106939-34-8

Basic information

• Product Name: Ethyl (S)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate
• Synonyms: Ethyl (S)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido;Levofloxacin cyclization ester;7h-Pyrido[1,2,3-De]-1,4-Benzoxazine-6-Carboxylic Acid;Levofloxacin Impurity 5;(S)-Ethyl 9,10-difluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carbox;ethyl (S)-9,10-difluoro-3-methyl-7- oxo-2,3-dihydro-7H- [1,4]oxazino[2,3,4-ij]quinoline-6- carboxylate;7h-Pyrido[1,2,3-De]-1,4-Benzoxazine-6-Carboxylic Acid, 9,10-Difluoro-2,3-Dihydro-3-Methyl-7-Oxo-, Ethyl Ester, (3s)-;Levofloxacin carboxylic acid, ethyl ester
• CAS NO: 106939-34-8
• Molecular Formula: C₁₅H₁₃F₂NO₄
• Molecular Weight: 309.26
• EINECS: 1806241-263-5
• Product Categories: LEVOFLOXACIN INTERMIDATE;Various Intermediates;Intermediates;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 106939-34-8.mol
• Article Data: 12

Chemical Properties

• Melting Point: 258-260°C
• Boiling Point: 442.2 °C at 760 mmHg
• Flash Point: 221.2 °C
• Appearance: off-white pale yellow solid
• Density: 1.43 g/cm³
• Vapor Pressure: 5.11E-08mmHg at 25°C
• Refractive Index: 1.582
• Storage Temp.: -20?C Freezer
• Solubility: Acetic Acid (Slightly), Chloroform (Slightly), Methanol (Slightly, Heated)
• PKA: -3.62±0.60(Predicted)
• CAS DataBase Reference: Ethyl (S)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate(CAS DataBase Reference)
• NIST Chemistry Reference: Ethyl (S)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate(106939-34-8)
• EPA Substance Registry System: Ethyl (S)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate(106939-34-8)

Safety Data

• Hazardous Substances Data: 106939-34-8(Hazardous Substances Data)

Usage

Chemical Properties

Off-White Pale Yellow Solid

Uses

Levofloxacin intermediate

InChI:InChI=1/C15H13F2NO4/c1-3-21-15(20)9-5-18-7(2)6-22-14-11(17)10(16)4-8(12(14)18)13(9)19/h4-5,7H,3,6H2,1-2H3/t7-/m0/s1

Synthetic route

(S)-Alaninol (2749-11-3) + ethyl acetate (141-78-6) + 2,3,4,5-tetrafluorobenzoyl chloride (94695-48-4) + formic acid ethyl ester (109-94-4) → ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8)

Conditions	Yield
Stage #1: ethyl acetate; formic acid ethyl ester With sodium hydride In toluene Stage #2: (S)-Alaninol; 2,3,4,5-tetrafluorobenzoyl chloride In toluene at 20℃; Reflux; Stage #3: With potassium fluoride In N,N-dimethyl-formamide Reflux;	99.4%

(-)-ethyl 9,10-difluoro-2,3-dihydro-3-iodomethyl-7-oxo-7H-pyrido<1,2,3-de><1,4>benzoxazine-6-carboxylate (113472-54-1) → ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8)

Conditions	Yield
With tri-n-butyl-tin hydride In ethanol at 50 - 60℃; for 1h;	73%

(S)-7,8-difluoro-3,4-dihydro-3-methyl-2H-1,4-benzoxazine (106939-42-8) + diethyl 2-ethoxymethylenemalonate (87-13-8) → ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8)

Conditions	Yield
With ethyl phosphate In diethyl ether	70%
With sodium chloride; sulfuric acid; sodium hydrogencarbonate; potassium carbonate In ice-water; diethyl ether; acetic anhydride

(+/-)-9,10-difluoro-3-hydroxymethyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid ethyl ester (91040-39-0) → ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: 75 percent / pyridine / tetrahydrofuran / 1.5 h / Heating 3: 91 percent / satd. NaHCO3 / ethanol / 2 h / 50 - 60 °C 4: 93 percent / triphenylphosphite methiodide / dimethylformamide / 1.5 h / Ambient temperature 5: 73 percent / tri-n-butyltin hydride / ethanol / 1 h / 50 - 60 °C View Scheme

(-)-ethyl 9,10-difluoro-2,3-dihydro-3-hydroxymethyl-7-oxo-7H-pyrido<1,2,3-de><1,4>benzoxazine-6-carboxylate (100986-87-6) → ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 93 percent / triphenylphosphite methiodide / dimethylformamide / 1.5 h / Ambient temperature 2: 73 percent / tri-n-butyltin hydride / ethanol / 1 h / 50 - 60 °C View Scheme

(+/-)-ethyl 9,10-difluoro-2,3-dihydro-3-(3,5-dinitrobenzoyloxy)methyl-7-oxo-7H-pyrido<1,2,3-de><1,4>benzoxazine-6-carboxylate (100986-91-2) → ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8)

Conditions	Yield
Multi-step reaction with 4 steps 2: 91 percent / satd. NaHCO3 / ethanol / 2 h / 50 - 60 °C 3: 93 percent / triphenylphosphite methiodide / dimethylformamide / 1.5 h / Ambient temperature 4: 73 percent / tri-n-butyltin hydride / ethanol / 1 h / 50 - 60 °C View Scheme

(S)-3-(3,5-Dinitro-benzoyloxymethyl)-8,9-difluoro-6-oxo-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid ethyl ester (106939-31-5) → ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 91 percent / satd. NaHCO3 / ethanol / 2 h / 50 - 60 °C 2: 93 percent / triphenylphosphite methiodide / dimethylformamide / 1.5 h / Ambient temperature 3: 73 percent / tri-n-butyltin hydride / ethanol / 1 h / 50 - 60 °C View Scheme

(+)-ethyl 2-<<<(S)-1-hydroxyprop-2-yl>amino>methylene>-3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate (110548-02-2) → ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 120℃;

(+)-ethyl 3-[(1-hydroxyprop-2(S)-yl)amino]acrylate → ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: ammonia / toluene / 4 h / 50 °C 2: toluene / 50 - 100 °C / pH < 7 3: hydrogenchloride / toluene; water / pH < 7 4: potassium fluoride / N,N-dimethyl-formamide / Reflux View Scheme

ethyl 3-(dimethylamino)acrylate (924-99-2, 1117-37-9, 114894-59-6) → ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: toluene / 8 h / 20 °C 2: ammonia / toluene / 4 h / 50 °C 3: toluene / 50 - 100 °C / pH < 7 4: hydrogenchloride / toluene; water / pH < 7 5: potassium fluoride / N,N-dimethyl-formamide / Reflux View Scheme
Multi-step reaction with 3 steps 1: triethylamine / toluene / 3 h / 40 °C / Green chemistry 2: 1 h / 40 - 90 °C / Green chemistry 3: potassium carbonate / N,N-dimethyl-formamide / 4 h / 100 °C / Green chemistry View Scheme
Multi-step reaction with 3 steps 1: triethylamine / toluene / 6 h / 60 °C 2: toluene / 2 h / 60 - 90 °C 3: potassium carbonate / N,N-dimethyl-formamide / 8 h / 150 °C View Scheme

C14H31NO3Si2 → ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: toluene / 50 - 100 °C / pH < 7 2: hydrogenchloride / toluene; water / pH < 7 3: potassium fluoride / N,N-dimethyl-formamide / Reflux View Scheme

3-(2-hydroxy-1-methylethylamino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylic acid ethyl ester → ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8)

Conditions	Yield
With potassium fluoride In N,N-dimethyl-formamide Reflux;
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 4h; Temperature; Green chemistry;
With potassium carbonate In N,N-dimethyl-formamide at 150℃; for 8h; Temperature;

2,3,4,5-tetrafluorobenzoyl chloride (94695-48-4) → ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / toluene / 3 h / 40 °C / Green chemistry 2: 1 h / 40 - 90 °C / Green chemistry 3: potassium carbonate / N,N-dimethyl-formamide / 4 h / 100 °C / Green chemistry View Scheme
Multi-step reaction with 3 steps 1: triethylamine / toluene / 6 h / 60 °C 2: toluene / 2 h / 60 - 90 °C 3: potassium carbonate / N,N-dimethyl-formamide / 8 h / 150 °C View Scheme
Multi-step reaction with 3 steps 1: triethylamine / toluene / 6.42 h / 12 - 75 °C 2: 3 h / 20 - 45 °C 3: potassium fluoride / N,N-dimethyl-formamide / 4 h / 160 °C View Scheme
Multi-step reaction with 3 steps 1: triethylamine / toluene / 3 h / 55 °C 2: 1 h / 40 - 90 °C 3: potassium carbonate / N,N-dimethyl-formamide / 4 h / 100 °C View Scheme
Multi-step reaction with 3 steps 1: triethylamine; Phenyl acetate / toluene / 8 h / 5 - 55 °C 2: toluene / 5 °C 3: potassium carbonate; Phenyl acetate; potassium fluoride / N,N-dimethyl-formamide / 2 h / 140 °C View Scheme

ethyl α<(N,N-dimethylamino)methylene>-2,3,4,5-tetrafluoro-β-oxobenzenepropanoate (138998-47-7) → ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1 h / 40 - 90 °C / Green chemistry 2: potassium carbonate / N,N-dimethyl-formamide / 4 h / 100 °C / Green chemistry View Scheme
Multi-step reaction with 2 steps 1: toluene / 2 h / 60 - 90 °C 2: potassium carbonate / N,N-dimethyl-formamide / 8 h / 150 °C View Scheme
Multi-step reaction with 2 steps 1: 1 h / 40 - 90 °C 2: potassium carbonate / N,N-dimethyl-formamide / 4 h / 100 °C View Scheme
Multi-step reaction with 2 steps 1: toluene / 5 °C 2: potassium carbonate; Phenyl acetate; potassium fluoride / N,N-dimethyl-formamide / 2 h / 140 °C View Scheme

ethyl 3-(2,3,4,5-tetrafkuorophenyl)-3-oxopropanoate (94695-50-8) → ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 0.5 h / 140 °C 1.2: 40 h / 140 °C 1.3: 96 h / 20 °C 2.1: potassium carbonate / N,N-dimethyl acetamide / 0.42 h / 160 °C / Microwave irradiation View Scheme

(-)-ethyl 2-<<<(R)-1-hydroxyprop-2-yl>amino>methylene>-3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate (110548-04-4) → ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8)

Conditions	Yield
With potassium carbonate In N,N-dimethyl acetamide at 160℃; for 0.416667h; Microwave irradiation;

boric acid (11113-50-1) + acetic anhydride (108-24-7) + ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → bis(acetato-O)[(3S)-9,10-difluoro-2,3-dihydro-3-methyl-7-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylato-O6,O7]boron

Conditions	Yield
Stage #1: boric acid; acetic anhydride With zinc(II) chloride at 20℃; for 0.5h; Large scale; Stage #2: ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate at 60℃; for 2h; Large scale;	94%
Stage #1: boric acid; acetic anhydride With zinc(II) chloride at 20℃; for 0.5h; Stage #2: ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate at 60℃; for 2h;	88%
Stage #1: boric acid; acetic anhydride With zinc(II) chloride at 20℃; for 0.5h; Stage #2: ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate at 60℃; for 6h;	83%

acetic anhydride (108-24-7) + ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → bis(acetato-O)[(3S)-9,10-difluoro-2,3-dihydro-3-methyl-7-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylato-O6,O7]boron

Conditions	Yield
With boric acid; zinc(II) chloride	93%

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → (-)-(S)-3-methyl-9,10-difluoro-2,3-dihydro-8-nitro-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid ethyl ester

Conditions	Yield
With sulfuric acid; potassium nitrate at 0 - 25℃; for 2h; Reagent/catalyst;	93%

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → levofloxacin Q-acid (100986-89-8)

Conditions	Yield
With hydrogenchloride; acetic acid	91%
In hydrogenchloride; acetic acid for 0.666667h; Heating;	61%
With hydrogenchloride; acetic acid

nitromethane (75-52-5) + ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → (S)-9-fluoro-3-methyl-10-nitromethyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid ethyl ester

Conditions	Yield
With sodium hydride In dimethyl sulfoxide at 50℃; for 4h;	89%
Stage #1: nitromethane With sodium hydride In dimethyl sulfoxide Stage #2: ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate In dimethyl sulfoxide at 65℃; for 4h; Further stages.;	89%

1-methyl-piperazine (109-01-3) + ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → levofloxacin (100986-85-4)

Conditions	Yield
With acetic acid In water; N,N-dimethyl-formamide at 70 - 105℃; for 10h; Temperature; Solvent; Reagent/catalyst;	85.7%

sodium cyanide (773837-37-9) + ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → (S)-9-fluoro-10-cyano-3-methyl-2,3-dihydro-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid ethyl ester

Conditions	Yield
In N,N-dimethyl-formamide at 80℃; for 10h; Solvent; Temperature;	60.8%
In N,N-dimethyl-formamide at 0 - 80℃; for 10.5h; Temperature;	60.8%

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → (S)-9-fluoro-3-methyl-10-formyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid ethyl ester (853336-60-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: 89 percent / NaH / dimethylsulfoxide / 4 h / 50 °C 2.1: KOH / methanol / 0.5 h / -10 - 5 °C 2.2: 66 percent / KMnO4; MgSO4 / H2O View Scheme

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → (R)-9-(4-{4-[(S)-5-(Acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenyl}-piperazin-1-yl)-8-fluoro-3-methyl-6-oxo-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid

Conditions	Yield
Multi-step reaction with 2 steps 1: aq. HCl; AcOH 2: N-methylmorpoline / dimethylsulfoxide / 110 °C View Scheme

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → (S)-9-fluoro-3-methyl-7-oxo-10-((1r,4s)-4-(phenoxymethyl)cyclohexanecarboxamido)-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium azide / N,N-dimethyl-formamide / 8 h / 90 - 95 °C 2: 5%-palladium/activated carbon; hydrogen / N,N-dimethyl-formamide / 70 °C 3: dmap; pyridine / toluene / 90 °C / Inert atmosphere 4: sodium hydroxide; water / ethanol / 10 °C View Scheme

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → (S)-10-((1r,4s)-4-((2,6-dimethylphenoxy)methyl)cyclohexanecarboxamido)-9-fluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium azide / N,N-dimethyl-formamide / 8 h / 90 - 95 °C 2: 5%-palladium/activated carbon; hydrogen / N,N-dimethyl-formamide / 70 °C 3: dmap; pyridine / toluene / 90 °C / Inert atmosphere 4: sodium hydroxide; water / ethanol / 10 °C View Scheme

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → (S)-10-((1r,4s)-4-((2,3-difluorophenoxy)methyl)cyclohexanecarboxamido)-9-fluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium azide / N,N-dimethyl-formamide / 8 h / 90 - 95 °C 2: 5%-palladium/activated carbon; hydrogen / N,N-dimethyl-formamide / 70 °C 3: dmap; pyridine / toluene / 90 °C / Inert atmosphere 4: sodium hydroxide; water / ethanol / 10 °C View Scheme

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → (S)-9-fluoro-3-methyl-10-((1r,4s)-4-((4-nitrophenoxy)methyl)cyclohexanecarboxamido)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium azide / N,N-dimethyl-formamide / 8 h / 90 - 95 °C 2: 5%-palladium/activated carbon; hydrogen / N,N-dimethyl-formamide / 70 °C 3: dmap; pyridine / toluene / 90 °C / Inert atmosphere 4: sodium hydroxide; water / ethanol / 10 °C View Scheme

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → (S)-9-fluoro-3-methyl-7-oxo-10-((1s,4r)-4-(phenoxymethyl)cyclohexanecarboxamido)-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium azide / N,N-dimethyl-formamide / 8 h / 90 - 95 °C 2: 5%-palladium/activated carbon; hydrogen / N,N-dimethyl-formamide / 70 °C 3: dmap; pyridine / toluene / 90 °C / Inert atmosphere 4: sodium hydroxide; water / ethanol / 10 °C View Scheme

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → (S)-10-((1s,4r)-4-((2,6-dimethylphenoxy)methyl)cyclohexanecarboxamido)-9-fluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium azide / N,N-dimethyl-formamide / 8 h / 90 - 95 °C 2: 5%-palladium/activated carbon; hydrogen / N,N-dimethyl-formamide / 70 °C 3: dmap; pyridine / toluene / 90 °C / Inert atmosphere 4: sodium hydroxide; water / ethanol / 10 °C View Scheme

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → (S)-10-((1s,4r)-4-((2,3-difluorophenoxy)methyl)cyclohexanecarboxamido)-9-fluoro-3-methyl-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium azide / N,N-dimethyl-formamide / 8 h / 90 - 95 °C 2: 5%-palladium/activated carbon; hydrogen / N,N-dimethyl-formamide / 70 °C 3: dmap; pyridine / toluene / 90 °C / Inert atmosphere 4: sodium hydroxide; water / ethanol / 10 °C View Scheme

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → (S)-9-fluoro-3-methyl-10-((1s,4r)-4-((4-nitrophenoxy)methyl)cyclohexanecarboxamido)-7-oxo-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium azide / N,N-dimethyl-formamide / 8 h / 90 - 95 °C 2: 5%-palladium/activated carbon; hydrogen / N,N-dimethyl-formamide / 70 °C 3: dmap; pyridine / toluene / 90 °C / Inert atmosphere 4: sodium hydroxide; water / ethanol / 10 °C View Scheme

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → ethyl (S)-10-azido-9-fluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate

Conditions	Yield
With sodium azide In N,N-dimethyl-formamide at 90 - 95℃; for 8h;	11.8 g

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → C29H31FN2O6

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium azide / N,N-dimethyl-formamide / 8 h / 90 - 95 °C 2: 5%-palladium/activated carbon; hydrogen / N,N-dimethyl-formamide / 70 °C 3: dmap; pyridine / toluene / 90 °C / Inert atmosphere View Scheme

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → C31H35FN2O6

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium azide / N,N-dimethyl-formamide / 8 h / 90 - 95 °C 2: 5%-palladium/activated carbon; hydrogen / N,N-dimethyl-formamide / 70 °C 3: dmap; pyridine / toluene / 90 °C / Inert atmosphere View Scheme

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → C29H29F3N2O6

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium azide / N,N-dimethyl-formamide / 8 h / 90 - 95 °C 2: 5%-palladium/activated carbon; hydrogen / N,N-dimethyl-formamide / 70 °C 3: dmap; pyridine / toluene / 90 °C / Inert atmosphere View Scheme

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → C29H30FN3O8

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium azide / N,N-dimethyl-formamide / 8 h / 90 - 95 °C 2: 5%-palladium/activated carbon; hydrogen / N,N-dimethyl-formamide / 70 °C 3: dmap; pyridine / toluene / 90 °C / Inert atmosphere View Scheme

Upstream product

• 110548-04-4 (-)-ethyl 2-<<<(R)-1-hydroxyprop-2-yl>amino>methylene>-3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate 
• 94695-50-8 ethyl 3-(2,3,4,5-tetrafkuorophenyl)-3-oxopropanoate 
• 2749-11-3 (S)-Alaninol 
• 141-78-6 ethyl acetate 
• 94695-48-4 2,3,4,5-tetrafluorobenzoyl chloride 
• 109-94-4 formic acid ethyl ester 
• 138998-47-7 ethyl α<(N,N-dimethylamino)methylene>-2,3,4,5-tetrafluoro-β-oxobenzenepropanoate 
• 924-99-2 ethyl 3-(dimethylamino)acrylate 
• 106939-42-8 (S)-7,8-difluoro-3,4-dihydro-3-methyl-2H-1,4-benzoxazine 
• 87-13-8 diethyl 2-ethoxymethylenemalonate 
• 110548-02-2 (+)-ethyl 2-<<<(S)-1-hydroxyprop-2-yl>amino>methylene>-3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate 
• 106939-31-5 (S)-3-(3,5-Dinitro-benzoyloxymethyl)-8,9-difluoro-6-oxo-2,3-dihydro-6H-1-oxa-3a-aza-phenalene-5-carboxylic acid ethyl ester 
• 100986-91-2 (+/-)-ethyl 9,10-difluoro-2,3-dihydro-3-(3,5-dinitrobenzoyloxy)methyl-7-oxo-7H-pyrido<1,2,3-de><1,4>benzoxazine-6-carboxylate 
• 100986-87-6 (-)-ethyl 9,10-difluoro-2,3-dihydro-3-hydroxymethyl-7-oxo-7H-pyrido<1,2,3-de><1,4>benzoxazine-6-carboxylate 

Downstream Products

• 100986-85-4 levofloxacin 
• 117707-40-1 S-(-)-9-fluoro-2,3-dihydro-3-methyl-10-(1-piperazinyl)-7-oxo-7H-pyrido-<1,2,3-de><1,4>benzoxazine-6-carboxylic acid 
• 176760-98-8 (3S)-10-(cyanomethyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid 
• 178912-62-4 (S)-(-)-10-fluoro-2,3-dihydro-3-methyl-9-(4-methyl-1-piperazinyl)-7H-pyrido[1,2,3-de]-[1,4]benzoxazine-6-carboxylic acid 
• 100986-89-8 levofloxacin Q-acid 

Relevant articles and documents

Improved method of preparation process of oxo-fluoro cyclization ester or levo-oxo-fluoro cyclization ester

The invention discloses an improved method of a preparation process of oxo-fluoro cyclization ester or levooxo-fluoro cyclization ester. Existing preparation methods of some levofloxacin intermediateshave many side reactions and are low in yield. According to the technical scheme in the invention, by means of 2,3,4,5-tetrafluorobenzoyl chloride, N,N-dimethylaminoethyl acrylate and (L-)aminopropanol as starting raw materials and toluene and N, N-dimethylformamide added with a water removal agent organic ester or anhydride as solvents, the oxygen-fluorine cyclization ester is prepared through aone-pot reaction. According to the method, organic ester or anhydride is added, so that the loss of raw materials and the generation of by-products are reduced, the reaction yield is increased, the product quality is ensured, and the yield of the (L-)oxo-fluoro cyclization ester can be increased from 75-80% to about 90%.

Synthesizing method of levofloxacin drug intermediate

The invention discloses a synthesizing method of a levofloxacin drug intermediate. The synthesizing method uses sodium hydride, toluene, ethyl acetate, ethyl formate, sodium formyl ethyl acetate, tetrafluorobenzyl chloride, S-(+)-2-amino-1-propanol, Co(NO3)2 6H20 and Zn(NO3)2 6H2O as the raw materials. The synthesizing method has the advantages that the intermediate (S)-(-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7-hydropyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid ethyl ester is prepared by subjecting the sodium formyl ethyl acetate and the tetrafluorobenzyl chloride to addition elimination, S-(+)-2-amino-1-propanol replacement and cyclization under the effect of a catalyst; the sodium formyl ethyl acetate is used to replace traditional N,N-dimethylamino ethyl acrylate DMA, so thatthe synthesizing route is shortened, preparation cost is lowered, pollution caused by dimethylamine gas generated during amino-1-propanol reaction is avoided, and the method is green, environmentallyfriendly and capable of greatly increasing the yield of the intermediate.

Method for preparing high-quality levofloxacin hydrochloride

The invention provides a method for preparing high-quality levofloxacin hydrochloride. The method comprises the following steps: preparation of 3-(2-hydroxy-1-methyl-ethylamino)-2-(2,3,4,5-tetrafluorobenzoyl)-ethyl acrylate, preparation of levo naphthenic acid and preparation of levofloxacin hydrochloride; the method is concise, the production cost is low, the product yield is high, quality is good, the method has the advantages of economic performance and environmental protection, three waste discharge capacity is little, effective separating and recycling on most by-product can be simultaneously realized, the method is convenient for industrial production, and has large popularization meaning.