100491-29-0

Basic information

• Product Name: ETHYL 1-(2,4-DIFLUOROPHENYL)-7-CHORO-6-FLUORO-4-OXO-HYDROPYRIDINO[2,3-B] PYRIDINE-3-CARBOXYLATE
• Synonyms: ETHYL 1-(2,4-DIFLUOROPHENYL)-7-CHORO-6-FLUORO-4-OXO-HYDROPYRIDINO[2,3-B] PYRIDINE-3-CARBOXYLATE;ETHYL 1-(2,4-DIFLUOROPHENYL)-7-CL-6-F-4-O-HYDROPYRIDINO[2,3-B]PYRIDINE-3-CARBOXYLATE;ethyl1-(2,4-difluorophenyl)-7-chloro-6-fluoro-4-oxohydropyridino[2,3-b]pyridine-3-c;ETHYL 7-CHLORO-1-(2,4-DIFLUOROPHENYL)-6-FLUORO-1,4-DIHYDRO-4-OXONAPHTHYRIDINE-3-CARBOXYLATE;Ethyl 1-(2,4-difluorophenyl)-7-Cl-6-F-4-O-hydropyridino[2,3-b]pyridine-3-carboxylate,99%;Ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate;Ethyl 1-(2,4-difluorophenyl)-7-chloro-6-fluoro-4-oxohydropyridino[2,3-b]pyridine-3-Carboxylate;7-Chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid ethyl ester
• CAS NO: 100491-29-0
• Molecular Formula: C₁₇H₁₀ClF₃N₂O₃
• Molecular Weight: 382.72
• EINECS: 422-360-1
• Product Categories: Heterocycles;Intermediates;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 100491-29-0.mol

Chemical Properties

• Melting Point: 212-215 °C
• Boiling Point: 502.504 °C at 760 mmHg
• Flash Point: 257.705 °C
• Appearance: almost white powder
• Density: 1.4752 (estimate)
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.589
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Solubility: DMSO (Slightly, Heated), Methanol (Very Slightly, Heated)
• PKA: -3.23±0.70(Predicted)
• CAS DataBase Reference: ETHYL 1-(2,4-DIFLUOROPHENYL)-7-CHORO-6-FLUORO-4-OXO-HYDROPYRIDINO[2,3-B] PYRIDINE-3-CARBOXYLATE(CAS DataBase Reference)
• NIST Chemistry Reference: ETHYL 1-(2,4-DIFLUOROPHENYL)-7-CHORO-6-FLUORO-4-OXO-HYDROPYRIDINO[2,3-B] PYRIDINE-3-CARBOXYLATE(100491-29-0)
• EPA Substance Registry System: ETHYL 1-(2,4-DIFLUOROPHENYL)-7-CHORO-6-FLUORO-4-OXO-HYDROPYRIDINO[2,3-B] PYRIDINE-3-CARBOXYLATE(100491-29-0)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 37/39-26
• Hazardous Substances Data: 100491-29-0(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
ETHYL 1-(2,4-DIFLUOROPHENYL)-7-CHORO-6-FLUORO-4-OXO-HYDROPYRIDINO[2,3-B] PYRIDINE-3-CARBOXYLATE is used as a chemical intermediate for the production of Trovafloxacin (T893000) and its analogs. Its role in the synthesis process is crucial for creating these antibiotics, which are designed to treat various bacterial infections. The compound's chemical properties make it a valuable component in the development of effective and targeted treatments for a range of illnesses.

InChI:InChI=1/C17H10ClF3N2O3/c1-2-26-17(25)10-7-23(13-4-3-8(19)5-11(13)20)16-9(14(10)24)6-12(21)15(18)22-16/h3-7H,2H2,1H3

Synthetic route

ethyl-3,1-(2,4-difluoroanilino)-2-(2,6-dichloro-5-fluoronicotinyl) acrylate (100490-99-1) → ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0)

Conditions	Yield
With sodium hydride In tetrahydrofuran for 1h; Heating;	86.5%
With sodium hydride In 1,4-dioxane for 1h; Ambient temperature;
With sodium hydride In tetrahydrofuran for 1.5h; Inert atmosphere; Reflux;	8 g
With sodium hydrogencarbonate In dichloromethane at 35℃; for 3h; Temperature; Solvent; Reagent/catalyst;

ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate → ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0)

Conditions	Yield
In diethyl ether; trichlorophosphate	85%

ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]acetate (105152-47-4) → ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0)

Conditions	Yield
With trichlorophosphate In diethyl ether; chloroform; water; N,N-dimethyl-formamide	72.2%

ethyl 3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxopropanoate (96568-04-6) → ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 1.) Ac2O / 1.) 130 deg C, 1 h, 2.) CH2Cl2, RT, 0.5 h 2: 86.5 percent / NaH / tetrahydrofuran / 1 h / Heating View Scheme
Multi-step reaction with 3 steps 1: Ac2O / 15 h / 130 °C 2: ethanol / 1 h / Ambient temperature 3: NaH / dioxane / 1 h / Ambient temperature View Scheme
Multi-step reaction with 2 steps 1.1: acetic anhydride / 1 h / 130 °C 1.2: 1 h 2.1: sodium hydride / tetrahydrofuran / 1.5 h / Inert atmosphere; Reflux View Scheme

2,6-dichloro-5-fluoro-3-nicotinoyl chloride (96568-02-4) → ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1.) n-BuLi, biquinoline / 1.) THF, hexane, from -30 deg C to -5 deg C, 2.) THF, hexane, RT, 1 h 2: 1.) Ac2O / 1.) 130 deg C, 1 h, 2.) CH2Cl2, RT, 0.5 h 3: 86.5 percent / NaH / tetrahydrofuran / 1 h / Heating View Scheme
Multi-step reaction with 4 steps 1: 2.) p-TsOH*H2O / 1.) ether, RT, 2 h, 2.) H2O, reflux, 2.5 h 2: Ac2O / 15 h / 130 °C 3: ethanol / 1 h / Ambient temperature 4: NaH / dioxane / 1 h / Ambient temperature View Scheme
Multi-step reaction with 3 steps 1.1: 2,2'-biquinoline; n-butyllithium / tetrahydrofuran; hexane / 1 h / -50 - 20 °C 2.1: acetic anhydride / 1 h / 130 °C 2.2: 1 h 3.1: sodium hydride / tetrahydrofuran / 1.5 h / Inert atmosphere; Reflux View Scheme

2,6-dichloro-5-fluoro-3-pyridinecarboxylic acid (82671-06-5) → ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: thionyl chloride / 2 h / 80 °C 2: 1.) n-BuLi, biquinoline / 1.) THF, hexane, from -30 deg C to -5 deg C, 2.) THF, hexane, RT, 1 h 3: 1.) Ac2O / 1.) 130 deg C, 1 h, 2.) CH2Cl2, RT, 0.5 h 4: 86.5 percent / NaH / tetrahydrofuran / 1 h / Heating View Scheme
Multi-step reaction with 5 steps 1: PCl5 / 0.13 h / 100 °C 2: 2.) p-TsOH*H2O / 1.) ether, RT, 2 h, 2.) H2O, reflux, 2.5 h 3: Ac2O / 15 h / 130 °C 4: ethanol / 1 h / Ambient temperature 5: NaH / dioxane / 1 h / Ambient temperature View Scheme
Multi-step reaction with 4 steps 1.1: thionyl chloride / 2.5 h / 85 °C 2.1: 2,2'-biquinoline; n-butyllithium / tetrahydrofuran; hexane / 1 h / -50 - 20 °C 3.1: acetic anhydride / 1 h / 130 °C 3.2: 1 h 4.1: sodium hydride / tetrahydrofuran / 1.5 h / Inert atmosphere; Reflux View Scheme

ethyl 2,6-dichloro-5-fluoropyridine-3-carboxylate (82671-03-2) → ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: 73.2 percent / trifluoroacetic acid, 7.5 N aq. HCl / 24 h / Heating 2: thionyl chloride / 2 h / 80 °C 3: 1.) n-BuLi, biquinoline / 1.) THF, hexane, from -30 deg C to -5 deg C, 2.) THF, hexane, RT, 1 h 4: 1.) Ac2O / 1.) 130 deg C, 1 h, 2.) CH2Cl2, RT, 0.5 h 5: 86.5 percent / NaH / tetrahydrofuran / 1 h / Heating View Scheme
Multi-step reaction with 5 steps 1.1: trifluoroacetic acid; hydrogenchloride / water / 26 h / Reflux 2.1: thionyl chloride / 2.5 h / 85 °C 3.1: 2,2'-biquinoline; n-butyllithium / tetrahydrofuran; hexane / 1 h / -50 - 20 °C 4.1: acetic anhydride / 1 h / 130 °C 4.2: 1 h 5.1: sodium hydride / tetrahydrofuran / 1.5 h / Inert atmosphere; Reflux View Scheme

2,4-difluorophenylamine (367-25-9) → ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: ethanol / 1 h / Ambient temperature 2: NaH / dioxane / 1 h / Ambient temperature View Scheme

2,6-dichloro-α-(ethoxymethylene)-5-fluoro-β-oxo-3-pyridinepropanoic acid ethyl ester (96568-05-7) → ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: ethanol / 1 h / Ambient temperature 2: NaH / dioxane / 1 h / Ambient temperature View Scheme

ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) + tert-butyl (1R,5S,6R)-3-azabicyclo[3.1.0]hexan-6-ylcarbamate (134575-17-0) → 7-([1α,5α,6α]-6-tert-Butoxycarbonylamino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,ethyl ester (134575-66-9)

Conditions	Yield
With triethylamine In methanol for 1h; Substitution; Heating;	99%

ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) → 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (100492-04-4)

Conditions	Yield
In hydrogenchloride; water	97.1%
With methanesulfonic acid for 1h; Hydrolysis; Heating;	89%
With methanesulfonic acid In tetrahydrofuran; water	41.3 g (89%)

ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) + (1α,5α,6α)-6-Nitro-3-azabicyclo[3.1.0]hexane hydrochloride → Ethyl (1α,5α,6α)-7-(6-nitro-3-azabicyclo[3.1.0]hexan-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (171176-55-9)

Conditions	Yield
With triethylamine In acetonitrile at 82℃; for 6.5h; Substitution;	89%

ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) + 5-chloro-1H-benzoimidazole-2-thiol (25369-78-2) → ethyl 7-((5-chloro-1H-benzo[d]imidazol-2-yl)thio)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

Conditions	Yield
With potassium carbonate In acetone at 40℃; for 12h;	88%

ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) + 2-Mercaptobenzothiazole (149-30-4) → ethyl 7-((benzo[d]thiazol-2-yl)thio)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

Conditions	Yield
With potassium carbonate In acetone at 40℃; for 12h;	86%

(RS)-2-methylpiperazine (109-07-9) + ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) → 1-(2,4-Difluoro-phenyl)-6-fluoro-7-(3-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (100491-63-2)

Conditions	Yield
With pyridine for 3h; Ambient temperature;	85.7%

1-methyl-piperazine (109-01-3) + ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) → 1-(2,4-Difluoro-phenyl)-6-fluoro-7-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (100492-07-7)

Conditions	Yield
With pyridine for 3h; Ambient temperature;	85.3%

1-Acetyl-1,2,3,6-tetrahydro-4-tributylstannyl-pyridine (130579-43-0) + ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) → ethyl 7-(1-acetyl-1,2,3,6-tetrahydro-4-pyridinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (134046-57-4)

Conditions	Yield
With 2,6-di-tert-butyl-4-methyl-phenol; bis-triphenylphosphine-palladium(II) chloride In N,N-dimethyl-formamide for 7h; Heating;	83%

ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) + dimethyl-(3-piperazin-1-yl-propyl)-amine (877-96-3) → ethyl 1-(2,4-difluorophenyl)-7-(4-(3-(dimethylamino)propyl)piperazin-1-yl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

Conditions	Yield
With potassium carbonate In acetone at 40℃; for 12h;	82%

piperazine (110-85-0) + ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) → ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylate (104051-62-9)

Conditions	Yield
With pyridine for 3h; Ambient temperature;	81.4%
With pyridine at 20℃; for 24h;

3-acetylaminopyrrolidine (79286-74-1) + ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) → ethyl 7-(3-acetylamino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (100491-94-9)

Conditions	Yield
With pyridine for 3h; Ambient temperature;	81.2%

ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) + 6,9-diazaspiro<4,5>decane dihydrochloride (145122-55-0) → ethyl 1-(2,4-difluorophenyl)-6-fluoro-7-(6,9-diazaspiro<4,5>decan-9-yl)-1,4-dihydro-4-oxo<1,8>naphthyridine-3-carboxylate (145122-71-0)

Conditions	Yield
With 1-methyl-pyrrolidin-2-one; 1,8-diazabicyclo[5.4.0]undec-7-ene at 100℃;	81%

ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) + 1α,5α,6β-6-dibenzylamino-3-azabicyclo[3.1.0]hexane (210165-65-4) → 7-((1R,5S,6R)-6-Dibenzylamino-3-aza-bicyclo[3.1.0]hex-3-yl)-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (210165-72-3)

Conditions	Yield
With triethylamine In acetonitrile at 60℃; for 5h;	80%

ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) + Benzimidazol-2-thiol (134469-07-1) → ethyl 7-((1H-benzo[d]imidazol-2-yl)thio)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

Conditions	Yield
With potassium carbonate In acetone at 40℃; for 12h;	80%

ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) + 5-methyl-1H-benzoimidazole-2-thiol (27231-36-3) → ethyl 1-(2,4-difluorophenyl)-6-fluoro-7-((6-methyl-1H-benzo[d]imidazol-2-yl)thio)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

Conditions	Yield
With potassium carbonate In acetone at 40℃; for 12h;	79%

ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) + (2S,4S)-4-Acetylamino-2-methylpyrrolidine (114677-00-8) → 7-((2S,4S)-4-Acetylamino-2-methyl-pyrrolidin-1-yl)-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (121332-89-6)

Conditions	Yield
With triethylamine In pyridine at 65℃; for 336h;	78%

5-nitro-2-mercaptobenzimidazole (6325-91-3) + ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) → ethyl 1-(2,4-difluorophenyl)-6-fluoro-7-((6-nitro-1H-benzo[d]imidazol-2-yl)thio)-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate

Conditions	Yield
With potassium carbonate In acetone at 40℃; for 12h;	78%

ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) → ethyl 1-(2,4-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylate

Conditions	Yield
With tetrabutyl ammonium fluoride In dimethyl sulfoxide at 20℃; for 0.166667h;	77%

[1α,2α,5α]-1-[(N-tert-Butoxycarbonyl)amino]-2-methyl-3-azabicyclo[3.1.0]hexane + ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) → 7-([1α,2α,5α]-1-tert-Butoxycarbonylamino-2-methyl-3-azabicyclo[3.1.0]hex-3-yl)-6-fluoro-1-(2,4-difluoro phenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, ethyl ester

Conditions	Yield
	72%
	72%

tert-butyl acetoacetate (1694-31-1) + ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) → 7-(1-tert-Butoxycarbonyl-2-oxo-propyl)-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (123822-15-1)

Conditions	Yield
With sodium hydride In N,N-dimethyl-formamide for 20h; Ambient temperature;	61%

ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) + 4,7-diazaspiro<2,5>octane dihydrochloride (145122-56-1) → ethyl 1-(2,4-difluorophenyl)-6-fluoro-7-(4,7-diazaspiro<2,5>octan-7-yl)-1,4-dihydro-4-oxo<1,8>naphthyridine-3-carboxylate (145122-69-6)

Conditions	Yield
With 1-methyl-pyrrolidin-2-one; 1,8-diazabicyclo[5.4.0]undec-7-ene at 100℃;	53%

1,1-dimethylethyl-<3-(tri-n-butylstannyl)-2-cyclopenten-1-yl>carbamate (129081-77-2) + ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) → ethyl 1-(2,4-difluorophenyl)-7-<3-<<(1,1-dimethylethoxy)carbonyl>amino>-1-cyclopenten-1-yl>-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (134046-56-3)

Conditions	Yield
With 2,6-di-tert-butyl-4-methyl-phenol; tetrakis(triphenylphosphine) palladium(0) In 1,4-dioxane for 55h; Heating;	42%

(1R,4R)-2,5-diazabicyclo<2.2.1>heptane (116183-84-7) + ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) → 7-(1R,4R)-2,5-Diaza-bicyclo[2.2.1]hept-2-yl-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 70℃; for 1h;

<1R,4R>-(1R-cis) 2,5-diazabicyclo<2.2.2>octane (132339-20-9) + ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) → 7-(1S,4S)-2,5-Diaza-bicyclo[2.2.1]hept-2-yl-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester

Conditions	Yield
With triethylamine In pyridine at 40℃; for 48h;

acetic anhydride (108-24-7) + ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) + (3S)-3-azido-1-(phenylmethyl)pyrrolidine (114636-29-2) → 7-((R)-3-Acetylamino-pyrrolidin-1-yl)-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester + 7-((S)-3-Acetylamino-pyrrolidin-1-yl)-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (114636-32-7)

Conditions	Yield
Yield given. Multistep reaction. Yields of byproduct given. Title compound not separated from byproducts;

ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (100491-29-0) + (1R,4R,6S)-6-methyl-5-(phenylmethyl)2,5-diazabicyclo<2.2.1>heptane dihydrobromide (141871-22-9, 141902-28-5) → 7-((1R,4R,6S)-5-Benzyl-6-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (143005-00-9)

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile

Upstream product

• 100490-99-1 ethyl-3,1-(2,4-difluoroanilino)-2-(2,6-dichloro-5-fluoronicotinyl) acrylate 
• 96568-02-4 2,6-dichloro-5-fluoro-3-nicotinoyl chloride 
• 82671-06-5 2,6-dichloro-5-fluoro-3-pyridinecarboxylic acid 
• 367-25-9 2,4-difluorophenylamine 
• 96568-05-7 2,6-dichloro-α-(ethoxymethylene)-5-fluoro-β-oxo-3-pyridinepropanoic acid ethyl ester 
• 105152-47-4 ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]acetate 
• 82671-03-2 ethyl 2,6-dichloro-5-fluoropyridine-3-carboxylate 
• 96568-04-6 ethyl 3-(2,6-dichloro-5-fluoropyridin-3-yl)-3-oxopropanoate 

Downstream Products

• 104051-62-9 ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylate 
• 100492-07-7 1-(2,4-Difluoro-phenyl)-6-fluoro-7-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester 
• 100491-63-2 1-(2,4-Difluoro-phenyl)-6-fluoro-7-(3-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester 
• 100491-94-9 ethyl 7-(3-acetylamino-1-pyrrolidinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 
• 134046-57-4 ethyl 7-(1-acetyl-1,2,3,6-tetrahydro-4-pyridinyl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 
• 134046-56-3 ethyl 1-(2,4-difluorophenyl)-7-<3-<<(1,1-dimethylethoxy)carbonyl>amino>-1-cyclopenten-1-yl>-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 
• 139524-62-2 1-(2,4-Difluoro-phenyl)-7-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester 
• 139524-61-1 1-(2,4-Difluoro-phenyl)-7-(1,4-dioxa-7-aza-spiro[4.4]non-7-yl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester 
• 123822-15-1 7-(1-tert-Butoxycarbonyl-2-oxo-propyl)-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester 
• 210165-72-3 7-((1R,5S,6R)-6-Dibenzylamino-3-aza-bicyclo[3.1.0]hex-3-yl)-1-(2,4-difluoro-phenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester 
• 134575-66-9 7-([1α,5α,6α]-6-tert-Butoxycarbonylamino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid,ethyl ester 
• 171176-56-0 Ethyl (1α,5α,6α)-7-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 
• 288628-59-1 Ethyl (1α,5α,6α)-7-(6-benzylideneamino-3-azabicyclo[3.1.0]hexan-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 
• 171176-55-9 Ethyl (1α,5α,6α)-7-(6-nitro-3-azabicyclo[3.1.0]hexan-3-yl)-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate 

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