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Synthetic method of apixaban intermediate 1-(4-nitrobenzophenone)-2-piperidone

A technology of nitrophenyl and apixaban, which is applied in the field of synthesis of apixaban intermediate 1--2-piperidone, can solve problems such as existing risks, and achieve low production cost and great economic benefits , the effect of high reaction yield

Inactive Publication Date: 2013-06-19
LANZHOU INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] CN101967145A adds p-nitroaniline and tertiary amine organic bases to anhydrous solvents, reacts with 5-chloropentanoyl chloride to generate amides, and continues to add highly basic metal organic bases, such as NaH and KOtBu, to the reaction solution. Anhydrous needs to be strictly controlled during the method, and metal-organic bases are used to generate hydrogen, which is dangerous during the amplification process

Method used

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  • Synthetic method of apixaban intermediate 1-(4-nitrobenzophenone)-2-piperidone

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Embodiment 1

[0023] Synthesis of 1-(4-nitrophenyl)-2-piperidone

[0024] Dissolve 15 (0.1mol) of p-nitroaniline in 300ml of dichloromethane, add the prepared alkali solution (12g of sodium hydroxide + 150ml of water), add 0.75g of tetrabutylammonium bromide, stir vigorously, drop 60g of 5-chloropentanoyl chloride was kept at 25°C for 16 hours. The TLC reaction was completed, and the layers were separated. The organic phase was washed with 100 ml of water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a yellow solid, which was then recrystallized with ethyl acetate to obtain 19.8 g of yellow crystals, with a yield of 90%.

[0025] 1 HNMR (400MHz, CDCl 3 , ppm) δ: 8.27(d, J=8.7Hz, 2H), 7.52(d, J=8.7Hz, 2H), 3.75(t, J=5.9Hz, 2H), 2.64(t, J=6.4Hz, 2H), 1.95-2.02(m, 4H).

Embodiment 2

[0027] Synthesis of 1-(4-nitrophenyl)-2-piperidone

[0028] Dissolve 150g (1mol) of p-nitroaniline in 3000ml of chloroform, add the prepared alkali solution (168g of sodium hydroxide + 1500ml of water), add 6g of tetrabutylammonium bromide, and add dropwise 600g of 5-chloro Valeryl chloride, kept at 25°C for 16 hours. The TLC reaction was completed, and the layers were separated. The organic phase was washed with 1000 ml of water, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain a yellow solid, which was then beaten with methyl tert-butyl ether to obtain 193.8 g of yellow crystals, with a yield of 88%.

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Abstract

The invention discloses a synthetic method of an apixaban intermediate 1-(4-nitrobenzophenone)-2-piperidone. The 1-(4-nitrobenzophenone)-2-piperidone is formed through an integrated reaction of paranitroaniline and halogenate valeryl chloride under the condition that phase transfer catalyst exists and in a mixed system of inorganic base aqueous solution and aprotic solvent. The synthetic method of the apixaban intermediate 1-(4-nitrobenzophenone)-2-piperidone is reasonable in process condition, easy to operate, high in reaction yield, low in production cost and almost free of discharging of the three wastes.

Description

technical field [0001] The invention relates to a synthesis method of an apixaban intermediate 1-(4-nitrophenyl)-2-piperidone. Background technique [0002] Apixaban (apixaban) belongs to aminobenzoxazole compounds, is a highly selective, reversible thrombin factor Xa inhibitor, first developed by Bristol-Myers Squibb, in 2007, Pfizer and Bristol-Myers- Bristol-Myers Squibb reached an agreement for joint development. It was approved by European medicines regulators in 2011 for thromboprophylaxis in patients who have undergone hip or knee replacement surgery. In addition, apixaban can also be used to treat patients with atrial fibrillation (AF) to prevent stroke. The structural formula of apixaban is as follows: [0003] [0004] In the synthetic method of apixaban, the most economical route all passes through intermediate 1-(4-nitrophenyl)-2-piperidone, as Chinese patent CN101065379, and Chinese patent CN101967145A all passes through 1-(4-nitrophenyl) phenyl)-2-piperi...

Claims

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Application Information

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IPC IPC(8): C07D211/76
Inventor 杨敏齐彦兴闫亮李静杨军
Owner LANZHOU INST OF CHEM PHYSICS CHINESE ACAD OF SCI
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