CN103373968A - Synthesis method for 3-amino-1,2,4-phentriazine-1,4-dioxide - Google Patents

Abstract

The invention relates to a synthesis method for 3-amino-1,2,4-phentriazine-1,4-dioxide. The invention provides a synthesis method for 3-amino-1,2,4-phentriazine-1,4-dioxide, which is low in toxicity, moderate in reaction conditions, simple to operate, high in safety, and stable in yield. The method disclosed by the invention comprises the following steps of: firstly, co-heating ortho-nitroaniline in 55% cyanamide aqueous solution and concentrated HCl, cooling, then adding NaOH solution, and finishing a ring-closure reaction to generate an intermediate product, namely, 3-amino-1,2,4-phentriazine-1-oxide; secondly, adding the intermediate product, namely, 3-amino-1,2,4-phentriazine-1-oxide in CH3COOH to form a suspended matter, then adding H2O2 solution, and reacting in the dark to obtain 3-amino-1,2,4-phentriazine-1,4-dioxide solution; and finally, performing rotary evaporation on the obtained 3-amino-1,2,4-phentriazine-1,4-dioxide solution to remove a solvent, separating out a red solid substance, filtering, and recrystallizing a filter cake by absolute ethyl alcohol to obtain a 3-amino-1,2,4-phentriazine-1,4-dioxide crystal.

Description

3-amino-1,2, the synthetic method of 4-phentriazine-Isosorbide-5-Nitrae-dioxide

Technical field

The present invention relates to the improvement of Win-59075 synthetic method.

Background technology

3-amino-1,2,4-phentriazine-Isosorbide-5-Nitrae-dioxide has another name called SR4233, and molecular formula is C ₇H ₆N ₂O ₂, molecular weight is 178.15, the scarlet powder, and 229 ℃ of fusing points are dissolved in methyl alcohol, and are unstable in basic solution.Can be by in anoxic cell, resolving into free radical damage dna, produce cellulotoxic effect, it is clinical for the tumor of head and neck III phase to be applied at present merge cis-platinum, and merging cis-platinum/Etoposide is carried out limited stage small cell lung and merged difficult controlled entity tumour I, the II phase clinical study that endoxan is used for children.

Existing 3-amino-1,2, the synthetic of 4-phentriazine-Isosorbide-5-Nitrae-dioxide all adopts the cyanamide solid as raw material, and the cyanamide solid is very unstable, causes its yield also unstable, and have high toxicity; Reaction conditions is also harsh, should not promote.

Summary of the invention

The present invention is exactly for the problems referred to above, provides a kind of low toxicity, reaction conditions gentle, simple to operate, safe, and the 3-of stable yield is amino-1,2, the synthetic method of 4-phentriazine-Isosorbide-5-Nitrae-dioxide.

For reaching above-mentioned purpose of the present invention, the present invention adopts following method:

1) o-Nitraniline is warm altogether at the 55% cyanamide aqueous solution and dense HCl, after the cooling, add NaOH solution, finish ring-closure reaction, generate intermediate product 3-amino-1,2,4-phentriazine-1-oxide compound;

2) with intermediate product 3-amino-1,2,4-phentriazine-1-oxide compound adds CH ₃COOH behind the formation suspended substance, adds H ₂O ₂Solution reacts in the dark; Get 3-amino-1,2,4-phentriazine-Isosorbide-5-Nitrae-dioxide solution;

3) with the 3-amino-1,2 of gained, 4-phentriazine-Isosorbide-5-Nitrae-dioxide solution rotating evaporation desolventizing is separated out the red solid material, filters, and filter cake dehydrated alcohol recrystallization gets 3-amino-1,2,4-phentriazine-Isosorbide-5-Nitrae-dioxide crystal.

Beneficial effect of the present invention:

The present invention reacts more abundant with the 55% cyanamide aqueous solution, and than cyanamide Pickering, low toxicity, and reaction conditions is gentle, simple to operate, safe, results are stable.

Description of drawings

Fig. 1 is synthesis route figure of the present invention.

Embodiment

The present invention adopts following methods to prepare 3-amino-1,2,4-phentriazine-Isosorbide-5-Nitrae-dioxide:

1) o-Nitraniline is warm altogether at the 55% cyanamide aqueous solution and dense HCl, after the cooling, add NaOH solution, finish ring-closure reaction, generate intermediate product 3-amino-1,2,4-phentriazine-1-oxide compound;

2) with intermediate product 3-amino-1,2,4-phentriazine-1-oxide compound adds CH ₃COOH behind the formation suspended substance, adds H ₂O ₂Solution reacts in the dark; Get 3-amino-1,2,4-phentriazine-Isosorbide-5-Nitrae-dioxide solution;

3) with the 3-amino-1,2 of gained, 4-phentriazine-Isosorbide-5-Nitrae-dioxide solution rotating evaporation desolventizing is separated out the red solid material, filters, and filter cake dehydrated alcohol recrystallization gets 3-amino-1,2,4-phentriazine-Isosorbide-5-Nitrae-dioxide crystal.

Embodiment:

1) claim the 15g o-Nitraniline to stir and be warming up to 50 ℃, slowly drip 55% cyanamide solution 18mL, after dropwising, be warming up to 100 ℃, continuous heating to solution transfers scarlet to; Be down to room temperature, have the safran solid to separate out, drip the dense HCl60mL of 12mol/L, dripped off in 20 minutes; Again be warming up to 100 ℃, stir after 20～40 minutes, be down to room temperature; Stream adds the NaOH solution 60mL of 16mol/L; Dripped off in 20 minutes, and be warming up to 100 ℃, reacted 15 hours, sticking shape solid suspension occurs, slowly stir; Add 100～200mL water, stir, be cooled to room temperature, yellow solid is separated out, filter, and washing, ethyl acetate is washed, the dry 3-amino-1,2 that gets the yellow powder powder, 4-phentriazine-1-oxide compound.

This step, the reaction times is abundant, and the cyanamide strength of solution is moderate, can get 19.7g 3-amino-1,2, and 4-phentriazine-1-oxide compound, yield are 90%.

2) claim 5g 3-amino-1,2,4-phentriazine-1-oxide compound adds the 215mL Glacial acetic acid in there-necked flask, stir, and forms suspension, is warming up to 50 ℃, drips 30% the H of 110mL ₂O ₂Solution, reaction 12h obtains pink 3-amino-1,2,4-phentriazine-Isosorbide-5-Nitrae-dioxide solution in the dark.

3) with the 3-amino-1,2 that obtains, 4-phentriazine-Isosorbide-5-Nitrae-dioxide solution rotating evaporation desolventizing is separated out the red solid material, filters, and filter cake dehydrated alcohol recrystallization gets 3-amino-1,2,4-phentriazine-Isosorbide-5-Nitrae-dioxide crystal.

This step can get 3-amino-1,2,4-phentriazine-Isosorbide-5-Nitrae-dioxide crystal 4 .36g, yield 87.2%, purity 98.5%.

Claims (2)

1.3-amino-1,2, the synthetic method of 4-phentriazine-Isosorbide-5-Nitrae-dioxide is characterized in that:

1) o-Nitraniline is warm altogether at the 55% cyanamide aqueous solution and dense HCl, after the cooling, add NaOH solution, finish ring-closure reaction, generate intermediate product 3-amino-1,2,4-phentriazine-1-oxide compound;

2) with intermediate product 3-amino-1,2,4-phentriazine-1-oxide compound adds CH ₃COOH behind the formation suspended substance, adds H ₂O ₂Solution reacts in the dark; Get 3-amino-1,2,4-phentriazine-Isosorbide-5-Nitrae-dioxide solution;

3) with the 3-amino-1,2 of gained, 4-phentriazine-Isosorbide-5-Nitrae-dioxide solution rotating evaporation desolventizing is separated out the red solid material, filters, and filter cake dehydrated alcohol recrystallization gets 3-amino-1,2,4-phentriazine-Isosorbide-5-Nitrae-dioxide crystal.

2. 3-according to claim 1 amino-1,2,4-phentriazine-1, the synthetic method of 4-dioxide, it is characterized in that: 1) claim the 15g o-Nitraniline to stir and be warming up to 50 ℃, slowly drip 55% cyanamide solution 18mL, after dropwising, be warming up to 100 ℃, continuous heating to solution transfers scarlet to; Be down to room temperature, have the safran solid to separate out, drip the dense HCl60mL of 12mol/L, dripped off in 20 minutes; Again be warming up to 100 ℃, stir after 20～40 minutes, be down to room temperature; Stream adds the NaOH solution 60mL of 16mol/L; Dripped off in 20 minutes, and be warming up to 100 ℃, reacted 15 hours, sticking shape solid suspension occurs, slowly stir; Add 100～200mL water, stir, be cooled to room temperature, yellow solid is separated out, filter, and washing, ethyl acetate is washed, the dry 3-amino-1,2 that gets the yellow powder powder, 4-phentriazine-1-oxide compound;

2) claim 5g 3-amino-1,2,4-phentriazine-1-oxide compound adds the 215mL Glacial acetic acid in there-necked flask, stir, and forms suspension, is warming up to 50 ℃, drips 30% the H of 110mL ₂O ₂Solution, reaction 12h obtains pink 3-amino-1,2,4-phentriazine-Isosorbide-5-Nitrae-dioxide solution in the dark;

3) with the 3-amino-1,2 that obtains, 4-phentriazine-Isosorbide-5-Nitrae-dioxide solution rotating evaporation desolventizing is separated out the red solid material, filters, and filter cake dehydrated alcohol recrystallization gets 3-amino-1,2,4-phentriazine-Isosorbide-5-Nitrae-dioxide crystal.

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