CN108358910A - A kind of process for purification of compound in triazine class - Google Patents

Abstract

The invention discloses a kind of process for purification of the compound in triazine class with Formulas I.

Description

A kind of process for purification of compound in triazine class

Technical field

The invention belongs to medicinal chemistry art, more particularly to a kind of process for purification of compound in triazine class.

Background technology

Chinese patent CN105175410A is reported with structure such as following formula I

The preparation method of compound and activity test, activity test show that compound I has good antitumor proliferation Effect.But according to the preparation method of its final step, as follows,

The impurity compound III shown in following formula that the step reaction is primarily present,

Its structure is confirmed by nuclear magnetic resonance spectroscopy and mass spectrum：1H NMR (400MHz, DMSO-d6)：δppm 8.02(d, 1H), 7.64(s,1H),7.43(d,1H),4.05(m,1H),3.74-3.72(m,6H),2.98-2.85(m,4H),2.65- 2.51(m,6H), 2.36(m,2H),2.04(s,1H),1.53(m,2H),1.12(d,6H)；ESI/MS：M/z=550 (M+H) +.According to the post-processing approach reported in patent, products obtained therefrom purity is 98.3%, the content of impurity III is 0.3%~ 0.5%.It does not meet in general drug standard in relation to single requirement of the miscellaneous content less than 0.1%.Moreover, because impurity content mistake Height, during the quality research of drug, it is necessary to related toxicological experiment research be carried out to impurity III, to which medicine can be greatly increased The cost and risk of object research and development.

Invention content

The present invention provides a kind of process for purification of compound I, it is therefore an objective to solve that product purity is low, and major impurity III contains Measure excessively high problem.

The purpose of the present invention is what is be achieved by the steps of：

The crude product of compound I is added to the in the mixed solvent of ethyl alcohol, water, sodium hydroxide, activated carbon, compound by step 1) I crude products and the mass ratio of in the mixed solvent ethyl alcohol, water, sodium hydroxide, activated carbon are equal to 1:10~15:10~15:3~5:0.05 ~0.1, it is heated to micro- reflux state, system temperature is 78~79 DEG C, continues return stirring 2~4 hours；

Step 2) filters while hot, and the system temperature filtered while hot is not less than 50 DEG C；

Step 3) filtrate stirs cooling crystallization to 0~5 DEG C, keeps the temperature 10~12 hours；

Step 4) and then filtering, filter cake is washed with 95% ethyl alcohol；

Filter cake is dried in vacuo 12~18h by step 5) at 40~45 DEG C, obtains the chemical combination of purity and single miscellaneous content qualification The sterling of object I.

The mass ratio of preferred compound I crude products and in the mixed solvent ethyl alcohol, water, sodium hydroxide, activated carbon is ethyl alcohol： Water：Sodium hydroxide：Activated carbon=1:1:10~12:10~12:3~4:0.05~0.07.

The preferred system temperature filtered while hot is not less than 55 DEG C.

The preferred vacuum drying time is 12~14h.

The present invention is easy to operate, the period is short, product purity is high, single miscellaneous content is controllable.

Specific implementation mode

Embodiment 1

In 500ml three-necked flasks be added 5g contents be 98.3% compound I, sequentially add 60g ethyl alcohol, 55g water, 15g sodium hydroxides, 0.25g activated carbons open stirring, are heated to micro- reflux state, and system temperature is 78~79 DEG C, continues to flow back Stirring 2 hours, is filtered while hot, keeps when filtering system temperature to be not less than 55 DEG C, filtrate stirs cooling crystallization to 3 DEG C, and heat preservation is stirred It mixes 10 hours, then filters, wash filter cake with 95% ethyl alcohol, filter cake is dried in vacuo, vacuum drying chamber temperature setting is 42 DEG C, The dry time is 10h, obtains the white crystals 4.2g of compound I, content 99.56%, impurity III contents 0.03%, other Single miscellaneous respectively less than 0.1%.

Embodiment 2

In 500ml three-necked flasks be added 5g contents be 98.3% compound I, sequentially add 50g ethyl alcohol, 50g water, 17g sodium hydroxides, 0.3g activated carbons open stirring, are heated to micro- reflux state, and system temperature is 78~79 DEG C, continues to flow back Stirring 2.5 hours, is filtered while hot, and system temperature is kept when filtering to be not less than 55 DEG C, and filtrate stirs cooling crystallization to 2 DEG C, heat preservation Stirring 11 hours, then filters, washs filter cake with 95% ethyl alcohol, filter cake is dried in vacuo, and vacuum drying chamber temperature setting is 42 DEG C, dry time is 10h, obtains the white crystals 4.1g of compound I, content 99.65%, impurity III contents 0.03%, He single miscellaneous respectively less than 0.1%.

Embodiment 3

In 500ml three-necked flasks be added 5g contents be 98.3% compound I, sequentially add 60g ethyl alcohol, 60g water, 15g sodium hydroxides, 0.3g activated carbons open stirring, are heated to micro- reflux state, and system temperature is 78~79 DEG C, continues to flow back Stirring 3 hours, is filtered while hot, keeps when filtering system temperature to be not less than 55 DEG C, filtrate stirs cooling crystallization to 2 DEG C, and heat preservation is stirred It mixes 12 hours, then filters, wash filter cake with 95% ethyl alcohol, filter cake is dried in vacuo, vacuum drying chamber temperature setting is 42 DEG C, The dry time is 10h, obtains the white crystals 4.4g of compound I, content 99.58%, impurity III contents 0.05%, other Single miscellaneous respectively less than 0.1%.

Embodiment 4

In 500ml three-necked flasks be added 5g contents be 98.3% compound I, sequentially add 50g ethyl alcohol, 60g water, 20g sodium hydroxides, 0.35g activated carbons open stirring, are heated to micro- reflux state, and system temperature is 78~79 DEG C, continues to flow back Stirring 4 hours, is filtered while hot, keeps when filtering system temperature to be not less than 55 DEG C, filtrate stirs cooling crystallization to 4 DEG C, and heat preservation is stirred It mixes 14 hours, then filters, wash filter cake with 95% ethyl alcohol, filter cake is dried in vacuo, vacuum drying chamber temperature setting is 42 DEG C, The dry time is 12h, obtains the white crystals 4.6g of compound I, content 99.68%, impurity III contents 0.04%, other Single miscellaneous respectively less than 0.1%.

Claims (1)

1. a kind of process for purification of the compound in triazine class with Formulas I, reduce has formula III structure as follows

Impurity content, purification step is：

The crude product of compound I is added to the in the mixed solvent of ethyl alcohol, water, sodium hydroxide, activated carbon by step 1), and compound I is thick The mass ratio of product and in the mixed solvent ethyl alcohol, water, sodium hydroxide, activated carbon is equal to 1:10~15:10~15:3~5:0.05~ 0.1, it is heated to micro- reflux state, system temperature is 78~79 DEG C, continues return stirring 2~4 hours；

Step 2) filters while hot, and the system temperature filtered while hot is not less than 50 DEG C；

Step 3) filtrate stirs cooling crystallization to 0~5 DEG C, keeps the temperature 10~12 hours；

Step 4) and then filtering, filter cake is washed with 95% ethyl alcohol；

Filter cake is dried in vacuo 12~18h by step 5) at 40~45 DEG C, obtains the compound I's of purity and single miscellaneous content qualification Sterling.