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Preparation method of N-methoxyl-N-methyl-1-tosylpiperidine-4-amide

A technology of tosyl piperidine and methoxy group, applied in the field of chemical synthesis, can solve the problems of long reaction time, inconvenient operation, and difficult conversion of carboxylic acid into acid chloride, etc., and achieves a short reaction period, convenient operation and low cost. Effect

Inactive Publication Date: 2011-07-27
NORTHWEST NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The methods reported in the literature for the preparation of the intermediate of the drug MDL-100907 - Weinreb amide are to first make the carboxylic acid into an acid chloride, and then react with N-methyl-N-methoxylamine hydrochloride in the presence of a base to generate Weinreb amide, this method has following disadvantages: (1) some carboxylic acids are not easily converted into acid chlorides, need to add catalyst (such as DMF), and acid chlorides are relatively active, which brings inconvenience to operation; (2) acid chlorides and N -Methyl-N-methoxylamine hydrochloride has a long reaction time, mostly in 3 to 15 hours

Method used

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  • Preparation method of N-methoxyl-N-methyl-1-tosylpiperidine-4-amide

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Embodiment 1

[0018] Embodiment 1, the preparation of N-methoxy-N-methyl-1-p-toluenesulfonylpiperidine-4-amide

[0019] (1) Synthesis of 1-tosylpiperidine-4-carboxylic acid

[0020] Piperidine-4-carboxylic acid (5g, 38.8mmol) and 1.67mol / L aqueous sodium hydroxide solution (3.1gNaOH, 46mlH 2 O) Add it to a 100ml reactor, cool to 0°C, slowly add a solution of TsCl in ether (7.4gTsCl, 38.8mmol, 40ml Et 2 O), stirred for 4 h, evaporated ether, and then acidified to pH=2 with concentrated hydrochloric acid, a large amount of white solid precipitated immediately, and dried in vacuo to obtain 4.5 g of 1-tosylpiperidine-4-carboxylic acid. Yield 90%.

[0021] Melting point: 165-167°C. 1 H NMR (400MHz, CDCl 3 ): δ: 2.46(s, 3H), 1.81-1.87(m, 2H), 1.99(d, J=3.9Hz, 1H) 2.01(d, J=3.2Hz, 1H) 2.26-2.30(m, 1H) , 2.45-2.48 (m, 1H), 7.33 (d, J=7.6Hz, 2H), 7.63 (d, J=8.0Hz, 2H).

[0022] (2) Preparation of N-methoxy-N-methyl-1-p-toluenesulfonylpiperidine-4-amide by NBS method

[0023] Add 1-toluenesulf...

Embodiment 2

[0026] Embodiment 2, the preparation of N-methoxy-N-methyl-1-p-toluenesulfonylpiperidine-4-amide

[0027] (1) Synthesis of 1-tosylpiperidine-4-carboxylic acid

[0028] With embodiment 1.

[0029] (2) Preparation of N-methoxy-N-methyl-1-p-toluenesulfonylpiperidine-4-amide by phosphoramidite method

[0030] Add 30ml of dry toluene to a 100ml one-necked bottle, quickly add phosphoramidite (2g, 9.5mmol), then add 1-toluenesulfonylpiperidine-4-carboxylic acid (3g, 5.3mmol), under nitrogen protection, React in an oil bath at 60°C for 30 minutes, cool, quench with saturated sodium bicarbonate solution, separate the layers, extract with ethyl acetate (3×10ml), dry the extract with anhydrous sodium sulfate, filter, and concentrate to obtain 3.4g of a white solid .

[0031] The reaction equation is as follows:

[0032]

[0033] Yield 96%. mp: 133-135°C. 1 H NMR (400MHz, CDCl 3 ): δ: 2.39(s, 3H), 3.09(s, 3H), 3.62(s, 3H), 1.78-1.89(m, 4H), 2.41-2.61(m, 2H), 3.77(t, J=8.0 Hz, 2...

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Abstract

The invention discloses a preparation method of N-methoxyl-N-methyl-1-tosylpiperidine-4-amide used as the intermediate of drug MDL-100907. The method comprises the following steps: firstly using TsCl as protective reagent to ensure piperidine-4-carboxylic acid to react with toluenesulfonyl chloride in alkaline condition, obtaining 1-tosylpiperidine-4-carboxylate, acidifying to obtain 1-tosylpiperidine-4-carboxylic acid, and then amidating 1-tosylpiperidine-4-carboxylic acid in the presence of acylating agent to obtain the target product. The preparation method of the invention firstly utilizes two kinds of acylation systems, namely NBS / PPh3 / NH(OMe)Me and P(NMeOMe)3 to directly react with 1-tosylpiperidine-4-carboxylic acid and prepare N-methoxyl-N-methyl-1-tosylpiperidine-4-amide; in addition, the raw materials are cheap and accessible, the reaction time is short, the conditions are mild, the operation is simple, the post-treatment is easy, the yield is high, and the preparation method of the invention provides good conditions for the industrial scale production and commercialization of the product.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and relates to a preparation method of N-methoxy-N-methyl-1-p-toluenesulfonylpiperidine-4-amide, an intermediate for preparing medicine MDL-100907. Background technique [0002] MDL-100907 Chemical name: (+)-(R)-1-[1-[2-(4-fluorophenyl)ethyl]piperidin-4-yl]-1-(2,3-dimethoxy Base phenyl) methanol, is a highly selective 5-HT2A receptor antagonist, can treat a variety of diseases, such as: schizophrenia, depression, various angina, anorexia nervosa, Raynaud's Phenomenon, intermittent claudication syndrome, coronary or peripheral vasospasm, fibromyoma, cardiac rhythm disorder, thromboangiitis, etc., and can assist neurolastic therapy in controlling the extrapyramidal system. Therefore, it is similar to atypical antineurotic drugs in terms of neurochemical, electrophysiological and behavioral effects and belongs to antineurotic drugs. Currently, there are four main routes in the synthesis...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/96
Inventor 胡雨来徐瑞东黄丹凤徐长明
Owner NORTHWEST NORMAL UNIVERSITY