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A kind of preparation method of high-purity pralatrexate intermediate

A technology of pralatrexate and an intermediate, applied in the field of medicine, can solve the problems of unsuitable filtration, long refining time, low purity, etc., and achieve the effects of shortening post-processing time, reducing solid viscosity and improving work efficiency

Active Publication Date: 2020-05-12
SHANDONG NEWTIME PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The intermediate 10-propargyl-10-methoxycarboxylate-4-deoxy-4-amino-10-deazapteroic acid methyl ester (PLQS-3) is due to the introduction of 6-(bromomethyl)- 2,4-Pteridine diamine hydrobromide (PLQS-B), due to the active chemical properties of 6-(bromomethyl)-2,4-Pteridine diamine hydrobromide, resulting in the synthesis of (PLQS-3 ) relatively low purity
Moreover, new impurities are produced during the hydrolysis of PLQS-3, resulting in lower purity of PLQS-4; the method of obtaining crude PLQS-3 in the prior art is to pour the reaction solution into purified water to adjust the pH to neutral, precipitate solids, and filter to obtain PLQS -3 crude product, but the PLQS-3 crude product obtained by this technology is relatively viscous and not suitable for filtration; for the refining of PLQS-3 crude product, WO2014016740A2 uses a certain proportion of methanol, dichloromethane and isopropanol mixed solvent to add hydrobromic acid dropwise , so that it can be salted and refined, but this method must be salted at low temperature, and the refining time is longer; therefore, improving the purity of PLQS-3 and PLQS-4 or preparing new intermediates is an urgent problem to be solved

Method used

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  • A kind of preparation method of high-purity pralatrexate intermediate

Examples

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Embodiment 1

[0028] Under the protection of inert gas, add 400ml DMF and 32.5g NaH into a 1L three-necked flask, and when the internal temperature drops to -5~0°C, start to add the anhydrous DMF solution of PLQS-2 dropwise (dissolve 50g PLQS-2 in 65ml in anhydrous DMF), the rate of addition was controlled so that the internal temperature was not higher than 0°C. After dropping, continue to stir at 0-5°C for 1 hour, lower the temperature, and when the internal temperature drops to -20--10°C, slowly add 600ml of PLQS-B anhydrous DMF solution dropwise, and control the rate of addition so that the internal temperature is not higher than - 10°C (about 2 to 3 hours to drop). After dripping, continue to insulate and stir for 0.5h. After the reaction is completed, pour the reaction solution into 5L of anhydrous ether. Solids are precipitated, continue to stir for 0.5h, and filter with suction. Add 2.0L of anhydrous methanol to the filter cake and heat to reflux for 2h. Cool down to room temperatu...

Embodiment 2

[0030] Under the protection of inert gas, add 400ml DMF and 32.5g NaH into a 1L three-necked flask, and when the internal temperature drops to -5~0°C, start to add the anhydrous DMF solution of PLQS-2 dropwise (dissolve 50g PLQS-2 in 65ml in anhydrous DMF), the rate of addition was controlled so that the internal temperature was not higher than 0°C. After dropping, continue to stir at 0-5°C for 1 hour, lower the temperature, and when the internal temperature drops to -20--10°C, slowly add 600ml of PLQS-B anhydrous DMF solution dropwise, and control the rate of addition so that the internal temperature is not higher than - 10°C (about 2 to 3 hours to drop). After dripping, continue to keep warm and stir for 0.5h. After the reaction is completed, pour the reaction solution into 5L of methyl tert-butyl ether. Solids precipitate, continue to stir for 0.5h, filter with suction, add 2.0L of absolute ethanol to the filter cake and heat to reflux After 2 hours, cool down to room temp...

Embodiment 3

[0032] Add 65g of PLQS-3 and 650ml of purified water into a 3L three-neck flask, cool down to about 10°C, add 1.55L of 1mol / L sodium hydroxide aqueous solution dropwise under stirring, and continue the heat preservation reaction for 24-30h after the addition is completed, sample HPLC, and react After completion, add concentrated hydrochloric acid dropwise to the reaction liquid at room temperature until the pH value is 3.5, solids precipitate out, stir for 2 hours, filter, add 10 times absolute ethanol to the filter cake and heat to reflux for 1 hour, filter out insoluble matter, and the filtrate naturally cools down and stirs to analyze Crystallization, when the solid precipitates, continue to stir and crystallize in an ice bath for 2h, filter with suction, wash the filter cake with 50ml of absolute ethanol, filter and dry it, and put it in a 50°C oven to dry to constant weight to obtain 60.65g of a brownish-yellow solid with a purity of : 98.7%, yield 84.3%.

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Abstract

The invention specifically relates to a preparation method for high-purity pralatrexate intermediate, belonging to the technical field of medicine. The preparation method is based on preparation of PLQS-3 and comprises the following steps: preparing crude PLQS-3 by using a crystallization solvent; then heating and washing the crude PLQS-3 with a single solvent, and carrying out filtering while the crude PLQS-3 is still hot so as to obtain high-purity PLQS-3; subjecting the PLQS-3 to hydrolysis with an appropriate amount of inorganic alkali liquor at a certain temperature; adding excess hydrochloric acid into a hydrolysis solution to obtain a hydrochloride; and refining the hydrochloride with a solvent such as anhydrous ethanol to obtain high-purity PLQS-4 hydrochloride. According to the invention, the purity of PLQS-4 is improved through refining of the crude PLQS-3; and the preparation method can be well used in the production of pralatrexate.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of a high-purity pralatrexate intermediate. Background technique [0002] Pralatrexate, trade name Folotyn, is the first new targeted folic acid preparation approved by the FDA for the treatment of peripheral T-cell lymphoma. The chemical name of pralatrexate is 10-propargyl-10-desazaaminopterin. First disclosed in "Synthesis and Antitumor Activity of 10-Propargyl-10-deazaaminopterin" J.Medical Chem.36:2228-2231 (1993) by Joseph I. DeGraw; J William T. Colwell et al. It was then studied by Sirotanak et al and O'Connor et al. Its molecular structure is as follows: [0003] [0004] Pralatrexate is synthesized from p-carboxyphenylacetic acid as a starting material through a series of chemical transformations. Firstly, the intermediate 4-methyl formate, methyl phenylacetate (PLQS-1), the intermediate ɑ-propargyl-(4-methyl formate)-methyl phen...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D475/08
CPCC07D475/08
Inventor 张贵民陈成富吴尽
Owner SHANDONG NEWTIME PHARMA
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