Preparation method of N-methoxy-N-methyl-1-p-toluenesulfonyl piperidine-4-amide

A technology of tosylpiperidine and methoxyamine, applied in the field of chemical synthesis, can solve the problems of difficult separation, inconvenient operation and high cost, and achieve the effects of simple post-processing process, shortened reaction period and simplified reaction

Inactive Publication Date: 2014-01-22
NORTHWEST NORMAL UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although these methods are used a lot, there are many shortcomings: if some carboxylic acids are not easily converted into acid chlorides, a catalyst needs to be added, and the acid chlorides are relatively active, so the operation is very inconvenient
However, since the phosphoramidite P(NMeOMe) 3 Unstable, difficult to separate, and the method has low yield and high cost, which brings many problems and difficulties to the industrialized production of Weinreb amide

Method used

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  • Preparation method of N-methoxy-N-methyl-1-p-toluenesulfonyl piperidine-4-amide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0028] Piperidine-4-carboxylic acid (5g, 38.8mmol) and 1.67mol / L sodium hydroxide aqueous solution (3.1gNaOH, 46mlH 2 O) Add it to a 100ml reactor, cool to 0°C, slowly add TsCl in ether solution (7.4g, 38.8mmolTsCl, 40mlEt 2 O), stirred for 4 hours, evaporated the ether, and acidified it to pH = 2 with concentrated hydrochloric acid, immediately precipitated a large amount of white solid, and dried it in vacuum to obtain 1-tosylpiperidine-4-carboxylic acid with a yield of 99%.

[0029] The reaction equation is as follows:

[0030]

[0031] Melting point: 167~169°C.

[0032] 1 HNMR (400HZ, CDCl 3 )δ:2.46(s,3H),1,81~1.87(m,2H),1.99(d, J =3.2Hz,1H),2.26~2.30(m,1H),2.45~2.48(m,1H),7.33(d, J= 8.0Hz,2H); 13 CNMR (400HZ, CDCl 3 ): 21.512ppm, 27.182ppm, 39.833ppm, 45.343ppm, 76.680ppm, 77.000ppm, 77.312ppm, 127.633ppm, 129.676ppm, 132.915ppm, 143.653ppm, 179.822ppm.

[0033] (2) Synthesis of N-methoxy-N-meth...

Embodiment 2

[0040] (1) Synthesis of 1-tosylpiperidine-4-carboxylic acid

[0041] Same as embodiment one.

[0042] (2) Synthesis of N-methoxy-N-methyl-1-p-toluenesulfonylpiperidine-4-amide

[0043]Add 1-toluenesulfonylpiperidine-4-carboxylic acid (0.5g, 1.67mmol) and N-methyl-N-methoxylamine (0.3g, 5mmol) into a 100ml single-necked bottle, add 10ml of toluene, and cool to 0°C, then add PCl 3 (0.1g, 0.84mmol) of toluene solution was slowly added dropwise, stirred at 0°C for 4-5h, quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (4×3ml), and the extract was dried over anhydrous magnesium sulfate , filtered, and concentrated to give a white solid. The yield is 96%.

[0044] Synthetic N-methoxy-N-methyl-1-p-toluenesulfonylpiperidine-4-amide, via 1 HNMR, 13 CNMR detects that its product is a pure compound, and its performance indicators or characterization data are the same as in Example 1.

Embodiment 3

[0046] (1) Synthesis of 1-tosylpiperidine-4-carboxylic acid

[0047] Same as Example 1

[0048] (2) Synthesis of N-methoxy-N-methyl-1-p-toluenesulfonylpiperidine-4-amide

[0049] Add 1-toluenesulfonylpiperidine-4-carboxylic acid (0.5g, 1.67mmol) and N-methyl-N-methoxylamine (0.3g, 5mmol) into a 100ml single-necked bottle, add 10ml of dichloromethane , cooled to 0°C, and then the PCl 3 (0.1g, 0.84mmol) dichloromethane solution was slowly added dropwise, stirred at room temperature for 6-8h, quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate (4×3ml), and the extract was washed with anhydrous magnesium sulfate Dry, filter, and concentrate to a white solid. The yield is 94%.

[0050] The above-mentioned synthetic N-methoxy-N-methyl-1-p-toluenesulfonylpiperidine-4-amide, through 1 HNMR, 13 CNMR detection, its product is a pure compound, its various performance indicators or characterization data Ketone Example 1.

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Abstract

The invention discloses a preparation method of N-methoxy-N-methyl-1-p-toluenesulfonyl piperidine-4-amide, which is an intermediate for producing a medicine MDL-100907 (Volinanserin), belonging to the technical field of chemical synthesis. In the method, PCl3 and N-methyl-N-methoxy amine are adopted as amidation reagents and directly act with 1-toluenesulfonyl piperidine-4-carboxylic acid to prepare the N-methoxy-N-methyl-1-p-toluenesulfonyl piperidine-4-amide by using a one-pot process, so that the step of separating and purifying phosphoramidite as the amidation reagent is omitted, the problem that the phosphoramidite is instable and is difficult to separate is solved, the reaction is greatly simplified and the reaction period is shortened; raw materials and various reagents are all cheap and easily obtainable, the cost is low, a post-processing process is simple and the yield is high; and the adopted raw materials are nontoxic, and a production process is pollution-free and environment-friendly, so that favorable conditions are created for industrialized scale production and commercialization of products.

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 of medicine MDL-100907. Background technique [0002] The chemical name of MDL-100907 is: (+)-(R)-1-[1-[2-(4-fluorophenyl)ethyl]piperidine-4-yl-1-(2,3-dimethyl Oxyphenyl)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 obsessive-compulsive syndrome, canned or peripheral vasospasm, fibrous tumors, cardiac arrhythmia thromboangiitis, etc., and can assist in nerve relaxation therapy in controlling the extravertebral system; in neurochemical, electrophysiological and Behavioral effects are similar to atypical antineuropathy drugs and belong to antineurotic drugs. [0003] The chemical structural formula of MDL-100907: [0004] ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/96
Inventor 黄丹凤张燕胡雨来
Owner NORTHWEST NORMAL UNIVERSITY
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