Method for preparing high-purity temsirolimus

A temsirolimus, high-purity technology, applied in the field of medicinal chemistry, can solve problems such as difficult to meet the quality requirements of injection forms, content control of starting material sirolimus, poor removal of impurities, etc., and achieve good industrial application prospects , the operator and the environment have little influence, and the effect of high repeatability

Inactive Publication Date: 2014-10-08
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The above-mentioned purification methods are all silica gel column chromatography, the obtained product is not high in purity, and the effect of removing impurities is poor, and the content of the starting material sirolimus is not controlled, so it is difficult to meet the quality requirements of the injection type for the raw material drug

Method used

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  • Method for preparing high-purity temsirolimus
  • Method for preparing high-purity temsirolimus
  • Method for preparing high-purity temsirolimus

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] 1) Preparation of semi-finished products of temsirolimus

[0041] Dissolve 8.3g of temsirolimus crude product (purity 75.68%, sirolimus 3.47%, isomer 16.48%, area normalization method, the same below) with 25mL ethyl acetate, and load it on normal phase silica spheres Packed column (Nanjing Baisai Biological Chromatography Technology Co., Ltd., the same below, particle size 5 μm), gradient elution with ethyl acetate: n-heptane mixed solvent system, 0 ~ 10min, ethyl acetate / n-heptane (v / v, the same below)=60:40, in 10~100min, ethyl acetate / n-heptane gradually changed from 60:40 to 100:0, the system temperature was 20°C, collected components, concentrated under reduced pressure at 30°C to After drying, 6.8 g of semi-finished temsirolimus (purity 84.78%, sirolimus 0.02%, isomer 13.23%) were obtained.

[0042] 2) Preparation of high-purity temsirolimus

[0043] After the above 6.8g temsirolimus semi-finished product was dissolved with 21mL acetonitrile, the sample was lo...

Embodiment 2

[0045] 1) Preparation of semi-finished products of temsirolimus

[0046] After dissolving 56g of temsirolimus crude product (purity 79.03%, sirolimus 2.54%, isomer 15.63%) with 560mL ethyl acetate, the sample was loaded on a normal-phase silica sphere packing column (10 μm), and the Gradient elution with mixed solvent system of n-hexane, 0-10min, ethyl acetate / n-hexane=60:40, 10-100min, ethyl acetate / n-hexane gradually changed from 60:40 to 100:0, system temperature 10°C, collected components, concentrated to dryness under reduced pressure at 20°C to obtain 46g semi-finished product of temsirolimus (purity 86.17%, sirolimus not detected, isomer 11.65%).

[0047] 2) Preparation of high-purity temsirolimus

[0048] After dissolving the above-mentioned 46g temsirolimus semi-finished product with 460mL acetonitrile, load the sample on a reversed-phase C6 packed column (10 μm), and carry out gradient elution with a mixed solvent system of acetonitrile and 20mmol / L potassium dihydr...

Embodiment 3

[0050] 1) Preparation of semi-finished products of temsirolimus

[0051] After dissolving 100g of temsirolimus crude product (purity 76.89%, sirolimus 1.95%, isomer 15.92%) with 500mL ethyl acetate, the sample was loaded on a normal-phase silica sphere packing column (20-45μm), washed with acetic acid Ethyl: n-heptane mixed solvent system for gradient elution, 0-10min, ethyl acetate / n-heptane = 60:40, 10-100min, ethyl acetate / n-heptane gradually changed from 60:40 to 100: 0, the system temperature was 15°C, the collected components were concentrated to dryness under reduced pressure at 30°C to obtain 84.4g semi-finished temsirolimus (purity 84.23%, sirolimus 0.01%, isomers: 13.47%).

[0052] 2) Preparation of temsirolimus finished product

[0053] Dissolve 84.4g of temsirolimus semi-finished product in 422mL of acetonitrile, load the sample on a reversed-phase C8 packed column (20-45μm), and use acetonitrile: 3.5μmol / L aqueous sodium bisulfate (pH5.5) mixed solvent system for...

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Abstract

The invention discloses a high-purity temsirolimus represented by the formula (I), the HPLC purity of the temsirolimus can be above 99.5%. The invention also provides a method for preparing high-purity temsirolimus by virtue of a preparative high performance liquid chromatographic separation system. The method comprises, but not limited to the sequence of the steps, the following steps of A) normal-phase high performance liquid chromatography and B) reverse phase high performance liquid chromatographic separation, wherein in the step A), gradient elution is carried out by taking a silicon ball filler as a stationary phase, ethyl acetate of which the concentration is 60-100v/v% and n-hexane or n-heptane of which the concentration is 40-0v/v% as mobile phases; in step B), gradient elution is carried out by taking C4, C6, C8 or C18 fillers as stationary phases and acetonitrile and aqueous solution of which the pH value is 3.5-6.0 as mobile phases; and the temperature of the system is 10-30 DEG C. The process is simple and environmentally friendly and high-purity and high-quality temsirolimus can be obtained by virtue of the process.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of high-purity temsirolimus. Background technique [0002] Temsirolimus (temsirolimus), also known as temsirolimus, trade name Torisel, chemical name 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropionate]-rapamycin element, molecular formula C 56 h 87 NO 16 , the structural formula is as follows: [0003] [0004] Tesirolimus is a protein kinase inhibitor targeting mTOR, which is a derivative of rapamycin (sirolimus) produced by fermentation of Streptomyces hygroscopicus FC904. In May 2007, the US FDA approved temsirolimus for the first-line treatment of refractory advanced renal cell carcinoma, and in November of the same year, the European EMBA also approved its marketing. As a molecular targeted therapy drug, temsirolimus has brought hope to patients with advanced metastatic renal cell carcinoma whose effects of surgical resection, radioth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/18
CPCC07D498/18
Inventor 赵俊张建义蔡继兰王易范昌俊高伟周宇智
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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