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Asymmetric synthesis method of nitrogen protected (3R,4R)-3-methylamino-4-methylpiperidine, and relevant intermediate and raw material preparation method

A synthetic method, the technology of methylpiperidine, applied in the field of preparation of pharmaceutical intermediates, can solve the problems of expensive, long reaction steps, etc., and achieve the effect of simple route, cheap raw materials, flexible and convenient selection of synthetic methods

Active Publication Date: 2014-07-02
SHANGHAI PUYI CHEM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0016] The disadvantage of this method is that when the hydrogenation reaction induces chirality, expensive chiral ligands need to be used, and the de value is only 71%; in addition, the reaction steps are long, and it takes 5 steps to obtain (3R,4R)- N-tert-butoxycarbonyl-3-methylamino-4-methylpiperidine (I)

Method used

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  • Asymmetric synthesis method of nitrogen protected (3R,4R)-3-methylamino-4-methylpiperidine, and relevant intermediate and raw material preparation method
  • Asymmetric synthesis method of nitrogen protected (3R,4R)-3-methylamino-4-methylpiperidine, and relevant intermediate and raw material preparation method
  • Asymmetric synthesis method of nitrogen protected (3R,4R)-3-methylamino-4-methylpiperidine, and relevant intermediate and raw material preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: Preparation of 1-benzyl-4-methyl-3-oxopiperidine-4-carboxylic acid methyl ester (1-2)

[0038]

[0039]Under nitrogen protection, add 1-benzyl-3-oxopiperidine-4-carboxylic acid methyl ester (1-1) (Shanghai Junyi Pharmaceutical Technology Co., Ltd.) 5.0g and potassium carbonate 8.4g into 100mL acetone , and then 5.8 g of methyl iodide was slowly added, and the reaction mixture was heated to 80° C. and refluxed for 12 hours. After the reaction was completed and cooled to room temperature, the solid was removed by filtration, and the solvent was evaporated under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate and 50 mL of water, and the organic phase was separated after layering. The organic phase was washed with salt water (50ml*2 times), dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain a light yellow viscous liquid 1-benzyl-4-methyl-3-oxopiperidine-4- 4.5 g of methyl carboxylate (1-2), yield: 85.0%. 1 H NMR (40...

Embodiment 2

[0040] Example 2: Preparation of 1-benzyl-4-methyl-piperidin-3-one (2-1)

[0041]

[0042] Add 10.0 g of 1-benzyl-4-methyl-3-oxopiperidine-4-carboxylic acid methyl ester (1-2) into 50 mL of 6 mol / L hydrochloric acid, and heat the reaction solution to 100°C and reflux for 5 Hour. After the reaction was completed, the temperature was lowered to room temperature, the solvent was distilled off under reduced pressure, the residue was dissolved in 50 mL of water, and the pH was adjusted to 10 with 2 mol / L aqueous sodium hydroxide solution, extracted three times by adding ethyl acetate, and the combined organic phase was washed with a small amount of salt water. Dry over anhydrous sodium sulfate and spin dry the organic solvent to obtain 6.8 g of yellow viscous liquid 1-benzyl-4-methyl-piperidin-3-one (2-1), yield: 87.5%. 1 H NMR (400MHz, CDCl 3 )δ7.30–7.25(m,5H),3.54(s,2H),3.20(d,J=12Hz,1H),2.89(m,1H),2.75(d,J=12Hz,1H),2.41– 2.31(m,2H),2.00(m,1H),1.62–1.60(m,1H),1.05(s,3H).ESI...

Embodiment 3

[0043] Example 3: Preparation of 1-tert-butoxycarbonyl-4-methyl-piperidin-3-one (3-1)

[0044]

[0045] Dissolve 5.0 g of 1-benzyl-4-methylpiperidin-3-one (2-1) in 50 mL of tetrahydrofuran, and add 0.5 g of Pd / C (5%) and 5.9 g of di-tert-butyl dicarbonate ester, and the reaction mixture was hydrogenated at room temperature and pressure for 12 hours. After the reaction was completed, filter with a sand core funnel lined with diatomaceous earth, and spin the filtrate to obtain 5.2 g of light yellow viscous liquid 1-tert-butoxycarbonyl-4-methylpiperidin-3-one (3-1). Yield: 99.9%. 1 H NMR (400MHz, CDCl 3 )δ3.91–3.99(m,2H),3.39(m,1H),2.48–2.43(m,1H),2.12–2.07(m,1H),1.64–1.50(m,2H),1.64(s, 9H),1.13(d,J=5.3Hz,3H).ESI-MS:m / z=214(M + +1).

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Abstract

The invention relates to a preparation method of nitrogen protected (3R,4R)-3-methylamino-4-methylpiperidine (I). The method comprises the following steps: carrying out a reductive amination reaction on a compound of formula (III) and (R)-1-phenylethylamine to obtain a compound of formula (II), removing chiral prosthetic groups from the compound of formula (II), and adding a methyl group to the amino group of the compound of formula (II) in order to obtain nitrogen protected (3R,4R)-3-methylamino-4-methylpiperidine (I), wherein R in each of the formula (I), the formula (II) and the formula (III) is an amino protection group or hydrogen, and the amino protection group can be C1-4 alkoxycarbonyl, benzyloxycarbonyl or benzyl groups which can be removed through hydrolysis or hydrogenation. The asymmetric synthesis method of nitrogen protected (3R,4R)-3-methylamino-4-methylpiperidine (I) has the advantages of reasonable technology, concise route, obtaining of the required product in a high ee value manner by constructing two chiral centers through chiral induced one-step reductive amination, cheap raw materials, and no waste isomer emission, and is suitable for large-scale industrialized production.

Description

technical field [0001] The present invention relates to the technical field of preparation of pharmaceutical intermediates, in particular to the technical field of preparation of chiral intermediates of rheumatoid arthritis treatment drug Xeljanz (tofacitinib, tofacitinib), specifically refers to a nitrogen-protected (3R,4R)- An asymmetric synthesis method of 3-methylamino-4-methylpiperidine, related intermediates and raw material preparation methods. Background technique [0002] Xeljanz (tofacitinib, CP-690550) is a JAK inhibitor being developed by Pfizer for adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate (MTX) therapy , which was first approved for marketing in the United States in November 2012. Nitrogen-protected (3R,4R)-3-methylamino-4-methylpiperidine (I) is a key intermediate for the synthesis of CP-690550. [0003] [0004] The original synthesis of nitrogen-protecte...

Claims

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Application Information

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IPC IPC(8): C07D211/56C07D211/74
CPCY02P20/55C07D211/56C07D211/74
Inventor 祁彦涛王博
Owner SHANGHAI PUYI CHEM CO LTD
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