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Anti-tumor compound preparation method

A technology of compounds and alkaline conditions, applied in the fields of anti-tumor drugs, organic chemistry, drug combinations, etc., can solve the problems of high side effects, large differences in individual treatment of patients, and low bioavailability.

Inactive Publication Date: 2009-12-09
BEIJING LABSOLUTIONS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The low bioavailability of Dasatinib is an important reason for the large differences in the treatment of individual patients, and the side effects are higher than that of Imatinib. At the same time, the low bioavailability also limits its wider application in anti-tumor diseases, and it can only be used as a second-line drug. drug use

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Example 1: Preparation of ethyl 2-(6-chloro-2-methylpyrimidine-4-amino)thiazole-5-carboxylate (IV)

[0076] Add 20ml DMF to a 100ml three-necked flask, stir magnetically, mix 2g ethyl 2-aminothiazole-5-carboxylate, 7.5g Cs 2 CO 3 (2eq), 2.85g (1.5eq) of 4,6-dichloro-2-methylpyrimidine was dissolved in 6 ml of DMF, and slowly dropped into the reaction flask. After the dropwise addition was completed, the ice-water bath was removed, and the mixture was naturally raised to room temperature (25° C.). After 24 hours of reaction, the reaction of ethyl 2-amino-thiazole-5-carboxylate was complete. The system was poured into 250ml of ice water, stirred, a solid precipitated out, filtered with suction, and the filter cake was washed twice with water and ethyl acetate (EA) successively, and dried to obtain 2.7g of a light white solid with a yield of 78%. The compound is C 11 h 11 ClN 4 o 2 S, the calculated value of MS-ESI (m / z) is 298.0; the measured value is 297.2 (100, M ...

Embodiment 2

[0077] Example 2: Preparation of ethyl 2-((6-chloro-2-methylpyrimidin-4-yl)(4-methoxybenzyl)amino)thiazole-5-carboxylate (VI)

[0078] Add 150ml DMF, 20g (IV) prepared in Example 1, 18.76g K 2 CO 3 (2eq), there are still some raw materials (IV) undissolved. 20.1g p-methoxybenzyl bromide (2eq) was dissolved in 50ml DMF, dropped into the reaction flask, the temperature rose to 5°C, after the dropwise addition was completed, the ice bath was removed, and the temperature was naturally raised to room temperature. After 18 hours of reaction, the raw material ( IV) The reaction is complete. The reaction solution was poured into 300ml of ice water, filtered with suction, washed with water and EA three times in turn, and dried to obtain 25g of white solid with a yield of 89.3%. The compound is C 19 h 19 ClN 4 o 3 S, the calculated value of MS-ESI (m / z) is 418.1; the measured value is 419.1 (100, MH + ).

Embodiment 3

[0079] Example 3: Preparation of 2-((6-chloro-2-methylpyrimidin-4-yl)(4-methoxybenzyl)amino)thiazole-5-carboxylic acid (VII)

[0080] Add 15ml of water, 90ml of THF, and 90ml of methanol into a 250ml three-necked flask, cool down to 0°C with an ice-water bath, add 8.38g of (VI) prepared in Example 2, and part of (VI) is not dissolved. Dissolve 8.0g (10eq) of sodium hydroxide in 15ml of ice water, slowly drop it into the reaction flask, remove the ice bath after the dropwise addition, the insoluble matter gradually dissolves, and after 5 hours of reaction (VI), the reaction is complete, and the organic solvent is evaporated , adding 100ml of water, filtering, washing with water twice, and drying to obtain 5.6g of white solid with a yield of 71.8%. The compound is C 17 h 15 ClN 4 o 3 S, the calculated value of MS-ESI (m / z) is 390.1; the measured value is 389.3 (M - ) and 345.3 (M - ).

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Abstract

The invention provides an anti-tumor compound preparation method, namely, a preparation method of a compound shown in general formula (I) or a salt of same which can be accepted in pharmacology; wherein, R is selected from H, optional substitutional alkyl, optional substitutional cycloalkyl, optional substitutional aryl, optional substitutional aralkyl or optional substitutional heterocyclic radical. The compound shown in the general formula (I) prepared by the invention can inhibit tyrosine kinase Bcr-Abl and other kinases (Lck, Fyn, SrC, Hck) of SRC family after decomposition in vivo so that the compound prepared by the invention shown in the general formula (I) or the salt can be accepted in pharmacology and can be used in the medical application of cancer treatment. Compared with the existing anti-tumor compounds, the compound of the invention has better curative effect and lower side effect.

Description

technical field [0001] The invention relates to a preparation method of an anti-tumor compound, in particular to a preparation method of an anti-tumor compound with better curative effect and less side effects. Background technique [0002] Leukemia is a common tumor disease, and its incidence rate is about 3 to 4 per 100,000 people, ranking sixth in the incidence rate of various tumor diseases. The incidence of leukemia in China is similar to that of other Asian countries, but higher than that of European and American countries. Among them, Chronic Myeloid Leukaemia (CML, also known as Chronic Myelogenous Leukemia) is more common. Chronic myelogenous leukemia is a hematopoietic stem cell disorder associated with the Philadelphia chromosome resulting from a reciprocal translocation of chromosomes 9 and 22. This chromosomal translocation results in the chimeric protein product Bcr-Abl, which is a constitutively active form of the ABL tyrosine kinase. Chronic myelogenous leu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12C07D417/14A61P35/00
Inventor 王建民
Owner BEIJING LABSOLUTIONS PHARMA
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