503615-03-0

Basic information

• Product Name: 3-Morpholino-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one
• Synonyms: 3-(4-Morpholinyl)-1-(4-nitrophenyl)-5,6-dihydro-2(1H)-pyridinone;5,6-Dihydro-3-(4-morpholinyl)-1-(4-nitrophenyl)-2(1H)-pyridinone;3-Morpholino-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one;Apixaban Intermediate3;5-morpholin-4-yl-1-(4-nitrophenyl)-2,3-dihydropyridin-6-one;3-(Morpholin-4-yl)-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one (Nitro MPDP);Apixaban Impurity 19;Apixaban Impurity 28
• CAS NO: 503615-03-0
• Molecular Formula: C₁₅H₁₇N₃O₄
• Molecular Weight: 303.31318
• Mol File: 503615-03-0.mol
• Article Data: 13

Chemical Properties

• Boiling Point: 506.532 °C at 760 mmHg
• Flash Point: 260.141 °C
• Appearance: /
• Density: 1.356
• Storage Temp.: Sealed in dry,Store in freezer, under -20°C
• PKA: 3.11±0.20(Predicted)
• CAS DataBase Reference: 3-Morpholino-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one(CAS DataBase Reference)
• NIST Chemistry Reference: 3-Morpholino-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one(503615-03-0)
• EPA Substance Registry System: 3-Morpholino-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one(503615-03-0)

Safety Data

• Hazardous Substances Data: 503615-03-0(Hazardous Substances Data)

Usage

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

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Downstream Products

• 536759-91-8 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo- 1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester 
• 1267610-26-3 1-(4-aminophenyl)-3-(morpholin-4-yl)-5,6-dihydropyridin-2(1H)-one 
• 1643330-62-4 5-chloropentanoic acid [4-(5-morpholin-4-yl-6-oxo-3,6-dihydro-2H-pyridin-1-yl)phenyl]amide 
• 545445-44-1 5,6?dihydro?3?(4?morpholinyl)?1?[4?(2?oxo?1?piperidinyl)phenyl]?2(1H)?pyridone 
• 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 
• 1423803-24-0 6-(4-aminophenyl)-1-(4-methoxyphenyl)-(4-methoxyphenyl)-7-carbonyl-1H-pyrazolo[3,4-c]-4,5,6,7-tetrahydropyridine-3-amide 
• 1437577-94-0 6-(4-(5-bromopentanamido)phenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide 
• 1449510-64-8 6-(4-(5-chloropentanamido)phenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide 

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.

Apixaban derivatives as well as preparation method and application thereof

The invention belongs to the technical field of medicines and discloses apixaban derivatives and analogues as well as a preparation method and application thereof. The structure of the compounds is shown as the following formula. Cheap and readily available paranitroaniline serves as an initial raw material. The preparation method comprises the following steps: performing amidation-cyclization, chlorination, condensation-elimination, cyclization-elimination, reduction, amidation-cyclization so as to obtain a key intermediate; and dehydrating, performing ammonolysis or chlorination, and condensing to synthesize the target compound. The method is simple in operation, convenient in after-treatment and high in yield. The in-vitro anti-coagulant activity of the target compound is investigated by determining the activated partial thromboplastin time (APTT) and thromboplastin time (PT). The EC2X(APTT) of result compounds APX-02, APX-15 and APX-16 is respectively 2.15mug/L, 3.65mug/L and 2.35mug/L, the EC2X(PT) of the result compounds is respectively 0.12mug/L, 3.57mug/L and 1.57mug/L, which are higher than the EC2X(APTT) value of 3.78mug/L and the EC2X(PT) value of 1.59mug/L of a positive control agent Apixaban. The compounds have high anti-coagulant activities. The EC2X(APTT) value of the rest compounds is between 5mug/L and 65mug/L, and the EC2X(PT) value is between 3mug/L and 18mug/L. The structural formula is as shown in the specification.

Process for the preparation of apixaban

A crystalline Form N-1 of apixaban substantially free from one or more of: 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; 7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1-phenyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; or methyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate, relative to apixaban by area percentage of HPLC and having a mean particle size equal to or greater than 100 μm.