A kind of synthetic method of n-benzyl-4-methylpiperidin-3-one hydrochloride

The technology of a methylpiperidine and a synthesis method is applied in the synthesis field of N-benzyl-4-methylpiperidin-3-one hydrochloride, can solve the problem of high production cost, and achieves good product quality and novel process , the effect of short synthesis steps

Active Publication Date: 2019-01-29
CHONGQING WORLD HAORUI PHARM CHEM
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  • Abstract
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  • Claims
  • Application Information

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Problems solved by technology

[0017] 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) is significantly improved compared with route (1), but still involves materials including sodium borohydride, tetrahydrofuran borane, pyridine sulfur trioxide, etc. , leading to higher production costs

Method used

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  • A kind of synthetic method of n-benzyl-4-methylpiperidin-3-one hydrochloride
  • A kind of synthetic method of n-benzyl-4-methylpiperidin-3-one hydrochloride
  • A kind of synthetic method of n-benzyl-4-methylpiperidin-3-one hydrochloride

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] (1) 96.5 g (0.5 mol) of N-benzylglycine ethyl ester and 123.5 g (0.75 mol) of ethyl 2-methyl-4-chlorobutyrate were added to a 2000 mL reaction flask, and 650 mL of carbon tetrachloride was added. and 76 g (0.75 mol) of triethylamine, heated to reflux, and reacted for 18 h. After detection of the completion of the reaction, the reaction solution was cooled to 22 °C, filtered, and the filtrate was concentrated under reduced pressure to obtain 165 g of intermediate XVIII as a brown oil. The purity detected by HPLC was 94.1%. , directly into the next reaction.

[0037] (2) Add 165 g of the concentrated intermediate XVIII prepared in the previous step to a 2000 mL reaction flask, add 850 mL of toluene to dissolve, add 96.1 g (1.0 mol) of sodium tert-butoxide, heat under reflux, and react for 5 hours. HPLC detects that the reaction of the raw materials is basically complete. , the reaction solution was cooled to room temperature, 55 g of acetic acid was added dropwise, the pH...

Embodiment 2

[0040] (1) 96.5g (0.5mol) of N-benzylglycine ethyl ester and 136g (0.65mol) of ethyl 2-methyl-4-bromobutanoate were added to a 2000mL reaction flask, 850mL of tetrahydrofuran and 69g of sodium carbonate were added (0.65 mol), heated to reflux, and reacted for 22 h. After detection of the completion of the reaction, the reaction solution was cooled to 22 °C, filtered, and the filtrate was concentrated under reduced pressure to obtain 164.6 g of a brown oily intermediate XVIII. The purity detected by HPLC was 94.8%. one-step reaction.

[0041] (2) Add 164.6g of brown oil prepared in the previous step into a 2000mL reaction flask, add 850ml of xylene, add 90.0g (0.8mol) of potassium tert-butoxide, heat to reflux, react for 4.5h, and HPLC detects that the reaction of the raw materials is basically complete After that, the reaction solution was cooled to room temperature, 44 g of acetic acid was added dropwise, the pH was adjusted to 6-8, 280 mL of saturated brine was added, the la...

Embodiment 3

[0044] (1) 96.5g (0.5mol) of N-benzylglycine ethyl ester and 136g (0.65mol) of ethyl 2-methyl-4-bromobutanoate were added to a 2000mL reaction flask, and 750mL of toluene and N,N - Diisopropylethylamine 76g (0.75 mol), heated to reflux, and reacted for 8 hours. After the reaction was detected, the reaction solution was cooled to 24°C, filtered, and the filtrate was detected by HPLC to have a purity of 93.3%. The filtrate was directly put into the next reaction.

[0045] (2) Add the toluene filtrate prepared in the previous step into a 2000mL reaction flask, add 65.0g (0.95mol) of sodium ethoxide, heat under reflux, and react for 6.5h. After HPLC detects that the reaction of the raw materials is basically complete, the reaction solution is cooled to room temperature, and the 55 g of acetic acid, adjusted to pH 6-8, added with 400 mL of tap water, stirred for layers, transferred to a separatory funnel, the organic layer was washed with saturated brine 300 mL × 2, then dried by ad...

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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 method for synthesizing N-benzyl-4-methylpiperidin-3-one hydrochloride, and 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 joint inflammation of the facet joints of the hands and feet, often accompanied by extra-articular organ involvement and positive serum rheumatoid factor, which can lead to joint deformity and loss of function. The prevalence of rheumatoid arthritis in China is 0.32% to 0.36%, with more women than men. The drug treatment of rheumatoid arthritis mainly includes non-steroidal anti-inflammatory drugs, slow-acting anti-rheumatic drugs, immunosuppressants, immune and biological agents and botanicals. [0003] Tofacitinib Citrate is a novel JAK kinase (Janus kinase) selective inhibitor developed by Pfize...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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