Preparation method for pralatrexate intermediate

A technology of pralatrexate and an intermediate, which is applied in the field of medicine, can solve the problems of long reaction time, low yield, low yield and purity, and can simplify the post-processing process, improve the yield and purity, and improve the operability. sexual effect

Active Publication Date: 2017-12-19
SHANDONG NEWTIME PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] There are many problems in the existing synthesis technology: when synthesizing the intermediate (PLQS-2), a mixture of monopropargyl and bispropargyl (impurity) is produced, that is, the intermediate containing 1 / 3 to 1 / 2 of the impurity (PLQS-2) (“J.Med.Chem.1993,36,2228-2231” Joseph I.De Graw; J William T.Colwell), the yield and purity of (PLQS-2) were low, and the impurities The production situation is shown in the following reaction equation:
[0007] US0183789A1 introduces the use of potassium carbonate as a nucleophile and TBAI as a phase transfer catalyst at 25-30°C for 20-26 hours. Through liquid phase detection, the ratio of the target product to the bispropargyl-substituted impurity is 85:15, and after two The refined purity reaches 99.2%. Although the reaction temperature of this technical method is mild, the reaction time is long, and the generated bispropargyl substitutes more impurities, which requires two refinements, and the yield is low, which is 65.6%.
[0008] This brings difficulties to the next reaction and post-processing

Method used

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  • Preparation method for pralatrexate intermediate
  • Preparation method for pralatrexate intermediate
  • Preparation method for pralatrexate intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Under the protection of argon, add 323g PLQS-1 and 2.26L THF into a 5L three-necked flask, and when the temperature is lowered and stirred to -10°C, pour 224ml of 3-bromopropyne into the reaction flask, keep stirring for 0.5h, and start to drop 1.8L THF solution of 1mol / L LiHMDS, control the dropping rate, and keep the reaction temperature at -10±3°C (about 2 to 3 hours to complete the dropping). After the dropwise addition, continue to stir for 0.5 h, and detect by HPLC. After the reaction is complete, pour the reaction liquid into 1.25 L of acetic acid aqueous solution, stir for 10 min, and then let stand to separate the liquids. Add about 1.3L of isopropanol, stir to precipitate a solid, then put it in a cold bath at 0-5°C, stir for 3-4h, filter, and wash with a mixed solvent of about 300ml of isopropanol: n-heptane = 1:6 filter cake. The filter cake was oven-dried at 50°C to finally obtain 332g of light yellow solid with a yield of 87.0%. The HPLC detection of the ...

Embodiment 2

[0028] Under the protection of argon, add 323g PLQS-1 and 2.26L THF into a 5L three-necked flask, cool down and stir to -20°C, pour 224ml 3-bromopropyne into the reaction flask, keep stirring for 0.5h, and start to drop 1.8L 1mol / L. THF solution of LiHMDS, control the rate of addition, and keep the reaction temperature at -20±3°C (about 2 to 3 hours to complete the drop). After the dropwise addition, continue to stir for 0.5 h, and detect by HPLC. After the reaction is complete, pour the reaction liquid into 1.25 L of acetic acid aqueous solution, stir for 10 min, and then let stand to separate the liquids. Add about 1.3L of isopropanol, stir to precipitate a solid, then put it in a cold bath at 0-5°C, stir for 3-4h, filter, and wash with a mixed solvent of about 300ml of isopropanol: n-heptane = 1:6 filter cake. Filter cake is oven-dried at 50 ℃, finally obtains 320g light yellow solid, yield is 83.8%, the HPLC detection of intermediate α-propargyl-(4-formic acid methyl este...

Embodiment 3

[0030] Under the protection of argon, add 323g PLQS-1 and 2.26L ethyl acetate into a 5L three-necked flask, cool down and stir to -10°C, pour 224ml 3-bromopropyne into the reaction flask, keep stirring for 0.5h, start Add 1.8L of 1mol / L.LiHMDS THF solution dropwise, control the dropping rate, and keep the temperature of the reaction bottle at -10±3°C (about 2 to 3 hours to complete the dropping). After the dropwise addition, continue to stir for 0.5 h, and detect by HPLC. After the reaction is complete, pour the reaction liquid into 1.25 L of acetic acid aqueous solution, stir for 10 min, and then let stand to separate the liquids. Add about 1.3L of isopropanol, stir to precipitate a solid, then put it in a cold bath at 0-5°C, stir for 3-4h, filter, and wash with a mixed solvent of about 300ml of isopropanol: n-heptane = 1:6 filter cake. Filter cake is oven-dried at 50 ℃, finally obtains 330g light yellow solid, yield is 86.4%, the HPLC detection of intermediate α-propargyl-(...

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Abstract

The invention specifically relates to a preparation method for a pralatrexate intermediate, belonging to the technical field of medicine. According to the preparation method for the intermediate alpha-propargyl-(4-methylformate)-methylphenyl acetate, operation is more convenient and the content of impurities is lower; and in particular, the ratio of dithropropyl impurities in the produced intermediate is obviously reduced, the yield of the target product alpha-propargyl-(4-methylformate)-methylphenyl acetate is significantly increased, and product purity is greatly improved. The preparation method can be applied to large-scale production of pralatrexate bulk drugs and preparation of pralatrexate intermediates.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of a 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. First, the intermediate 4-methyl formate, methyl phenylacetate (PLQS-1), the intermediate α-propargyl-(4-methyl formate)-methyl phenylacetate (PLQ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/343C07C69/76
CPCC07C67/343C07C69/76
Inventor 张贵民陈成富魏传兵
Owner SHANDONG NEWTIME PHARMA
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