature and acetone (240 ml) was added. Heated the reaction mass to reflux temperature and stirred for about 30 minutes. The reaction mass was cooled to ambient temperature, filtered the solid obtained, washed the cake with acetone (120 ml) and dried to get (40 g) the title compound.

Reference： [1]Patent: US2016/39803,2016,A1 .Location in patent: Paragraph 0043

15
[ 168828-81-7 ]
[ 161596-47-0 ]
[ 168828-89-5 ]

Yield	Reaction Conditions	Operation in experiment
84%		2L in three-mouth bottle, respectively adding N-benzyloxycarbonyl-3-fluoro-4-morpholinoaniline 99g (0.3mol), N, N-dimethyl formamide 180 ml and tetrahydrofuran 540 ml, after stirring to dissolve cooling to 5 C the following lithium t-butoxide 48g (0.6mol) was added dropwise, preserving heat and stirring 30 minutes, add (S)-N - (2,3-epoxy propyl) phthalimide 81.2g (0.4mol), stirring the mixture at room temperature for reaction 24 hours. TLC (methylene chloride: ethyl acetate = 12:1) display the reaction substantially completely, by adding saturated ammonium chloride solution 600 ml, ethyl acetate for 2L × 2 extraction, the organic phase with water and saturated salt water washing, dry anhydrous sodium sulfate, filtered, concentrated crystallization, getting white solid 107.1g, yield 84%.

Reference： [1]Patent: CN103420933,2016,B .Location in patent: Paragraph 0032; 0060-0061

16
[ 212325-40-1 ]
[ 161596-47-0 ]
[ 168828-89-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	With lithium tert-butoxide; In N,N-dimethyl-formamide; at 25 - 85℃;	To a mixture of methyl (3-fluoro-4-morpholinophenyl) carbamate (100 g, 0.392 moles), in dimethyl formamide (200 ml) 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3 (2H)-dione (100 g, 0.492 moles) and lithium tertiary butoxide (5.0 gm, 0.0625 moles) were added in one lot at a temperature of 25 to 30 C. The temperature was raised to 80-85 C. and maintained for about 4-6 hrs. The reaction mixture was cooled to ambient temperature, followed by addition of purified water (500 ml) and stirred for 30 min at 25-30 C. The resultant solid was filtered off and washed with purified water (100 ml). The obtained crude solid was recrystallized from ethyl acetate to get pure (5S)-2-[3-(3-fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-isoindole-1,3-dione. Yield: 140 g (85%)
70%	With lithium tert-butoxide; In ethyl acetate; at 25 - 75℃;	Example-3: (0131) Preparation of (S) 2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5- ylmethyl] -isoindole-1, 3-Dione (0132) A mixture of methyl (3-fluoro-4-morpholinophenyl) carbamate (50 g, 0.196 moles) in Ethyl acetate (100 ml) and stirred for 10 min at 25 to 30C. 2-[(2S)-oxiran-2-ylmethyl]- lH-isoindole-1, 3(2H)-Dione (50 g, 0.246 moles) and Lithium tertiary but oxide (5.0 gm,0.0624 moles ) was added in one lot at 25 to 30C, and the temperature was slowly raised to 70-75C and maintain at the same temperature for about 6-8 hrs. The reaction mixture was cooled to ambient temperature, ethyl acetate (50 ml) was added, and resultant slurry was stir for 30 min at 25-30 C & filtered the solid. The resultant crude solid was added to ethyl acetate ( 250 ml) at 25-30C and heated to 70-75C, stirred for 15-20 min, cooled the slurry to 25-30C & Stir for 30 min. The obtain solid was filtered and washed with ethyl acetate ( 50 ml) to get a pure (5S)2-[3-(3-Fluoro-4- morpholin-4-yl-phenyl)-2-oxo-oxazolidin-isoindole-l,3-dione. Yield: 70 g (85% yields on theoretical)

Reference： [1]Patent: US9643939,2017,B1 .Location in patent: Page/Page column 17
[2]Patent: WO2017/182853,2017,A1 .Location in patent: Page/Page column 17

17
[ 51594-55-9 ]
[ 1074-82-4 ]
[ 79-22-1 ]
[ 93246-53-8 ]
[ 168828-89-5 ]

Yield	Reaction Conditions	Operation in experiment
83%		3-Fluoro-4-morpholinoaniline (100 gm) was added in n-butanol (300 ml) and charged Alumia sulfonic acid at ambient temperature. Cool the mass, added(R)-Epichlorohydrin (72 gm) and maintain the reaction mass at below 20C. Confirmed the completion of reaction, separated the catalyst. Added sodiumbicarbonate, cool the mass temperature to 0-5C and added methylchloro formate (56 gm) . After completion of reaction, evaporated the n- butanol and charged Nu,Nu-dimethylformamide (500 ml), potassium phthalimide (122 gm). The reaction temperature maintained at 95- 100C for 3 hours. Cool the mass temperature to ambient temperature, quenched the mass into water. Filtered the mass and washed the product with water. Dried the material up to get constant weight .The obtained (S)-N- [[3-[3-FIuoro-4--[4---morphoIi.nyI]phenyl.]-- 2--oxo-H5--oxazoliclinyl]methyl] phthalimide was 180 gm (83% yield) .

Reference： [1]Patent: WO2018/55499,2018,A1 .Location in patent: Page/Page column 10-11

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H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 168828-89-5 ] {[proInfo.proName]}

Quality Control of [ 168828-89-5 ]

Related Doc. of [ 168828-89-5 ]

Product Details of [ 168828-89-5 ]

Safety of [ 168828-89-5 ]

Application In Synthesis of [ 168828-89-5 ]

[ 168828-89-5 ] Synthesis Path-Downstream 1~17

Precautionary Statements-General

Prevention

Response

Storage

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Physical hazards

Health hazards

Environmental hazards

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