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Synthesis method of N-benzyl-4-methylpiperidine-3-one hydrochloride

The technology of a kind of methylpiperidine and synthesis method is applied in the field of synthesis of N-benzyl-4-methylpiperidin-3-one hydrochloride, which can solve the problems of high production cost and achieve good product quality and simple synthesis steps. The effect of short, simple process operation

Active Publication Date: 2016-08-31
CHONGQING WORLD HAORUI PHARM CHEM
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0012] It can be seen from the reaction equation that the intermediate XV (N-benzyl-4-methylpiperidin-3-one) and its salt in the route (2) can be reacted in one step to obtain the key intermediate VI of tofacitinib citrate (1 -benzyl-4-methyl-3-methylaminopiperidine), route (2) has obvious improvement compared with route (1), but still involves materials such as sodium borohydride, tetrahydrofuran borane, sulfur trioxide pyridine , leading to higher production costs

Method used

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  • Synthesis method of N-benzyl-4-methylpiperidine-3-one hydrochloride
  • Synthesis method of N-benzyl-4-methylpiperidine-3-one hydrochloride
  • Synthesis method of N-benzyl-4-methylpiperidine-3-one hydrochloride

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Embodiment 1

[0031] (1) Add 96.5g (0.5mol) of N-benzylglycine ethyl ester and 123.5g (0.75mol) of ethyl 2-methyl-4-chlorobutyrate into a 2000mL reaction flask, add 650mL of carbon tetrachloride and triethylamine 76g (0.75mol), heated to reflux, reacted for 18h, after the detection of complete reaction, the reaction solution was cooled to 22 ° C, filtered, and the filtrate was concentrated under reduced pressure to obtain 165g of brown oil intermediate XVIII, the purity of which was detected by HPLC was 94.1% , directly into the next reaction.

[0032] (2) Add 165g of the concentrate intermediate XVIII prepared in the previous step to a 2000mL reaction flask, add 850mL of toluene to dissolve, add 96.1g (1.0mol) of sodium tert-butoxide, heat to reflux, and react for 5h. After the reaction of the raw materials is basically complete after HPLC detection , the reaction solution was cooled to room temperature, 55g of acetic acid was added dropwise, and the pH was adjusted to 6-8, 300mL of satura...

Embodiment 2

[0035] (1) Add 96.5g (0.5mol) of ethyl N-benzylglycine and 136g (0.65mol) of ethyl 2-methyl-4-bromobutyrate into a 2000mL reaction flask, add 850mL of tetrahydrofuran and 69g of sodium carbonate (0.65mol), heated to reflux, reacted for 22h, after detecting that the reaction was complete, the reaction solution was cooled to 22°C, filtered, and the filtrate was concentrated under reduced pressure to obtain 164.6g of brown oil intermediate XVIII, the purity of which was detected by HPLC was 94.8%. One step reaction.

[0036] (2) Add 164.6g of the brown oil prepared in the previous step to a 2000mL reaction flask, add 850ml of xylene, add 90.0g (0.8mol) of potassium tert-butoxide, heat to reflux, and react for 4.5h. The reaction of the raw materials is basically complete as detected by HPLC. Afterwards, the reaction solution was cooled to room temperature, 44 g of acetic acid was added dropwise to adjust the pH to 6-8, 280 mL of saturated saline was added, the layers were stirred ...

Embodiment 3

[0039](1) Add 96.5g (0.5mol) of ethyl N-benzylglycine and 136g (0.65mol) of ethyl 2-methyl-4-bromobutyrate into a 2000mL reaction flask, add 750mL of toluene and N,N - 76g (0.75mol) of diisopropylethylamine, heated to reflux, and reacted for 8h. After the reaction was detected to be complete, the reaction liquid was cooled to 24°C and filtered. The purity of the filtrate was detected by HPLC to be 93.3%, and the filtrate was directly put into the next reaction.

[0040] (2) Add the toluene filtrate prepared in the previous step into a 2000mL reaction flask, add 65.0g (0.95mol) of sodium ethoxide, heat to reflux, and react for 6.5h. 55g of acetic acid, adjust the pH to 6-8, add 400mL of tap water, stir to separate layers, transfer to a separatory funnel, wash the organic layer with saturated brine 300mL×2, then add anhydrous sodium sulfate to dry, filter, and concentrate the filtrate to obtain intermediate XIX 122.6 g (0.445 mol weight) of the oily matter, the HPLC detection pu...

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Abstract

The invention discloses a synthesis method of N-benzyl-4-methylpiperidine-3-one hydrochloride. The synthesis method includes the steps of: a) with N-benzyl glycine ethyl ester as a raw material, performing a condensation reaction to the raw material with 2-methyl-4-halogenated ethyl acetate; and b) after the reaction is finished, performing an intramolecular cyclization reaction and finally performing hydrolytic decarboxylation to prepare the product. Compared with methods reported in references, the method establishes a novel synthesis route which is short in process, is novel in technology, employs low-cost raw materials and simple process operations, has good product quality and high total yield, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis method of N-benzyl-4-methylpiperidin-3-one hydrochloride, which belongs to the technical field of organic synthesis. Background technique [0002] Rheumatoid arthritis (RA) is a chronic, inflammatory synovitis-based systemic disease of unknown etiology. It is characterized by polyarticular, symmetrical, and aggressive arthritis of the small joints of the hands and feet, often accompanied by involvement of extra-articular organs and positive serum rheumatoid factor, which can lead to joint deformities and loss of function. The prevalence of rheumatoid arthritis in China is 0.32% to 0.36%, and women are more than men. Drug therapy for rheumatoid arthritis mainly includes non-steroidal anti-inflammatory drugs, slow-acting anti-rheumatic drugs, immunosuppressants, immune and biological agents, and herbal medicines. [0003] Tofacitinib Citrate (Tofacitinib Citrate) is a new selective inhibitor of JAK kinase (Janus kin...

Claims

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Application Information

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IPC IPC(8): C07D211/74
CPCC07D211/74
Inventor 颜伟伟陈晓朋林国跃
Owner CHONGQING WORLD HAORUI PHARM CHEM
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