3-Morpholino-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one Chemical Properties

Boiling point:

506.5±50.0 °C(Predicted)

Density 

1.356

storage temp. 

Sealed in dry,Store in freezer, under -20°C

solubility 

Chloroform (Slightly), Methanol (Slightly, Heated)

form 

Solid

pka

3.11±0.20(Predicted)

color 

Light Yellow

InChI

InChI=1S/C15H17N3O4/c19-15-14(16-8-10-22-11-9-16)2-1-7-17(15)12-3-5-13(6-4-12)18(20)21/h2-6H,1,7-11H2

InChIKey

LBFAEOWNWSDWRZ-UHFFFAOYSA-N

SMILES

C1(=O)N(C2=CC=C([N+]([O-])=O)C=C2)CCC=C1N1CCOCC1

3-Morpholino-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one Usage And Synthesis

Description

3-(4-Morpholinyl)-1-(4-nitrophenyl)-5, 6-dihydro-2(1H)-pyridinone is the intermediate for the synthesis of apixaban, which is an anticoagulant for the treatment of venous thromboembolic events. 

References

Chao, H. E., et al. "Synthesis of Apixaban." Chinese Journal of Pharmaceuticals (2014).
https://en.wikipedia.org/wiki/Apixaban

Chemical Properties

5,6-Dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridinone contains a nitro unit and a morpholine group in its chemical structure, which has excellent chemical reactivity and poor chemical stability, and the double-bonded unit in its structure can be reduced by hydrogen under certain conditions. Hydrogen reduction usually requires appropriate catalysts and reaction conditions.

Uses

3-(Morpholinyl)-N-(4-nitrophenyl)-5,6-dihydropyridin-2-one is a reagent in the synthesis of 4,5-dehydro Apixaban (D229385) an impurity of Apixaban (A726700), a potent, direct, selective, and orally active inhibitor of coagulation factor Xa. It is a potential new oral coagulant that may be useful prevention of venous thromboembolism in total hip, knee replacement orthopedic surgery and stroke in treatment of patient with venous thromboembolic disorder or with atrial fibrillation

Synthesis

The reaction mixture was quenched with 1-(4-nitrophenyl)-2-piperidone (33 g, 0.15 mol) and phosphorus pentachloride (109 g, 0.52 mol) by slowly pouring into 500 mL of ice water. The aqueous layer was separated and the aqueous phase was extracted with chloroform (3 x 100 mL). The organic phases were combined and the reaction mixture was extracted with ethyl acetate. Subsequently, the combined organic phases were washed once with 500 mL of saturated sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure to give 57 g of a yellow solid. The solid (57 g) was placed in a reaction flask, morpholine (307 mL) was added, slowly heated to reflux, and the reaction was maintained for 2 hours. Upon completion of the reaction, it was cooled to room temperature and the morpholine hydrochloride solid precipitated. 600 mL of water was added to precipitate the product, and the yellow solid was collected by filtration and dried to give 30 g of the target compound 5,6-dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridinone in a total yield of 66% for the two-step reaction.

References

[1] Patent: CN103626689, 2016, B. Location in patent: Paragraph 0033; 0044-0046
[2] Journal of Medicinal Chemistry, 2007, vol. 50, # 22, p. 5339 - 5356
[3] Patent: US2003/232804, 2003, A1. Location in patent: Page 102
[4] Patent: US2003/232804, 2003, A1. Location in patent: Page 96
[5] Patent: WO2014/203275, 2014, A2. Location in patent: Page/Page column 35

3-Morpholino-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one(503615-03-0)Related Product Information

• ethyl 6-(4-aMinophenyl)-1-(4-Methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate
• 5-chloro-N-(4-(5-morpholino-6-oxo-3,6-dihydropyridin-1(2H)-yl)phenyl)pentanamide
• Acetic acid, 2-chloro-2-[2-(4-methoxyphenyl)hydrazinylidene], ethyl ester
• 3-Morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin-2(1H)-one
• 1-(4-AMinophenyl)-5,6-dihydro-3-(4-Morpholinyl)-2(1h)-pyridinone
• 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 ethyl ester
• 1-(4-Nitrophenyl)-2-piperidinone
• 4,5,6,7-Tetrahydro-1-(4-methoxyphenyl)-6-[4-(5-methyl-2-oxo-1-piperidinyl)phenyl]-7-oxo-1H-pyrazolo[3,4-c]pyridine-3-carboxamide
• 1-(4-Methoxyphenyl)-6-(4-(2-Methyl-6-oxopiperidin-1-yl)phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxaMide
• Apixaban IMpurity 6
• 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
• Apixaban Impurity 12
• Apixaban
• 1-(4-chlorophenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxaMide
• 1-(4-Methoxyphenyl)-6-(4-iodophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester
• Apixaban IMpurity 3
• Apixaban Impurity 17
• Apixaban IMpurity 4 (BMS-728626-01)