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Impurity g produced by the preparation process of methylphenidate hydrochloride and its purification method and use

A technology of methylphenidate hydrochloride and preparation process, applied in the field of impurity G and purification thereof, can solve problems such as no records or reports of impurities, and achieve the effects of easy operation, high reaction yield and low price

Active Publication Date: 2018-07-10
HEFEI LIFEON PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

During the quality inspection of methylphenidate hydrochloride, it was found that a compound may exist as an impurity in methylphenidate hydrochloride and its preparations. After consulting relevant literature, there is no record or report of the above-mentioned impurity

Method used

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  • Impurity g produced by the preparation process of methylphenidate hydrochloride and its purification method and use
  • Impurity g produced by the preparation process of methylphenidate hydrochloride and its purification method and use
  • Impurity g produced by the preparation process of methylphenidate hydrochloride and its purification method and use

Examples

Experimental program
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Effect test

preparation example Construction

[0060] 1. Preparation of crude product of impurity G

[0061] a), the preparation of intermediate 1

[0062] A. Synthetic reaction equation:

[0063]

[0064] B. Process description

[0065] Add 1.0Lg of methanol into a dry and clean 3L three-necked flask, start stirring, add 0.37kg of piperidine and 0.59kg of methyl benzoylformate in sequence, heat up to 50-55°C and keep it warm for 2 hours, then monitor the reaction process by TLC (GF254 Silica gel plate; developing agent: ethyl acetate / petroleum ether = 1 / 2), stop the reaction when the raw material point disappears, put the material into a clean and dry sesame cake and slowly cool down to 0-5°C to fully separate out the solid, filter, filter The cake was stirred and washed twice with methanol pre-cooled to -5 ~ 0°C, each time 0.5kg, and air-dried at 60°C overnight to obtain 0.65kg of intermediate 1, a white solid, which was detected by the HPLC area normalization method. The content of body 1 is 99.50%, and the yield ...

Embodiment 1

[0078] Example 1 12 times of n-heptane dissolved impurity G crude product, 6 times of methanol refining

[0079] 1) Add 40.0g of impurity G crude product and 480.0g of n-heptane to a dry and clean 1000mL three-neck flask, start stirring, raise the temperature to 95°C to dissolve the sample, filter to remove a small amount of insoluble matter, and slowly cool the filtrate to 55°C for crystallization. After the solid was precipitated, it was filtered to obtain a filter cake, and dried at 60° C. to obtain 2.8 g of a white solid.

[0080] 2) Add 2.8g of the obtained solid into a dry and clean 50mL eggplant-shaped bottle, add 16.8g of methanol, start stirring, heat to dissolve, slowly cool down to 2°C after dissolution, keep stirring for 45 minutes, filter, and dry to weight at 50°C Without subtraction, 1.3g of impurity G fine product was obtained as a white solid, and the content of impurity G fine product was 99.60% as measured by HPLC area normalization method.

[0081] 3) Deco...

Embodiment 2

[0083] Example 2 10 times the crude product of n-heptane dissolved impurity G, refined by 6 times methanol

[0084] 1) Add 40.0g of impurity G crude product and 400.0g of n-heptane to a dry and clean 1000mL three-necked flask, start stirring, raise the temperature to 80°C to dissolve the sample, filter to remove a small amount of insoluble matter, and slowly cool the filtrate to 55°C to crystallize. After the solid was precipitated, it was filtered to obtain a filter cake, which was dried at 60° C. to obtain 2.9 g of a white solid.

[0085] 2) Add 2.9g of the obtained solid into a dry and clean 50mL eggplant-shaped bottle, add 17.4g of methanol, start stirring, heat to dissolve, slowly cool down to 2°C after dissolution, keep stirring for 45 minutes, filter, and dry to weight at 50°C Without subtraction, 1.5g of impurity G fine product was obtained as a white solid, and the content of impurity G fine product was 99.20% as measured by HPLC area normalization method.

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Abstract

The invention provides an impurity G generated in a preparation process of methylphenidate hydrochloride, a purifying method and application thereof. The purifying method comprises the following steps of: 1) adding a crude product of the impurity G into a first solvent, heating and dissolving, filtering and removing undissolved substance, slowly reducing temperature and devitrifying, filtering and drying the solid, thereby acquiring a filter cake; and 2) adding the filter cake acquired in the step 1) into a second solvent, heating and dissolving, slowly reducing temperature and devitrifying while stirring under kept temperature, filtering and drying the solid, thereby acquiring a fine product of the impurity G. The impurity G provided by the invention is compounded in an intermediate step in the preparation process of methylphenidate hydrochloride; the impurity G is acquired by separating and purifying the reaction filtrate; the purity of the impurity G is greater than 99%; the impurity in the production of methylphenidate hydrochloride is quantitatively and qualitatively treated; the impurity is used for analyzing and determining the purity and content of methylphenidate hydrochloride; the impurity G can be used for controlling the quality of the raw materials and preparation of methylphenidate hydrochloride and can guarantee the safe medication of the masses.

Description

technical field [0001] The invention relates to the field of pharmaceutical preparations, in particular to an impurity G produced during the preparation of methylphenidate hydrochloride and its purification method and application. Background technique: [0002] Methylphenidate hydrochloride (Methylphenidate hyrochloride, chemical name: α-phenyl-2-piperidine acetate methyl ester hydrochloride), for mild disorders of brain function attention deficit hyperactivity disorder (children hyperactivity syndrome, mild brain function disorders), narcolepsy, and coma caused by overdose of central depressants such as barbiturates and chloral hydrate. The methylphenidate compound was first synthesized by Panizzon et al. in 1944 (Panizzon, L. Helvetica Chimica Acta 1944, 27, 1748.), and was listed in the United States under the trade name Ritalin in 1950. [0003] In the field of medicine, it is often necessary to synthesize and isolate high-purity known impurity compounds. The impurity c...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/06G01N30/02
CPCC07D211/06G01N30/02
Inventor 裴林李冰胡德金陈军高美华季俊虬
Owner HEFEI LIFEON PHARMA
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