545445-44-1

Basic information

• Product Name: 3-Morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin-2(1H)-one
• Synonyms: 3-Morpholin-4-yl-1-[4-(2-oxopiperidin-1-yl)phenyl]-5,6-dihydro-1H-pyridin-2-one;5,6-Dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1H)-pyridinone;3-Morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin-2(1H)-one;Apixaba inretMediate B;Apixaban Intermediate B;Apixaban Intermediate 2;5-morpholin-4-yl-1-[4-(2-oxopiperidin-1-yl)phenyl]-2,3-dihydropyridin-6-one;3-Morpholino-1-(4-(2-oxopiperidin-1-yl)
• CAS NO: 545445-44-1
• Molecular Formula: C₂₀H₂₅N₃O₃
• Molecular Weight: 355
• EINECS: 1308068-626-2
• Mol File: 545445-44-1.mol
• Article Data: 21

Chemical Properties

• Boiling Point: 624.979 °C at 760 mmHg
• Flash Point: 331.775 °C
• Appearance: /
• Density: 1.267
• Storage Temp.: 2-8°C
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 3.25±0.20(Predicted)
• CAS DataBase Reference: 3-Morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin-2(1H)-one(CAS DataBase Reference)
• NIST Chemistry Reference: 3-Morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin-2(1H)-one(545445-44-1)
• EPA Substance Registry System: 3-Morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin-2(1H)-one(545445-44-1)

Safety Data

• Hazardous Substances Data: 545445-44-1(Hazardous Substances Data)

Usage

Uses

3-Morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropy can be used as an organic synthesis intermediate, mainly used in laboratory research and development and chemical production processes.

Synthesis

2 g compound C (compound Ib) and 50 ml acetonitrile were added into a three-necked flask to obtain a turbid solution. The turbid solution was stirred and cooled to 0° C. in an ice bath. 1.75 g (6 eq) sodium hydroxide was added and stirred in the ice bath for 10 min. Then 1.9 ml of 5-chloro-valeryl chloride (2 eq) (diluted with 2 ml acetonitrile) was dropwise added while controlling the temperature to 0-5° C. After completing the addition, the ice bath was removed and the temperature was naturally raised to 30° C. The reaction was performed for 5 hours. After observing the absence of the starting material and the intermediate state of the reaction, the reaction solution was cooled to 0° C. in an ice bath, and adjusted to a neutral pH with 6 N of hydrochloric acid. The reaction solution was concentrated to dryness, pulpifying for 1 hour after adding 8 ml saturated sodium bicarbonate solution, and filtered to obtain 2.29 g yellow solid. Yield: 87.5%. Purity: 95.3% (HPLC). EI-MS (m/z): 355.2. HNMR (400 MHz, DMSO, ppm) δ7.32 (d, J=8.8 Hz, 2H), 7.26 (d, J=8.8 Hz, 2H), 5.71 (t, J=4.8 Hz, 1H), 3.72-3.69 (m, 2H), 3.65-3.63 (m, 4H), 3.60-3.57 (m, 2H), 2.79-2.77 (m, 4H), 2.44-2.41 (m, 2H), 2.40-2.39 (m, 2H), 1.88-1.82 (m, 4H).

Synthetic route

morpholine (110-91-8) + 1-(piperidin-2-one-1-yl)-4-(5,6-dihydro-3-chloropyridine-2(1H)-one-1-yl)benzene → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Stage #1: 1-(piperidin-2-one-1-yl)-4-(5,6-dihydro-3-chloropyridine-2(1H)-one-1-yl)benzene With bromine; sodium hydroxide In dichloromethane; water at 25 - 35℃; for 4h; Stage #2: morpholine With triethylamine In N,N-dimethyl-formamide at 95 - 100℃; for 5h; Reagent/catalyst; Solvent; Temperature;	95.2%

5-Chlorovaleroyl chloride (1575-61-7) + 1-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-2(1H)-one (1267610-26-3) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Stage #1: 5-Chlorovaleroyl chloride; 1-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-2(1H)-one With tetrabutylammomium bromide; sodium hydroxide In dichloromethane; water at 0 - 5℃; for 1h; Stage #2: With potassium hydroxide In dichloromethane; water at 20℃; Reagent/catalyst; Solvent; Temperature;	94.27%
Stage #1: 1-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-2(1H)-one With tetraethylammonium hydroxide In 1,2-dichloro-ethane at 0℃; for 0.166667h; Stage #2: 5-Chlorovaleroyl chloride In 1,2-dichloro-ethane at 0 - 85℃; for 5h; Solvent; Temperature; Reagent/catalyst;	89%
Stage #1: 1-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-2(1H)-one With sodium hydroxide In acetonitrile at 0℃; for 0.166667h; Green chemistry; Stage #2: 5-Chlorovaleroyl chloride In acetonitrile at 0 - 30℃; for 5h; Reagent/catalyst; Solvent; Temperature; Green chemistry;	87.5%

piperidin-2-one (675-20-7) + 1-(4-chlorophenyl)-3-morpholine-5,6-dihydropyridine-2(1H)-one → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
With bis-triphenylphosphine-palladium(II) chloride; sodium hydride In dimethyl sulfoxide at 20℃; for 2h; Solvent;	93.1%
With copper(l) iodide; potassium tert-butylate In N,N-dimethyl-formamide at 150℃; for 16h; Reagent/catalyst; Solvent; Temperature; Inert atmosphere;	76%

3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (545445-40-7) + (2-oxopiperidine-1-yl)chlorobenzene → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
With palladium diacetate; caesium carbonate In dimethyl sulfoxide at 20℃; for 6h; Reagent/catalyst; Inert atmosphere;	93%

1-(2-oxopiperidin-1-yl)-4-iodobenzene (385425-15-0) + 3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (545445-40-7) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
With copper(l) iodide; 1,10-Phenanthroline; potassium carbonate In dimethyl sulfoxide at 110℃; for 12h; Inert atmosphere;	86%

5-chloropentanoic acid [4-(5-morpholin-4-yl-6-oxo-3,6-dihydro-2H-pyridin-1-yl)phenyl]amide → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
With sodium hydride In tetrahydrofuran at 10 - 25℃; Inert atmosphere;	84.5%
With potassium tert-butylate In tetrahydrofuran at 5 - 50℃; for 8.5h; Inert atmosphere;	3.02 g

1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (473927-69-4) + piperidin-2-one (675-20-7) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
With bromotris(triphenylphosphine)copper(I) In 5,5-dimethyl-1,3-cyclohexadiene Dean-Stark; Reflux;	84%
With potassium phosphate; bromotris(triphenylphosphine)copper(I) In 5,5-dimethyl-1,3-cyclohexadiene Reflux; Dean-Stark;	84%
Stage #1: 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one; piperidin-2-one In o-xylene at 25 - 30℃; for 0.166667h; Stage #2: With copper(l) iodide; potassium carbonate In o-xylene at 140 - 145℃; for 6h;	35 g

5-bromovaleroyl chloride (4509-90-4) + 1-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-2(1H)-one (1267610-26-3) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Stage #1: 5-bromovaleroyl chloride; 1-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-2(1H)-one With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0 - 40℃; for 1h; Stage #2: With sodium hydride In ethyl acetate; tert-butyl alcohol at 10 - 40℃; for 3h; Solvent;	76%

1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one (473927-69-4) + piperidin-2-one (675-20-7) + Cu(PPh3)3Br → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
With ammonium hydroxide; caesium carbonate In ethyl acetate; toluene

1-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-2(1H)-one (1267610-26-3) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 2 h / 5 - 50 °C / Inert atmosphere 2: potassium tert-butylate / tetrahydrofuran / 8.5 h / 5 - 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 10 - 25 °C / Inert atmosphere 2: sodium hydride / tetrahydrofuran / 10 - 25 °C / Inert atmosphere View Scheme

4-nitro-aniline (100-01-6) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 7 steps 1: triethylamine / tetrahydrofuran / 5 h / 5 - 20 °C / Inert atmosphere 2: potassium tert-butylate / tetrahydrofuran / 2.5 h / 5 - 20 °C / Inert atmosphere 3: phosphorus pentachloride / chloroform / Reflux 4: 1 h / Reflux 5: water; sodiumsulfide nonahydrate / ethanol / 4 h / 50 °C 6: triethylamine / tetrahydrofuran / 2 h / 5 - 50 °C / Inert atmosphere 7: potassium tert-butylate / tetrahydrofuran / 8.5 h / 5 - 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 7 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 5 - 25 °C / Inert atmosphere 2: sodium hydride / tetrahydrofuran / 10 - 25 °C / Inert atmosphere 3: phosphorus pentachloride / dichloromethane / 40 °C / Cooling with ice; Inert atmosphere 4: 2 h / 120 °C / Inert atmosphere 5: water; sodium sulfide / ethanol / 50 °C / Inert atmosphere 6: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 10 - 25 °C / Inert atmosphere 7: sodium hydride / tetrahydrofuran / 10 - 25 °C / Inert atmosphere View Scheme

5-Chlorovaleroyl chloride (1575-61-7) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 7 steps 1: triethylamine / tetrahydrofuran / 5 h / 5 - 20 °C / Inert atmosphere 2: potassium tert-butylate / tetrahydrofuran / 2.5 h / 5 - 20 °C / Inert atmosphere 3: phosphorus pentachloride / chloroform / Reflux 4: 1 h / Reflux 5: water; sodiumsulfide nonahydrate / ethanol / 4 h / 50 °C 6: triethylamine / tetrahydrofuran / 2 h / 5 - 50 °C / Inert atmosphere 7: potassium tert-butylate / tetrahydrofuran / 8.5 h / 5 - 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 7 steps 1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 5 - 25 °C / Inert atmosphere 2: sodium hydride / tetrahydrofuran / 10 - 25 °C / Inert atmosphere 3: phosphorus pentachloride / dichloromethane / 40 °C / Cooling with ice; Inert atmosphere 4: 2 h / 120 °C / Inert atmosphere 5: water; sodium sulfide / ethanol / 50 °C / Inert atmosphere 6: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 10 - 25 °C / Inert atmosphere 7: sodium hydride / tetrahydrofuran / 10 - 25 °C / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1.1: triethylamine / tetrahydrofuran 2.1: sodium t-butanolate / tetrahydrofuran / 4 h / 0 - 40 °C 3.1: sulfuric acid; nitric acid / 2 h / -5 - 40 °C 4.1: phosphorus pentachloride / Cooling with ice 4.2: 2 h / Reflux 5.1: sodiumsulfide nonahydrate / ethanol / 1 h / 60 °C 6.1: triethylamine / tetrahydrofuran / 1 h / 0 - 40 °C 6.2: 3 h / 10 - 40 °C View Scheme

5-chloro-N-(4-nitrophenyl)pentanamide (1039914-85-6) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 6 steps 1: potassium tert-butylate / tetrahydrofuran / 2.5 h / 5 - 20 °C / Inert atmosphere 2: phosphorus pentachloride / chloroform / Reflux 3: 1 h / Reflux 4: water; sodiumsulfide nonahydrate / ethanol / 4 h / 50 °C 5: triethylamine / tetrahydrofuran / 2 h / 5 - 50 °C / Inert atmosphere 6: potassium tert-butylate / tetrahydrofuran / 8.5 h / 5 - 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 6 steps 1: sodium hydride / tetrahydrofuran / 10 - 25 °C / Inert atmosphere 2: phosphorus pentachloride / dichloromethane / 40 °C / Cooling with ice; Inert atmosphere 3: 2 h / 120 °C / Inert atmosphere 4: water; sodium sulfide / ethanol / 50 °C / Inert atmosphere 5: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 10 - 25 °C / Inert atmosphere 6: sodium hydride / tetrahydrofuran / 10 - 25 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1.1: tetrabutylammomium bromide; potassium hydroxide / water; tetrahydrofuran / 0 - 20 °C 2.1: phosphorus pentachloride / toluene / 1 h / 25 - 80 °C 3.1: N,N-dimethyl-formamide / 1 h / Reflux 4.1: hydrazine hydrate / water; ethanol / 0.5 h / 60 - 65 °C 5.1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane; water / 1 h / 0 - 5 °C 5.2: 20 °C View Scheme

1-(4-nitrophenyl)piperidine-2-one (38560-30-4) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 5 steps 1: phosphorus pentachloride / chloroform / Reflux 2: 1 h / Reflux 3: water; sodiumsulfide nonahydrate / ethanol / 4 h / 50 °C 4: triethylamine / tetrahydrofuran / 2 h / 5 - 50 °C / Inert atmosphere 5: potassium tert-butylate / tetrahydrofuran / 8.5 h / 5 - 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: phosphorus pentachloride / dichloromethane / 40 °C / Cooling with ice; Inert atmosphere 2: 2 h / 120 °C / Inert atmosphere 3: water; sodium sulfide / ethanol / 50 °C / Inert atmosphere 4: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 10 - 25 °C / Inert atmosphere 5: sodium hydride / tetrahydrofuran / 10 - 25 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: phosphorus pentachloride / Cooling with ice 1.2: 2 h / Reflux 2.1: sodiumsulfide nonahydrate / ethanol / 1 h / 60 °C 3.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 0 - 40 °C 3.2: 3 h / 10 - 40 °C View Scheme
Multi-step reaction with 3 steps 1.1: phosphorus pentachloride / Cooling with ice 1.2: 2 h / Reflux 2.1: sodiumsulfide nonahydrate / ethanol / 1 h / 60 °C 3.1: triethylamine / tetrahydrofuran / 1 h / 0 - 40 °C 3.2: 3 h / 10 - 40 °C View Scheme
Multi-step reaction with 4 steps 1.1: phosphorus pentachloride / toluene / 1 h / 25 - 80 °C 2.1: N,N-dimethyl-formamide / 1 h / Reflux 3.1: hydrazine hydrate / water; ethanol / 0.5 h / 60 - 65 °C 4.1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane; water / 1 h / 0 - 5 °C 4.2: 20 °C View Scheme

C11H11ClN2O3 → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1 h / Reflux 2: water; sodiumsulfide nonahydrate / ethanol / 4 h / 50 °C 3: triethylamine / tetrahydrofuran / 2 h / 5 - 50 °C / Inert atmosphere 4: potassium tert-butylate / tetrahydrofuran / 8.5 h / 5 - 50 °C / Inert atmosphere View Scheme

3-(morpholin-4-yl)-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one (503615-03-0) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: water; sodiumsulfide nonahydrate / ethanol / 4 h / 50 °C 2: triethylamine / tetrahydrofuran / 2 h / 5 - 50 °C / Inert atmosphere 3: potassium tert-butylate / tetrahydrofuran / 8.5 h / 5 - 50 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1: water; sodium sulfide / ethanol / 50 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 10 - 25 °C / Inert atmosphere 3: sodium hydride / tetrahydrofuran / 10 - 25 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: sodiumsulfide nonahydrate / ethanol / 1 h / 60 °C 2.1: triethylamine / tetrahydrofuran / 1 h / 0 - 40 °C 2.2: 3 h / 10 - 40 °C View Scheme

5-bromopentanoic acid (2067-33-6) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 2 h / 40 - 45 °C 1.2: 2 h / 0 - 30 °C / Inert atmosphere 2.1: sodium t-butanolate / toluene / 2 h / 0 - 5 °C 3.1: phosphorus pentachloride / dichloromethane / 4 h / 25 - 40 °C 4.1: sodium chloride; lithium carbonate / N,N-dimethyl-formamide / 6 h / 25 - 120 °C 5.1: toluene / 8 h / 30 - 120 °C 6.1: o-xylene / 0.17 h / 25 - 30 °C 6.2: 6 h / 140 - 145 °C View Scheme

p-aminoiodobenzene (540-37-4) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / toluene / 2 h / 40 - 45 °C 1.2: 2 h / 0 - 30 °C / Inert atmosphere 2.1: sodium t-butanolate / toluene / 2 h / 0 - 5 °C 3.1: phosphorus pentachloride / dichloromethane / 4 h / 25 - 40 °C 4.1: sodium chloride; lithium carbonate / N,N-dimethyl-formamide / 6 h / 25 - 120 °C 5.1: toluene / 8 h / 30 - 120 °C 6.1: o-xylene / 0.17 h / 25 - 30 °C 6.2: 6 h / 140 - 145 °C View Scheme
Multi-step reaction with 5 steps 1: triethylamine; dmap / ethyl acetate / 5 - 15 °C 2: potassium phosphate / N,N-dimethyl-formamide; toluene / 7 h / 110 °C 3: phosphorus pentachloride / dichloromethane / Reflux 4: N,N-dimethyl-formamide / 105 - 110 °C 5: bromotris(triphenylphosphine)copper(I) / 5,5-dimethyl-1,3-cyclohexadiene / Dean-Stark; Reflux View Scheme
Multi-step reaction with 5 steps 1: triethylamine; dmap / ethyl acetate / 5 - 15 °C 2: potassium phosphate / toluene; N,N-dimethyl-formamide / 7 h / 110 °C 3: phosphorus pentachloride / dichloromethane / Reflux 4: N,N-dimethyl-formamide / 105 - 110 °C 5: bromotris(triphenylphosphine)copper(I); potassium phosphate / 5,5-dimethyl-1,3-cyclohexadiene / Reflux; Dean-Stark View Scheme

5-bromo-pentanoic acid-(4-iodophenyl)amide → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium t-butanolate / toluene / 2 h / 0 - 5 °C 2.1: phosphorus pentachloride / dichloromethane / 4 h / 25 - 40 °C 3.1: sodium chloride; lithium carbonate / N,N-dimethyl-formamide / 6 h / 25 - 120 °C 4.1: toluene / 8 h / 30 - 120 °C 5.1: o-xylene / 0.17 h / 25 - 30 °C 5.2: 6 h / 140 - 145 °C View Scheme
Multi-step reaction with 4 steps 1: potassium phosphate / N,N-dimethyl-formamide; toluene / 7 h / 110 °C 2: phosphorus pentachloride / dichloromethane / Reflux 3: N,N-dimethyl-formamide / 105 - 110 °C 4: bromotris(triphenylphosphine)copper(I) / 5,5-dimethyl-1,3-cyclohexadiene / Dean-Stark; Reflux View Scheme
Multi-step reaction with 4 steps 1: potassium phosphate / toluene; N,N-dimethyl-formamide / 7 h / 110 °C 2: phosphorus pentachloride / dichloromethane / Reflux 3: N,N-dimethyl-formamide / 105 - 110 °C 4: bromotris(triphenylphosphine)copper(I); potassium phosphate / 5,5-dimethyl-1,3-cyclohexadiene / Reflux; Dean-Stark View Scheme

1-(2-oxopiperidin-1-yl)-4-iodobenzene (385425-15-0) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: phosphorus pentachloride / dichloromethane / 4 h / 25 - 40 °C 2.1: sodium chloride; lithium carbonate / N,N-dimethyl-formamide / 6 h / 25 - 120 °C 3.1: toluene / 8 h / 30 - 120 °C 4.1: o-xylene / 0.17 h / 25 - 30 °C 4.2: 6 h / 140 - 145 °C View Scheme
Multi-step reaction with 3 steps 1: phosphorus pentachloride / dichloromethane / Reflux 2: N,N-dimethyl-formamide / 105 - 110 °C 3: bromotris(triphenylphosphine)copper(I) / 5,5-dimethyl-1,3-cyclohexadiene / Dean-Stark; Reflux View Scheme
Multi-step reaction with 3 steps 1: phosphorus pentachloride / dichloromethane / Reflux 2: N,N-dimethyl-formamide / 105 - 110 °C 3: bromotris(triphenylphosphine)copper(I); potassium phosphate / 5,5-dimethyl-1,3-cyclohexadiene / Reflux; Dean-Stark View Scheme

3,3-dichloro-1-(4-iodo-phenyl)piperidin-2-one (545445-10-1) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium chloride; lithium carbonate / N,N-dimethyl-formamide / 6 h / 25 - 120 °C 2.1: toluene / 8 h / 30 - 120 °C 3.1: o-xylene / 0.17 h / 25 - 30 °C 3.2: 6 h / 140 - 145 °C View Scheme
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 105 - 110 °C 2: bromotris(triphenylphosphine)copper(I) / 5,5-dimethyl-1,3-cyclohexadiene / Dean-Stark; Reflux View Scheme
Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 105 - 110 °C 2: bromotris(triphenylphosphine)copper(I); potassium phosphate / 5,5-dimethyl-1,3-cyclohexadiene / Reflux; Dean-Stark View Scheme

3-chloro-1-(4-iodophenyl)-5,6-dihydropyridin-2(1H)-one → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: toluene / 8 h / 30 - 120 °C 2.1: o-xylene / 0.17 h / 25 - 30 °C 2.2: 6 h / 140 - 145 °C View Scheme

3,3-dichloro-1-(4-nitrophenyl)piperidine-2-one (881386-01-2) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: 2 h / 120 °C / Inert atmosphere 2: water; sodium sulfide / ethanol / 50 °C / Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 10 - 25 °C / Inert atmosphere 4: sodium hydride / tetrahydrofuran / 10 - 25 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: N,N-dimethyl-formamide / 1 h / Reflux 2.1: hydrazine hydrate / water; ethanol / 0.5 h / 60 - 65 °C 3.1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane; water / 1 h / 0 - 5 °C 3.2: 20 °C View Scheme

5-chloro-pentanoic acid phenylamide (91131-23-6) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium t-butanolate / tetrahydrofuran / 4 h / 0 - 40 °C 2.1: sulfuric acid; nitric acid / 2 h / -5 - 40 °C 3.1: phosphorus pentachloride / Cooling with ice 3.2: 2 h / Reflux 4.1: sodiumsulfide nonahydrate / ethanol / 1 h / 60 °C 5.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 0 - 40 °C 5.2: 3 h / 10 - 40 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium t-butanolate / tetrahydrofuran / 4 h / 0 - 40 °C 2.1: sulfuric acid; nitric acid / 2 h / -5 - 40 °C 3.1: phosphorus pentachloride / Cooling with ice 3.2: 2 h / Reflux 4.1: sodiumsulfide nonahydrate / ethanol / 1 h / 60 °C 5.1: triethylamine / tetrahydrofuran / 1 h / 0 - 40 °C 5.2: 3 h / 10 - 40 °C View Scheme
Multi-step reaction with 6 steps 1.1: potassium hydroxide / dichloromethane; N,N-dimethyl-formamide / 1 h / 0 - 20 °C / Inert atmosphere 2.1: nitric acid; sulfuric acid / 0 - 5 °C 3.1: phosphorus pentachloride / toluene / 1 h / 25 - 80 °C 4.1: N,N-dimethyl-formamide / 1 h / Reflux 5.1: hydrazine hydrate / water; ethanol / 0.5 h / 60 - 65 °C 6.1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane; water / 1 h / 0 - 5 °C 6.2: 20 °C View Scheme

aniline (62-53-3) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: triethylamine / tetrahydrofuran 2.1: sodium t-butanolate / tetrahydrofuran / 4 h / 0 - 40 °C 3.1: sulfuric acid; nitric acid / 2 h / -5 - 40 °C 4.1: phosphorus pentachloride / Cooling with ice 4.2: 2 h / Reflux 5.1: sodiumsulfide nonahydrate / ethanol / 1 h / 60 °C 6.1: triethylamine / tetrahydrofuran / 1 h / 0 - 40 °C 6.2: 3 h / 10 - 40 °C View Scheme
Multi-step reaction with 6 steps 1.1: triethylamine / tetrahydrofuran 2.1: sodium t-butanolate / tetrahydrofuran / 4 h / 0 - 40 °C 3.1: sulfuric acid; nitric acid / 2 h / -5 - 40 °C 4.1: phosphorus pentachloride / Cooling with ice 4.2: 2 h / Reflux 5.1: sodiumsulfide nonahydrate / ethanol / 1 h / 60 °C 6.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 0 - 40 °C 6.2: 3 h / 10 - 40 °C View Scheme
Multi-step reaction with 6 steps 1.1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane; water / 1 h / 0 - 5 °C 1.2: 20 °C 2.1: nitric acid; sulfuric acid / 0 - 5 °C 3.1: phosphorus pentachloride / toluene / 1 h / 25 - 80 °C 4.1: N,N-dimethyl-formamide / 1 h / Reflux 5.1: hydrazine hydrate / water; ethanol / 0.5 h / 60 - 65 °C 6.1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane; water / 1 h / 0 - 5 °C 6.2: 20 °C View Scheme
Multi-step reaction with 7 steps 1.1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane; water / 1 h / 25 - 30 °C 2.1: potassium hydroxide / dichloromethane; N,N-dimethyl-formamide / 1 h / 0 - 20 °C / Inert atmosphere 3.1: nitric acid; sulfuric acid / 0 - 5 °C 4.1: phosphorus pentachloride / toluene / 1 h / 25 - 80 °C 5.1: N,N-dimethyl-formamide / 1 h / Reflux 6.1: hydrazine hydrate / water; ethanol / 0.5 h / 60 - 65 °C 7.1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane; water / 1 h / 0 - 5 °C 7.2: 20 °C View Scheme

1-phenylpiperidin-2-one (4789-09-7) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sulfuric acid; nitric acid / 2 h / -5 - 40 °C 2.1: phosphorus pentachloride / Cooling with ice 2.2: 2 h / Reflux 3.1: sodiumsulfide nonahydrate / ethanol / 1 h / 60 °C 4.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 1 h / 0 - 40 °C 4.2: 3 h / 10 - 40 °C View Scheme
Multi-step reaction with 4 steps 1.1: sulfuric acid; nitric acid / 2 h / -5 - 40 °C 2.1: phosphorus pentachloride / Cooling with ice 2.2: 2 h / Reflux 3.1: sodiumsulfide nonahydrate / ethanol / 1 h / 60 °C 4.1: triethylamine / tetrahydrofuran / 1 h / 0 - 40 °C 4.2: 3 h / 10 - 40 °C View Scheme
Multi-step reaction with 5 steps 1.1: nitric acid; sulfuric acid / 0 - 5 °C 2.1: phosphorus pentachloride / toluene / 1 h / 25 - 80 °C 3.1: N,N-dimethyl-formamide / 1 h / Reflux 4.1: hydrazine hydrate / water; ethanol / 0.5 h / 60 - 65 °C 5.1: sodium hydroxide; tetrabutylammomium bromide / dichloromethane; water / 1 h / 0 - 5 °C 5.2: 20 °C View Scheme

4-chloro-aniline (106-47-8) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / tetrahydrofuran / -5 - 20 °C 1.2: 80 °C 2.1: palladium diacetate; caesium carbonate / dimethyl sulfoxide / 6 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: triethylamine / tetrahydrofuran / 1 h / 0 °C 2: sodium hydroxide / dichloromethane / 2 h / 20 °C 3: phosphorus pentachloride / acetonitrile / 2 h / Reflux 4: acetonitrile / 2 h / Reflux 5: bis-triphenylphosphine-palladium(II) chloride; sodium hydride / dimethyl sulfoxide / 2 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: acetic acid / 8 h / 50 °C 2.1: thionyl chloride / dichloromethane / 2 h / 10 - 20 °C 2.2: 2.5 h / 20 °C 3.1: sodium bis(2-methoxyethoxy)aluminium dihydride / tetrahydrofuran; toluene / 1 h / 0 °C 4.1: sodium t-butanolate / tert-butyl alcohol / 3 h / 85 °C 5.1: copper(l) iodide; potassium tert-butylate / N,N-dimethyl-formamide / 16 h / 150 °C / Inert atmosphere View Scheme

5-bromovaleroyl chloride (4509-90-4) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine / tetrahydrofuran / -5 - 20 °C 1.2: 80 °C 2.1: palladium diacetate; caesium carbonate / dimethyl sulfoxide / 6 h / 20 °C / Inert atmosphere View Scheme
Multi-step reaction with 5 steps 1: triethylamine; dmap / ethyl acetate / 5 - 15 °C 2: potassium phosphate / N,N-dimethyl-formamide; toluene / 7 h / 110 °C 3: phosphorus pentachloride / dichloromethane / Reflux 4: N,N-dimethyl-formamide / 105 - 110 °C 5: bromotris(triphenylphosphine)copper(I) / 5,5-dimethyl-1,3-cyclohexadiene / Dean-Stark; Reflux View Scheme
Multi-step reaction with 5 steps 1: triethylamine; dmap / ethyl acetate / 5 - 15 °C 2: potassium phosphate / toluene; N,N-dimethyl-formamide / 7 h / 110 °C 3: phosphorus pentachloride / dichloromethane / Reflux 4: N,N-dimethyl-formamide / 105 - 110 °C 5: bromotris(triphenylphosphine)copper(I); potassium phosphate / 5,5-dimethyl-1,3-cyclohexadiene / Reflux; Dean-Stark View Scheme
Multi-step reaction with 5 steps 1: triethylamine / tetrahydrofuran / 1 h / 0 °C 2: sodium hydroxide / dichloromethane / 2 h / 20 °C 3: phosphorus pentachloride / acetonitrile / 2 h / Reflux 4: acetonitrile / 2 h / Reflux 5: bis-triphenylphosphine-palladium(II) chloride; sodium hydride / dimethyl sulfoxide / 2 h / 20 °C View Scheme

5-bromo-N-{4-[5-(morpholin-4-yl)-6-oxo-3,6-dihydropyridin-1(2H)-yl]phenyl}pentanamide → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
With SPGS-550-M; potassium tert-butylate; potassium iodide In water at 35 - 40℃; Reagent/catalyst; Temperature;

5-chloro-N-(4-chlorophenyl)pentanamide (27471-36-9) → 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydroxide / dichloromethane / 2 h / 20 °C 2: phosphorus pentachloride / acetonitrile / 2 h / Reflux 3: acetonitrile / 2 h / Reflux 4: bis-triphenylphosphine-palladium(II) chloride; sodium hydride / dimethyl sulfoxide / 2 h / 20 °C View Scheme

5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1) + Ethyl oxalyl chloride (4755-77-5) → ethyl {5-hydroxy-6-oxo-1-[4-(2-oxopiperidin-1-yl)phenyl]-1,2,3,6-tetrahydropyridin-4-yl}(oxo)acetate (1609409-53-1)

Conditions	Yield
Stage #1: 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone; Ethyl oxalyl chloride With pyridine at 25 - 30℃; for 3h; Stage #2: With hydrogenchloride; water In ethyl acetate for 1h;	90%

5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1) + ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (27143-07-3) → 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (503614-91-3)

Conditions	Yield
With triethylamine; potassium iodide In ethyl acetate for 24h; Reflux;	89.9%
With potassium carbonate; carbonic acid dimethyl ester at 82℃; for 0.5h; Temperature; Reagent/catalyst;	80.33%
With triethylamine In ethyl acetate; toluene at 85℃; for 7h;	76%
With triethylamine; potassium iodide In ethyl acetate at 25 - 80℃; for 24h;	54 mg
Stage #1: 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone; ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate With triethylamine Stage #2: With hydrogenchloride In water

5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1) + [(4-methoxyphenyl)hydrazino]chloroacetic acid ethyl ester → 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (503614-91-3)

Conditions	Yield
Stage #1: 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone; [(4-methoxyphenyl)hydrazino]chloroacetic acid ethyl ester With N-benzyl-N,N,N-triethylammonium chloride; sodium carbonate In toluene for 3h; Reflux; Stage #2: With sulfuric acid In dichloromethane at 20℃; for 3.5h; Reagent/catalyst;	89.6%

5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1) + C9H10ClN3O2 → apixaban

Conditions	Yield
Stage #1: 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone; C9H10ClN3O2 With triethylamine; potassium iodide In ethyl acetate at 0 - 5℃; for 4h; Reflux; Stage #2: With hydrogenchloride In water at 20℃; for 1h;	89%

5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1) + 2-chloro-2-(2-(3-fluoro-4-methoxyphenyl)hydrazono)acetic acid ethyl ester → C27H27FN4O5

Conditions	Yield
With triethylamine In ethyl acetate at 80℃; Inert atmosphere;	86.2%

5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1) + ethyl (2Z)-chloro[2-(4-methoxyphenyl)hydrazinylidene]ethanoate (473927-63-8) → 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (503614-91-3)

Conditions	Yield
With triethylamine; potassium iodide In dichloromethane at 42 - 45℃; Solvent; Temperature;	85%
Stage #1: 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone; ethyl (2Z)-chloro[2-(4-methoxyphenyl)hydrazinylidene]ethanoate With triethylamine; potassium iodide In ethyl acetate for 6h; Reflux; Stage #2: With hydrogenchloride In water; ethyl acetate at 0 - 20℃;	75%
Stage #1: 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone; ethyl (2Z)-chloro[2-(4-methoxyphenyl)hydrazinylidene]ethanoate With sodium carbonate In acetone at 45 - 50℃; for 3h; Stage #2: With hydrogenchloride In water at 25 - 30℃; for 2h;	35 g

5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1) + ethyl (2Z)-chloro[2-(4-methoxyphenyl)hydrazinylidene]ethanoate (473927-63-8) → 1-(4-methoxy-phenyl)-7a-morpholin-4-yl-7-oxo-6-[4-(2-oxo-piperidin-1-yl)phenyl]-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester

Conditions	Yield
With potassium carbonate In ethyl acetate at 0℃; Reagent/catalyst; Reflux;	80.5%
With triethylamine In ethyl acetate at 0 - 5℃; Reagent/catalyst; Reflux;	80%

5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1) + ethyl 2-chloro-(4-tolylhydrazono)acetate (27171-88-6, 132815-69-1) → C27H28N4O4

Conditions	Yield
With triethylamine In ethyl acetate at 80℃; Inert atmosphere;	79.3%

5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1) → 3-morpholinyl-1-(4-(2-oxopiperidin-1-yl)phenyl)pyridine-2(1H)-one

Conditions	Yield
Stage #1: 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone With N-Bromosuccinimide In dichloromethane at 20℃; for 3.5h; Stage #2: With potassium tert-butylate In tetrahydrofuran at 0 - 5℃; for 4h;	72.4%
With 2,3-dicyano-5,6-dichloro-p-benzoquinone In chlorobenzene at 150℃; for 24h; Temperature; Solvent;	3.6 g

5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1) + [(2-fluorophenyl)hydrazono]chloroacetic acid ethyl ester (64989-74-8) → C26H25FN4O4

Conditions	Yield
With triethylamine In ethyl acetate at 80℃; Inert atmosphere;	67.9%

5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1) + [(4-methylthio-phenyl)hydrazono]chloroacetic acid ethyl ester → C27H28N4O4S

Conditions	Yield
With triethylamine In ethyl acetate at 80℃; Inert atmosphere;	50.8%

chloro((4-methoxyphenyl)hydrazono]acetic acid ethyl ester + 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1) → 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (503614-91-3)

Conditions	Yield
With hydrogenchloride; triethylamine In ethyl acetate

5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1) + Na-Oxalsaeure-ethylester (74381-54-7) → {5-hydroxy-6-oxo-1-[4-(2-oxopiperidin-1-yl)phenyl]-1,2,3,6-tetrahydropyridin-4-yl}(oxo)acetic acid (1609409-54-2)

Conditions	Yield
Stage #1: 5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone; Na-Oxalsaeure-ethylester In ethanol Stage #2: With hydrogenchloride; water for 1h;

5,6‑dihydro‑3‑(4‑morpholinyl)‑1‑[4‑(2‑oxo‑1‑piperidinyl)phenyl]‑2(1H)‑pyridone (545445-44-1) → apixaban

Conditions	Yield
Multi-step reaction with 3 steps 1.1: pyridine / 3 h / 25 - 30 °C 1.2: 1 h 2.1: isopropyl alcohol; water / 50 - 55 °C 3.1: ammonia / ethylene glycol / 1.5 h / 115 - 120 °C / Autoclave View Scheme
Multi-step reaction with 4 steps 1.1: ethanol 1.2: 1 h 2.1: hydrogenchloride / Reflux 3.1: isopropyl alcohol; water / 50 - 55 °C 4.1: ammonia / ethylene glycol / 1.5 h / 115 - 120 °C / Autoclave View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / ethyl acetate / 0 °C / Reflux 2: hydrogenchloride / isopropyl alcohol; water / 0 - 5 °C 3: formamide; sodium methylate / N,N-dimethyl-formamide / 0 - 30 °C View Scheme
Multi-step reaction with 3 steps 1: triethylamine / ethyl acetate / 0 - 5 °C / Reflux 2: hydrogenchloride / isopropyl alcohol; water / 0 - 5 °C 3: sodium methylate; formamide / N,N-dimethyl-formamide / 0 - 30 °C View Scheme

Upstream product

• 473927-69-4 1-(4-iodo-phenyl)-3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one 
• 675-20-7 piperidin-2-one 
• 2067-33-6 5-bromopentanoic acid 
• 540-37-4 p-aminoiodobenzene 
• 385425-15-0 1-(2-oxopiperidin-1-yl)-4-iodobenzene 
• 545445-10-1 3,3-dichloro-1-(4-iodophenyl)-piperidin-2-one 
• 106-50-3 1,4-phenylenediamine 
• 110-91-8 morpholine 
• 21911-88-6 methyl 3-(4-chlorophenylamino)propanoate 
• 27471-37-0 (2-oxopiperidine-1-yl)chlorobenzene 
• 27471-36-9 5-chloro-N-(4-chlorophenyl)pentanamide 
• 4509-90-4 5-bromovaleroyl chloride 
• 106-47-8 4-chloro-aniline 
• 545445-40-7 3-morpholin-4-yl-5,6-dihydro-1H-pyridin-2-one 

Downstream Products

• 503614-91-3 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 
• 503614-92-4 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid 
• 1620494-29-2 1-(4-benzyloxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 
• 1609409-53-1 ethyl {5-hydroxy-6-oxo-1-[4-(2-oxopiperidin-1-yl)phenyl]-1,2,3,6-tetrahydropyridin-4-yl}(oxo)acetate 
• 1609409-54-2 {5-hydroxy-6-oxo-1-[4-(2-oxopiperidin-1-yl)phenyl]-1,2,3,6-tetrahydropyridin-4-yl}(oxo)acetic acid 

Relevant articles and documents

Preparation method of apixaban intermediate suitable for industrial production

The invention discloses a synthesis method of an apixaban intermediate suitable for industrial production. The method comprises the following steps: carrying out phase-transfer catalytic amidation reaction on paranitroaniline and 5-chlorovaleryl chloride in an organic phase and water phase two-phase system under an inorganic weakly alkaline condition to obtain an APM01 solution, and adding a sodium hydroxide water solution, and cyclizing in a pot to obtain an APM02 solution; directly carrying out alpha-reactive hydrogen dichlorination on an APM02 organic solution and phosphorus pentachloride after simple acid pickling, liquid separation and drying to obtain an APM03 solution; carrying out condensation-elimination reaction on the APM03 solution and excessive morpholine after simple acid pickling and liquid separation, and carrying out simple crystallization and purification treatment to separate out an APM04 solid, and reducing the APM04 into APM05 by sodium sulfide; and carrying out amidation-cyclization two-step one-pot reaction on the APM05 and 5-chlorovaleryl chloride to prepare a key intermediate APM07. According to the method, the synthesis efficiency of the apixaban intermediate is improved, the reaction is mild, and dangerous NaH and other expensive reagents are not used, so that the production cost is saved, the operation is simple, and the method is suitable for industrial popularization.

Preparation method of 5,6-dihydropyridine-2 (1H)-one derivative

The invention provides a preparation method of a 5,6-dihydropyridine-2 (1H)-one derivative, and particularly relates to a 1-(piperidine-2-keto-1-yl)-4-(5,6-dihydro-3-R substituent pyridine-2 (1H)-keto-1-yl) benzene preparation method, wherein the R substituent is chlorine or morpholine-4-yl. According to the invention, p-acetamido aniline is used as a raw material, and amidation with delta-valerolactone, halogenation with a halogenation reagent or sulfonylation with sulfonyl chloride, condensation, deacetylation, amidation with 2,2-dichloro-delta-valerolactone, halogenation with a halogenationreagent or sulfonylation with sulfonyl chloride, condensation elimination or condensation elimination substitution in the presence of morpholine are performed to obtain the target product. Accordingto the invention, the raw materials used in the preparation method are cheap, easy to obtain and low in cost; the process operation is simple, reaction conditions are easy to realize, the wastewater yield is low, and safety and greenness are realized; and the reaction selectivity of each step is high, the product yield and purity are high, and industrial production is facilitated.

Preparation method of dihydropyridone derivatives

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of dihydropyridone derivatives. The preparation method comprises the following steps: reacting 1-(4-aminophenyl)-3-morpholinyl-5,6-dihydropyridin-2(1H)-one serving as a raw material with a first reactant in a first solvent under the condition of a first alkali to generate an amide compound;under the condition of a second alkali, heating the amide compound to obtain an intermediate; reacting the intermediate with a second reactant in a second solvent at room temperature; after the reaction is finished, performing reduced-pressure distillation to obtain the second solvent; and under an ice bath condition, adding a third alkali, and carrying out a reaction in a third solvent to obtainthe dihydropyridone derivatives. According to the preparation method of the dihydropyridone derivatives provided by the invention, the preparation method of the dihydropyridone derivatives of 3-morpholinyl-1-(4-(2-oxopiperidine-1-yl)phenyl)pyridin-2(1H)-one is provided for the first time, and the preparation method has important significance for effective control of the quality of apixaban.